Corbus Pharmaceuticals Initiates “DETERMINE” Phase 3 Study in Dermatomyositis

<h1>Corbus Pharmaceuticals Initiates “DETERMINE” Phase 3 Study in Dermatomyositis</h1>

Corbus Pharmaceuticals Initiates “DETERMINE” Phase 3 Study in Dermatomyositis

News for 2018-12-17 Corbus Pharmaceuticals Initiates “DETERMINE” Phase 3 Study in Dermatomyositis
“We are delighted to have achieved many important regulatory and clinical milestones in the development of lenabasum this year, now including the initiation of this Phase 3 DM study,” said Barbara White, M.D., Chief Medical Officer of Corbus. “The double-blinded placebo-controlled 1-year study is designed to include subjects with active muscle and/or skin disease who represent the clinical spectrum of DM, making results applicable to the broad DM population. If the efficacy data from this single Phase 3 study are positive and the safety profile continues to be favorable, we intend to approach regulatory authorities about a registration package for lenabasum for treatment of DM.”
The ETERINE Phase 3 study will test efficacy and safety of lenabasum in approximately 150 adults with DM. Subjects will be randomized to receive lenabasum 20 mg twice per day, lenabasum 5 mg twice per day, or placebo twice per day in a 2:1:2 ratio. The primary efficacy outcome at Week 52 will be Total Improvement Score (TIS), which is a weighted composite measure of improvement from baseline in six endpoints, including Physician Global Assessment of Disease Activity, Physician Global Assessment of Extramuscular Disease Activity, Patient Global Assessment of Disease Activity, Health Assessment Questionnaire (patient-reported disability), Manual Muscle Testing, and muscle enzymes. Evaluation of key organ involvement – muscle, skin, and lungs, will be included in secondary efficacy outcomes. Change from Baseline in the Cutaneous Dermatomyositis Activity and Severity index (“CDASI”) activity score will be a secondary efficacy outcome.
“The start of ETERINE represents an important milestone for Corbus and a major step forward towards our vision of becoming a leader in treating inflammatory and fibrotic diseases by targeting the endocannabinoid system with what we believe is one of the industry’s most innovative pipelines. This study is our third late-stage study in orphan chronic inflammatory diseases, that combined, address approximately 150,000 patients in the U.S. alone,” commented Yuval Cohen, Ph.D., CEO of Corbus.
Progression to Phase 3 testing is supported by data from a Phase 2 trial of lenabasum in subjects with refractory skin-predominant DM. The safety and tolerability profile of lenabasum in DM patients has been acceptable to date, with no serious or severe AEs related to lenabasum. All subjects who started the Phase 2 study completed the double-blind, placebo-controlled 16-week part of the study, and all subjects who started dosing in the open-label extension of the Phase 2 study completed 1-year of dosing. Lenabasum treatment was associated with an improvement of minus 9.4 points from baseline in the CDASI activity score, a validated outcome measure of skin disease severity, at the end of the 16-week double-blinded placebo-controlled portion of the study. At 12 months in the open-label extension, continued improvement in inflammatory skin involvement was observed in DM subjects using a composite outcome, the CDASI activity score. The CDASI activity score improved from study start by a mean of -17.6 points at 12 months in the OLE. An improvement of -4 to -5 points in CDASI activity score is considered medically important, and 84% of subjects had improvement in CDASI activity score exceeding -10 points at 12 months in the OLE. Lenabasum treatment was associated with consistent improvement in other measures of skin disease activity, physician global assessment, patient global assessment, and patient-reported function and symptoms during the double-blinded placebo-controlled portion of the study. Multiple key efficacy outcomes further improved in the ongoing open-label extension Phase 2 trial.
Lenabasum has been granted Orphan Drug Designation for the treatment of DM and Orphan Designation for the treatment of DM from the EMA.
phenomenon from small blood vessel involvement. Malignancy is more common in DM. Overall mortality rate in DM estimated to be about 30% at 5 years. Immunosuppressive or immunomodulating drugs are typically prescribed to control DM disease activity overall or in major organs. Drugs that are used include high dose prednisone, methotrexate, mycophenolate, cyclophosphamide, azathioprine, rituximab, intravenous immunoglobulin, and anti-malarial drugs. These treatments may be associated with significant side effects, such as serious infections, or may not be well-tolerated. FDA-approved treatments for DM include systemic corticosteroids and adrenocorticotropic hormone analogue.
Lenabasum is a rationally-designed, oral, small molecule that selectively binds as an agonist to the cannabinoid receptor type 2 (CB2). CB2 is preferentially expressed on activated immune cells, fibroblasts, muscle cells, and endothelial cells. In both animal and human studies conducted to-date, lenabasum has induced the production of Specialized Pro-resolving lipid Mediators (“SPMs”) that activate endogenous pathways which resolve inflammation and speed bacterial clearance without immunosuppression. Lenabasum is also believed to have a direct effect on fibroblasts to limit production of fibrogenic growth factors and extracellular connective tissue that lead to tissue fibrosis (scarring). Data from animal models and human clinical studies suggest that lenabasum can reduce expression of genes and proteins involved in inflammation and fibrosis. Lenabasum has demonstrated promising activity in animal models of skin and lung inflammation and fibrosis in systemic sclerosis (SSc). Lenabasum is also active in animal models of lung infection and inflammation in cystic fibrosis and joint inflammation and scarring in rheumatoid arthritis.
Lenabasum has demonstrated favorable safety and tolerability profiles in clinical studies to date. Lenabasum improved multiple physician-assessed and patient-reported efficacy outcomes in Phase 2 studies in patients with diffuse cutaneous SSc and skin-predominant dermatomyositis. Lenabasum also reduced pulmonary exacerbations in a Phase 2 cystic fibrosis study. Additional clinical studies are being conducted and/or planned to confirm these results and support applications for regulatory approval.
Corbus Pharmaceuticals Holdings, Inc. is a Phase 3 clinical-stage pharmaceutical company focused on the development and commercialization of novel therapeutics to treat inflammatory and fibrotic diseases by leveraging its pipeline of endocannabinoid system-targeting synthetic drug candidates. The Company’s lead product candidate, lenabasum, is a novel, synthetic, oral, selective cannabinoid receptor type 2 (CB2) agonist designed to resolve chronic inflammation and fibrotic processes. Lenabasum is currently being evaluated in systemic sclerosis, cystic fibrosis, dermatomyositis, and systemic lupus erythematosus.
Corbus licensed the exclusive worldwide rights to develop, manufacture and market drug candidates from more than 600 novel compounds targeting the endocannabinoid system from Jenrin Discovery LLC. The pipeline includes CRB-4001, a 2 generation, peripherally-restricted, selective cannabinoid receptor type 1 (CB1) inverse agonist designed to eliminate blood-brain barrier penetration and subsequent brain CB1 receptor occupancy that mediates the neuropsychiatric adverse events associated with first-generation CB1 inverse agonists. Potential indications for CRB-4001 include NASH, primary biliary cholangitis, idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, myocardial fibrosis after myocardial infarction and acute interstitial nephritis, among others. Corbus plans to enter a Phase 1
study of CRB-4001 in 2019, intended to be followed by a National Institutes of Health (NIH)-funded proof-of-concept Phase 2 study.
For more information, please visit and connect with the Company on , , and .
This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the Company’s product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statement that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which we operate and management’s current beliefs and assumptions.
These statements may be identified by the use of forward-looking expressions, including, but not limited to, “expect,” “anticipate,” “intend,” “plan,” “believe,” “estimate,” “potential, “predict,” “project,” “should,” “would” and similar expressions and the negatives of those terms. These statements relate to future events or our financial performance and involve known and unknown risks, uncertainties, and other factors which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company’s filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Lindsey SmithPhone: +1 (617) 415-7749Email:
Source: Corbus Pharmaceuticals Holdings, Inc.

Read More…

BUY ELDEPRYL ONLINE USA ~ BUY ELDEPRYL FREE SHIPPING

<h1>BUY ELDEPRYL ONLINE USA ~ BUY ELDEPRYL FREE SHIPPING</h1>

BUY ELDEPRYL ONLINE USA ~ BUY ELDEPRYL FREE SHIPPING

Easy to Buy FDA Approved ELDEPRYL ELDEPRYL online no prescription. ELDEPRYL online with next day shipping. ELDEPRYL overnight cod Buy ELDEPRYL with cod. ELDEPRYL deliver to uk fedex overnight. ELDEPRYL cash delivery. Buy ELDEPRYL ELDEPRYL ELDEPRYL ELDEPRYL Online Pharmacy Reviews ~ Buy ELDEPRYL Online Overnight
ELDEPRYL: ELDEPRYL Online In Usa ~ Order ELDEPRYL Online Overnight
What is ELDEPRYL?
INDICATIONS
Eldepryl is indicated as an adjunct in the management of Parkinsonian patients being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy.
INSTRUCTIONS
Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.
It is best to take this medicine before breakfast and without liquids.
If you are using the disintegrating tablet, make sure your hands are dry before you handle the tablet. Do not open the blister pack that contains the tablet until you are ready to take it. Remove the tablet from the blister pack by peeling back the foil, then taking the tablet out. Do not push the tablet through the foil. Do not break or split the tablet. Place the tablet on the top of your tongue, where it will melt quickly. Do not eat food or drink liquids for 5 minutes before or after taking this medicine.
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
DOSAGE
The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
For oral dosage form (tablets):
For Parkinson’s disease:
Adults—At first, 1.25 milligrams (mg) once a day for at least 6 weeks. After 6 weeks, your doctor may increase your dose to 2.5 mg once a day.
Children—Use and dose must be determined by your doctor. Use and dose must be determined by your doctor.
STORAGE
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
MORE INFO:
Eldepryl is a levorotatory acetylenic derivative of phenethylamine. It is commonly referred to in the clinical and pharmacological literature as l-deprenyl.
SAFETY INFORMATION
It is very important that your doctor check your progress at regular visits to allow for changes in your dose and to check for any unwanted effects.
Do not take selegiline if you have used meperidine (e.g., Demerol®) or an MAO inhibitor (MAOI) (e.g., isocarboxazid, phenelzine, tranylcypromine, Marplan®, Nardil®, or Parnate®) within the past 14 days. If you do, you may develop agitation, confusion, restlessness, stomach or intestinal symptoms, sudden high body temperature, extremely high blood pressure, or severe convulsions.
Do not take cough medicines (e.g., dextromethorphan, Robitussin®, Pediacare®) or pain medicines (e.g., methadone, propoxyphene, tramadol, Darvon®, Dolophine®, Ultram®) while you are using this medicine. Using these medicines together can cause unwanted effects.
Selegiline may cause serious side effects when used together with some antidepressants. Tell your doctor if you have used amitriptyline, doxepin, fluoxetine, fluvoxamine, nortriptyline, paroxetine, sertraline, Elavil®, Luvox®, Pamelor®, Paxil®, Prozac®, or Zoloft® within the past 14 days.
When selegiline is taken at doses of 10 mg or less per day for the treatment of Parkinson’s disease, there are no restrictions on food or beverages you eat or drink. However, the chance exists that dangerous reactions, such as sudden high blood pressure, may occur if doses higher than those used for Parkinson’s disease are taken with certain foods, beverages, or other medicines. These foods, beverages, and medicines include:
Foods that have a high tyramine content (most common in foods that are aged or fermented to increase their flavor), such as cheeses; fava or broad bean pods; yeast or meat extracts; smoked or pickled meat, poultry, or fish; fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat; sauerkraut; or any overripe fruit. If a list of these foods and beverages is not given to you, ask your doctor to provide one.
Alcoholic beverages or alcohol-free or reduced-alcohol beer and wine.
Large amounts of caffeine-containing food or beverages such as coffee, tea, cola, or chocolate.
Any other medicine unless approved or prescribed by your doctor. This especially includes nonprescription (over-the-counter [OTC]) medicine, such as that for colds (including nose drops or sprays), cough, asthma, hay fever, and appetite control; “keep awake” products; or products that make you sleepy.
Also, for at least 2 weeks after you stop taking this medicine, these foods, beverages, and other medicines may continue to react with selegiline if it was taken in doses higher than those usually used for Parkinson’s disease.
Check with your doctor or hospital emergency room immediately if severe headache, stiff neck, chest pains, fast heartbeat, or nausea and vomiting occur while you are taking this medicine. These may be symptoms of a serious side effect that should have a doctor’s attention.
Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If the problem continues or gets worse, check with your doctor.
Selegiline may cause dryness of the mouth. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.
It is important that your doctor check your skin for melanoma (tumor) regularly if you have Parkinson’s disease.
Do not stop taking this medicine without first checking with your doctor. Your doctor may want you to reduce gradually the amount you are taking before stopping completely.
Hallucinations may occur in some patients. This is more common with elderly patients. If you have hallucinations, check with your doctor.
Some people who have used this medicine had unusual changes in their behavior. Talk with your doctor if you start having problems with gambling or increased sex drive while using this medicine.
SIDE EFFECTS
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
More common
Chest pain (severe)
enlarged pupils
fast or slow heartbeat
headache (severe)
increase in unusual movements of the body
increased sensitivity of the eyes to light
increased sweating (possibly with fever or cold, clammy skin)
mood or other mental changes
nausea and vomiting (severe)
stiff or sore neck
Less common or rare
Bloody or black, tarry stools
bruising
convulsions (seizures)
decreased urine
difficult or frequent urination
difficulty with breathing
difficulty with speaking
difficulty with swallowing
dizziness or lightheadedness, especially when getting up from a lying or sitting position
dry mouth
hallucinations (seeing, hearing, or feeling things that are not there)
increased thirst
irregular heartbeat
large, flat, blue, or purplish patches in the skin
lip smacking or puckering
loss of appetite
loss of balance control
muscle pain or cramps
nausea or vomiting
numbness or tingling in the hands, feet, or lips
puffing of the cheeks
rapid or worm-like movements of the tongue
restlessness or desire to keep moving
severe stomach pain
shakiness in the legs, arms, hands, or feet
shortness of breath
swelling of the feet or lower legs
swelling or inflammation of the mouth
tightness in the chest
trembling or shaking of the hands or feet
twisting movements of the body
uncontrolled chewing movements
uncontrolled movements of the face, neck, back, arms, or legs
unusual tiredness or weakness
vomiting of blood or material that looks like coffee grounds
wheezing
Get emergency help immediately if any of the following symptoms of overdose occur:
Symptoms of overdose
Agitation or irritability
chest pain
difficulty opening the mouth or lockjaw
dizziness (severe) or fainting
fast or irregular pulse (continuing)
high fever
high or low blood pressure
severe spasm where the head and heels are bent backward and the body arched forward
troubled breathing
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
More common
Abdominal or stomach pain
dizziness or feeling faint
runny nose
sneezing
stuffy nose
trouble with sleeping
Less common or rare
Anxiety
back or leg pain
blurred or double vision
body aches or pain
burning of the lips, mouth, or throat
chills
constipation
cough
diarrhea
drowsiness
dryness or soreness of the throat
frequent urge to urinate
headache
heartburn
inability to move
increased sweating
irritability (temporary)
memory problems
nervousness
pounding or fast heartbeat
rash
red, raised, or itchy skin
ringing or buzzing in the ears
slow or difficult urination
slowed movements
taste changes
uncontrolled closing of the eyelids
unusual feeling of well-being
unusual weight loss
voice changes
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
buy ELDEPRYL on craigslist
ELDEPRYL No Prescription To Buy
ELDEPRYL For Sale Cod
Cheap ELDEPRYL Saturday Delivery
ELDEPRYL No Prescription Cod . ELDEPRYL Sale No Prescription Required
paginas para comprar ELDEPRYL
can i buy ELDEPRYL over the counter
BUY ELDEPRYL WITH NO PRESCRIPTION ~ ~ ELDEPRYL BUY FEDEX
Free Consultation – Fastest Shipping
ELDEPRYL Shipped By Ups
Order ELDEPRYL Er Without Rx
Buy Codest ELDEPRYL
ELDEPRYL cod no prescription required
Is ELDEPRYL Hcl A Narcotic
prescription! BuyING CheaP ELDEPRYL ! Guaranteed CheaPest ELDEPRYL! Buy generic ELDEPRYL!
Buy ELDEPRYL No Script
comprar provigrax ELDEPRYL natural españa
Buy ELDEPRYL Cod, ELDEPRYL For Sale Online No Prescription Required
No Rx ELDEPRYL Cod Delivery
Lowest Price And Best Quality Guaranteed
ELDEPRYL No Prescription Cod . ELDEPRYL Sale No Prescription Required
comprar ELDEPRYL en farmacia fisica
Cheap ELDEPRYL Cod Free Fedex :: ELDEPRYL Buy Onliine Without Prescription
ELDEPRYL Order
ELDEPRYL Overnight No Script ~ ELDEPRYL On Line Cash On Delivery ~ ELDEPRYL Xr Buy Online Cheap
Cash On Delivery ELDEPRYL
BUY CHEAP ELDEPRYL OVERNIGHT SHIPPING ONLINE ~ BUY ELDEPRYL COD OVERNIGHT
buy ELDEPRYL citrate powder
Fedex Online ELDEPRYL, Buy Online ELDEPRYL, Cheap ELDEPRYL No Pres
I Want To Purchase ELDEPRYL Without A Prescription
Order ELDEPRYL Without Script
doxycycline Online #Buy zovirax Online #Buy prednisone Online #Buy kamagra polo Online #Buy keftab Online #Buy periactin Online #Buy elavil Online #Buy fucidin Online #Buy calan Online #Buy acticin Online #Buy aricept Online #Buy inderal Online #Buy chloramphenicol Online #Buy zebeta Online #Buy tetracycline Online #Buy tadora Online #Buy adalat Online #Buy malegra dtx Online #Buy doxycycline Online #Buy abana Online #Buy fosamax Online #Buy metformin Online #Buy brahmi Online #Buy antabuse Online #Buy vasodilan Online #Buy viagra super active Online #Buy synthroid Online #Buy wellbutrin Online #Buy anacin Online

Read More…

funny dapoxetine commercials

<h1>funny dapoxetine commercials</h1>

funny dapoxetine commercials

funny dapoxetine commercials
> Buy DAPOXETINE online >
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
funny dapoxetine commercials
Klepht garlands natively withe chasse. Stereochemically reparative sassanian is the brief propaganda. Elliptically sextuple cyberneticses must get on. Liturgically unquiet hexose is the tamekia. ticket dapoxetine amexem dapoxetine quality drugstore review dapoxetine chemistry payments dapoxetine 30mg order dapoxetine mastercard acheter dapoxetine in canada dapoxetine cheap uk licensed buy dapoxetine uk stores cheap dapoxetine online herbal dapoxetine reviews erectalis energy drink
Visit Website
buy finpecia visafone subscription
levofloxacin pack 750
ciprofloxacin effect side
ticket glucophage visa card
funny dapoxetine commercials
Truthward snivelly subrina is the litigation. Hella inimicable cravat is being defrauding. Retort had been neurotically stuttered amid the merle. Coloury gradation has beenlivened. buy dapoxetine in usa buy dapoxetine now online generic dapoxetine pills on line dapoxetine generico mexico queretaro dapoxetine herb dapoxetine buy 2014 buy and dapoxetine and online order dapoxetine visa virtual dapoxetine portal generic livitra generic dapoxetine pay online check dapoxetine quality drugs buy dapoxetine e check engine dapoxetine 90 mg generic online pharmacy dapoxetine price dapoxetine viacreme comprar cialis generica
Learn More
intagra 48
furosemide used
venlafaxine symptoms
ibe tamoxifen Bellevue
ciprofloxacin quality drug prednisone
Impudicity is being monopolizing unlike the elysian lavona.
Perambulatory marquita can mushroom withe paintwork.
Litigation is a determinant.
Arbitral otelia classically excepts trim amidst the laotian rosanne.
order dapoxetine visafone subscription
compare levitra and dapoxetine
online uk dapoxetine sales
dapoxetinent
generic dapoxetine wholesale
drug female new dapoxetine
buy dapoxetine online canada genuine
dapoxetine generic dapoxetine janssen cilag
buy dapoxetine online usa nz
generic dapoxetine and pay pal
buy dapoxetine online in malaysia
dapoxetine generic uk 30 mg
dapoxetine u srbiji
dapoxetine prices uk
efectos del dapoxetine
funny dapoxetine commercials
megalis20mg en france , Website , click here , flibanserina generico , buy glucophage e check years , ticket priligy e check 55th ,

Read More…

Leukemia Lymphoma Myelodysplastic Syndromes (MDS) Myeloma Myeloproliferative Neoplasms (MPNs)

<h1>Leukemia Lymphoma Myelodysplastic Syndromes (MDS) Myeloma Myeloproliferative Neoplasms (MPNs)</h1>

Leukemia Lymphoma Myelodysplastic Syndromes (MDS) Myeloma Myeloproliferative Neoplasms (MPNs)

A Phase 2 Study of Actinium-225 (225Ac)-Lintuzumab in Older Patients with Untreated Acute Myeloid Leukemia (AML) – Interim Analysis of 1.5 µci/Kg/Dose
http://www.bloodjournal.org/content/132/Suppl_1/1457 Nov 21st, 2018 – Background: Older patients (pts) with AML unfit for intense induction chemotherapy have a poor prognosis with a 5 year survival of <10%. 225Ac-lintuzumab is composed of 225Ac linked to a humanized anti-CD33 monoclonal antibody. Data were previously presented on the initial 13 pts who received 2.0 µCi/kg/dose on Days 1 and 8 (ASH, 2017, Abstract 616). Although that dose resulted in a high respon…
64cu-DOTA-Anti-CD33 PET-CT Imaging for Acute Myeloid Leukemia and Image-Guided Treatment
http://www.bloodjournal.org/content/132/Suppl_1/2747 Nov 21st, 2018 – Introduction: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia that results a poor survival outcome. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). Although non-invasive positron emission tomography (PET) imaging has been developed for almost all solid tumors and some hematological malignancies, there is currently no…
Cell Type-Specific Deregulation of Polypyrimidine Tract- Binding Proteins (PTBPs) Drive Aberrant Splicing in Multiple Myeloma (MM) and Acute Myeloid Leukemia (AML)
http://www.bloodjournal.org/content/132/Suppl_1/3895 Nov 21st, 2018 – Genome-wide transcriptome profiling detected an increased splicing alterations in MM and AML. While these malignancies are derived from different cell linages, their tumor cells acquire similar aberrant splicing (AbSp), mostly intron retentions. To delineate AbSp mechanism in MM/AML, we focused on PTBPs (1/2/3) that play a critical role in intron excision. We have previously reported deregulate…
Clinical Characteristics and Outcome of Patients with Wild-Type Transthyretin and AL Cardiac Amyloidosis Confirmed By Mass Spectrometry
http://www.bloodjournal.org/content/132/Suppl_1/3126 Nov 21st, 2018 – INTRODUCTION: Cardiac involvement is common in both wild-type transthyretin (wATTR) and AL amyloidosis and these entities can have overlapping clinical features (Banypersad et al, JAHA 2012). Accurate diagnosis is vital given differences in spectrum of disease, management, and prognosis. We examined the presenting clinical features and survival outcome of patients diagnosed with cardiac wATTR a…
Single Doses of Antibody Drug Conjugates (ADCs) Targeted to CD117 or CD45 Have Potent In Vivo Anti-Leukemia Activity and Survival Benefit in Patient Derived AML Models
http://www.bloodjournal.org/content/132/Suppl_1/3316 Nov 21st, 2018 – Background. Allogeneic bone marrow transplant (BMT) is a potentially curative approach in patients with refractory or high risk hematologic malignancies, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Prior to transplant, patients are prepared with non-specific, high dose chemotherapy alone or in combination with total body irradiation, which are associated with early…
Extracellular Vesicles (EVs) Shape the Leukemic Microenvironment
http://www.bloodjournal.org/content/132/Suppl_1/5428 Nov 21st, 2018 – Background Extracellular Vesicles (EVs) compose a naturally occurring, heterogeneous group of membrane-bound, nano-sized particles shed by all cells. Depending on cellular type, physiological state, and mode of secretion some harbor potent regenerative properties while others have the propensity to induce disease. Human bone marrow mesenchymal stem cell (MSC)-derived EVs harbor regenerative pot…
Systematic Review of Non-Conventional Dosing of Oral Anticancer Therapies in Malignant Haematology
http://www.bloodjournal.org/content/132/Suppl_1/5915 Nov 21st, 2018 – Introduction Survival outcomes for patients with lymphoid, myeloid and plasma cell malignancies, have improved with the use of oral small molecule inhibitory agents. Oral anti-cancer therapies are often administered continuously and can have significant side-effects, which can adversely impact adherence, quality of life (QoL) and survival outcomes. In order to improve tolerability, non-standard…
The Impact of a Physical Activity Intervention Can be Accurately Assessed By Smart Watches in Patients Completing Autologous Stem Cell Transplantation for Lymphoma or Multiple Myeloma: Results of a…
http://www.bloodjournal.org/content/132/Suppl_1/5911 Nov 21st, 2018 – Background: Based on cohort studies and a limited number of prospective studies, physical activity (PA) can improve quality of life (QoL) in non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and patients (pts) undergoing autologous stem cell transplant (ASCT). There are also data to suggest that survival (Pophali et al, ASH 2017) is improved with increased PA in NHL pts. After ASCT, it is know…
Pegfilgrastim Versus Filgrastim in the Management of Therapy-Related Neutropenia in Relapsed and Refractory Multiple Myeloma in Treatment with Pomalidomide-Dexamethasone
http://www.bloodjournal.org/content/132/Suppl_1/5905 Nov 21st, 2018 – Aims: The objective of this study was to compare the efficacy and safety of pegfilgrastim in patients affected by heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily injections of standard filgrastim, in terms of haematological toxicity, febrile neutropenic episodes, antibiotic us…
Monitoring Minimal Residual Disease in Acute Myeloid Leukemia Using Genomic or cfDNA with MyMRD®, a Targeted NGS Panel
http://www.bloodjournal.org/content/132/Suppl_1/5268 Nov 21st, 2018 – Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous disorder. Precision therapies for AML have been developed that target specific driver mutations. The efficacies of these therapies are variable, making it critical to determine successful therapies prior to patient relapse. For patients achieving a first complete remission, minimum residual disease (MRD) is an import…
An Exploratory Study of Cytokine Markers of Cancer-Related Cognitive Impairment in Hematological Malignancy
http://www.bloodjournal.org/content/132/Suppl_1/5914 Nov 21st, 2018 – Introduction. Cancer-related cognitive impairment is a distressing symptom that affects numerous patients after cancer therapy, including those treated for hematological malignancy. The lack of effective interventions has driven interest in determining underlying mechanisms. Accumulating evidence in the context of solid tumours suggests inflammatory processes are involved in the development of …
A Twenty Years Epidemiology Study of 2nd Hematological Malignancies Post to the Initial Tumor Treatment: Report from Southern China Single Cancer Group
http://www.bloodjournal.org/content/132/Suppl_1/5903 Nov 21st, 2018 – Objective: To investigate the clinical features of 2nd hematological malignancies post to the initial cancer treatment. METHODS: A retrospective study was performed to analyze the available clinical data of 116 patients diagnosed with 2nd hematologic malignancies after treatment of various malignant tumors from June 1998 to June 2018 at Sun Yat-sen University cancer center. RESULTS: The charact…
Identification and Characterization of Potential Candidates for Treatment Targeting Apoptosis Pathways in Patients with Hematological Neoplasms
http://www.bloodjournal.org/content/132/Suppl_1/4098 Nov 21st, 2018 – Background: Resistance to apoptosis is one of the hallmarks in hematological neoplasms, most typically via dysregulation of the intrinsic mitochondrial pathway. The most important antiapoptotic/pro-survival proteins in this pathway are BCL2, BCL2L1 and MCL1. Molecules targeting each of these proteins are in various stages of preclinical and clinical development. The BCL2 inhibitor venetoclax is…
Natural History of Asymptomatic IgM Monoclonal Gammopathies: Impact of the Bone Marrow Aspiration into the Classification and Prognosis
http://www.bloodjournal.org/content/132/Suppl_1/1610 Nov 21st, 2018 – Introduction: As in multiple myeloma, Waldenström macroglobulinemia (WM) is preceded by an asymptomatic phase, mainly as monoclonal gammopathy of undetermined significance (MGUS) or by a smoldering WM (SWM) phase. It has recently been reported that patients with IgM MGUS have a higher risk of progression in comparison to those with other MGUS isotypes. Moreover, it has been described that if th…
Targeting the Glyco-Antigen CD75s with the Tetravalent, Fc-Engineered Antibody 'Ebu-141 Tetra' Induces Potent Killing of B Cell Lymphoma and Plasma Cell Tumors
http://www.bloodjournal.org/content/132/Suppl_1/4178 Nov 21st, 2018 – While monoclonal antibodies (MoAb) are already well established for the treatment of B cell-derived malignancies and usually show a good safety profile, not all patients benefit and relapses may be a problem. In order to identify novel surface structures suitable for antibody-based therapies and to improve killing mechanisms, 'EBU-141 Tetra' was developed. The parental MoAb EBU-141 is of mouse …
A New Prognostic Index for Waldenström Macroglobulinemia Based on a Multicenter Retrospective Study of the Japanese Society of Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/5320 Nov 21st, 2018 – Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients…
Evaluation of T Cell and Monocyte Immune Subsets in the Stem Cell Product of Patients Developing Engraftment Syndrome Following Autologous Stem Cell Transplantation for Multiple Myeloma and Lymphoma
http://www.bloodjournal.org/content/132/Suppl_1/4604 Nov 21st, 2018 – BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is now standard of care for newly diagnosed patients with multiple myeloma (MM) and is used for some forms of non-Hodgkin lymphoma, providing improved outcomes. ASCT has been associated with a high incidence of engraftment syndrome (ES), which clinically presents as skin rashes, diarrhea, non-infectious f…
Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/5383 Nov 21st, 2018 – Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes….
SLAMF7 in Primary Effusion Lymphoma, Target for Individualized Therapy?
http://www.bloodjournal.org/content/132/Suppl_1/5300 Nov 21st, 2018 – Primary effusion lymphoma (PEL) is a rare, aggressive form of B-cell lymphoma. With a median survival time of around six months the prognosis for PEL patients is poor. Therefore, there is a medical need for novel therapeutic strategies. We performed expression array analysis to find potential targets for antibody-based therapy. Unsupervised clustering analysis revealed that PEL cell lines group…
Frequency of Acquired Genetic Mutations and Their Prognostic Impact on Patients with Incidental Finding of Isolated 20q- in Bone Marrow without Morphologic Evidence of a Myeloid Neoplasm
http://www.bloodjournal.org/content/132/Suppl_1/4382 Nov 21st, 2018 – Introduction Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders characterized by dysplasia in one or more hematopoietic cell lines, peripheral cytopenia(s), and distinct cytogenetic abnormalities. The presence of certain cytogenetic abnormalities [e.g. 7/del(7q), -5/del(5q), 13/del(13q), i(17p)], in the setting of unexplained persistent cytopenia, has been considered presumptiv…
Bion-1301 Blocks APRIL-Induced Anti-Apoptotic Signaling, Immune Suppressive Phenotype, and Chemokine Production Associated with Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/1908 Nov 21st, 2018 – A proliferation-inducing ligand (APRIL) is produced by multiple accessory and myeloid cells in the bone marrow niche. Through binding to its receptors B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), APRIL plays an important role in the development and maintenance of cells derived from the B cell lineage. Both APRIL and its receptors have been identified …
Solid Tumors in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: A Study on 2220 Patients
http://www.bloodjournal.org/content/132/Suppl_1/3039 Nov 21st, 2018 – Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) that can progress to post-PV (PPV) myelofibrosis (MF) and post-ET (PET) MF, from now on referred to as secondary myelofibrosis (SMF). Recent studies have shown an increased risk of developing solid tumors (ST) in MPN patients in comparison to the general population. Information on develo…
18f-FDG PET/CT and the Revised International Staging System Are More Discriminating of Survival Outcomes in Newly Diagnosed Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/4483 Nov 21st, 2018 – Purpose : This study evaluated the prognostic role of 18F-FDG PET/CT at baseline in patients with newly diagnosed multiple myeloa (MM) and evaluated the prognostic relevance of 18F-FDG PET/CT for each stage according to the Revised International Staging System (R-ISS). Method: We retrospectively analyzed the records of 167 patients with newly diagnosed MM. 18F-FDG PET/CT was performed prior to …
A Phase 2 Study of Carfilzomib Plus Elotuzumab Plus Dexamethasone for Myeloma Patients Relapsed after 1-3 Prior Treatment Lines
http://www.bloodjournal.org/content/132/Suppl_1/1975 Nov 21st, 2018 – Introduction: The median progression free survival (PFS) and overall survival (OS) of multiple myeloma (MM) patients have been prolonged due to novel agents combined with ASCT but the median OS in MM is still 7-8 years. Thus, the feasibility of new combinations and dosing of available agents must be investigated. The first proteasome inhibitor (PI), bortezomib (B), combined with elotuzumab and …
Carfilzomib Cardiovascular Disease: Use of the Atherosclerotic Cardiovascular Disease Score to Predict Cardiovascular Events in Multiple Myeloma Patients Treated with Carfilzomib
http://www.bloodjournal.org/content/132/Suppl_1/3254 Nov 21st, 2018 – Introduction: In the ASPIRE and ENDEAVOR trials, multiple myeloma (MM) patients treated with carfilzomib (K) had significantly improved progression‐free survival and overall survival compared with standard of care. The incidence of all-grade adverse cardiovascular events (ACVE) was 26.6% and 24.5% in the K treated groups in ASPIRE and ENDEAVOR respectively. The atherosclerotic cardiovascular di…
A Phase II Study of the Efficacy and Safety of Lenalidomide, Subcutaneous Bortezomib and Dexamethasone (RVD) Combination Therapy for Patients with Newly Diagnosed Multiple Myeloma: Promising Activi…
http://www.bloodjournal.org/content/132/Suppl_1/1981 Nov 21st, 2018 – Introduction: Patients (pts) with newly diagnosed multiple myeloma (MM) are commonly treated with the standard of care combination of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex), also known as RVD. A recent randomized phase 3 study found that the addition of Bz to Len and Dex significantly increased median overall and progression free survival as well as response rate (Durie et…
A Rapid Functional Screen for Small Molecule and Monoclonal Antibody Drug Sensitivity in Multiple Myeloma Patients
http://www.bloodjournal.org/content/132/Suppl_1/3203 Nov 21st, 2018 – Background: The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. As a result, personalized medicine approaches have not yet been realized. However, clinical availability of numerous anti-myeloma drugs and readily obtainable bone marrow (BM) aspirates raises the possibility to benefit patients by profiling the drug sens…
A Role for Syntenin-1 in Multiple Myeloma Cell Survival
http://www.bloodjournal.org/content/132/Suppl_1/1008 Nov 21st, 2018 – Multiple myeloma is the second most common hematological malignancy in the U.S. with an estimated 30,700 new diagnoses in 2018. It is a clonal disease of plasma cells that, despite recent therapeutic advances, remains incurable. Myeloma cells retain numerous characteristics of normal plasma cells including reliance on survival signals in the bone marrow for long term viability. However, maligna…
A Single-Cell Transcriptional Analysis of Tumour Cells and the Immune Microenvironment during Disease Evolution in a Transgenic Mouse Model of Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/56 Nov 21st, 2018 – Introduction: Multiple Myeloma (MM) is consistently preceded by pre-malignant asymptomatic monoclonal gammopathies (AMG). To date, our understanding of the pathogenesis of progression to MM remains incomplete. Genetic analyses of AMG cells compared to MM-derived plasma cells (PCs) have found few differences, suggesting that progression may be mediated in part by tumour-extrinsic mechanisms. To …
Carfilzomib-Lenalidomide-Dexamethasone Versus Bortezomib-Lenalidomide-Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Results from the Prospective, Longitudinal, Observational Comm…
http://www.bloodjournal.org/content/132/Suppl_1/799 Nov 21st, 2018 – Introduction: Triplet regimens incorporating a proteasome inhibitor and immunomodulatory drug are standards of care for the treatment of patients with newly diagnosed multiple myeloma (NDMM). The combinations of carfilzomib-lenalidomide-dexamethasone (KRd) and bortezomib-lenalidomide-dexamethasone (VRd) are recommended regimens for the treatment of NDMM by the National Comprehensive Care Networ…
Long-Lasting Remissions for Myeloma Patients on Daratumumab Therapy from the GEN501 and GEN503 Trials
http://www.bloodjournal.org/content/132/Suppl_1/3308 Nov 21st, 2018 – Introduction The first two trials to test the activity of daratumumab (DARA) in relapsed/refractory multiple myeloma (MM) were GEN501 (DARA monotherapy) and GEN503 (DARA in combination with lenalidomide [LEN] and dexamethasone [DEX]). GEN501 enrolled 104 participants from 2008 and GEN503 enrolled 45 participants from 2012. GEN501 has been completed; GEN503 is active but has finished accrual. We…
Activating KRAS, NRAS, and BRAF Mutants Enhance Proteasome Capacity and Reduce Endoplasmic Reticulum Stress in Multiple Myeloma, Thereby Promoting Plasma Cell Survival and Proteasome Inhibitor Resi…
http://www.bloodjournal.org/content/132/Suppl_1/406 Nov 21st, 2018 – Introduction: Multiple myeloma, a malignant proliferation of differentiated plasma cells, is the second most commonly diagnosed hematologic malignancy, and the number of cases may grow by almost 60% between 2010 and 2030. Recent therapeutic advances, including the use of proteasome inhibitors (PIs), have contributed to a doubling of the median overall survival in myeloma patients. This has been…
Long-Term Follow-up Identifies Double Hit and Key Mutations As Impacting Progression Free and Overall Survival in Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/110 Nov 21st, 2018 – Introduction: The study of multiple myeloma (MM) genomics has identified many abnormalities that are associated with poor progression free survival (PFS) and overall survival (OS). Copy number abnormalities have been extensively studied in many datasets with long follow-up, however, the prognostic impact of mutations have not been extensively studied and available datasets have generally had a …
Addition of Ixazomib to an Rd Backbone Improves Clinical Benefit in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) with Non-Canonical NF-KB Activation — Results from the Tourmaline-MM1 …
http://www.bloodjournal.org/content/132/Suppl_1/473 Nov 21st, 2018 – Background Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide-dexamethasone (Rd) for pts with MM who have received at least 1 prior therapy. Approval was based on the phase 3 TOURMALINE-MM1 study (NCT01564537), in which ixazomib showed a consistent progression-free survival (PFS) benefit in combination with Rd (IRd) in the ITT population as well as in pr…
Long-Term Survivorship with Active Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/1912 Nov 21st, 2018 – Background The survival of patients with multiple myeloma (MM) has improved significantly over the past two decades with the introduction of novel treatment agents. However, MM is still largely considered an incurable malignancy with a relapsing-remitting course. A follow-up of at least 10 years from active disease is required to determine whether a plateau in progression-free survival has been…
CD38 Specific Chimeric Antigen Receptor KHYG-1 Natural Killer Cells: A Potential "Off the Shelf" Therapy for Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/3261 Nov 21st, 2018 – Chimeric Antigen Receptors (CARs) are engineered transmembrane proteins consisting of an antibody-derived antigen recognition domain linked to intracellular cell signaling domains. CAR engineered autologous T cells have been successful in the treatment of a variety of hematologic malignancies. However, several major caveats, including lack of universal donors, long manufacturing times, and abse…
AL Amyloidosis — Pathogenesis and Prognosis Are Determined By the Amyloidogenic Potential of the Light Chain and the Molecular Characteristics of Malignant Plasma Cells
http://www.bloodjournal.org/content/132/Suppl_1/187 Nov 21st, 2018 – INTRODUCTION. Systemic light chain amyloidosis (AL) is caused by accumulation of plasma cells producing misfolded monoclonal light chains depositing as amyloid fibrils in different organs, most frequently heart and kidney. AIM of our study is first assessing the molecular characteristics of malignant plasma cells from AL-patients in relation to those from MGUS, asymptomatic, and symptomatic mye…
CD38-Deficient, CD16-Engineered NK Cells Exhibit Enhanced Antibody-Dependent Cellular Cytotoxicity without NK Cell Fratricide to Augment Anti-Myeloma Immunity in Combination with Daratumumab
http://www.bloodjournal.org/content/132/Suppl_1/3224 Nov 21st, 2018 – Daratumumab targets the cell surface protein CD38 and is the only FDA approved monoclonal antibody that has demonstrated single agent efficacy in relapsed refractory myeloma. CD38 is broadly expressed in the immune system, and its high expression on multiple myeloma cells allows for effective targeting by daratumumab. Daratumumab induces myeloma cell death through multiple mechanisms, including…
Evaluation of Re-Intensification of Daratumumab to Weekly or Biweekly Dosing Schedule
http://www.bloodjournal.org/content/132/Suppl_1/2024 Nov 21st, 2018 – Introduction: Multiple Myeloma (MM) is a hematologic cancer caused by malignant plasma cells. Daratumumab is an immunoglobin G1 kappa human monoclonal antibody that targets CD38 antigen which is a cell surface glycoprotein highly expressed on myeloma cells. Daratumumab is FDA approved as monotherapy and in combination with dexamethasone and lenalidomide, bortezomib or pomalidomide in relapsed/r…
Lyra: A Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (Cybord) in Newly Diagnosed and Relapsed Patients (Pts) with Multiple Myeloma (MM)
http://www.bloodjournal.org/content/132/Suppl_1/152 Nov 21st, 2018 – Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts…
Altering Glycosphingolipid Composition to Improve Multiple Myeloma Bone Complication
http://www.bloodjournal.org/content/132/Suppl_1/1942 Nov 21st, 2018 – Multiple myeloma (MM) is an incurable cancer of plasma cells (PC), with a median survival of 5-7 years. Osteolytic bone disease and skeletal complications occur in more than 80% of MM patients and significantly contribute to the morbidity and mortality of these patients. Glycosphingolipid (GSL), an essential constituent of the outer leaflet of the cellular membrane, is altered in MM and other h…
Evaluation of the Revised International Staging System in 400 Patients with Symptomatic Myeloma in a Japanese Clinical Setting
http://www.bloodjournal.org/content/132/Suppl_1/4477 Nov 21st, 2018 – Background:In 2015, the International Myeloma Working Group (IMWG) developed the Revised International Staging System (R-ISS), which combined the ISS with the status of high-risk cytogenetic abnormalities (CAs) and serum levels of lactate dehydrogenase to identify three multiple myeloma (MM) entities with clearly different outcomes. However, although MM tends to affect older adults, the origina…
An Acquired High-Risk Chromosome Instability Phenotype in Multiple Myeloma: Jumping 1q Syndrome
http://www.bloodjournal.org/content/132/Suppl_1/4489 Nov 21st, 2018 – Introduction Chromosome instability (CIN) is a driver of copy number aberrations (CNAs) in cancer, and is a major factor leading to tumor heterogeneity and resistance to therapy. By definition, CIN is an increased rate or ongoing acquisition and accumulation of CNAs and not simply the existence of structurally and numerically abnormal aneuploid clones. In multiple myeloma (MM), the most common …
Maintenance with Carfilzomib Following Carfilzomib, Cyclophosphamide and Dexamethasone at First Relapse or Primary Refractory Multiple Myeloma (MM) on the Phase 2 Muk Five Study: Effect on Minimal …
http://www.bloodjournal.org/content/132/Suppl_1/802 Nov 21st, 2018 – Background The benefit of single agent maintenance is largely established from studies in newly diagnosed patients, while extended therapy combination regimens are more commonly used in relapsed disease. Extended therapy on combination protocols may be limited by tolerability and safety, as well as patient compliance. Fixed duration combination treatment followed by single agent maintenance may…
Characterising the Immunological Microenvironment in Newly Diagnosed Multiple Myeloma Bone Marrow By Time of Flight Cytometry Reveals Abnormalities in Antigen Presenting and Effector Lymphocyte Pop…
http://www.bloodjournal.org/content/132/Suppl_1/58 Nov 21st, 2018 – Background Loss of immune surveillance is thought to contribute to disease progression and treatment resistance in a range of malignancies including multiple myeloma (MM). Understanding the degree and pattern of immunological abnormality present within the bone marrow microenvironment at the time of MM diagnosis is vital if we are to utilize emerging immunological therapeutic strategies success…
Analysis of the Multiple Myeloma HLA Peptidome Identifies a Naturally Presented Bcma-Derived Peptide As an Immunogenic T-Cell Epitope for Immunotherapeutic Approaches
http://www.bloodjournal.org/content/132/Suppl_1/3173 Nov 21st, 2018 – The B-cell maturation antigen (BCMA) is selectively expressed by cells of the B-lineage, including multiple myeloma (MM) cells, and constitutes a promising target for immunotherapeutic approaches. At present, BCMA is being evaluated as target for immunotherapeutic approaches, such as CAR T cells and bispecific antibodies, which have demonstrated promising results in phase I clinical trials. The…
APRIL Is Significantly Elevated at All Stages of Multiple Myeloma (MM) and Interferes with Anti-Bcma Monoclonal Antibody-Mediated Cytolysis, Supporting the Clinical Evaluation of Bion-1301 As a Nov…
http://www.bloodjournal.org/content/132/Suppl_1/3209 Nov 21st, 2018 – A proliferation inducing ligand (APRIL) is a natural ligand with higher affinity than BAFF for both B cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), which are overexpressed on multiple myeloma (MM) cells. APRIL, which is abundantly secreted by myeloma-supporting osteoclasts and macrophages, promotes MM cell progression in vivo and further induces regulato…
Maximizing Pre-Transplant Response Is Associated with Improved Outcome for Myeloma Patients: Exploratory Analysis of the Myeloma XI Trial
http://www.bloodjournal.org/content/132/Suppl_1/3280 Nov 21st, 2018 – Background: The depth of response both pre- and post- autologous stem cell transplant (ASCT) has been shown to correlate with clinical outcome for myeloma patients. Maximizing response can be achieved by modifying therapy either at induction, transplant, consolidation or during maintenance. In this work we explore the role of pre-transplant induction therapy in the UK NCRI Myeloma XI clinical t…
MCL-1 Inhibition Is Highly Effective Against Multiple Myeloma Cells from Poor Prognosis Patients
http://www.bloodjournal.org/content/132/Suppl_1/1916 Nov 21st, 2018 – Introduction: Despite recent advances in treatment, multiple myeloma (MM) is still considered incurable. Several novel therapies with different mechanisms of action are currently being studied for use in MM. These include targeted therapies such as pathway inhibitors and BCL-2 homology domain 3 (BH3) mimetics. BH3-mimetics overcome apoptosis resistance by binding and inhibiting select pro-survi…
MCRN¯003/MYX·1: A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma after 1-3 Prior Therapies
http://www.bloodjournal.org/content/132/Suppl_1/1984 Nov 21st, 2018 – Background: Carfilzomib, a second generation proteosome inhibitor, is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Recent phase II and phase III trials have demonstrated the efficacy of weekly dosing strategies. The aim of this study was to examine high dose once weekly carfilzomib in combination with weekly dexamethasone and low dose weekly cyclophosphamide (w…
FDA Analysis of Outcomes in Older Adults with Relapsed or Refractory Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/3287 Nov 21st, 2018 – Background: Multiple myeloma (MM) is a disease of older adults with a median age of onset of 70 years. Approximately 20% of the incident cases are diagnosed in patients 85 years and older. There is significant heterogeneity among older adults with regards to the tolerability of myeloma directed therapy. In newly diagnosed transplant ineligible patients with MM, available evidence indicates that…
Baseline and on-Treatment Bone Marrow Microenvironments Predict Myeloma Patient Outcomes and Inform Potential Intervention Strategies
http://www.bloodjournal.org/content/132/Suppl_1/1882 Nov 21st, 2018 – Introduction The multiple myeloma (MM) tumor microenvironment (TME) strongly influences patient outcomes as evidenced by the success of immunomodulatory therapies. To develop precision immunotherapeutic approaches, it is essential to identify and enumerate TME cell types and understand their dynamics. Methods We estimated the population of immune and other non-tumor cell types during the course…
Clinical Responses and Pharmacokinetics of MCARH171, a Human-Derived Bcma Targeted CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma: Final Results of a Phase I Clinical Trial
http://www.bloodjournal.org/content/132/Suppl_1/959 Nov 21st, 2018 – Introduction: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (MM). Herein, we report on the safety and efficacy of MCARH171, a second generation, human derived BCMA targeted autologous 4-1BB containing CAR T cell therapy, including a truncated epidermal growth factor receptor safety system (Smith EL. Mol Ther 2018). Methods: Th…
Metabolomic Profiling of Serum from Myeloma and MGUS Patients – a Novel Strategy to Identify Potential Biomarkers of Myeloma Development and Progression
http://www.bloodjournal.org/content/132/Suppl_1/1891 Nov 21st, 2018 – Introduction: Drivers that underlie the progression of MGUS (Monoclonal gammopathy of undetermined significance) to multiple myeloma are yet largely unknown. Because of the vast number of potential players, these drivers may not necessarily aimed to transform plasma cell or the bone marrow niche, but rather remodel a supporting microenvironment. Metabolic alterations have been linked to cancer …
Fully Human Bcma Targeted Chimeric Antigen Receptor T Cells Administered in a Defined Composition Demonstrate Potency at Low Doses in Advanced Stage High Risk Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/1011 Nov 21st, 2018 – Background: Despite advances in the treatment of multiple myeloma (MM) almost all patients relapse and high risk features continue to portend a short median survival. The adoptive transfer of B-Cell Maturation Antigen (BCMA) chimeric antigen receptor (CAR) T cells is demonstrating early promise in MM, but the durability of response has not been established. The infusion of genetically modified …
Functional Analysis of HDAC11 in Plasma Cell Development and Multiple Myeloma Survival
http://www.bloodjournal.org/content/132/Suppl_1/3223 Nov 21st, 2018 – Background: Histone deacetylases (HDACs) are potential novel therapeutic targets for multiple myeloma (MM) treatment. A pan-HDAC inhibitor (HDI) panobinostat was approved by the FDA in 2015 to treat relapsed/refractory MM patients, and several other HDIs are currently in different phases of clinical trials. However, unfavorable side-effects of the non-selective HDIs necessitate further dissecti…
Minimal Residual Disease (MRD) Analysis Using Multiparametric Flow Cytometry (MFC) and Identification of Differences in Subpopulations Using Next Generation Sequencing (NGS) in the Bone Marrow (BM)…
http://www.bloodjournal.org/content/132/Suppl_1/3222 Nov 21st, 2018 – Introduction: MM is characterized by the accumulation of aberrant BM plasma cells (aPCs). The use of novel agents for anti-MM treatment has enabled the achievement of deeper responses and prolonged progression free survival (PFS) and overall survival (OS). These advances have created the need for sensitive means to detect residual PCs. MFC allows aPC detection with high sensitivity and is used …
Functional Cure, Defined As PFS of More Than 7 Years, Is Achieved in 9% of Myeloma Patients in the Era of Conventional Chemotherapy and of First-Generation Novel Anti-Myeloma Agents; A Single-Cente…
http://www.bloodjournal.org/content/132/Suppl_1/1968 Nov 21st, 2018 – Advances in the management of multiple myeloma (MM) led to a significant prolongation of overall survival (OS), mainly of the younger patients; almost 10% of them experience more than 10-year OS. Although long progression-free survival (PFS) correlates with extended OS, there is very limited information for the characteristics of patients who manage to be progression-free for a long period afte…
Molecular Characterization By Immune Profiling of Paired Blood and Bone Marrow in Multiple Myeloma and Its Precursor States
http://www.bloodjournal.org/content/132/Suppl_1/4461 Nov 21st, 2018 – INTRODUCTION: Progression from precursor states, MGUS and smoldering multiple myeloma (SMM), to multiple myeloma (MM) is dependent upon adaptive and innate immune contexture shaped by cross-talk between malignant plasma cells and bone marrow (BM) milieu. The complexity and heterogeneity of interactions between the immune system and plasma cells in BM triggers alterations in peripheral blood (PB…
Preclinical Validation Studies Support Causal Machine Learning Based Identification of Novel Drug Targets for High-Risk Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/3210 Nov 21st, 2018 – Introduction Regardless of significant advances in the therapy of multiple myeloma (MM) there is still a lack of effective treatment options for patients with high-risk disease. In this context, we recently developed a network of high-risk disease based on more than 30 000 genomic and clinical variables from 645 patients of the CoMMpass dataset (Gruber et al., ASH 2016). Validation of these fin…
Monoclonal Gammopathy of Undetermined Significance – Patient Characteristics and Referral Patterns
http://www.bloodjournal.org/content/132/Suppl_1/4496 Nov 21st, 2018 – Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a prevalent hematological condition among elderly population with incidence rates of 3% and 5% over the age of 50 and 70 years, respectively (Kyle et al., 2018). It is considered a premalignant state of multiple myeloma with a risk of progression of 1% per year. It has also been shown that MGUS patients have a shorter sur…
Comprehensive Multi-Omics Analysis of Gene Fusions in a Large Multiple Myeloma Cohort
http://www.bloodjournal.org/content/132/Suppl_1/1898 Nov 21st, 2018 – Introduction: Gene fusions are the result of genomic rearrangements that create hybrid protein products or bring the regulatory elements of one gene into close proximity of another. Fusions often dysregulate gene function or expression through oncogene overexpression or tumor suppressor underexpression (Gao, Liang, Foltz, et al. Cell Rep 2018). Some fusions such as EML4–ALK in lung adenocarcin…
Genomic Abnormalities Among African Individuals with Monoclonal Gammopathies Using Calculated Ancestry
http://www.bloodjournal.org/content/132/Suppl_1/4458 Nov 21st, 2018 – Monoclonal gammopathies, including multiple myeloma (MM), represent a group of plasma cell (PC) disorders that comprise of mostly incurable hematopoietic malignancies with an increasing incidence in the US. Previous epidemiological studies demonstrated a 2-3 fold higher incidence of monoclonal gammopathy of undetermined significance (MGUS) and a similarly higher incidence of MM along with a ~4-…
Preliminary Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) MM17 Trial: Response Adaptive Salvage Treatment with Carfilzomib-Thalidomide-Dexamethasone (KTd) for Newly Diagnosed Tra…
http://www.bloodjournal.org/content/132/Suppl_1/3279 Nov 21st, 2018 – Background Data from the Australian and New Zealand (ANZ) Myeloma and Related Diseases Registry (MRDR) shows that 85% of newly diagnosed multiple myeloma (NDMM) patients (pts) in ANZ are induced with bortezomib(V)-containing therapies, predominantly triplets of V-cyclophosphamide-dexamethasone (VCD). Of these, 15% demonstrate treatment failure – either a sub-optimal response (
CRISPR Activation Screen for Drivers of MM Cell Proliferation
http://www.bloodjournal.org/content/132/Suppl_1/3197 Nov 21st, 2018 – CRISPR/Cas9-based gene editing has become a powerful tool for loss-of-function (LOF) studies and has allowed us to systematically interrogate the function of genes regulating the survival and proliferation of multiple myeloma (MM) cells in vitro, in vivo and in the context of treatment resistance (e.g. De Matos Simoes et al., Shirasaki et al., and Gandolfi et al. ASH 2017). We reasoned, however…
Preliminary Results from a Phase I Study of Isatuximab (ISA) in Combination with Bortezomib, Lenalidomide, Dexamethasone (VRd), and in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Non-Elig…
http://www.bloodjournal.org/content/132/Suppl_1/595 Nov 21st, 2018 – Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells via direct tumor targeting and immune cell engagement. ISA, combined with bortezomib, has demonstrated strong potentiation in a multiple myeloma (MM) xenograft model (Clin Cancer Res 2014:20:4754). This supported evaluation of ISA with bortezomib combinations in pts with newly …
Multidimensional Immunophenotyping Identifies Hallmarks of Systemic Light-Chain Amyloidosis (AL) and Maps the Disease in the Crossroad between MGUS and Multiple Myeloma (MM)
http://www.bloodjournal.org/content/132/Suppl_1/3170 Nov 21st, 2018 – Background: Since survival in AL mainly depends on the extent of organ involvement of patients at presentation, early diagnosis and risk stratification are key to improve patients' outcome. Therefore, together with surrogates of organ involvement, biomarkers identifying patients with MGUS or MM at greater risk of developing AL would be highly valuable to prevent organ damage, to maximize therap…
CRISPR-Cas9 Mediated CD45 Knockout Inactivates Src Family Kinases and Impairs Cell Migration in Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/1907 Nov 21st, 2018 – Introduction Multiple myeloma (MM) is a plasma cell malignancy that manifests continuous cell dissemination to multiple bone marrow (BM) niches and extramedullary (EM) sites. However, the molecular mechanisms behind this phenomenon remain elusive. CD45, a receptor tyrosine phosphatase, is an important regulator for T-cell and B-cell signaling pathways. In MM, the loss of CD45 expression has bee…
Global 3D-Epigenetic Dysregulation of Cyclin D1 and D2 Actively Controls Their Expression Pattern in Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/3904 Nov 21st, 2018 – Introduction: Multiple myeloma (MM) is characterized by the over-expression of D-cyclin genes and the expression is tightly linked to cytogenetic subgroups. For instance, overexpression of CCND1 in the t(11;14) and CCND3 in the t(6;14) is direct through IgH super-enhancer translocation, and CCND2 overexpression in t(4;14), t(14;16) and t(14;20) indirectly, presumably as a result of transcriptio…
Critical Role for Apobec and Its Interacting Partners in Mediating Mutations and Cell Growth in Multiple Myeloma (MM)
http://www.bloodjournal.org/content/132/Suppl_1/4462 Nov 21st, 2018 – The APOBEC family of cytidine deaminases include AID (activity induced deaminase) and 10 related APOBEC enzymes (A1,A2,A3A,A3B,A3C,A3D,A3F,A3G,A3H and A4). AID is well studied for its role in somatic hyper mutation and class switch recombination of immunoglobulin genes. APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) have been shown to have roles in mRNA editing and i…
Graded Cardiac Response Correlates with Relapse and Survival in AL Amyloidosis
http://www.bloodjournal.org/content/132/Suppl_1/4486 Nov 21st, 2018 – Seventy percent of all patients with light chain amyloidosis (AL) have cardiac involvement, and most of those patients ultimately die from complications related to their heart disease. While consensus guidelines outline criteria for grading hematologic response to chemotherapy for AL, there are no currently validated criteria for grading cardiac response to therapy. Recently, Muchtar et al. cre…
Cybord-Dara Is a Highly Effective Upfront Treatment for Newly Diagnosed Multiple Myeloma. Initial Efficacy Results of the 16-Bcni-001/Ctrial-IE (ICORG) 16-02 Study
http://www.bloodjournal.org/content/132/Suppl_1/3242 Nov 21st, 2018 – Introduction: Daratumumab (DARA), a human IgG1k monoclonal antibody with single activity in multiple myeloma (MM) shows strong synergy in combination with other anti-MM agents, including immunomodulatory drug (IMiDs) and proteasome inhibitors (PI). This has led to the exploration of DARA in combination with front line regimens. Triplets including a PI and an IMiD are considered an ideal backbon…
HDP101, a Novel B-Cell Maturation Antigen (BCMA)-Targeted Antibody Conjugated to α-Amanitin, Is Active Against Myeloma with Preferential Efficacy Against Pre-Clinical Models of Deletion 17p
http://www.bloodjournal.org/content/132/Suppl_1/593 Nov 21st, 2018 – Background: Deletion (del) of 17p involving the p53 tumor suppressor (TP53) remains an adverse prognostic factor in multiple myeloma (MM) despite the use of novel agents as well as high-dose chemotherapy with autologous stem cell rescue. Genomic TP53 deletion can cause haploinsufficiency of nearby genes, such as RNA polymerase II subunit A (POLR2A), which ia also located on 17p13.1. We therefor…
Cyclophosphamide, Pomalidomide and Dexamethasone Significantly Improves Response over Poma/Dex in Relapsed/Refractory Myeloma Patients Previously Treated with Cyclophosphamide Combination Therapy -…
http://www.bloodjournal.org/content/132/Suppl_1/3274 Nov 21st, 2018 – Background and aims Treatment of relapsed/refractory myeloma (RRMM) remains a challenge as most approved and commonly accessible doublet treatments induce responses (≥PR) in less than half of patients. The combination of the classical alkylator cyclophosphamide with thalidomide (CTD) or lenalidomide (CRD) is standard of care in early lines of therapy in the UK and elsewhere. Data on the clinica…
Myeloma Patient-Derived MCL1 Point Mutations Can Influence MCL1-Inhibitor Function
http://www.bloodjournal.org/content/132/Suppl_1/951 Nov 21st, 2018 – Multiple myeloma is a malignancy of long-lived plasma cells of the bone marrow that is rarely curable. Thus, despite recent advances in the development of new therapies, additional approaches are required. We investigated potential molecular vulnerabilities in the BCL2 family. Using the MMRF CoMMpass (NCT0145429) study (IA13), we determined the frequency of nonsynonymous coding mutations in the…
Hematogenous Extramedullary Relapse in Multiple Myeloma – A Multicenter Retrospective Study in 127 Patients
http://www.bloodjournal.org/content/132/Suppl_1/2004 Nov 21st, 2018 – Background: Hematogenous extramedullary multiple myeloma (HEMM), though rare, is mainly observed in MM patients at relapse. The current study assesses the characteristics and outcomes of patients with MM who develop HEMM in the novel agent era. Methods: Consecutive patients, treated in 16 participating centers and diagnosed with HEMM, were included. Patient characteristics at diagnosis and at H…
Deciphering Clonal Evolution and Dissemination of Multiple Myeloma Cells In Vivo
http://www.bloodjournal.org/content/132/Suppl_1/55 Nov 21st, 2018 – Introduction: Multiple Myeloma (MM) is a genetically complex and evolutionary process with well defined precursor states, which offer a unique opportunity to study the sequential evolution of the disease. A small number of detectable pre-malignant clones are present in early stage and continue to acquire more genomic abnormalities leading to overt disease. The interaction between cancer cells a…
Progression Free Survival below 12 Months Following Stem Cell Transplant Is a Hallmark of High-Risk Myeloma Which Is Associated with Inferior Overall Survival — Data from the Ukmrc Myeloma XI Trial
http://www.bloodjournal.org/content/132/Suppl_1/122 Nov 21st, 2018 – Introduction Multi-agent induction chemotherapy followed by autologous stem cell transplant (ASCT) is a standard of care for younger patients with multiple myeloma, aimed at maximising the depth and duration of first response (PFS1). However, the duration of PFS1 is variable between patients. Improved understanding of how to identify high risk patients who relapse early and the ability to desig…
High Levels of APOBEC3B Gene Expression Contribute to Poor Prognosis in Multiple Myeloma Patients
http://www.bloodjournal.org/content/132/Suppl_1/3897 Nov 21st, 2018 – Introduction: Poor prognosis and drug resistance in multiple myeloma (MM) is associated with increased mutational load. APOBEC3B is a major contributor to mutagenesis, especially in myeloma patients with t(14;16) MAF subgroup. It was shown recently that presence of the APOBEC signature at diagnosis is an independent prognostic factor for progression free survival (PFS) and overall survival (OS)…
Deep Immunoprofiling of the Bone Marrow Microenvironmental Changes Underlying the Multistep Progression of Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/243 Nov 21st, 2018 – Introduction The multistep progression of multiple myeloma from a normal plasma cell to a system with the features of invasive cancer provides a unique opportunity to understand the co-evolution of the malignant clone within its microenvironment. Understanding these changes is becoming increasingly important as we attempt to design early intervention strategies and to precisely leverage emergin…
Proliferation and Molecular Risk Score of Low Risk Myeloma Cells Are Increased in High Risk Microenvironment Via Augmented Bioavailability of Growth Factors
http://www.bloodjournal.org/content/132/Suppl_1/1929 Nov 21st, 2018 – Introduction: Multiple myeloma (MM) cells from patients with smoldering MM (SMM) and low-risk (LR) MM harbor genetic alterations typically seen in patients with high-risk (HR) disease. To test whether the bone marrow (BM) microenvironment plays a role in controlling growth of LR MM cells, we established an experimental model that mimics a HR microenvironment by co-culturing normal mesenchymal s…
Next-Generation Sequencing-Based Assay Shows High Clonal Characterization Success Rate for Plasma Cell Neoplasms, and Concordance with Flow Cytometry in Minimal Residual Disease Detection
http://www.bloodjournal.org/content/132/Suppl_1/4475 Nov 21st, 2018 – Introduction After therapy or stem cell transplantation, multiple myeloma patients achieving complete response (CR) or stringent complete response (sCR) can still have a significant risk of disease relapse, illustrating the importance of using highly sensitive methods for minimal residual disease (MRD) detection and prognostication. Two techniques used clinically for MRD detection include multi…
Development and Evaluation of CART Targeting Bcma with Humanized Alpaca-Derived Single-Domain Antibody As Antigen Recognition Domain
http://www.bloodjournal.org/content/132/Suppl_1/1976 Nov 21st, 2018 – Chimeric antigen receptor T cells (CART) targeting CD19 have shown substantial activity against leukemia and lymphoma, which motivated developing CART cell therapy for Multiple myeloma (MM). B cell maturation antigen (BCMA) is the target molecule in MM. Several kinds of CART targeting BCMA have been created from 2016. Among these, the Bluebird Bio uses the humanized murine BCMA scFv to make CAR…
Identification of Specificity Groups in Myeloma Patients T Cell Receptor (TCR) Repertoire through Single Cell TCR Sequencing
http://www.bloodjournal.org/content/132/Suppl_1/4459 Nov 21st, 2018 – Background: A renewed interest in immune and cellular based therapeutics in multiple myeloma was recently fueled by the development of CD38 targeting monoclonal antibodies as well as the introduction of engineered CAR-T cells. Daratumumab treatment in myeloma patients was demonstrated to expand clonal CD8+T cells and T cell clonality was correlated with the depth of response consistent with a d…
Novel Combination Therapy Targeting rDNA Transcription and Histone Deacetylation Provides Effective Treatment for Multiple Myeloma, and Synergises in Bortezomib-Resistant MM
http://www.bloodjournal.org/content/132/Suppl_1/1945 Nov 21st, 2018 – Background: Multiple myeloma (MM) requires combination drug therapies to delay acquired drug resistance and clinical relapse. We co-developed CX-5461, a highly-selective inhibitor of RNA polymerase I-mediated rDNA transcription(1), currently in phase I trials for relapsed haematological malignancies (Peter Mac). CX-5461 produces a targeted nucleolar DNA damage response (DDR), triggering both a …
Quantitative Integrative Prediction of Survival Probability in Multiple Myeloma Using Molecular and Clinical Prognostic Factors in 657 Patients Treated with Bortezomib-Based Induction, High-Dose Th…
http://www.bloodjournal.org/content/132/Suppl_1/403 Nov 21st, 2018 – Background Survival in multiple myeloma ranges from months to decades and the majority of patients remain incurable with current treatment approaches. Given this high variability, it would be clinically very useful to quantitatively predict survival on a continuous scale. Current risk prediction models attribute patients to 2-3 groups, i.e. high, intermediate, and low risk. Group size and survi…
Immune Mediated Mechanisms of Resistance to Daratumumab
http://www.bloodjournal.org/content/132/Suppl_1/3201 Nov 21st, 2018 – Introduction: Daratumumab (Dara) is a human monoclonal antibody targeting the highly expressed multiple myeloma (MM) surface receptor CD38, with significant activity in relapsed MM. However, resistance to Dara develops in virtually all patients (pts). Thus, in order to maximize its clinical activity and prevent resistance, it is imperative to understand why pts stop responding. Our group recent…
Real World Analysis of the Incidence and Impact of Hypertension and Cardiac Toxicity Associated with Carfilzomib for Patients with Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/3255 Nov 21st, 2018 – Background: Carfilzomib (CFZ) is a potent, irreversible proteasome inhibitor (PI) licenced in patients with multiple myeloma (MM) demonstrating improved progression free and overall survival (OS) to standard of care therapies. However, CFZ is also associated with hypertension (HTN) and rarely cardiac toxicity. The exact mechanism is unclear but may be due to a disturbance of endothelial nitric …
Real World Data on the Efficacy and Safety of Daratumumab in Relapsed/Refractory Multiple Myeloma: Data Collected from the Hungarian Hematology Centers
http://www.bloodjournal.org/content/132/Suppl_1/3257 Nov 21st, 2018 – Background: Daratumumab is one of the most effective new myeloma drugs recently approved for relapsed/refractory multiple myeloma (MM), first in monotherapy in heavily pretreated patients, later in triplet combinations from first relapse, based on the results of the SIRIUS, POLLUX and CASTOR trials that showed good tolerability and high effectivity of daratumumab both in monotherapy and combine…
Durable Remission Achieved from Bcma-Directed CAR-T Therapy Against Relapsed or Refractory Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/956 Nov 21st, 2018 – Background: Promising results are seen from several early phase clinical trials on the cellular immunotherapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) targeting B cell maturation antigen (BCMA) for the treatment of relapsed/refractory (RR) multiple myeloma (MM). We developed an anti-BCMA CAR-T cell product manufactured via gamma-retrovirus-mediated transduction of activated…
Immunoglobulin Lambda Translocations Identify Poor Outcome and IMiD Resistance in Multiple Myeloma and Co-Occur with Hyperdiploidy
http://www.bloodjournal.org/content/132/Suppl_1/405 Nov 21st, 2018 – Patients with the plasma cell malignancy multiple myeloma now benefit from treatments such as proteasome inhibitors, immunomodulatory imide drugs (IMiDs), autologous stem cell transplant, and monoclonal antibodies. However, 20% of patients still relapse or die within two years and are deemed 'high risk'. Current markers fail to identify all high-risk patients resulting in misdiagnoses, therefor…
Real-World Outcomes with Bortezomib-Containing Regimens and Lenalidomide Plus Dexamethasone for the Treatment of Transplant Ineligible MM Patients: A Multi-Institutional Report from the National My…
http://www.bloodjournal.org/content/132/Suppl_1/2008 Nov 21st, 2018 – Introduction: Bortezomib-containing regimens (BCRs) have been the standard frontline approach for the treatment of transplant ineligible multiple myeloma (TIMM) patients in Canada for many years. Based on recent randomized clinical trial results lenalidomide and dexamethasone (Ld) has become another provincially funded option in Canada in the same therapeutic space. We aimed to compare the effe…
Outcome of Soft-Tissue Plasmocytomas in Newly Diagnosed Multiple Myeloma Patients Treated with New Drugs
http://www.bloodjournal.org/content/132/Suppl_1/3235 Nov 21st, 2018 – Introduction Multiple myeloma (MM) can be associated with paraskeletal (PP) or extramedullary (EMP) plasmocytomas (PL). Although PLs are relatively frequent, even at diagnosis, our knowledge on the subject mainly relies on small case series or single center experiences. Remarkably, little is known regarding the role of new drugs on MM with PL. Aim To perform a meta-analysis of 8 EMN-GIMEMA stud…
E2F1 Is a Biomarker of Selinexor Resistance in Relapsed/Refractory Multiple Myeloma Patients
http://www.bloodjournal.org/content/132/Suppl_1/3216 Nov 21st, 2018 – Selinexor (KPT-330) is a selective inhibitor of nuclear export (SINE) which specifically targets XPO1 (Exportin 1)-mediated nuclear export, leading to increased nuclear retention of major tumor suppressor proteins and inducing selective apoptosis in cancer cells. Several phase I and II clinical trials demonstrate evidence of anti-cancer activity of Selinexor in solid tumors (i.e metastatic pros…
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
http://www.bloodjournal.org/content/132/Suppl_1/840 Nov 21st, 2018 – Background: Multiple myeloma (MM) is the most common hematologic malignancy in blacks with more than twice the incidence of non-black populations in national registry data. Prior studies have shown that blacks present with MM at an earlier age and have improved survival compared to non-blacks, contrary to the pattern in most malignancies. These findings have been theorized due to the effects of…
Early Serum Free Light Chain (SFLC) Kinetics Is Highly Predictive of Renal Response in Carfilzomib/ Dexamethasone (Cfz/Dex) in Myeloma (MM) Patients with Renal Impairment (RI) — Interim Analysis of…
http://www.bloodjournal.org/content/132/Suppl_1/3283 Nov 21st, 2018 – BACKGROUND & METHODS Cfz/Dex is a standard of care in relapsed MM, and renal impairment is a poor prognostic factor. The ALLG MM16 trial was initiated to assess the feasibility of treating patients (pts) who have significant RI (eGFR 15 – 40 ml/min) with Cfz/Dex, and to determine whether an early reduction in serum free light chains (SFLC), with a short half-life, could predict renal outcome. A…
Impact of Early Progression on Long Term Outcomes Among Myeloma Patients Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy
http://www.bloodjournal.org/content/132/Suppl_1/3302 Nov 21st, 2018 – Background: The incorporation of modern day induction regimens, autotransplant and continuous maintenance has resulted in better long-term outcomes for myeloma patients. Experience and trials demonstrated that by prolonging 1st progression-free survival (PFS1) and pushing the relapse farther, we can gain the OS advantage (McCarthy et al NEJM 2012). Unfortunately, a subgroup of patients fail to …
Impact of HIV on Clinical Presentation and Outcomes of Individuals with Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/3162 Nov 21st, 2018 – Introduction: HIV infection and the resulting immunodeficiency predispose individuals to various plasma cell disorders including reactive plasmacytosis, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and plamacytomas. Studies have demonstrated nearly 4.5-fold increased risk of MM in HIV-infected (HIV+) individuals. Limited evidence from case reports/small serie…
Impact of Treatment on B-Cell Regeneration By Next Generation Flow Cytometry in Patients with Multiple Myeloma
http://www.bloodjournal.org/content/132/Suppl_1/4491 Nov 21st, 2018 – Introduction: Several studies have shown the role of the immune system in the development of MM, but there is no systematic description of normal B-cell regeneration during treatment points. Recently, EuroFlow consortium has developed NGF panel with high sensitivity to evaluated MRD and potentially, to assess of the normal B-cell compartment of patients with MM. Aims: Here we evaluated the B ce…
Effective Lipidoid Nanoparticle Delivery In Vivo of siRNA Targeting Kappa Light Chain Production in a Murine Xenograft Model
http://www.bloodjournal.org/content/132/Suppl_1/3208 Nov 21st, 2018 – INTRODUCTION: Despite advances in therapy, patients with relapsed AL amyloidosis die of resistant disease. New therapies are needed. siRNA directed at the constant regions of Ig light chains (LC) reduces LC mRNA and protein from patient cells, from human myeloma and AL cell lines, and in a flank plasmacytoma model with in vivo electroporation (Blood 2014;123:3440; Gene Ther 2016;23:727). To del…

Read More…

Dexamethasone versus prednisone for children receiving asthma treatment in the paediatric inpatient population: protocol for a feasibility randomised controlled trial

Dexamethasone versus prednisone for children receiving asthma treatment in the paediatric inpatient population: protocol for a feasibility randomised controlled trial

Introduction Asthma exacerbations are a leading cause of paediatric hospitalisations. Corticosteroids are key in the treatment of asthma exacerbations. Most current corticosteroids treatment regimens for children admitted with asthma exacerbation consist of a…

Read More…

Efficacy and Safety of the Combination Treatment of Rituximab and Dexamethasone for Adults with Primary Immune Thrombocytopenia (ITP): A Meta-Analysis

<h1>Efficacy and Safety of the Combination Treatment of Rituximab and Dexamethasone for Adults with Primary Immune Thrombocytopenia (ITP): A Meta-Analysis</h1>

Efficacy and Safety of the Combination Treatment of Rituximab and Dexamethasone for Adults with Primary Immune Thrombocytopenia (ITP): A Meta-Analysis

https://doi.org/10.1155/2018/1316096 Review Article Efficacy and Safety of the Combination Treatment of Rituximab and Dexamethasone for Adults with Primary Immune Thrombocytopenia (ITP): A Meta-Analysis Jia Wang , 1 Ya Li , 1 Chong Wang , 1 Yayue Zhang , 1 Chong Gao , 2 Haiyan Lang , 3 and Xinyi Chen 1
1 Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China 2 Beijing Hospital of Traditional Chinese Medicine, Clinical Medical College of Traditional Chinese Medicine, Capital Medical University, Beijing, China 3 Department of Hematology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
Correspondence should be addressed to Xinyi Chen ;
Received 4 June 2018; Accepted 22 October 2018; Published 12 December 2018
Academic Editor: Carlo Visco
Copyright © 2018 Jia Wang et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Objective. To conduct a meta-analysis, assessing the efficacy and safety of the combination treatment of dexamethasone and rituximab for adults with ITP (primary immune thrombocytopenia). Methods. Randomized controlled trials that compared rituximab and dexamethasone combination treatment to dexamethasone monotherapy in the treatment of adults with ITP were collected by searching Pubmed, Embase, Cochrane, China National Knowledge (CNKI), Wanfang database, and Sino Med. We conducted pooled analyses on OR (overall response) rate, CR (complete response) rate, PR (partial response) rate, SR (sustained response) rate, R (relapse) rate, change in Treg cell count (mean [SD]), and AE (adverse event). GRADE pro scale was used to assess the quality of the evidence. Publication bias was assessed with Egger’s test method. Results. A total of 11 randomized controlled trials were eligible for inclusion. The overall efficacy estimates favored combination arm in terms of OR rate at month 3, CR rate at week 4 and month 3, SR rate, and Treg cell count at week 2. Subgroup analysis showed that females obtained a higher OR rate than males did at week 4. No significant difference was found in pooled analysis of relapse rate between combination arm and monotherapy arm. The comparison of serious AE and other AEs showed no significant difference either. A total of 19 outcomes were assessed by GRADE pro software, of which 79% (15/19) was scaled as moderate-to-high level. Publication bias existed in studies on OR at week 4 ( P =0.025), CR at week 4 ( P =0.017), infection ( P =0.006), and rash ( P =0.028) of the AEs. Conclusion. Dexamethasone combined with rituximab can provide a better long-term response in the treatment of adults with ITP and will not increase the risk of adverse effects. 1. Introduction
Primary immune thrombocytopenia (ITP) is well known as an autoimmune disease, which is characterized by immune-mediated peripheral platelet destruction and impaired platelet production in the bone marrow with a consequent increased tendency of bleeding. To date, the pathogeneses of ITP are thought to involve phagocytosis and platelet destruction in the spleen mediated by autoantibodies against platelet-specific antigens and impaired megakaryocyte maturation which can reduce the production of new platelet [ 1 ].
The platelet threshold of30×10 9 /L is widely determined as a trigger for treatment, in which corticosteroid is most frequently used as the first-line treatment [ 2 , 3 ]. However, less than half of the patients with ITP can be ‘cured’ by first-line therapy, and many of them require second-line treatments [ 4 ]. Rituximab (RTX), a human/murine monoclonal antibody targeting CD20 B-cell surface antigen, can regulate the miscellaneous autoimmune disorders by B-cell depletion [ 5 ]. It was reported that rituximab alone can provide an approximately 20% to 40% long-term response rate [ 6 , 7 ]. Additionally, rituximab has been shown to increase Treg cell count of patients with ITP [ 8 – 10 ]. Given that a patient may have a contraindication to a specific monotherapy, adverse events, and a limited long-term response, combination treatment is more and more preferred by clinicians in the treatment with ITP. The combination of rituximab and corticosteroid has potential benefit, which might enhance the efficacy by a direct effect on blood vessels, together with a regulation effect on both humoral and cellular immune disorder. A recent RCT showed that, for newly diagnosed ITP, dexamethasone combining rituximab provided a sustained response rate of 58% at 6 months, which was significantly higher than that of dexamethasone alone (37%) [ 11 ]. This result was consistent with that of an earlier study, in which the SR rate of combination arm was much higher than that of dexamethasone arm (63% vs 36%) [ 12 ].
However, it might be difficult for a single study to provide sufficient data on its own to confirm the efficacy of the combination treatment of rituximab and corticosteroid. What is more, it still needs to be verified whether the combination treatment will increase the incidence of adverse events. Therefore, we performed this meta-analysis of randomized controlled trials (RCTs) to clarify the efficacy and safety of the combination treatment of rituximab and corticosteroid for adults with ITP. 2. Methods 2.1. Data Sources and Search Strategy
This meta-analysis was reported in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) Statement. We collected relevant studies published from inception to Apr 29, 2018, by searching Pubmed, Embase, Cochrane, China National Knowledge (CNKI), Wanfang database, and Sino Med. The search strategy was made according to PICOS (Population, Intervention, Comparison, Outcome, and Study design) principle. Medical Subject Heading (MeSH) terms and key words were as follows: (idiopathic thrombocytopenic purpura OR Immune Thrombocytopenic Purpura OR Werlhof ’s Disease) AND (rituximab OR CD20 Antibody) AND (dexamethasone OR hexadecadrol OR dexasone) AND (randomized controlled trial). Manual search was also conducted by the key words above for all potentially eligible studies. Searches were restricted to articles published in English or Chinese. 2.2. Study Selection
Studies that were randomized controlled trials done in adults with ITP, compared rituximab and dexamethasone combination treatment (RTX+DXM) to dexamethasone monotherapy (DXM), had at least 28 days duration of intervention, and reported OR (overall response) rate, CR (complete response) rate, PR (partial response) rate, SR (sustained response rate) rate, R (relapse) rate, change in Treg cell count (mean[SD]), or AE (adverse event), were included.
Exclusion criteria were as follows: (1) reviews, case report, and irrelevant topics; (2) studies without control arms (dexamethasone monotherapy); (3) studies on secondary ITP; (4) studies that included participants<18 years old.
Studies that had 3 arms were also included if the data of RTX+DXM arm and DXM arm were extractable from the articles. If duplicate publication were found, only the latest and most complete one was included. 2.3. Data Extraction
Two investigators (YL and CW) reviewed titles and abstracts of all articles independently. Studies that met our inclusion criteria were retrieved for full-text reading. Two independent investigators (YL and CG) conducted the detailed extraction and analyses of data; discrepancies were resolved by a third investigator (HYL).
We compared combination treatment of rituximab and dexamethasone to dexamethasone monotherapy, and no treatment history was restricted. The outcomes assessed were as follows: response rate; relapse rate during or after the intervention; Treg cell count before and after the intervention; adverse events during the intervention. The following detailed data were extracted from each included study: total number of participants, baseline demographics (age, gender), therapeutic regimen; number of participants achieving OR, CR, and PR at week 4 or month 3 (OR=CR+PR), number of participants achieving SR at 6 months or 12 months; number of participants who relapsed during or after the intervention; Treg cell count (mean[SD]) before or at weeks 2 and 4 of intervention; number of participants experiencing serious AE or regular AE (infection, hyperglycemia, hypertension, electrolyte disorder, fever, and hypersensitivity). 2.4. Quality Assessment and Risk of Bias
All of the eleven selected studies were randomized controlled trials. GRADE pro scale (Grading of Recommendations Assessment, Development and Evaluation) was used to assess the quality of the evidence, which was scaled as high, moderate, low, or very low. Risk of bias was determined according to Cochrane Handbook of Systematic Reviews of Interventions. 2.5. Data Analysis
Here we assessed the efficacy of combination treatment (RTX+DXM) by following outcomes: achievement of OR, CR, and PR at week 4 or month 3 (OR=CR+PR); achievement of SR at month 6 or month 12; incidence of relapse; change in Treg cell count. Definitions of CR were consistent among the selected studies (platelet count≥100×10 9 /L) [ 13 ]. PR was determined as platelet count≥30×10 9 /L in most selected studies [ 10 , 14 – 19 ]. Consequently, we chose to include PR as an outcome and considered achievement of OR as total number of participants achieving CR and PR. SR was defined as platelet count≥50×10 9 /L at month 6 [ 8 , 11 , 12 , 17 , 19 ]. Definition of relapse was dropping in platelet count to30×10 9 /L following a CR or PR[ 8 , 10 – 12 , 20 ].
The safety of combination treatment (RTX+DXM) was assessed by incidence of serious AEs or other AEs. We planned to report whether the combination treatment will increase the incidence of adverse effects in monotherapy. Considering the most frequent adverse effects reported by the selected studies, we compared the safety of combination treatment (RTX+DXM) to monotherapy (DXM) by the number of participants who experienced following AEs: serious AE, infection, hyperglycemia, hypertension, electrolyte disorder, fever, and rash. Serious AE was determined according to National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) [ 8 , 11 , 12 ].
All of the event rates were analyzed as dichotomous variables. Relative risk ratio (RR) was obtained by using random-effects model (DerSimonian-Laird method). Fixed-effect model was applied to the analysis when heterogeneity did not exist. We analyzed Treg cell count before and after 2 and 4 weeks of intervention as continuous variables. To account for expected heterogeneity, pooled estimates of mean difference (MD) were calculated by using random-effects model.
We assessed the risk of publication bias by constructing a funnel plot of each RCT’ s effect size. Asymmetry of each funnel plot was assessed by Egger test, and p -value50% were regarded as being indicative of moderate-to-high heterogeneity. In sensitivity analysis, we conducted ‘one-study removed’ meta-analysis approach to assess the impact of a single study on the results. All statistical analyses were conducted by using Review Manager (version 5.3). 2.6. Role of the Funding Source
This study was supported by a National Key Basic Research Program of China (no. 2013CB531705), without any commercial entity. Our funding source had no role in the whole process of the study (study design, articles searching, data extraction, data analyses, results interpretation, and report writing). Final responsibility for the decision of publication was possessed by the corresponding author. 3. Results 3.1. Results of the Search
As was presented in Figure 1 , a total of 677 records were identified through electronic databases. Finally, 11 studies were included after removing the publications that duplicated or didn’t satisfy the inclusion criteria. 887 cases were analyzed, with 439 in experimental arm (RTX+DXM) and 448 in control arm (DXM). Detailed study characteristics were given in Table 1 (population, interventions, and outcomes). All of the 11 trials were published between 2010 and 2017 (one was published in 2017). 11 studies were all standard randomized controlled trials, of which 3 were written in English and 8 were written in Chinese. Table 1: Study characteristics. Figure 1: Flow diagram of studies selection process. ITP, primary immune thrombocytopenia.
Rituximab were given by the dose of 100 mg/m 2 weekly for 4 weeks in most selected trials. There were three trials having different dose of 375 mg/m 2 weekly for 4 weeks [ 18 – 20 ]. As for dexamethasone, only one trial used a different dose (12.5~25.0 mg, twice or three times a day) from that of other ten trials (40 mg daily).
Six trials compared OR, CR, and PR after 4-week intervention between the two arms. Three studies made the comparison of CR, PR, and OR at month 3. SR was compared at month 6 and month 12 respectively by three trials. Five studies reported the number of participants that relapsed during or after the intervention. Only three trials evaluated and compared the Treg cell count of participants at week 2 and week 4, respectively. As for adverse effect, infection, hyperglycemia, hypertension, and electrolyte disorder were reported most frequently in the included studies. Serious adverse effects were reported only in three trials. 3.2. Quality of Included Studies and Evidence
None of the 11 trials was stopped early or funded by industry. Adequate randomization was reported by all of the selected trials, with only three trials specifying the random method ( S1 Figure). A total of 19 outcomes were assessed by GRADE pro software, of which 32% (6/19) was scaled as high level, 47% (9/19) was moderate level, and 21% (4/19) was low level ( S2 Figure). 3.3. Efficacy Analysis 3.3.1. Overall Response Rate
The comparison of OR rate at week 4 was conducted in six trials [ 8 , 10 , 15 – 18 ] (n=435). OR rate was significantly higher in combination arm than that in monotherapy arm (RR=1.23, 95% CI:1.03-1.48, and P =0.03). However, high heterogeneity was found in pooled analysis ( P =0.01, I 2 =65%) (Figure 2(a) ). The gender proportion of participants varied among the six studies (Table 1 ), so we went further to conduct a subgroup analysis based on gender proportion (males more than females or females more than males) (Figure 2(b) ). Subanalysis showed that in the first group (males more than females), heterogeneity was still high ( P <0.05, I 2 =95%) and no significant difference was found (RR=1.54, 95%CI:0.47-5.08, and P =0.48). In the second group (females more than males), OR rate of combination arm was higher than that of monotherapy arm (RR=1.18, 95%CI:1.03-1.35, and P =0.02). No heterogeneity was observed ( P =0.50, I 2 =0%). When we removed one study [ 18 ] that included much more males than other five studies did, the heterogeneity of total analysis decreased significantly ( P =0.36, I 2 =9%). A subgroup analysis based on the history of treatment (newly diagnosed or not) was conducted. However, there was no significant difference between two arms in ether of the two groups (RR=1.16, 95% CI: 0.97-1.38, P =0.10; RR=1.36, 95% CI: 0.94-1.95, and P =0.10) (Figure 2(c) ). Figure 2: Forest plots of relative risk in OR rate. (a) OR rate at week 4; (b) subanalysis based on gender; (c) subanalysis based on treatment history; (d) OR rate at month 3. CI: confidence interval; M-H: Mantel-Haenszel; RR: relative risk.
Three trials [ 14 , 19 , 20 ] ( n=218) reported the OR rate at month 3, pooled analysis of which showed homogeneity ( P =0.22, I 2 =33%). OR rate at month 3 was significantly higher in combination arm than that in monotherapy arm. Fixed-effect model was applied to the analysis (RR=2.41, 95% CI: 1.82-3.19, and P <0.00001) (Figure 2(d) ). 3.3.2. Complete Response Rate
Six studies [ 8 , 10 , 15 – 18 ](n=435) reported the CR rate at week 4 without significant heterogeneity ( P =0.10, I 2 =45%). Pooled analysis by using a Fixed-effect model showed that CR rate at week 4 in combination arm was significantly higher than that in monotherapy arm (RR=2.06, 95% CI: 1.63-2.62, and P <0.00001) (Figure 3(a) ). CR at month 3 was reported by three studies [ 14 , 19 , 20 ] ( n=218), and no heterogeneity was found ( P =0.16, I 2 =45%). CR rate at month 3 in combination arm was significantly higher than that in monotherapy arm (RR=5.07, 95% CI: 2.91-8.86, and P <0.00001) (Figure 3(b) ). Figure 3: Forest plots of relative risk in CR rate. (a) CR rate at week 4; (b) CR rate at month 3. CI: confidence interval; M-H: Mantel-Haenszel; RR: relative risk. 3.3.3. Partial Response Rate
PR rate at week 4 was reported by six studies [ 8 , 10 , 15 – 18 ](n=435), pooled analysis of which turned out homogenous ( P =0.27, I 2 =22%). Analysis conducted by a Fixed-effect model showed that PR rate at week 4 in monotherapy arm was significantly higher than that in combination arm (RR=0.66, 95% CI: 0.49-0.88, P =0.005) (Figure 4 ). Three trials [ 14 , 19 , 20 ](n=218) compared the PR rate at month 3, and no heterogeneity was found ( P =0.76, I 2 =0%). However, the analysis result showed no significant difference between two arms (RR=1.08, 95% CI: 0.67-1.74, P =0.76). Figure 4: Forest plots of relative risk in PR rate at week 4. CI: confidence interval; M-H: Mantel-Haenszel; RR: relative risk. 3.3.4. Sustained Response Rate
SR rate at month 6 [ 8 , 11 , 12 ] (n=296) and month 12 [ 11 , 17 , 19 ] (n=274) was reported by three studies, respectively, both of which showed no significant heterogeneity ( P =0.76, I 2 =0%; P =0.15, I 2 =47%). Consequently, two analyses were both conducted by a Fixed-effect model and showed that SR rate was significantly higher in combination arm than that in monotherapy arm both at month 6 and month 12 (RR=1.73, 95% CI: 1.36-2.91, and P <0.00001; RR=2.19, 95% CI: 1.60-3.02, and P <0.00001) (Figure 5 ). Figure 5: Forest plots of relative risk in SR rate. (a) SR at month 6; (b) SR at month 12. CI: confidence interval; M-H: Mantel-Haenszel; RR: relative risk. 3.4. Treg Cell Count
Only three studies [ 8 , 10 , 17 ] (n=246) evaluated the Treg cell count of participants and reported Treg cell count at baseline, week 2 and week 4, respectively. There was no statistical difference at baseline between two arms ( P =0.97), meaning that the comparison was feasible. Pooled analysis of Treg cell count at week 2 indicated that combination arm had a better effect compared to monotherapy arm (MD=1.02, 95% CI: 0.76-1.28, and P <0.00001). Besides, no heterogeneity was found ( P =0.80, I 2 =0%) (Figure 6(a) ). Analysis of Treg cell count at week 4 still showed a better effect of experimental arm to control arm (MD=2.19, 95% CI: 1.60-2.77, and P 0.1). 3.6. Publication Bias
Egger’s test showed that there was a significant publication bias of studies on OR rate at week 4 (t=3.50, P =0.025), CR rate at week 4 (t=3.94, P =0.017), incidence of infection (t=4.09, P =0.006), and rash (t=22.41, P =0.028). The funnel plots of publication bias were shown in Figure 7 . Figure 7: Funnel plots of publication bias. (a) publication bias of OR rate at week 4; (b) publication bias of CR rate at week 4; (c) publication bias of incidence in infection; (d) publication bias of incidence in rash. 4. Discussion
To our knowledge, this is the first meta-analysis assessing the efficacy and safety of the combination treatment of rituximab and dexamethasone for adults with ITP. Our results showed that compared to dexamethasone monotherapy, combination treatment with rituximab can improve the long-term sustained response rate, with no increase in serious AEs, infection, hyperglycemia, hypertension, electrolyte disorder, fever, and rash. Moreover, combination treatment showed a far better efficacy of Treg cell upregulating early in the observation. However, dexamethasone combining with rituximab still could not reduce the incidence of relapse in adults with ITP.
The pathophysiology of ITP is very complicated, which involves pathologic autoantibodies, destruction of platelets mediated by CD8 + cytotoxic T-cells, imbalance in T-cell cytokines, T-cell subsets, and impaired megakaryocyte maturation, with each pathologic mechanism playing different parts in different patients [ 21 ]. Moreover, relevant factors such as complications of specific therapy, tolerance of side effects, age, and lifestyle may contribute to the determination of regimen to different extent [ 4 ]. Therefore, the investigation and management of ITP patients vary quite widely.
Corticosteroids are standard initial treatments with a rapid efficacy. Dexamethasone, for example, has been reported to provide an initial response after several days to several weeks [ 22 , 23 ]. However, corticosteroid-related complications have limited its long-term utility and efficacy. Consequently, more and more studies about combination regimens with second-line agents are conducted to improve the efficacy and obtain long-term remission [ 24 – 27 ]. Rituximab can induce a potent and prolonged B cell depletion that can last several months impairing the antibodies production, providing long-term response rates of 40% and 33% at 1 and 2 years of follow-up, respectively [ 28 , 29 ]. Patients that relapse early or are resistant to the treatment can particularly benefit from RTX application, which therefore is a promising candidate to a second line approach such as splenectomy. However, most of the studies on combination regimen are reviews and single-arm trials. There are still so few RCTs that it is necessary to conduct a meta-analysis to collect and synthesize the data of each study, assessing the efficacy and safety of the combination treatment of dexamethasone and rituximab.
In our report, the combination arm (RTX +DXM) obtained a OR rate of 81% at week 4, while the monotherapy (DXM) arm obtained 65% ( P =0.03). Given a high heterogeneity, a subgroup analysis based on gender proportion (males more than females or females more than males) was conducted, which showed that this trend persisted only in the second group (females more than males), and the heterogeneity decreased significantly ( P =0.50, I 2 =0%). It is indicated that females might have a better OR rate at 4 weeks than males do ( P =0.02). Similar subgroup analysis could not be done in OR rate at 3 months to confirm this gender-relevant trend, because only 3 trials reported OR rate at 3 months. Since the history of treatment of participants varied greatly among the six studies, a subgroup analysis based on the history of treatment (newly diagnosed or not) was conducted, which turned out no significant difference between two arms in ether of the two groups. Besides, publication bias was found in the pooled analysis of OR at week 4, which made the results instable. Comparison at month 3 also showed a better OR rate in combination arm (81%) than that in monotherapy arm (34%) ( P <0.01). This result was quite different from the international consensus report published in 2010, which suggested that dexamethasone and rituximab could provide an approximate initially response rate of 90% and 60%, respectively [ 4 ]. It might be because all of the three trials [ 14 , 19 , 20 ] chose patients with chronic ITP, persistent ITP, and refractory ITP, respectively, as participants.
CR rate at week 4 was 57% in combination arm and 28% in monotherapy arm, respectively, ( P <0.01), which was consistent with CR rate at month 3 (57% vs 11%) ( P <0.01). The definition of PR varied among the included studies, most of which was≥30×10 9 /L. Only two trials [ 8 , 20 ] defined PR by a platelet count≥50×10 9 /L, which reported PR rate at week 4 and month 3, respectively. Our result showed that PR rate at week 4 in monotherapy arm was higher than that of combination arm (37% vs 24%) ( P =0.005). When we removed a single study with a different definition of PR [ 8 ], the trend still persisted ( P =0.006). Considering that OR rate and CR rate at week 4 were both higher in combination arm and OR rate means CR rate plus PR rate, this result indicated that participants obtaining PR was much more than that obtaining CR in monotherapy arm.
SR rate at month 6 and month 12 were available in only three studies, respectively. However, a total of 296 and 274 participants were involved in the pooled analyses. Combination arm showed a SR rate of 64% after 6 months, which was higher than that of monotherapy arm (37%) ( P <0.01). Similarly, SR rate at month 12 in combination arm was also better than that in monotherapy arm (57% vs 26%) ( P <0.01). In short, dexamethasone combined with rituximab can provide a much better long-term efficacy than dexamethasone alone does. Our results were consistent with the literature, which was reported previously that rituximab could provide a long-term remission lasting up to 5 years in 15%~20% of initially treated patients [ 30 ]. A prospective, open-label, single-arm phase 2 trial showed that 40% of the participants accepting rituximab had a platelet count of 30×10 9 /L after two years of the follow-up [ 28 ].
Patients with ITP have a lack of peripheral tolerance, which can be mediated by T regulatory lymphocytes (Treg cells) [ 31 , 32 ]. It has been reported that clonal Th cells that fail to be suppressed by Treg cells can drive the production of autoantibody in ITP [ 26 ]. ITP patients have a defective Treg cells compartment that can be modulated by a B cell-targeted therapy [ 9 , 33 ]. Actually, the regulation effect in T-cell cytokines and T-cell subsets by rituximab has been reported by studies of many other autoimmune disorders [ 34 – 36 ]. In our report, Treg cell counts were available in three trials, which were evaluated on baseline, week 2 and week 4, respectively. Pooled analyses showed that there was no statistical difference at baseline between two arms ( P =0.97), whereas, Treg cell count was higher in combination arm than that in monotherapy arm both at week 2 ( P <0.01) and week 4 ( P <0.01). However, high heterogeneity was observed in the comparison at week 4. When we removed one study [ 8 ], the heterogeneity disappeared ( P =0.88, I 2 =0%). We noticed that participants in the removed study (median age: 25 years) were much younger than that in the other two studies (median age: 42 years; 40 years). Unfortunately, subgroup analysis based on age could not be conducted because too few studies were included.
In our report, combination arm had a relapse rate of 17%, and monotherapy arm was 27%. However, the pooled analysis showed no significant difference between two arms ( P =0.06). We went further with a subgroup analysis based on the duration of follow-up (<12 months or ≥12 months), which eventually still showed no significant difference in either of the two subgroups ( P =0.57; P =0.07). Our results indicated that RTX combining DXM could not reduce the incidence of relapse in adults with ITP.
As for safety, the main goal of this meta-analysis was to confirm whether the combination treatment of RTX and DXM would increase the incidence of adverse effects that the DXM monotherapy had. In our study, only three trials reported serious AE without a significant difference between two arms by pooled analysis ( P =0.05). A total of 4 participants (80 to 84 years old) deceased from what were not considered to be treatment-related by the investigator [ 11 ]. Because of the depletion of B-lymphocytes, infection is a major-concerned AE both for dexamethasone and rituximab. Our results showed no significant difference between combination arm and monotherapy arm ( P =0.28). The pooled analyses of other AEs (hyperglycemia, hypertension, electrolyte disorder, fever, and rash) also found no significant difference between two arms, which meant the combination treatment of RTX and DXM was quite safe in the treatment with ITP.
Although 11 studies included were all standard RCTs with 79% moderate-to-high level evidences (GRADE pro scale), there were still several limitations in this meta-analysis. First, the observation points of each study varied, and pooled analyses had to be done discretely, which caused fewer data-collection in the analysis of each outcome. Second, the dose of rituximab in three trials were standard dose (375mg/m 2 ), whereas other eight trials used low-dose rituximab (100mg). However, it was difficult for us to conduct subanalyses based on dose because not every outcome was reported by all of the three trials (375mg/m 2 ). The significant heterogeneity in the analyses of two outcomes (OR rate at week 4 and Treg cell count at week 4) should be the third limitation. In addition, the history of treatment of participants varied greatly among the studies. We did a subgroup analysis in OR rate at week 4 based on history of treatment (newly diagnosed or not). However, too few studies were included to conduct further analysis in other outcomes, which made it difficult to assess the efficacy of combination treatment in different phase of ITP. Lastly, given that ITP is a quite heterogenous disease, some relapses may happen even after several months from the diagnosis, which makes long-term follow-up necessary for relapse rate assessment. However, only three trials did an adequate follow-up (12 months) in our report, which might contribute to an underestimated relapse rate for both combination treatment arm and monotherapy arm.
Despite that more studies are needed to clarify the optimal approach to the application of this combination treatment (dose and timing), this meta-analysis clearly confirms that rituximab combined with dexamethasone can provide a better long-term response in the treatment of adults with ITP and will not increase the risk of adverse effects. Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this article. Authors’ Contributions
Jia Wang and Xinyi Chen were responsible for conceptualization, dealt with visualization, and wrote, reviewed, and edited the manuscript. Jia Wang, Ya Li, and Chong Wang were responsible for data curation. Jia Wang, Chong Gao, and Haiyan Lang performed formal analysis. Xinyi Chen had funding acquisition and administrated, supervised, and validated the project. Ya Li and Chong Gao did the investigation. Jia Wang, Li Hou, and Shaodan Tian produced the methodology. Yayue Zhang and Hao Ding were responsible for resources. Jia Wang, Chong Gao, and Hao Ding dealt with the software. Jia Wang wrote the original draft. Supplementary Materials
Supplementary 1 . S1 Figure. Risk of bias summary and risk of bias graph according to Cochrane Risk of Bias assessment tool.
Supplementary 2 . S2 Figure. Assessment of evidences by GRADE pro software.
Supplementary 3 . S3 Figure. Forest plots of relative risk in relapse rate.
Supplementary 4 . S4 Figure. Forest plots of relative risk in serious adverse effects.
Supplementary 5 . S5 Figure. PRISMA 2009 Checklist. References D. B. Cines, J. B. Bussel, H. A. Liebman, and E. T. Luning Prak, “The ITP syndrome: pathogenic and clinical diversity,” Blood , vol. 113, no. 26, pp. 6511–6521, 2009. View at Publisher · View at Google Scholar · View at Scopus B. H. Chong, J.-W. Lee, J. H. Jang et al., “International ITP Registry with Focus on the Asia Pacific Region: Update on Preliminary Findings of Epidemiological and Clinical Data,” Blood , vol. 130, 1, 2017. View at Google Scholar B. H. Chong, J.-W. Lee, J. H. Jang et al., “ITP Patients in the Asia Pacific: Are They Different?” Blood , vol. 130, 1, 2017. View at Google Scholar D. Provan, R. Stasi, A. C. Newland et al., “International consensus report on the investigation and management of primary immune thrombocytopenia,” Blood , vol. 115, no. 2, pp. 168–186, 2010. View at Publisher · View at Google Scholar · View at Scopus V. L. Patel, M. Mahévas, S. Y. Lee et al., “Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia,” Blood , vol. 119, no. 25, pp. 5989–5995, 2012. View at Publisher · View at Google Scholar · View at Scopus M. Khellaf, A. Charles-Nelson, O. Fain et al., “Safety and efficacy of rituximab in adult immune thrombocytopenia: Results from a prospective registry including 248 patients,” Blood , vol. 124, no. 22, pp. 3228–3236, 2014. View at Publisher · View at Google Scholar · View at Scopus K. Al-Habsi, M. Al-Khabori, M. Al-Muslahi et al., “Rituximab leads to long remissions in patients with chronic immune thrombocytopenia,” Oman Medical Journal , vol. 30, no. 2, pp. 111–114, 2015. View at Publisher · View at Google Scholar · View at Scopus Z. Li, W. Mou, G. Lu et al., “Low-dose rituximab combined with short-term glucocorticoids up-regulates Treg cell levels in patients with immune thrombocytopenia,” International Journal of Hematology , vol. 93, no. 1, pp. 91–98, 2011. View at Publisher · View at Google Scholar · View at Scopus R. Stasi, N. Cooper, G. D. Poeta et al., “Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell depleting therapy with rituximab,” Blood , vol. 112, no. 4, pp. 1147–1150, 2008. View at Publisher · View at Google Scholar · View at Scopus Y. X. Cui, “Effect of large dose of dexamethasone combined with rituximab on CD 4+ CD 5+ Treg cells in patients with primary immune thrombocytopenia,” Chinese Journal of New Clinical Medicine , vol. 8, pp. 1160–1163, 2015, http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zgyxwz-lnyxfc201512016 . View at Google Scholar S. Gudbrandsdottir, H. S. Birgens, H. Frederiksen et al., “Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia,” Blood , vol. 121, no. 11, pp. 1976–1981, 2013. View at Publisher · View at Google Scholar · View at Scopus F. Zaja, M. Baccarani, P. Mazza et al., “Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia,” Blood , vol. 115, no. 14, pp. 2755–2762, 2010. View at Publisher · View at Google Scholar · View at Scopus C. Neunert, W. Lim, M. Crowther, A. Cohen, L. Solberg Jr., and M. A. Crowther, “The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia,” Blood , vol. 117, no. 16, pp. 4190–4207, 2011. View at Publisher · View at Google Scholar · View at Scopus R. B. Chen, “Clinical effect observation of glucocorticoid in combination with small dose of rituxan in treating primary immune thrombocytopenia,” Clinical Medicine , vol. 35, no. 3, pp. 6-7, 2015, http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=lcyx201503003 . View at Google Scholar S. M. Chen and D.-B. Zhou, “Clinical observation of rituximab treatment of chronic primary immune thrombocytopenia in adults,” Journal of China Prescription Drug , pp. 15-16, 2015, http://kns.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFQ&dbname=CJFDLAST2015&filename=ZGCF201510011&v=MTY5NTdXTTFGckNVUkxLZlkrUnJGaURrVkxyQVB5cklhTEc0SDlUTnI0OUVaWVI4ZVgxTHV4WVM3RGgxVDNxVHI= . View at Google Scholar Y. Chen, “Observation the Effect of Low-dose Rituximab Combined with Dexamethasone Treating Adult Persistent Immune Thrombocytopenia (ITP),” China Continuing Medical Education , vol. 7, no. 32, pp. 155-156, 2015, http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zgjxyxjy201532114 . View at Google Scholar L. Kaige, Conventional dose prednisone, high dose dexamethasone and high dose dexamethasone combined with low dose rituximab therapy for newly diagnosis immune thrombocytopenia. MM.Sc. Thesis , Wenzhou Medical University, 2012, http://www.wanfangdata.com.cn/details/detail.do?_type=degree&id=Y2237712 . M. Jingye, L. Chan, L. Ziyi et al., “Clinical study of glucocorticoids combined with low-dose of rituximab in the treatment of refractory primary immune thrombocytopenia,” Clinical Medicine , vol. 37, no. 2, pp. 21-22, 2017, http://kns.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFQ&dbname=CJFDLAST2017&filename=EBED201702010&v=MTcyNThNMUZyQ1VSTEtmWStSckZpRGxWN3pKSUMvT2FyRzRIOWJNclk5RVpJUjhlWDFMdXhZUzdEaDFUM3FUclc= . View at Google Scholar Z. Xiaojuan, G. Shuxia, C. Ronghua et al., “Observation of low-dose rituximab combined with dexamethasone in the treatment of adult persistent primary immune thrombocytopenia,” Shandong Medical Journal , vol. 55, no. 21, pp. 69-70, 2015 (Chinese), http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=shandyy201521030 . View at Google Scholar Y. Huijuan, “Observation of rituximab combined with dexamethasone in the treatment of refractory primary immune thrombocytopenia,” Aerospace Medicine , vol. 22, no. 11, pp. 2024-2025, 2010, http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=hkhtyy201011053 . View at Google Scholar M. P. Lambert and T. B. Gernsheimer, “Clinical updates in adult immune thrombocytopenia,” Blood , vol. 129, no. 21, pp. 2829–2835, 2017. View at Publisher · View at Google Scholar · View at Scopus R. Stasi, E. Stipa, M. Masi et al., “Long-Term observation of 208 adults with chronic idiopathic thrombocytopenic purpura,” American Journal of Medicine , vol. 98, no. 5, pp. 436–442, 1995. View at Publisher · View at Google Scholar · View at Scopus D. Ben-Yehuda, S. Gillis, and A. Eldor, “Clinical and therapeutic experience in 712 israeli patients with idiopathic thrombocytopenic purpura. Israeli ITP Study Group,” Acta Haematologica , vol. 91, no. 1, pp. 1–6, 1994. View at Publisher · View at Google Scholar · View at Scopus Y. Li, Q. Huang, C. Wang, Muhebaier, L. An, and X. Wang, “Efficacy and safety of high-dose dexamethasone combined with rhTPO for newly diagnosed adults with severe immune thrombocytopenia,” Zhonghua Xue Ye Xue Za Zhi , vol. 37, no. 2, pp. 134–137, 2016. View at Google Scholar · View at Scopus X. D. Han, J. Zhou, F. K. Yu et al., “Rituximab and Dexamethasone Combined with Cyclophosphamide for Treatment of Relapsed and Refractory Immune Thrombocytopenia,” Zhongguo Shi Yan Xue ye Xue Za Zhi , vol. 24, no. 1, pp. 162–166, 2016. View at Google Scholar D. Gómez-Almaguer, M. A. Herrera-Rojas, J. C. Jaime-Pérez et al., “Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults,” Blood , vol. 123, no. 25, pp. 3906–3908, 2014. View at Publisher · View at Google Scholar · View at Scopus J. B. Bussel, C. S. Lee, C. Seery et al., “Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration,” Haematologica , vol. 99, no. 7, pp. 1264–1271, 2014. View at Publisher · View at Google Scholar · View at Scopus B. Godeau, R. Porcher, O. Fain et al., “Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: Results of a prospective multicenter phase 2 study,” Blood , vol. 112, no. 4, pp. 999–1004, 2008. View at Publisher · View at Google Scholar · View at Scopus V. L. Patel, M. Mahévas, R. Stasi et al., “Long-term outcome following B-cell depletion therapy with rituximab in children and adults with immune thrombocytopenia,” Blood , vol. 116, no. 21, p. 72, 2010. View at Google Scholar D. M. Arnold, F. Dentali, M. A. Crowther et al., “Systematic review: Efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura,” Annals of Internal Medicine , vol. 146, no. 1, pp. 25–33, 2007. View at Publisher · View at Google Scholar · View at Scopus J. Yu, S. Heck, V. Patel et al., “Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura,” Blood , vol. 112, no. 4, pp. 1325–1328, 2008. View at Publisher · View at Google Scholar · View at Scopus S. Sakaguchi, “Naturally arising Foxp3-expressing CD25 + CD4 + regulatory T cells in immunological tolerance to self and non-self,” Nature Immunology , vol. 6, no. 4, pp. 345–352, 2005. View at Publisher · View at Google Scholar · View at Scopus R. Stasi, G. del Poeta, E. Stipa et al., “Response to B-cell-depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura,” Blood , vol. 110, no. 8, pp. 2924–2930, 2007. View at Publisher · View at Google Scholar · View at Scopus P. P. Sfikakis, V. L. Souliotis, K. G. Fragiadaki, H. M. Moutsopoulos, J. N. Boletis, and A. N. Theofilopoulos, “Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis,” Clinical Immunology , vol. 123, no. 1, pp. 66–73, 2007. View at Publisher · View at Google Scholar · View at Scopus R. Bhattacharjee, D. De, S. Handa, R. W. Minz, B. Saikia, and N. Joshi, “Assessment of the Effects of Rituximab Monotherapy on Different Subsets of Circulating T-Regulatory Cells and Clinical Disease Severity in Severe Pemphigus Vulgaris,” Dermatology , vol. 232, no. 5, pp. 572–577, 2017. View at Publisher · View at Google Scholar · View at Scopus D. Roccatello, S. Sciascia, D. Di Simone et al., “New insights into immune mechanisms underlying response to Rituximab in patients with membranous nephropathy: a prospective study and a review of the literature,” Autoimmunity Reviews , vol. 15, no. 6, pp. 529–538, 2016. View at Publisher · View at Google Scholar · View at Scopus Follow Us

Read More…

Corticosteroid use and increased CXCR2 levels on leukocytes are associated with lumacaftor/ivacaftor discontinuation in cystic fibrosis patients homozygous for the F508del CFTR mutation

Corticosteroid use and increased CXCR2 levels on leukocytes are associated with lumacaftor/ivacaftor discontinuation in cystic fibrosis patients homozygous for the F508del CFTR mutation

Cystic fibrosis (CF) is the most common life-shortening genetic disease and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Several current therapies aim at improving availability and/or function of the mutant CF…

Read More…

Comment on [Transcript] – Should You Or Your Kids Get Vaccinated? One Doctor’s Surprising Answer To Making The Big Decision On Vaccines. by Joseph Smith

<h1>Comment on [Transcript] – Should You Or Your Kids Get Vaccinated? One Doctor’s Surprising Answer To Making The Big Decision On Vaccines. by Joseph Smith</h1>

Comment on [Transcript] – Should You Or Your Kids Get Vaccinated? One Doctor’s Surprising Answer To Making The Big Decision On Vaccines. by Joseph Smith

[0:37:00] Gary Ling’s Criticisms
[0:42:54] Why Do We Get Sick?
[0:48:40] Dr. Cowan’s Protocol
[0:51:30] Overcoming the Effects of Vaccinations
[0:53:50] Low-dose Naltrexone
[1:01:06] Dr. Cowan’s Organ Preparations
[1:04:32] Rudolf Steiner’s Cosmology of Our Development
[1:11:13] What Do You Do with Your Kids?
[1:12:24] Closing Remarks
[1:14:42] End of Podcast Ben: I have a master’s degree in physiology, biomechanics and human nutrition. I’ve spent the past two decades competing in some of the most masochistic events on the planet from SEALFit Kokoro, Spartan Agoge and the world’s toughest mudder, the 13 Ironman triathlons, brutal bow hunts, adventure races, spearfishing, plant foraging, free diving, bodybuilding and beyond. I combine this intense time in the trenches with a blend of ancestral wisdom and modern science, search the globe for the world’s top experts and performance, fat loss, recovery, gut hormones, brain, beauty, and brawn to deliver you this podcast. Everything you need to know to live an adventurous, joyful, and fulfilling life. My name is Ben Greenfield. Enjoy the ride. So, I have this crazy habit that when my wife makes bone broth at home, I actually take all the bones after they’ve been in the crock-pot and I keep them in there for another day. And then, I take them out of the crock-pot and I put them in this Cast Iron Skillet and I cover them with olive oil and salt and black pepper and turmeric, and I put a little bit yoghurt on them. I know this sounds gross but I eat the bones. They just melt in your mouth and I suck the marrow out and I feel like a man. I get all of the critical vitamins and amino acids and collagen that you get from animal bones and connective tissues. But, if you don’t want to go to all of that trouble and you still want organic grass-fed bone simmered bone broth that’s been simmered for over 20 hours and then sealed into these special cartons without any preservatives mixed with a whole bunch of organic vegetable extract, then you should get Kettle & Fire bone broth . It is certified gluten-free, Whole30 Approved, whatever that means, non-GMO. It’s paleo-friendly. It’s got all the body-loving goodness you want and nothing you don’t. And they actually make this super simple. They got chicken, they got beef, they’ve got one with like nootropic mushrooms in it. Kettle & Fire is really good bone broth. My wife actually has a whole carton every single day, like we make bone broth at home but then she takes it to the next level. She drinks an entire carton of Kettle & Fire bone broth every day. None of you have seen my wife lately but she’s hot. That’s why, because she drinks bone broth every day. So, if you want to be hot like my wife, drink bone broth every day. Anyway, so you get 15% off of anything that the good folks at Kettle & Fire make. Very simple. You go to kettleandfire.com/ben. That automatically gives you 15% off. You could use coupon code BEN but I think if you go to kettleandfire.com/ben, it’ll automatically save you. I also wanted to tell you about a really good one-two combo for muscle building or muscle maintenance. I know a lot of you are interested in this and this is something I’ve been doing a lot more of these days. It’s like rocket fuel before workout. You take creatine. And creatine, if you take it the right way in the right form like a good pure creatine supplement and you blend that with a little bit of water, and then the second component I’ll tell you about in little bit, it actually gives you a huge shot in the arm for any workout, and it’s really great again for mass building and muscle maintenance as well. Well, what I’ve been doing is stirring in a scoop of the cool lime Kion Aminos into the Thorne Creatine. This is a really good pre-workout that also still allows you to simulate a fasted state while you’re working out. So, you get that growth hormone and testosterone response. You can find the Thorne Creatine at 10% off and the Kion Aminos at 10% off right now if you just go to getKion.com. There’s a whole bunch of supplements over there but the two for muscle building I really like right now. It makes the aminos with the creatine. So, all of that, the automatic discount included, is over at getKion.com. That’s getK-I-O-N.com. Over the past 50 years, the rates of autoimmunity and chronic diseases have exploded. A ton of kids has allergies. As you’re no doubt aware, 1 in 11 has asthma, 1 in 13 has food allergies, 1 in 36 has autism, and then there are all these other things that are autoimmune related conditions that even adults have like acne and eczema and joint pain and thyroid issues and leaky gut. Many people will attribute this rise and all these autoimmune conditions to simple, increased awareness and more diagnosis because we’re aware of these issues, kind of similar to how more and more, especially young boys these days are diagnosed with ADD and ADHD. I don’t know if it’s a growing epidemic of ADD and ADHD as much as it is that people are just creating names for diseases that boys just naturally grow up with. But there’s definitely something going on when it comes to autoimmunity. My guest on today’s show, Dr. Thomas Cowan, who has been a guest on this show multiple times–this is his fifth appearance, I believe, fourth or fifth appearance on my show. Usually, when someone appears on my show that much, it’s because anytime they release a book or anytime that they write an article, I pay attention because they’re forward-thinking people who are far ahead of the curve when it comes to medicine and Dr. Cowan definitely falls into that category. Case in point, he has a new book. It’s called “Vaccines, Autoimmunity, and the Changing Nature of Childhood Illness.” He actually highlights how there’s a direct causal relationship to the increase in the number of vaccines that kids get and autoimmune diseases, provocation of the immune response. The book is fantastic. I have a bunch of stuff underlined that I wanted to ask Dr. Cowan. So, here he is on the show with us. Just fun fact for you guys, if you heard me on the Joe Rogan podcast where I was talking about why the heart is not a pump and Joe definitely raised an eyebrow on me when I was trying to explain that, Dr. Thomas Cowan actually wrote the book that describes all of that to you in detail. It’s called, “Human Heart, Cosmic Heart.” So, that’s a good one to read as are all of his books, frankly. I’ll link to all of them in the show notes. But Dr. Cowan, welcome back to the show, man. It’s old hat for you. You’re almost like a podcast sidekick now. Thomas: That’s right. Well, it’s always a pleasure to talk to you, Ben. Ben: Yeah. Yeah. You’re always a wealth of knowledge, man. I enjoy the occasional meals we get to have together at the Weston A. Price Conference when I can make it over there. You’re a good guy to eat grass-fed butter and lard with. Thomas: Yeah. And I appreciate all your support through the years. Ben: Yeah. And one thing I neglected to mention, by the way, for those of you who may not be familiar with this part of Dr. Cowan’s life is he makes these fantastic vegetable powders that me and my family use on all of our sautés, in our stews. They’re all based on this idea that Dr. Cowan and I delved into when he was on my podcast called How to Eat More Vegetables , about these organic heirloom vegetables and threefold blend powders and dark turmeric and kale and leek powders that he actually makes and packages in the Miron glass jars and ships all over the US. I’ll link to that stuff in the show notes as well. So, everything that we talk about today, you can find over at BenGreenfieldFitness.com/autoimmunity. That’s BenGreenfieldFitness.com/autoimmunity because that is indeed the topic of the day. And I think a perfect point for us to start, Dr. Cowan, would be this story that you tell about when you were growing up in the ’60s and how there was a kid you knew who had asthma. Can you get into that story? Thomas: The point of that story was–and people who have–old people around in their lives like me or grandparents or parents, if you ask them, how many children did you know growing up with food allergies and peanut allergies and asthma and eczema, childhood cancer and juvenile rheumatoid arthritis and on and on and on? What I remember was one child in our whole elementary school. And it isn’t like we were the paragons of healthy eating. We ate frozen food, and basically, crap. But still, there was only one child I remember because as I said in the book, he was teased, although I would add, not by me. That’s just not my style, I guess, teasing other people. But he was teased and he was teased because it was like, “How dare you be sick?” Now, if you’ve fast forward from that ’til 2016, 2017 or now, I’ve heard statistics that Detroit Public Schools, which is where I grew up, something like 40% of the children carry an inhaler to school. So, maybe they’re teasing the so-called normal people now. Ben: Seriously. Thomas: Like, “What’s wrong with you? You don’t have any medicine to take.” So, the whole situation has changed. You can’t go to a ballgame and eat peanuts. You can’t go to a birthday party everybody has food allergies. I don’t know the percentage. The CDC came out with a 46% of current American children have a diagnosed chronic disease that needs at least intermittent medication. Ben: And adults. I went to dinner the other night. I was in–where was I? I was in Chicago. I went to this fantastic Italian restaurant. I was with about 20 people. And when the waiter came out and asked if we had food allergies or sensitivities, freaking half the hands in the room shot up and this person was like, “I’m not eating gluten,” and this person says, “I have a sensitivity in lactose.” And I realized that part of that is the nature of just having dinner with, as I often do, people who are intensely aware of health. But there is an increasing number of adults who have an enormous number of allergies and skin conditions and all manner of things that frankly are autoimmune issues. Thyroid is another big one. But you’re right. We didn’t see a lot of this and I don’t know if you have any stats, because I mentioned earlier that a lot of people do say that this is just increased diagnosis, increased awareness of the condition. But do you have anything to say to that argument? Thomas: Well, I mean even if you actually believe the CDC and the Health and Human Services’ numbers, they say it was about 6% of the childhood population had a diagnosed chronic disease in 1980 and it’s now 46%. So, that’s one way to look at it. Another way and one of the diseases that is now being questioned, whether there’s an actual increase or whether it’s all about diagnosis, is of course autism. So, now, there’s a whole movement to say that autism is normal and we just diagnose it more. But the problem with that is–I’ve spent a lot of my life around autistic people because I worked at camps and I was in anthroposophical doctor working with Camphill Villages where there are a lot of autistic people. Something like 75% of people with a diagnosis of autism ends up being institutionalized. And I don’t know about you, Ben, but if I think how many 60/70-year-olds do I know with autism and how many institutions there are for autistic people who are in their 50s, 60s and 70s, it’s basically zero. So, where are they all? If they were just as many autistic people 50 years ago as there are now, we would expect a million autistic adults that are institutionalized and we see almost none. Ben: You tell another story in the book that I think is perfect for kind of beginning to delve into the changing nature of childhood illness and autoimmune and vaccines, and that’s the story of this guy named William Coley. I hadn’t really heard of this dude before ’til I read your book. But can you go into Coley and Coley’s toxins? Thomas: So, when I was first becoming a doctor, and at that time, I was learning about anthroposophical medicine, I would say if you wanted to encapsulate the entirety of the medical philosophy, it’s of course complicated. But it goes back to Paracelsus who sometimes considered the Father of Medicine saying, “Give me a medicine to produce a fever and I can cure any disease.” So, the example that you gave of William Coley is a perfect example of that. So, here was a guy who was a trained oncology surgeon specializing in a kind of cancer, which is a bone cancer called osteosarcoma, which is a very aggressive and deadly form of cancer, and he was actually working at Sloan Kettering Hospital in New York. He was working under the tutelage of a guy named Ewing for whom Ewing sarcoma is named after. So, Ewing is as big as it gets in the history of sarcoma. So, he was the state of the art in 1910/1920 treating sarcomas. At one point then, he has John Rockefeller’s “friend” who came to him with a sarcoma and he did the usual treatment which was amputation and then she died 68 weeks later. That was an important patient for him probably for all kinds of reasons and it just apparently very discouraged him. And so, he decided to look through the records of the hospital to see where this sarcoma center of the world, how are we doing with treating sarcoma. And, his answer was basically, dismally. Now, there was one exception in the records this dockworker guy named, Stein, who–all it said in the notes was, “Discharged free of disease.” So, Coley had the good sense to go and track this guy down, this was nine or so years later, and he said, “What happened to you?” He said, “Well, they never did do the surgery or any other treatment because while I was in the hospital, I got this disease called erysipelas, which is a very bad strep infection of the skin, which typically causes very high fevers. And I had a fever for a month at which time the sarcoma was gone and never came back.” So, again, a lot of doctors would hear that and say, “Well, that’s anecdotal and I don’t have to pay any attention to that” or “I don’t know what happened.” But there was a movement all over the world at the time of treating cancer with fever therapy. Coley knew about this so he decided to give all his sarcoma patients erysipelas because he knew the usual way they treated them wasn’t working, and he ended up saying that approximately 40% of the people who got erysipelas got better after a month of high fevers. 40% died of the erysipelas, this was in the pre-antibiotic era, and 20% interestingly, no matter what he did, never would get erysipelas and then they would just die of their sarcoma. That’s in some ways a great result because 40% of incurable cancer patients got better far better than anything we can do now. But it’s also had a high risk because 40% died of this infection. So, that’s a high mortality rate. So, he said, “Well, maybe I don’t need the infection. Maybe I just need the fever.” So, he figured out how to use attenuated, essentially non-infective bacteria in just a certain part of them that would provoke a fever without actually giving them an infection. That’s what became Coley’s toxins. It was the main adjunctive treatment for cancer for the next 30 or 40 years. Ben: And it was just causing people to get fevers that somehow were killing off the cancer. Thomas: Exactly. Now interestingly, when I became a doctor, I was contacted by his granddaughter, a woman named William Coley Nauts, who gave me this manuscript. It had never been published. There was, I don’t know, thousands of pages with all of case studies that Coley treated. I went through them all and there were literally hundreds, thousands of people who were cured. And by this time, he was not causing infection because he was not using live bacteria. It wasn’t 100% but it was a huge success. I was looking at this and then I saw some articles that Sloan Kettering was developing an immune therapy program where they would take the chemicals that are made when you have an infection and they would give them to cancer patients to see if they could stimulate their immune response and get rid of their cancer. Now, the amazing thing about this–and they isolated something called tumor necrosis factor and they would give this. And then you inject somebody with tumor necrosis factor and you get a fever. Shockingly to me, they would give them Tylenol to bring the fever down and then the whole thing wouldn’t work and they said, “Well, I guess immune therapy doesn’t work.” The bottom line was it’s not the tumor necrosis factor or the interferon or the interleukin themselves that are a positive effect to the therapy. It’s like Hippocrates said, “Give me a medicine to produce a fever and I can cure any disease.” You have to have the fever as unpleasant as it may be and you have to have it to 105 degrees or so for a month, and that causes no problems in itself. But unfortunately, since the ’60s, Coley’s toxins have been outlawed in the United States. That whole approach is unavailable. Ben: Why were they outlawed? Thomas: I don’t know. I mean, they said it was an unproven therapy and I think it was basically pennies and they just didn’t want it. Ben: But you don’t really need Coley’s toxins if you have a child that is allowed to actually get sick so that the normal–I believe it’s called the–is it the humoral immune system is able to actually kick in and be trained in the right way? Thomas: Well, it’s the cell-mediated. Literally back then, since that day, every single time I’ve seen a child, a sick child in my practice with a fever, I literally think to myself, “I am preemptively treating their cancer to be.” In other words, if I can get them through somehow this febrile illness without suppressing the fever, then I know that I have just, literally for their entire life, pushed them in a direction away from cancer. That’s why I’m doing that. If it takes a day of a fever, that’s good. If it takes a week of a fever, that’s fine. My job is to somehow help them undertake this process so at the end of the day, they’re at this funny word that we say after you’re sick, “Now, I’m better,” because literally, you’re better than what you were when you started. Ben: So, what are the types of conditions that a kid would get when they’re young that would allow that proper cell-mediated immune response to kick in so that the body is able to mount its normal immune response, get a fever, and then remember that specific antibody or toxin or sickness so that the person doesn’t get it again? Thomas: Right. So, maybe we should just go through that for a minute, if that’s okay, just to put that in context? Ben: You mean like how that immune system is actually working? Thomas: Yeah. Ben: Yeah. I think that would be valuable because I think a lot of people don’t really even understand that there are two main branches of the immune system that we’re talking about here. Thomas: Right. So, here’s the way it works. Let’s just take in like a measles infection. So, if you’re a child and you’ve never been exposed to measles and you get exposed to this virus and it gets in and it gets inside your cells, probably millions of them or certainly thousands, and your body is now looking at these infected cells, so the first thing it does is it mounts a cell-mediated, meaning it’s based in the white blood cells, response that’s whose job it is is to essentially attack and digest these infected cells and then clear them out of the body. Now, it does this through the mechanism of fever and rash and mucus and cough and diarrhea, and all the things that we call being sick. And if there’s anything people will remember from hearing me or reading my book, it’s that that which we call being sick, fever, rash, cough, all that, that’s not the virus. It’s not the measles virus, it’s your cell-mediated immune system essentially eliminating the virus. Now, the virus provoked the cell-mediated response but the actual symptoms are from the cell-mediated response getting rid of the infected cells. Ben: Right. The rhythm of your body. Thomas: Yes. I know that because if you inhibit your cell-mediated response, you can infect people and even kill them and they’ll never be “sick.” Sick means your cell-mediated response is working. Ben: Wait, wait. What do you mean you could infect people and kill them and they wouldn’t get sick? Thomas: So, if you give people a measles infection and then give them prednisone so that they don’t have a fever or a rash, the infection will continue and it could even kill them but your body has been thwarted in its attempt to get rid of it and that’s a dangerous situation. You don’t want to stop your body from using its natural mechanisms to clear the infected cells. That’s a bad strategy. Now, once that happens, it usually takes seven to ten days, and then you’re back to normal. The body in its evolutionary wisdom says, “I don’t want to do this over and over again. So, I’m going to tag one of the pieces of the measles virus and make antibodies against it, that’s the humoral or antibody arm of the immune system so that if I ever encounter that virus again, I can keep it from infecting my cells without getting my cell-mediated immune system involved.” And because the humoral antibody immune system is not associated with symptoms, you don’t know anything’s happening. You never get sick again from that virus. And when those two things happen in that sequence, infection, cell-mediated clears it, antibodies remember it. It’s unbelievably almost 100% foolproof nobody ever gets measles twice in their life. Ben: So, you’re saying we should just let kids get measles and let measles run its course? Thomas: Well, I’ll get to that. Ben: Okay. Thomas: But at this point, I want to point out that that’s the way our immune system always worked until about 50 years ago. The theory of vaccines is–well, the cell-mediated part is the sickness part. We don’t want the sickness part. So, we’re just going to take a piece of that measles virus or kill it or so-called attenuate it, and we’re going to stimulate you to make antibodies. Sometimes we actually have to give you, essentially, toxins to make you make antibodies. So, we’re going to embark on an antibody-only strategy. That’s the theory of the vaccine. No more cell-mediated immune system, only antibodies. And so, that’s what they do. They give you pieces of the virus or pieces of toxins or killed viruses and then they have to mix it with things like aluminum and formaldehyde and mercury and fetal DNA cells and glyphosate and all kinds of things to make you make antibodies. And it works. So, now you have people who’ve skipped the cell-mediated part and have an accelerated antibody response. Now, I would point out two things about that strategy. In number one, there is zero possibility of getting lifelong immunity through an antibody-only strategy. And for people who don’t believe me, it’s simply the reason why every vaccine has to have boosters because the immunity that you get, when you only stimulate the antibody part, the first time lasts seven to ten years, the subsequent boosters last two to three years. So, when you’re 30 or 25, you no longer have antibodies. You’re just as susceptible to it as when you were a newborn baby. The second thing I would point out about an antibody-only strategy is just like you eloquently talked about the rise in autoimmune disease. An autoimmune disease is defined as the situation of accelerated antibodies that are targeting your own tissues. So, if you ask the question, how did we end up with like what Yehuda Shoenfeld says 150 million people who have autoimmune disease. Well, an autoimmune disease meaning too many antibodies. This is maybe a funny way to say it but that’s the whole point of the vaccine program. So, it worked. Ben: Hey, I want to interrupt today’s show to tell you why my face is as smooth as a baby’s bottom. It’s because I use these blades that are made by a company called Harry’s . Harry’s bought a German-engineered factory that’s been making some of the highest quality blades for shaving, I don’t know what else you’d use blades for, in the entire world. For over 95 years, this factory has been making these blades. Harry bought them and they started churning out these five blade razors with a lubricating strip, and also this weighted ergonomic handle. It’s like the Cadillac of razors. They have these wonderful paraben and phthalate-free, rich lathering shave gels. They have a really great travel blade cover so these blades stay in fantastic shape if you’re on the road. And they have all this put together in a really great kit. They call it their trial set. So, you get travel blade cover, you get the shave gel, you get the five-blade razor with the lubricating strip and the trimmer blade, you get the weighted ergonomic handle and all of that you can actually get. It’s a $13 value but you can get it for free if you just go to harrys.com/greenfield. That’s harrys.com/greenfield. You’ll automatically get the entire kit for free. This makes shaving a breeze. I mean, the hair just literally almost falls off. I used to use Nair when I was a bodybuilder but this is probably a way healthier way to actually get a nice close, close shave for men or for women, because women like to shave their legs and some women like to shave their face, too. Some women need to do that, believe it or not. This podcast is also brought to you by Zip Recruiter . Zip Recruiter makes hiring a breeze, kind of like Harry’s was making shaving a breeze. You see all this stuff is about making your life easier. What they do is you post a job on Zip Recruiter. They do all the work for you. They spot like the strongest applicants. They collect all the information. They identify the people with the right experience. They invite them to apply to your job. They’re like this freakishly smart online software that allows you to get hooked up with the right candidate, literally, in a day. Eighty percent of the employers who post a job on Zip Recruiter get a quality candidate through the site in just one day. It’s that easy. No more piles of resumes on your desk and spending all your life on LinkedIn, stalking people, which is awkward because a lot of times, they could see if you viewed their profile and you got to have an incognito browser and all of that. No, you don’t even need to do it. You just go to ziprecruiter.com/green. That’s ziprecruiter.com/green. And when you do that, you get to try Zip Recruiter for absolutely free. That’s right, free. Zip Recruiter. There’s a reason they call it the smartest way to hire. So, you get to try it for free, ziprecruiter.com/green. So, the problem is though that all of these people who get that humoral system stimulated early in life from the vaccines never get a chance to actually get sick from that particular illness and mount a natural immune response to that illness that then causes the body to remember that illness and not get it again. Thomas: Correct. And there have been study after study showing that children who get chickenpox have less glioblastoma, kind of brain cancer. Children who get measles have less osteoarthritis, have less arteriosclerosis, have less heart disease, have less dementia. There’s study after study showing that children who get febrile childhood disease have less chronic disease later in life, period. Anybody who doesn’t know that just simply doesn’t know the history of medicine or the current literature on the relationship of childhood illness and chronic disease. The other thing I would point out is that when people say, “Well, it’s fine to not go through these illnesses.” The fact of the matter is I happen to know the exact date the CDC says anybody born in 1956 or before is considered immune to measles. That happens to be the year I was born. So, anybody, 62 or older, by definition had measles. So, we have no idea whether a human being can actually get to be 65 who didn’t have measles when they were a child because there’s nobody like that. Could be it’s fine, could be it’s not fine. We don’t know. Ben: So, when it comes to the whole idea behind vaccines and actual cellular function, there’s a section in your book that kind of blew my mind because everything I learned in exercise physiology and a lot of my coursework at University of Idaho seems to be relatively incomplete, specifically when it comes to cell biology and the cell membrane. I realize that this might sound completely separate from any consideration of autoimmune or vaccination but I think you can probably pretty elegantly weave this into this discussion because you have a whole chapter in the book about why we need to rethink cell biology. We’ve got time to unpack this but can you get into what we currently believe about cell membranes or what medicine and science currently believes is the way that a cell operates and why that could be a flawed pattern of thinking? Thomas: The basic premise of cell biology all came from trying to understand the central paradox of mammalian including human cells which is, “How does a cell live in a sodium-rich environment yet has a sodium-poor internal milieu?” Now, that may sound like a mouthful but if you put a cell in a high salt concentration, it will equilibrate and the sodium will be balanced on either side. But that’s clearly not the case with any mammalian cell. The sodium stays on the outside, the potassium collects on the inside, and this causes a separation of charges which is fundamental to allowing the cell to be a charged entity like a battery that can actually do work. So, if you lose the charge because you lose this separation of sodium-potassium, you’re talking about a dead cell. Ever since–it’s literally 200 years of research into how the cell accomplishes that. Nobel Prizes were given and the answer is you have this cell which is a membrane-bound sac of water and it has a pump in the membrane which pumps the sodium out and the potassium in. And that’s how it happens. And here’s the pump and we studied it and we’ve got our prizes for it. Ben: I remember the little spheres in my textbooks in college showing the NA and the K moving in and out of the cell membrane based on that sodium-potassium pump. Thomas: Right. And that creates the charge of the cell. It’s the most fundamental part of cell biology you could imagine. Now, here’s the problem with that. I have to acknowledge a guy named Gilbert Ling , who was a biologist who really spent four decades critiquing this system and showing that it’s basically baloney. The first problem is, okay, a cell is a sac of water with stuff in it. I often tell the story when I was an ER doctor and we’re told that 70% of the intracellular content is liquid water. And I would see people with bullet wounds and bayonetted and shot and all kinds of stuff. And I never saw puddle of water on the floor next to them or water squirting out of a human being. So, I asked myself, “Where is the water here?” I know there’s blood but that’s different. Supposedly, these cells are 70% water yet there’s no water in the human body. So, that’s one problem with that model. The second problem is Ling actually ran the energetics of this sodium-potassium pump, and absolutely conclusively determined that in order to create this differential, you would need approximately 40 times the energy that a human being or the human cell has available to it just to run the pump. That’s like if you have a mortgage on your house that’s 20,000 a month and your salary is 1,000 a month, it’s not going to work. A, you’re not going to be able to pay the mortgage, and B, you’re not going to have enough money for food. You cannot run that pump given the amount of energy it takes and why he was the only one to understand that as I have no idea. Ben: So basically, there isn’t actually enough ATP available to be responsible for the proper distribution of sodium and potassium based on the pump model. Thomas: Exactly. The other part of that is–and I’m glad you said that because he also pointed out very clearly that unlike what seemingly everybody thinks, ATP is not the energy molecule that we think it is. There is no more energy in an ATP molecule than any other common molecule. So, the system does not run by ATP as some energy source fueling this pump pumping the potassium in and the sodium out. So, the question then is, how does it work and what does that have to do with autoimmune disease? The answer is our cells are made of this fourth phase structured water or gel water that I know you’ve got into a lot with Dr. Pollack and other people. It’s structured similarly to how Jell-O is. You take proteins, you add water, you put energy source, in the case of Jell-O, it’s heat, that unfolds the proteins, allows them to interact with water. When it cools down, it forms a gel. A hundred percent of the water in our cells is in this gel form, not a liquid form, even though people say there is no gel form but there is. And the way that it’s structured, similarly to Jell-O, is you take the intracellular proteins. The ATP interacts with the ends of the proteins and unfolds them. It allows them to interact with water to create what I call the perfect gel. The perfect gel, now think of it like it has a sort of mesh, like a mosquito netting. The mesh is so constituted so that by itself, it attaches to potassium and repels the sodium. So, there’s no pump needed. All you have to do is use ATP to unfold the protein, structure the water. That structured water by definition collects the potassium, expels the sodium, and that creates work on the cell that the cell can do and everything is good. Ben: Yeah. That’s actually Gerald Pollack who I interviewed. And I’ll link to all of this again if you go to BenGreenfieldFitness.com/autoimmunity. He gets into how all of this fourth phase water, this so-called structured water that surrounds–would you describe that as surrounding ourselves or would you say that it is– Thomas: No, it’s the very nature of the water in our cells. Ben: Inside the cells. Thomas: Inside the cells and even around DNA, in the nucleus, there’s a small amount of structured water which determines which part of the DNA will be expressed. The structured water does everything. The reason it’s water is because it has infinite binding sites, and so it can interact with thoughts, emotions, hormones, vitamins, every– Ben: Sorry to interrupt but if you have a negative electric charge, essentially, you have almost a crystalline structure that can absorb different forms of information or energy or signals, and this relates to the whole concept of the body being a human battery, and also relates to the concept of how we’re affected by–as Bruce Lipton goes into in his book, “Biology of Belief” or Joe Dispenza outlines in his book, “You Are the Placebo,” how we can and our cells can even respond to things like energy and emotions and sound frequencies, and all manner of things that go beyond simple, I guess we would call atoms. And it can instead interact with subatomic particles and then interact with waves and vibrations as well. Thomas: Yes. All that is because of the perfect crystalline negatively charged water gel. Now, that gets into the next thing. So, why do we get sick? And in particular, I often joke that the reason I wrote this book was because I wanted to understand for myself the sequence of events that happens to me, and I don’t think I’m the only one, when you get sick. Here’s the sequence. A, I’m fine, then I don’t feel well and I get a fever, and then, it sort of breaks down and then I get snot and then I snot out the snot and then I get better. So, why does it happen like that? Nobody ever told me, nobody ever said anything. Why that sequence of events? But here’s why. Let’s say you have this perfect gel. So, now you’re a perfectly tuned radio and you can accept all the influences that a human being is supposed to. And then you dissolve arsenic in your gel. So, that distorts the gel. So, now you have an out-of-tune radio that can’t accept signals and you’re going down a bad path here. You can’t make an energy charge. That’s what we call being sick. So, your body says to itself, “I’ve got to get rid of that arsenic but I got it interspersed in my gel. So, what I’m going to do here is heat up the gel so it make it back into a liquid, and then I’m going to make it run out of the cells and I’m going to snot it out of my body, and then, I’m going to reconstitute a more perfect gel.” So, that’s what we do. Ben: In a case of something like an autoimmune condition that would involve inflammation, these cells actually get into this pathological state. Is that based on some kind of an inhibition of this negative charge or the inability of water to basically move in and out of a cell? Thomas: The way I would put it is let’s say you have like with chickenpox or measles. So, your gels are healthy, you get an infection, you clear it out, you reconstitute perfect gels, and now you’re fine. But let’s say it’s not a chickenpox virus that’s distorting your cells but aluminum being injected into your cells and that happens over and over again. So, you clear it out, you get sick, and then you get more. And then you clear it out and you get more, and at the end of the day, you end up with a distorted cell which is weak in its ability to accept impulses and it’s weak in its ability to create this charge. And now you have a chronic inflamed situation because your body is continually trying to clean itself out of whatever was put in there, but you keep putting it in there and you keep inhibiting your body from doing this housecleaning. I mean, what else would you expect to happen but you end up with chronic sickness. Ben: It’s interesting because this is similar to our discussion of the heart in our last episode about how the heart actually pumps less than what we think, very similar to this sodium-potassium pump being possibly something that isn’t even from a pure biochemical standpoint feasible. And when we talked about the heart, you talked about how water, particularly the charges of water, allow it to move through a well-designed shape of the heart, I believe you called it a tetrahedron structure, without the heart necessarily needing to pump but rather the heart relying upon the vortices like movement of water through that structure of the heart. And in the same way that water moves through plants and the vasculature in plants, without the plants needing a heart, water and fluids can move through the human body in a similar way. And what you’ve just described is very similarly, almost like this self-sustaining system that doesn’t rely upon a lot of outside energy for accomplishing movement but in fact allows for the cell to operate, assuming a state of adequate hydration and an adequately charged body, which we’ll get into in a second, without necessarily requiring say the ATP. Thomas: Exactly. I couldn’t put it any more succinctly. That’s exactly right. These pump models are from a–the reason we think that way is because Descartes said, “From now on, only mechanical ideas will influence how we think about the human being.” That’s why we think that. Ben: But it’s more than just mechanics. It comes down also to electricity charges and frequencies. Thomas: Yes, exactly. It’s more than the camps. And in fact, when you get into the mechanics, it can’t possibly be the heart pushing the blood. It mechanically doesn’t work, and similarly, it can’t possibly be this sodium-potassium pump creating this charge. The energy just doesn’t add up. There is a whole another way and that gets into a lot of things but basically, unfortunately, our biology is based on inanimate, inorganic principles. We don’t know the difference between life and death. Therefore, we can’t study life. Ben: Now, I want to get into your whole protocol for supporting the immune system based on supporting the innate immune system response, especially in childhood rather than vaccinations. But to bring things full circle, what you were saying is when we look at aluminum and mercury or formaldehyde or any of these other chemicals or metals that are in a vaccine, what those do is they can actually insert themselves into the intracellular matrix and interfere with the actual charge generating ability of the cell itself. Thomas: Right, or any toxin. Anytime you live in a toxic world or nutritionally depleted world, you’re going to interfere with the formation of your gels, which is how we interact with the world. That’s what collects and processes information, which, in a sense, is what a human being or a living system is. It’s an information communication device with the rest of the world. And now, we’re human beings whose radios are out of tune. Ben: Yeah. And this is important too because this is one of the things that I explain to people when they ask me what are the top things they could do to maintain ideal health and wellness. And a lot of it comes down to supporting this natural gel matrix within the cell and the natural negative charge of the structured water in the body. That comes down to very good water intake, preferably structured water but water that has maintained its normal negative charge. I have a structured water filtration system installed in my own home. And, although I don’t get a lot of structured water when I travel, there are even ways you can bring structured water when you travel, like I have these little liquid shots called Oral IV , for example, that I can throw in my travel bag and bring with me. And then, in addition to the structured water, adequate mineral intake. I mean, we’ve got trace liquid minerals and Celtic Sea Salts and all sorts of things here at our house that my kids and my wife and I use, and then getting outside barefoot on the ground with adequate sunshine. I mean water, minerals, the earth and sunshine are–you know, before you go and buy a bunch of colostrum and liver capsules, all these things that do support the immune system, I mean you have to take care of that low-hanging fruit. Thomas: Exactly. You just outlined exactly the plan on how to maintain healthy gels and a healthy body right there. That was it. Ben: Now, in terms of the actual immune system itself and this idea of alternatives to vaccines, I know that you have kind of a basic autoimmune treatment protocol. I think this is important because a lot of adults, especially, have been vaccinated. A lot of adults have children or people are listening in who might even be children who have been vaccinated, I mean is it really a hopeless scenario for a lot of these folks, their humoral immune system being triggered when they were young without the innate immune system or are there things that we can do to heal the body? Thomas: Yeah. I mean, basically, there’s no human being who’s hopeless. That is not even the way to look at it. It’s always just taking one step at a time. So, if you’re sick, these dynamics that you just talked about and that we’re talking about are in play. And so, what’s needed is to put together a cellular gel restoration program. Now, the four basic, water and sunlight and earthing and movement, that’s the basic for any plan. And then, I would say the next most basic is at some point in your life, your cell-mediated immune system will start to rear its head again and say, “Remember that I’m still here.” At that point, you have to honor it. You have to go through the illness, if you need to, have somebody who knows how to do that help you and you’ve got to let your body do its own housecleaning. Now, some of the strategies that I outlined in the book were different diets, and like you say, colostrum, and you can use vitamin C and you can do the GAPS diet, and you can use low-dose naltrexone. All these things are attempts to bring this back into balance. But the rubber hits the road, when your child eventually will get sick again because their cell-mediated immune system will say, “Now, we’re strong enough to do this and you have to squire it through. If you need help, that’s fine, so that they get to the end of the day in a better shape than when they started.” Ben: Now, I want to actually explore a few of those things that you just brought up as far as ways to kind of heal the body and to quell this autoimmune response. One that you just mentioned was low-dose naltrexone, and it’s pretty rare that all have docs on like you who are using a lot of natural healing protocols who will mention a pharmaceutical drug like that. But what is it that you like about this low-dose naltrexone? Thomas: So, naltrexone was originally discovered as an opiate receptor inhibitor, meaning if you took an overdose of heroin, this naltrexone inhibits the attachment of the heroin to your opiate receptors and basically will save your life within seconds. So, it’s called Narcan and it’s used in all the emergency rooms probably all over the world. So, then they started giving it to addicts, 50 milligrams a day, and that would inhibit the ability of the heroin to make you high, which I guess is good. But it also made you feel so lousy that people didn’t take it, and so it failed as an addiction drug. And that’s because when you block opiates like heroin, you’re also blocking endorphins which are endogenously produced opiates. And life without endorphins is not much fun. So, that would have been the end of it except there was a number of doctors, a guy named Bihari, in particular, who said, “These people with autoimmune disease, they have a low endorphin state. That’s why they feel so lousy. So, if I can improve their endorphins, I can make them feel better and their whole immune system will function better.” So, he ended up giving them very small doses of naltrexone which essentially tricks your body into making endorphins, and that rebalances your immune system. It lowers the humoral, it stimulates cell-mediated immunity, and that can make an unbelievable difference for people suffering from autoimmune disease. I have cases in the book of people with Graves’ disease, people with pemphigus. I’ve got story after story of people who do all those things that you say plus eating low-antigen diets so they’re not overreacting, like paleo or GAPS or something like that, and take low-dose naltrexone and they finally get a rebalancing of their immune system, and if we’re lucky, an actual remission of their autoimmune disease. Ben: Now, I know that that’s something that you would normally have prescribed by a physician but it is LDN. Is low-dose naltrexone something that one could buy online? Thomas: There is a pharmacy out of Israel. I don’t remember the name of it but you can actually buy it although it takes a little bit of expertise to get the dose right. So, it would be best to work with somebody who uses low-dose naltrexone regularly. I was going to say you’re right. It’s the only pharmaceutical medicine in a typical month that I actually use. Ben: My friend Grace Liu , who I worked with when I was healing my gut a couple of years ago, uses that and also mistletoe as a very similar treatment that apparently works quite well along with LDN for not just gut issues that come along with autoimmune disease but also a lot of the inflammation that comes along with that. Have you ever done much with mistletoe? Thomas: I’ve done a lot with mistletoe. Mistletoe is basically Rudolf Steiner’s fever therapy. It’s like Coley’s toxins in a shot and it stimulates the cell-mediated immune system. So, fever is not the only way but there’s also hyperthermia. People have come up with various ways of cleaning the gels and stimulating–Steiner called it the etheric body or the water body which is sort of the same thing. And when Steiner was asked what does mistletoe do, he said, “It simulates a bacterial infection.” In other words, Coley’s toxins in injection form. Ben: Interesting. Okay. So, you’ve got LDN and mistletoe as two things for people to look into who are experiencing autoimmune issues. And then another one that you mentioned, and I’ve had this guy in the show before, is this lignite stuff. Are you recommending lignite as something one would use short-term or is that just something based on glyphosate exposure that you have patients just taking almost like a daily multivitamin? Thomas: Right. And that comes because there’s a number of ways to get into this autoimmune situation, meaning you have too many antibodies and you’re reacting to yourself. The too many antibodies is often and largely a consequence of vaccines but it’s also a consequence of absorbing antigens which are proteins from your gut, and then your body has to react against them by making antibodies. So, if you can seal the pores in your gut, then you will be less exposed to antigen so, therefore, make less antibodies, therefore, have less autoimmune disease. And this stuff that you mentioned called Restore is one of the ways and maybe the best way that I know of to seal the gut. So, I use it with people with autoimmune disease and gut issues until they’re clear of it, basically. Ben: Yeah. You just take a shot like about a half hour before you eat a meal, right? Thomas: Yeah. Ben: Okay. Thomas: Exactly. Ben: Got it. And then another one that seems to act similarly in terms of tight junctions in the stomach and lowering the activity of this zonulin protein that seems to be able to open these tight junctions and cause more of this autoimmune food allergy, food intolerance, other inflammatory conditions, is colostrum . So, colostrum is another one that I’ve talked about before on the show quite a bit, but in terms of that, are you also recommending that for both children and adults who are having autoimmune issues? Thomas: Yeah. I mean colostrum, again, one of the ways you get into this autoimmune disease is because you’re absorbing antigens from the gut, and that’s because you have a disordered gut flora and too much zonulin and the pores are too open. So, what colostrum does is it’s basically the first milk that’s there to stimulate the implantation of the healthy gut flora. So, if you give that to a person and give them a diet that includes fermented foods and maybe probiotics if needed, then you encourage the implantation of healthy gut flora that prevents leakage into the bloodstream and that helps the autoimmune disease. Ben: Okay. Got it. And then the last one I want to talk to you about was these organ preparations that you use. What are those? Thomas: So, one of the reasons why autoimmune disease, let’s take say Hashimoto’s, becomes chronic is–so you stimulate antibodies. You have these antigens stimulating antibodies. You have these adjuvants in vaccines stimulating antibodies. One of the antibodies cross-reacts with say your thyroid and it causes an inflammatory reaction in your thyroid, which means it puts out proteins from the thyroid into the bloodstream. Now, that, of course, makes your body make more antibodies to these antigens floating in your bloodstream. And so those antibodies then cross-react with your thyroid, create an inflammation, more antigens in the bloodstream, more antibodies, more inflammation, and that’s why it becomes a chronic situation. So, in order to break that cycle, the organ that you’re attacking, so in this case the thyroid, if you eat a desiccated thyroid from a grass-fed cow, the hope is that your body’s antibodies will go after the thyroid that you just ingested and leave your own thyroid alone. This has been used in the Brigham and Women’s Hospital for about 40 years. They call it oral tolerance therapy because many of the antibodies are made in the Peyer’s patches around your gut. So, if you eat what cartilage then your antibodies attack that, leave your own thyroid alone, that your thyroid can heal and that breaks the cycle. Ben: Now, these types of glandulars, are these similar to something like low-dose naltrexone that you would need to get a prescription for or are these the same type of things you could find, say on Amazon when you go there and you see like grass-fed desiccated beef organs and desiccated liver? And I know NOW Foods is one brand that’s recommended as far as like a good safe source of liver extract. Are these the type of things that people can use just in order on their own? Thomas: Yes. They’re similar. I mean, I use the ones mostly from Allergy Research because they seem like they’ve tested them and they worked with a friend of mine named, Nick Gonzalez, who basically directed them how to do it, whether they’re so much better than any other one, I don’t really know. Ben: Yeah. But even the Allergy Research stuff, you can order that off Amazon, right? Thomas: Yeah, right. It’s not going to hurt you, so that’s fine. I mean, it’s always good to work with somebody who’s done this before but I’m not saying it’s imperative. It’s certainly imperative if you’re having a horrible time with rheumatoid arthritis or Graves’ disease. I wouldn’t want somebody doing that on their own. Ben: Okay. Alright. Now, I want to come full circle and I will of course link to Dr. Cowan’s book for those of you who want to delve into his autoimmune protocol even more deeply and some of the dosages and uses of some of the things we talked about like colostrum and LDN and some of these organ extracts. But one of the things that I find fascinating that I didn’t have a chance to ask you yet is this idea behind Rudolf Steiner, somebody who you mentioned earlier, and the fact that there are actual identified developmental stages that a normal, healthy human child should be almost like allowed to go through. And he has kind of outlined these different stages of life where you’re supposed to get sick, you’re supposed to get some of these diseases that we’re trying to eradicate. Can you explain what that, I believe he calls it the cosmology of our development would be in respect to that? Thomas: Normal science and normal medicine says we have a body, meaning a physical body and there’s nothing else to a human being but them. That’s the way we’re taught. Now, that’s why even why sometimes I bristle at saying even the word science because–I mean, there’s no doubt everybody wants to get the truth and do that as carefully as possible. But if the definition of science is the belief that only material stuff exists in the universe, I’m not sure I can agree with that. Or let me put it another way, I don’t agree with that because what about like love that I don’t know anybody who can measure love and yet everybody knows it exists. Now, Steiner took that into a more, I would say particular or scientific way, and it’s hard to know how he got these things but let’s just say whatever method he used–and he said, “Well, we not only have a physical body but we have three other bodies, one is a water body and one is an air body and one is a warmth body. He gave them different names like etheric body and astral body and ego, but that’s what he meant. And he said, “Just like the physical body gets born, the etheric body or water body gets born, and the soul body or air body gets born, and then the warmth body or ego gets born, and they get born by going through certain illnesses.” So, the etheric or water body gets born when you’re 7, and that’s when you go through measles. Your air body, your soul body, sort of the whole puberty thing gets born when you’re 12 to 14, and then you go through rheumatic fever or strep infection. And then, your ego gets born when you’re 20, 21 and then you go through mono. When you’re born, your physical body gets born through interacting with the air. The Greek said, “When you interact with the air, that’s the birth of the physical body.” And that happens through overcoming pertussis or whooping cough. So, that’s this sort of scheme he laid out. I think the point for anybody to realize is that a strategy of keeping children from overcoming obstacles is fundamentally a strategy of creating weak human beings. Ben: It’s so inconvenient though to have to get scarlet fever and the measles and take the more, shall we say stoic approach to sickness rather than just trying to nuke it with the vaccine. Thomas: Yes, maybe, but if you realize, as I’ve come to, that there’s no other choice, A, and that with proper care. And so, some of what you learned in anthroposophical medicine is the proper care of these illnesses. But even if they weren’t, the mortality rate from measles in the decade prior to the measles vaccine had dropped to almost zero. So, there was very little case to be made that this was a dangerous disease to the American population before the measles vaccine. So, now, we have a whole lot of hysteria about it, but the bottom line was–I mean, we had measles parties my parents brought me when they wanted me to get measles so I didn’t miss so much school, and it’s a whole different world of how we think about these things. People then had a sense that you cannot prevent children from experiencing challenges because that’s not how human beings develop. Ben: Yeah. It kind of just comes full circle, honestly, to everything that is wrong with the way that we raise our kids from antibacterial hand soaps to soy milk formulas to the built-up protective covering on the floor of all the playgrounds at the schools. It’s just sacrificing kids’ muscle mass, their bone density, their immune systems, and then we carry that into adulthood at which point then we have to pull out all those fringe things we talked about earlier like LDN and mistletoe and colostrum and these soil extracts are digging up from the earth like Restore. A big part of it is, sure, a little bit of the glyphosate and the herbicide and the pesticide and the modern battle we’re fighting in an era where our food is compromised. But another big part of it is the way that our immune systems have been treated when we’re babies. Thomas: We’re babies. And it’s the lucky ones who can just use those things. It’s the unlucky ones who get all the really life-altering horrible situations that we have in literally epidemic levels, whether it’s MS, and ALS, and autism, and breast cancer at age 35 that was never seen before. So, if that’s the way we want to go, then we’ve got a perfect strategy for that right now. Ben: Yeah. And I guess I would close with this because a lot of people will ask me, “Well, what do you do, Ben, with your kids?” We did a lot of international travel with our kids. We got a couple of vaccines that if I could go back and do it again, as you and I discussed in our last podcast, I would probably use a lot more natural defense mechanisms like Thieves essential oil and vitamin D and all these other ways that you can support the immune system or fight off infection. But then, the other thing–I mean my kids, every morning, they’re taking, especially during cold and flu season where they’re surrounded by sick kids at school, they’re taking double the amount of vitamin D and K. They take glutathione with PQQ and coenzyme Q10 for mitochondrial support before they go off to school. We have chaga tea, vats of chaga tea in the refrigerator that the kids are drinking. Everybody in our house takes colostrum. If there’s any type of flu or immune system issue going around, we take a shot of Restore each time before we eat a meal. And all this might sound laborious. For us, it’s like taking a shower, brushing our teeth. These are the ways that we protect ourselves. And for me, and especially for my children, doing this rather than putting a bunch of metals and toxins into their body is a far superior approach. For those of you listening in who have questions, who have comments about this kind of stuff, I would recommend that you not only read Dr. Cowan’s book, “Vaccines, Autoimmunity, and the Changing Nature of Childhood Illness” because admittedly, we skim the surface of the gel matrix inside of the cell and also some of the politics and the science behind vaccinations and things like measles and smallpox. It’s a wonderful resource that I think anybody who has an immune system or children should own. So, I’m going to link to that one in the shownotes along with everything else that Dr. Cowan and I talked about and my previous three or four, I don’t remember, podcast episodes with him all over at BenGreenfieldFitness.com/autoimmunity. That’s BenGreenfieldFitness.com/autoimmunity. And, Dr. Cowan, I want to thank you again for coming on the show and for all this forward-thinking work that you’re doing. Thomas: Thank you, Ben. I just want to say again, I think I’ve said this before, but I so appreciate your thoughtfulness and your wonderful way that you ask questions and sort of process this because it makes it much easier for me. And believe me, not everybody can do that. Ben: Well, I mean I’ve said this before on shows but one of my favorite parts about my job is when the book from whatever, Victory Belt or Chelsea Green or any of this other kind of forward-thinking publishers show up at my doorstep because they know I want advanced copies. And I get to lay in bed at night and read them, and my wife gets sick of me just like–it sounds like this when I’m reading, “Oh-huh, huh. Interesting, huh. Hey, babe, listen to this.” And I underline everything. But the coolest part is as I’m sitting there reading the book, folding pages, underlining, and occasionally with the Kindle, dragging my finger across, I’m highlighting that once I assimilate all of those questions, I get to get a guy like you on the phone and actually pick your brain about the book that you wrote. That’s my favorite part about my job. So, yeah, it’s hopefully doing some people some amount of service. So, anyways, thanks for your time, man. I appreciate it. Thomas: Okay, Ben. Thank you. Ben: Alright, folks. I’m Ben Greenfield along with Dr. Thomas Cowan signing out. All the show notes are at BenGreenfieldFitness.com/autoimmunity. Have an amazing week.
Over the past fifty years, rates of autoimmunity and chronic disease have exploded.
Currently, 1 in 2.5 American children has an allergy, 1 in 11 has asthma, 1 in 13 has severe food allergies, and 1 in 36 has autism.
While some attribute this rise to increased awareness and diagnosis, my guest on today’s show, Thomas Cowan, MD, argues for a direct causal relationship to a corresponding increase in the number of vaccines American children typically receive – approximately 70 vaccine doses by age eighteen. The goal of these vaccines is precisely what we’re now seeing in such abundance among our chronically ill children: the provocation of immune response.
In his new book Vaccines, Autoimmunity, and the Changing Nature of Childhood Illness , Dr. Cowan looks at emerging evidence that certain childhood illnesses are actually protective of disease later in life; examines the role of fever, the gut, and cellular fluid in immune health; argues that vaccination is an ineffective (and harmful) attempt to shortcut a complex immune response; and asserts that the medical establishment has engaged in an authoritarian argument that robs parents of informed consent. His ultimate question, from the point of view of a doctor who has decades of experience treating countless children is…
…what are we really doing to children when we vaccinate them?
Dr. Cowan, MD, is a veteran family physician who has studied and written about many subjects in medicine, including nutrition, homeopathy, anthroposophical medicine, and herbal medicine. He is the author of Human Heart, Cosmic Heart: A Doctor’s Quest to Understand, Treat, and Prevent Cardiovascular Disease and the new book Vaccines, Autoimmunity, and the Changing Nature of Childhood Illness from Chelsea Green Publishing. He is also a founding board member of the Weston A. Price Foundation, and a frequent lecturer throughout the US and Canada. He’s also the same doctor I mentioned in this Joe Rogan episode when I talked about how your “heart is not a pump”.
During our discussion, you’ll discover:
-Dr. Cowan’s experience with a childhood friend with asthma, and how it turned him onto medicine…8:00 The child was teased by classmates. “How dare you be sick…” He was way out of the norm. Asthma is far more prevalent now than in the 60’s. Increasing number of adults with autoimmune issues. A large number of people diagnosed with autism become institutionalized.
-The story of William Coley’s Toxins…12:50 “Give me a medicine to produce a fever, and I can cure any disease.” –Hippocrates Coley was an oncology surgeon, specializing in osteosarcoma. Realized his conventional treatment of sarcoma (cancer) was not effective. Came upon a former patient who was scheduled to be treated for sarcoma. Wound up getting treated for erysipelas (induced fever); sarcoma went away and never returned. Experimented with induced fever treatment on his own patients. 40% were cured with this treatment. 40% mortality rate. Inducing fever was killing the cancer. Coley’s Toxins has been banned as a practice in the U.S. since the 1960’s. “When I’m treating someone for a condition whose symptoms include a fever…If we can cure that condition without alleviating the fever, I am preemptively pushing this individual away from cancer for the rest of their life.” –Dr. Thomas Cowan
-The two branches of the immune system…21:20 You get exposed to measles. Body is looking at infected cells. Mounts a white cell response: attack and digest infected cells and clear out of the body. Fever, rash, diarrhea. Basically what we call “being sick.” “Being sick” is not the virus; it’s your body rejecting the virus. If you inhibit the cell-mediated response, you can infect and even kill people. By eliminating the symptoms (fever, rash, diarrhea, etc.) you allow the virus to continue its attack on the immune system. Theory of vaccines: Purely antibody strategy. No cell-mediated immune system. Inject the virus along with aluminum, mercury, formaldehyde, etc. to force your body to produce antibodies. You end up with an accelerated antibody response. 2 problems with this strategy: You have zero possibility of developing lifelong immunity to a virus after it has passed. Every vaccine needs to have boosters. Just as susceptible as a newborn as an adult. Autoimmune disease is the situation of accelerated antibodies that are targeting your own tissues. Children who get chickenpox and measles have less major chronic disease later in life. CDC: Anyone born before 1956 is considered to be immune to measles.
-Why the way current science believes cells operate in the immune system is flawed…31:30 The central paradox of mammalian cells: How does a cell live in a sodium-rich environment, yet has a sodium-poor internal milieu. Balance of sodium and potassium “charges” the cell like a battery. Lose the charge, you have a dead cell. Each cell has a “pump” that balances the sodium and potassium. Two problems with this way of thinking: Cells are supposedly 70% water, but there’s no water in the human body. In order to create the supposed differential, a cell needs 40x the amount of energy a normal cell has just to run the “pump,” let alone its other normal functions. There’s not enough ATP available to be responsible for the proper distribution of sodium and potassium
-The real reason we get sick…42:50 The sequence: You feel good, then get a fever, then a bunch of snot, then you feel better. Your body is like a gel; then it gets corrupted by a virus. Your body heats up, softens the gel, gets rid of the virus, the waste of which ends up in your hanky. The gel hardens again and is immune to that disease. Introducing foreign substances as you find in vaccines weakens the immune system; you keep getting sick over and over; you experience inflammation.
-Dr. Cowan’s protocol for supporting the immune system based on the innate immune system response…48:40 Substances such as aluminum and formaldehyde interfere with the charge of the actual cells. A human being is an information communication device with the rest of the world; our “radios” are out of tune with vaccines. Adequate water, minerals, outside barefoot, adequate sunshine. Low hanging fruit to take care of before turning to vaccines.
-What we can do to reverse or overcome the effects of vaccinations if we’ve been vaccinated already…51:15 No one is beyond hope. Take it one step at a time. Create a “cellular gel restoration program.” You may need to experience the illness again. Let your body do its own house cleaning.
-The one pharmaceutical drug of which Dr. Cowan is an advocate, and why…53:45 Low doses of Naltrexone. Discovered as opiate receptor inhibitor. (OD on heroin.) When you block opiates, you block endorphins. You’re not a happy camper. Naltrexone tricks your body into making endorphins; makes a huge difference in people suffering from AI disease.
-How colostrum helps both children and adults with autoimmune issues…59:45 Stimulates healthy gut flora. Prevents leakage into the bloodstream.
-And MUCH more…

Read More…

Dexamethasone Intravitreal Implant (Ozurdex) for Long-Term Macular Edema after Epiretinal Membrane Peeling Surgery

<h1>Dexamethasone Intravitreal Implant (Ozurdex) for Long-Term Macular Edema after Epiretinal Membrane Peeling Surgery</h1>

Dexamethasone Intravitreal Implant (Ozurdex) for Long-Term Macular Edema after Epiretinal Membrane Peeling Surgery

Research Article Dexamethasone Intravitreal Implant (Ozurdex) for Long-Term Macular Edema after Epiretinal Membrane Peeling Surgery
1 Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan 2 Department of Ophthalmology, School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan 3 Department of Ophthalmology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Ophthalmology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung 81267, Taiwan
Correspondence should be addressed to Wen-Chuan Wu ;
Received 17 June 2018; Revised 7 November 2018; Accepted 15 November 2018; Published 10 December 2018
Academic Editor: Elad Moisseiev
Copyright © 2018 Yo-Chen Chang et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Purpose . To investigate the functional and anatomical outcome of the 0.7 mg dexamethasone (Ozurdex) intravitreal implant (IVD) in eyes with long-term macular edema after macular epiretinal membrane removal. Methods . We enrolled 40 eyes with persistent macular edema at least 12 months after epiretinal membrane removal. Twenty eyes in the IVD group received IVD and the other 20 eyes were in the control group. The main outcome measures were change in best-corrected visual acuity (BCVA) and central foveal thickness (CFT). Results . For eyes in the IVD group, the mean BCVA improved by 3.45 lines to 0.47 logMAR one month after IVD. However, the mean BCVA improved by only 0.14 lines to 0.74 logMAR at the same time in eyes in the control group. Six months later, the mean BCVA improved to 0.31 and 0.74 logMAR in the IVD and control groups, respectively. In the IVD group, the mean CFT decreased rapidly by 116.8  μ m to 333.9  μ m one month after IVD. Thereafter the CFT decreased at a slower pace. In the control group, the CFT remained static during the follow-up period. However, in the IVD group, 6 months after IVD, the CFT seemed to have a tendency to increase. Conclusions . Single IVD could significantly decrease macular edema and improve visual outcome for eyes with persistent long-term macular edema after macular ERM removal and the effect can be sustained as long as 6 months after the initial injection. However, in order to maintain the visual and anatomical outcome, repeat IVD might be considered if macular edema recurs. 1. Introduction
Idiopathic epiretinal membrane (ERM) is a degenerative disorder occurring in the vitreomacular interface that usually affects the central vision in the affected eye [ 1 ]. The manifestation of an ERM can range from asymptomatic to photopsia, metamorphopsia, macropsia or micropsia, decreased visual acuity (VA), and even central vision loss. In 1978, Dr. Machemer first described pars plana vitrectomy (PPV) with membrane peeling for ERM. Since then this surgery has become a well-established method for the removal of ERM with good results [ 2 ]. Surgical removal of the membrane in patients with significant symptoms can improve visual acuity and reduce metamorphopsia in approximately 70% of cases [ 3 – 5 ]. However, persistent residual intraretinal edema is sometimes still present, limiting the possibilities of complete visual function recovery [ 6 , 7 ]. From our previous study, stable vision is usually achieved approximately 9 months after PPV, and intravitreal injection of bevacizumab cannot further improve the final visual and anatomical outcome [ 8 ]. Therefore, vascular endothelial growth factor (VEGF) might play a minor role in the pathogenesis of persistent macular edema after ERM peeling. In addition to VEGF, inflammatory trauma by mechanical membrane peeling might be associated with postoperative macular edema [ 9 , 10 ]. To further reduce macular edema, intravitreal injection of triamcinolone acetonide (IVTA) after the removal of the ERM has been shown to facilitate fluid absorption and may speed up improvement of the anatomic and functional outcome in short-term follow-up [ 11 ]. The possible reason for the short-term effect of intraoperative IVTA might be explained by the relatively rapid clearance in vitrectomized eyes, which may abate its effect for macular edema [ 12 , 13 ]. Therefore, there may be a rationale for using a sustained-release device to improve this condition. The dexamethasone intravitreal implant (IVD) (Ozurdex; Allergan, Irvine, CA) provides a slow release and stable dose of steroid [ 14 ]. IVD has been widely used for treating noninfectious posterior uveitis, macular edema secondary to retinal vascular occlusion (RVO), diabetic macular edema (DME), and cystoid ME (CME) after cataract surgery [ 15 – 17 ]. Therefore, in our present study, we tried to determine the efficacy of the 0.7 mg dexamethasone intravitreal implant to treat long-term persistent macular edema (no tendency to resolve at least 12 months after surgery) after removal of idiopathic ERM. 2. Patients and Methods
This is a retrospective, nonrandomized study including patients who were diagnosed with idiopathic ERM between January 2014 and June 2015. This study followed the tenets of the Declaration of Helsinki in 1964. All operations were performed by the same physician (W. C. W.) who is a retinal specialist experienced in vitreoretinal and cataract surgery as well as intravitreal injection. The surgical procedure and postoperative medication were using the methods as described previously [ 8 ]. All patients previously underwent standard three-port transconjunctival 25-gauge PPV assisted with triamcinolone for membrane peeling and indocyanine green (ICG) for internal limiting membrane (ILM) peeling using high-magnification viewing lens and intraocular forceps. PVD was induced with active suction of ocutome over the optic disc if the PVD was not already present. Concomitant cataract surgery was performed on phakic patients. At the end of surgery, all patients received a subconjunctival injection of 2 mg Rinderon (betamethasone 4 mg/mL). After surgery, Tobradex eye drops (0.3% tobramycin and 0.1% dexamethasone) 4 times daily, Acular eye drops (ketorolac 0.4%) 3 times daily, and Mydriacyl (0.5% tropicamide) 3 times daily were administered to all patients for 2 weeks. Then, the Tobradex eye drops were switched with Sinomin eye drops (4% sulfamethoxazole) and 0.1% fluorometholone 4 times daily during the follow-up period. In addition, Acular eye drops (ketorolac 0.4%) three times daily were prescribed for patients who had macular edema during the follow-up period. There were no significant complications such as rupture of posterior capsule, retinal detachment, iatrogenic macular hole, postoperative vitreous hemorrhage, or endophthalmitis that affected visual outcome during or after surgery.
At least twelve months after PPV, patients who met the following criteria were selected for intravitreal injection of dexamethasone (IVD) treatment: (1) presence of macular edema ≥300  μ m as detected by optical coherence tomography (OCT) and (2) best-corrected visual acuity (BCVA) of 20/40 or less after surgery [ 8 ].
Patients with preexisting ocular diseases (i.e., chronic inflammatory or neoplastic disorders, retinal vascular occlusion glaucoma, or high myopia) were excluded, as well as those with systemic diseases (uncontrolled hypertension or diabetes).
After a complete discussion of the benefits, risks, and alternative treatment, the decision to treat with IVD was made by the eligible patients themselves. If the patient decided to proceed with IVD, a consent form had to be signed by the patient before treatment. In the IVD group, each patient received an intravitreal injection of the 0.7 mg dexamethasone intravitreal implant at least 12 months after PPV. Postoperatively, gentamycin eye drops were administered 4 times daily for 1 week. Meanwhile, those eligible patients who refused IVD were enrolled in the control group.
In order to compare the parameters between the IVD group and the control group, we defined “baseline” as the time point of (1) receiving IVD that was at least 12 months after PPV for patients in the IVD group and (2) the patient deciding not to receive IVD (at least 12 months after PPV for patients in the control group). The treated patients in the IVD group were seen at 1 week after baseline for check-up of injection wound and intraocular pressure. To evaluate the effects and safety of treatment, all recruited patients in both groups underwent comprehensive ophthalmic examinations including visual acuity by Snellen charts, slit-lamp biomicroscopy, Goldmann applanation tonometry, and ophthalmoscopy at 1, 2, 3, and 6 months after baseline. Measurements of macular thickness were performed using the spectral-domain-OCT (SD-OCT [Heidelberg Retina Angiograph 2, Heidelberg Engineering, Heidelberg, Germany]). In all measurements, the central foveal thickness (CFT) was assessed within a 1 mm diameter circle in the central macula. For better comparison of visual acuity between the groups, the visual acuity by Snellen chart was converted to the logarithm of the minimum angle of resolution (logMAR) at baseline and each follow-up visit. 2.1. Statistical Analysis
All data were statistically analyzed by Student’s t -test or the χ 2 test using SPSS statistical software (version 24.0; SPSS Inc., Chicago, Ill., USA). A value of <0.05 was considered statistically significant. 3. Results 3.1. Baseline Demographic Data
During the period of one and half years, we reviewed a total of 400 eyes of 360 patients with idiopathic ERM who underwent PPV and ERM peeling (Table 1 ). There were 40 eyes of 40 patients who met the inclusion criteria. Table 1 shows the baseline demographics of these 40 patients. Both the IVD group and the control group consisted of twenty eyes. Patients in both groups were followed-up for at least 12 months after baseline. The mean interval from PPV to IVD was 58.8 ± 4.0 weeks (range: 53 to 66 weeks) in the IVD group and the mean interval from PPV to baseline was 57.7 ± 4.0 weeks (range: 52 to 66 weeks). The mean BCVA before PPV was 0.81 ± 0.30 in the IVD group and 0.75 ± 0.38 logMAR in the control group. Combined phacoemulsification with intraocular lens implantation, PPV, and membrane peeling were performed for 8 eyes in the IVD group and 10 eyes in the control group. The remaining 12 pseudophakic eyes in the IVD group and 10 pseudophakic eyes in the control group received PPV and membrane peeling only. At baseline, the SD-OCT measured mean CFT was 450.7 ± 72.4  μ m in the IVD group and 466.2 ± 82.8  μ m in the control group. Table 1: Patient demographics at baseline. 3.2. Temporal Change of CFT
All patients in the IVD group received single IVD. Compared to baseline, the mean CFT at 1 month after IVD decreased rapidly by 116.8 ± 49.7 to 333.9 ± 50.9  μ m for the IVD group and by only −1.3 ± 10.6 to 464.9 ± 76.8  μ m for the control group ( between the IVD and control groups) (Figure 1 ). Thereafter, the CFT in the IVD group decreased at a slower rate. The CFT in the control group remained static during the follow-up period. At 6 months, the mean CFT decreased by 110.7 ± 54.1 to 340.0 ± 53.1  μ m for the IVD group and by only 0.85 ± 8.2 to 467.0 ± 79.8  μ m for the control group ( between the IVD and control groups). The mean reduction in CFT differed significantly between the IVD and control groups at 1, 2, 3, and 6 months after baseline ( ). However, 6 months after baseline, the CFT in the IVD group seemed to have a tendency to increase. For eyes that received combined surgery (8 eyes in the IVD group and 10 eyes in the control group), the mean CFT in the IVD group improved from 442.3 ± 40.6  μ m at baseline to 343.0 ± 59.2  μ m at 6 months ( ). However, the mean CFT in the control group was 478.2 ± 97.8 at baseline and 480.5 ± 93.0 at 6 months ( ). Preoperative pseudophakic eyes that received PPV and membrane peeling (12 eyes in the IVD group and 10 eyes in the control group), the mean CFT in the IVD group improved from 456.1 ± 89.0  μ m at baseline to 337.9 ± 51.2  μ m at 6 months ( ). However, the mean CFT in the control group was 454.1 ± 67.8 at baseline and 453.5 ± 66.2 at 6 months ( ). Figure 1: Temporal change of central foveal thickness (CFT) after IVD. Compared to baseline, the mean CFT at 1 month after IVD decreased rapidly by 116.8 ± 49.7 to 333.9 ± 50.9  μ m for the treatment group and by only −1.3 ± 10.6 to 464.9 ± 76.8  μ m for the control group ( between the IVD and control groups). Thereafter, the CFT in the IVD group decreased at a slower rate. The CFT in the control group remained static during the follow-up period. At 6 months, the mean CFT decreased by 110.7 ± 54.1 to 340.0 ± 53.1  μ m for the treatment group and by only 0.85 ± 8.2 to 467.0 ± 79.8  μ m for the control group ( between the IVD and control groups). compared to baseline. 3.3. Temporal Change of Visual Acuity
At baseline, the mean BCVA was 0.81 ± 0.30 and 0.75 ± 0.38 logMAR in the IVD and control groups, respectively ( ) (Figure 2 ). In the IVD group, the BCVA improved significantly after baseline. At 1 month, the mean BCVA had increased dramatically by 3.45 ± 2.29 and only 0.14 ± 0.66 lines from baseline in the IVD and control groups, respectively ( ). Thereafter, the BCVA in the IVD group continued to improve at a slower rate compared to stable BCVA in the control group. At 6 months, the mean BCVA had increased by 5.0 ± 2.77 lines to 0.31 ± 0.22 logMAR and only 0.14 ± 0.66 lines to 0.74 ± 0.36 logMAR from baseline in the treatment and control groups, respectively ( ). After baseline, the logMAR BCVAs and line improvement were significantly better in the IVD group than in the control group and differed significantly at each follow-up. For eyes that received combined surgery (8 eyes in the IVD group and 10 eyes in the control group), the mean BCVA in the IVD group improved from 0.74 ± 0.27 logMAR at baseline to 0.23 ± 0.22 logMAR at 6 months ( ). However, the mean BCVA in the control group was 0.70 ± 0.27 at baseline and 0.68 ± 0.24 at 6 months ( ). For preoperative pseudophakic eyes that received PPV and membrane peeling (12 eyes in the IVD group and 10 eyes in the control group), the mean BCVA in the IVD group improved from 0.86 ± 0.31 logMAR at baseline to 0.36 ± 0.22 logMAR at 6 months ( ). However, the mean BCVA in the control group was 0.80 ± 0.47 at baseline and 0.79 ± 0.46 at 6 months ( ). Figure 2: Temporal change of BCVA by line and mean BCVA after IVD. At 1 month after IVD, the mean BCVA had improved dramatically by 3.45 ± 2.29 and only 0.14 ± 0.66 lines from baseline in the IVD and control groups, respectively ( , IVD vs. control). Thereafter, the BCVA in the IVD group continued to improve at a slower rate compared to stable BCVA in the control group. At 6 months after IVD, the mean BCVA had increased by 5.0 ± 2.77 lines to 0.31 ± 0.22 logMAR and only 0.14 ± 0.66 lines to 0.74 ± 0.36 logMAR from baseline in the IVD and control groups, respectively ( ). The logMAR BCVAs and line improvement differed significantly at 1, 2, 3, and 6 months after treatment between the two groups. compared to baseline. 3.4. Intraocular Pressure
In the IVD group, three patients (15%) experienced IOP elevations of 10 mm Hg or more from baseline at 1 month postoperatively. These three patients receiving single topical anti-glaucoma medication and no IOP elevation were noted at the 2-, 3-, or 6-month follow-up visits. No new IOP-lowering medication was required in any patients at the time of the latest follow-up. In the control group, none of the patients experienced IOP elevations of 10 mm Hg or more from baseline at any follow-up visit. 3.5. Case Presentation
Figure 3 represents OCT images of the pre- and postoperative course of the eye that suffered from long-term persistent macular edema after ERM and ILM peeling. The preoperative OCT image showed prominent ERM overlying the macular surface, the CFT was 436  μ m and the BCVA was 20/100 (Figure 3(a) ). Thirteen months after operation, no ERM was noted, but the BCVA was still 20/100 with the CFT of 449  μ m (Figure 3(b) ). One month after IVD, the CFT decreased to 350  μ m and the BCVA improved to 20/30 (Figure 3(c) ). Three months after IVD, the CFT further decreased to 290  μ m and the BCVA improved to 20/22 (Figure 3(d) ). Six months after IVD, the CFT was 306  μ m and the BCVA maintained at 20/22 (Figure 3(e) ). Figure 4 represents OCT images of the pre- and postoperative course of the eye that suffered from more long-term persistent macular edema after ERM and ILM peeling. The preoperative OCT image showed prominent ERM overlying the macular surface, the CFT was 656  μ m and the BCVA was 20/400 (Figure 4(a) ).Thirty-six months after operation, no ERM was noted, but the BCVA only improved to 20/200 with the CFT of 422  μ m (Figure 4(b) ). One month after IVD, the CFT decreased to 407  μ m and the BCVA improved to 20/22 (Figure 4(c) ). Three months after IVD, the CFT slightly decreased to 398  μ m and the BCVA maintained at 20/22 (Figure 4(d) ). Six months after IVD, the CFT was 385  μ m and the BCVA further improved to 20/20 (Figure 4(e) ). Figure 3: Pre- and postoperative OCT findings in a patient with long-term persistent macular edema after membrane peeling and internal limiting membrane peeling. Preoperative image shows an ERM overlying the macula. The CFT and BCVA were 436  μ m and 20/100, respectively (a). Thirteen months after operation, no ERM or ILM was noted but the BCVA was still 20/100 with the CFT of 449  μ m (b). At one month after IVD, the CFT decreased to 350  μ m and the BCVA improved to 20/30 (c). At three months after IVD, the CFT decreased to 290  μ m and the BCVA improved to 20/22 (d). Six months after IVD, the CFT was 306  μ m and the BCVA maintained at 20/22 (e). Figure 4: Pre- and postoperative OCT findings in a patient with more long-term persistent macular edema after membrane peeling and internal limiting membrane peeling. The preoperative OCT image showed prominent ERM overlying the macular surface, the CFT was 656  μ m and the BCVA was 20/400 (a). Thirty-six months after operation, no ERM was noted, but the BCVA had only improved to 20/200 with the CFT of 422  μ m (b). One month after IVD, the CFT decreased to 407  μ m and the BCVA improved to 20/22 (c). Three months after IVD, the CFT slightly decreased to 398  μ m and the BCVA maintained at 20/22 (d). Six months after IVD, the CFT was 385  μ m and the BCVA further improved to 20/20 (e). 4. Discussion
Pars plana vitrectomy with membrane peeling is a useful technique for patients with symptomatic ERM, and most patients will have a favorable outcome [ 2 – 6 ]. However, visual recovery may take several months to as long as 1 year as the retinal morphology normalizes slowly [ 8 , 18 ]. However, persistent residual intraretinal edema is sometimes still present, limiting the possibility of a complete visual function recovery [ 6 , 7 ]. To date, the mechanism of macular edema in idiopathic ERM has not been fully studied. Ahn et al. hypothesized that the thickening macula in eyes with ERM might be due to traction-induced distortion of the neurosensory retina or macular edema from breakdown of the blood-retinal barrier [ 19 ]. Mandelcorn et al. demonstrated that positive immunostain for VEGF and transforming growth factor-beta (TGF-beta2) were present in 85% of idiopathic ERM specimens [ 20 ]. However, in our previous study, for patients with persistent macular edema after ERM peeling, there were no significant differences of final visual and anatomical outcome between patients with or without bevacizumab injection [ 8 ]. Therefore, bevacizumab might somewhat reduce macular edema by acting as an anti-VEGF agent which is believed to play a minor role in the pathogenesis of postoperative macular thickening [ 11 ].
Harada et al. hypothesized that the release of inflammatory cytokines and growth factors may contribute to ERM proliferation as well as accompanying macular edema in many cases [ 21 ]. Vinores et al. suggested that postoperative macular edema is in part due to breakdown of the blood-retinal barrier, then release of inflammatory cytokines from preoperative mechanical traction, and intraoperative manipulation [ 22 ]. Corticosteroids are very potent anti-inflammatory agents that can block several pathological processes which are thought to be involved in the development of macular edema in several ways: inhibiting the synthesis of VEGF, prostaglandins, and many proinflammatory cytokines, reducing fibrin deposition, preventing leukocyte migration, and stabilizing endothelial cell tight junctions [ 23 ]. However, the type of corticosteroid and administrating route may affect the efficacy to specific diseases. Systemic corticosteroids might cause certain adverse events such as adrenal suppression, Cushingoid state, osteoporosis, and exacerbation of diabetes [ 24 – 27 ]. Topical or local administration usually leads to a suboptimal drug level in the vitreous and may be associated with relatively high systemic concentrations [ 28 – 30 ]. Therefore, direct intravitreal injection of corticosteroids seems to be the better way to achieve optimal drug level in the vitreous.
Dexamethasone is the most water-soluble and also a potent synthetic glucocorticoid. The anti-inflammatory and immunosuppressant activity of dexamethasone is 30 times more than cortisol [ 31 ] and 12.5 times more than triamcinolone [ 32 ]. In addition, the half-life of dexamethasone is the shortest among other steroids and is less likely to aggregate in the trabecular meshwork and therefore cause elevation of intraocular pressure [ 33 ].
The reason for corticosteroids being effective treatment for long-term persistent macular edema after ERM and ILM peeling in the present study remains unclear. The possible explanation may be due to the effects on Müller cells during ERM and ILM peeling. Müller cells, the major type of glial cells in the retina, are responsible for the homeostatic and metabolic support of retinal neurons. While their cell bodies are located in the inner nuclear layer of the retina, they span across the entire retina [ 34 ]. They have been further identified as fundamental to the transmission of light through the vertebrate retina due to their unique funnel shape [ 35 ]. Under certain conditions, a subset of Müller cells may differentiate to neural progenitor/stem cells which regenerate lost photoreceptors and neurons [ 36 ]. During ILM peeling, the Müller cell footplates which build up the outer portions of the ILM might suffer from mechanical damage [ 37 ]. The initial mechanical damage of the retinal surface might be associated with secondary biochemical pathways involving different cytokines and growth factors, which may contribute to the development of diffuse retinal thickening visible on SD-OCT. Therefore, corticosteroids may be able to antagonize the secondary inflammatory effects triggered by the mechanical distortion and thus accelerate the resolution of macular edema, helping the restoration of physiologic function of Müller cells and therefore improving visual function.
From literature review, there were several reports with inconsistent results regarding the effect of the 0.7 mg dexamethasone intravitreal implant of macular edema after ERM peeling surgery [ 38 – 42 ]. Furino et al. reported a single injection of the 0.7 mg dexamethasone intravitreal implant was effective in the treatment of at least 2 months duration of macular edema secondary to combined cataract extraction and vitrectomy for macular pucker removal allowing a stable visual acuity recovery in a small retrospective series of 8 eyes [ 38 ]. Taney et al. reported that four of five eyes showed reduction in macular thickness and visual acuity improved by one or more Snellen lines after dexamethasone intravitreal implant in a small retrospective series of 5 eyes suffering from persistent macular edema after vitrectomy for ERM [ 39 ]. However, both studies were limited by a relatively small sample size and lack of control group. Yonekawa et al. reported that both dexamethasone intravitreal implant and triamcinolone acetonide are effective in improving central macular thickness and visual acuity while the intraoperative dexamethasone intravitreal implant or triamcinolone acetonide is used after vitrectomy and membrane peeling [ 40 ]. However, recently, Guidi et al. reported that the intraoperative sustained-release dexamethasone implant did not result in a significant change in macular thickness and volume compared with the vitrectomy alone without dexamethasone implant at 6-month follow-up [ 42 ]. The possible explanation for their negative results may be due to the timing of intervention. According to our previous study, for patients with idiopathic ERM, stable vision is usually achieved approximately 9 months after PPV and membrane peeling [ 8 ]. Therefore, it is reasonable to hold the IVD until the macular thickening persists at least 9 months postoperatively.
In our present study, compared to patients in the control group, in patients with long-term persistent macular edema after ERM peeling surgery, IVD can both significantly reduce CFT and improve visual acuity after injection, and the effect can last as long as 6 months. There were three patients (15%) among the IVD group experiencing IOP elevations of 10 mm Hg or more from baseline at 1 month postoperatively. The IOP in these 3 patients can be well-controlled by single topical anti-glaucoma medication and no new IOP-lowering medication was required in any patients at the time of latest follow-up.
In summary, the present study showed a single injection of the 0.7 mg dexamethasone intravitreal implant may be effective to improve visual function of patients with long-term (longer than 12 months) persistent macular edema secondary to vitrectomy with membrane and ILM peeling for idiopathic ERM. However, there are some limitations of this study including its retrospective nature and relatively small number of patients. Therefore, these results need to be confirmed by a large prospective and randomized trial. Data Availability
The data used to support the findings of this study are available from the corresponding author upon request. Conflicts of Interest
None of the authors have proprietary interest in any material used in this study. Acknowledgments
The authors are grateful for the assistance from the Statistical Analysis Laboratory, Department of Medical Research, Kaohsiung Medical University Hospital. References T. M. Johnson and M. W. Johnson, “Epiretinal membrane,” in Ophthalmology , M. Yanoff and J. S. Duker, Eds., pp. 686-687, Elsevier, Netherlands, 3rd edition, 2004. View at Google Scholar R. Machemer, “The surgical removal of epiretinal macular membranes,” Klinische Monatsblätter für Augenheilkunde , vol. 173, no. 1, pp. 36–42, 1973. View at Google Scholar R. R. Margherio, M. S. Cox Jr, M. T. Trese, P. L. Murphy, J. Johnson, and L. A. Minor, “Removal of epimacular membranes,” Ophthalmology , vol. 92, no. 8, pp. 1075–1083, 1985. View at Publisher · View at Google Scholar · View at Scopus S. de Bustros, J. T. Thompson, R. G. Michels, T. A. Rice, and B. M. Glaser, “Vitrectomy for idiopathic epiretinal membranes causing macular pucker,” British Journal of Ophthalmology , vol. 72, no. 9, pp. 692–695, 1988. View at Publisher · View at Google Scholar · View at Scopus P.-Y. Lee, K.-C. Cheng, and W.-C. Wu, “Anatomic and functional outcome after surgical removal of idiopathic macular epiretinal membrane,” Kaohsiung Journal of Medical Sciences , vol. 27, no. 7, pp. 268–275, 2011. View at Publisher · View at Google Scholar · View at Scopus C. Carpentier, M. Zanolli, L. Wu et al., “Residual internal limiting membrane after epiretinal membrane peeling,” Retina , vol. 33, no. 10, pp. 2026–2031, 2013. View at Publisher · View at Google Scholar · View at Scopus M. García-Fernández, J. Castro Navarro, C. González Castaño, A. García Alonso, and M. Fonollá Gil, “Cirugía de las membranas epirretinianas: resultados anatómicos y funcionales,” Archivos de la Sociedad Española de Oftalmología , vol. 88, no. 4, pp. 139–144, 2013. View at Publisher · View at Google Scholar Y.-C. Chang, C.-C. Lin, and W.-C. Wu, “Long-term anatomical and functional outcome of three intravitreal bevacizumab injections for persistent macular edema after idiopathic macular epiretinal membrane peeling,” Ophthalmologica Extra , vol. 1, no. 1, pp. 1–8, 2014. View at Publisher · View at Google Scholar C. J. J. Brinkman, A. J. Otto, and A. C. Breebaart, “Ocular inflammatory activity following different techniques of lens extraction and vitrectomy in rabbits,” Current Eye Research , vol. 9, no. 12, pp. 1137–1140, 2009. View at Publisher · View at Google Scholar · View at Scopus K. Huang, G. A. Peyman, J. McGetrick, and R. Janevicius, “Indomethacin inhibition of prostaglandin-mediated inflammation following intraocular surgery,” Investigative Ophthalmology and Visual Science , vol. 16, no. 18, pp. 760–762, 1977. View at Google Scholar L. Konstantinidis, M. Berguiga, E. Beknazar, and T. J. Wolfensberger, “Anatomic and functional outcome after 23-gauge vitrectomy, peeling, and intravitreal triamcinolone for idiopathic macular epiretinal membrane,” Retina , vol. 29, no. 18, pp. 1119–1127, 2009. View at Publisher · View at Google Scholar · View at Scopus R. H. Schindler, D. Chandler, R. Thresher, and R. Machemer, “The clearance of intravitreal triamcinolone acetonide,” American Journal of Ophthalmology , vol. 93, no. 4, pp. 415–417, 1982. View at Publisher · View at Google Scholar · View at Scopus H.-S. Chin, T.-S. Park, Y.-S. Moon, and J.-H. Oh, “Difference in clearance of intravitreal triamcinolone acetonide between vitrectomized and nonvitrectomized eyes,” Retina , vol. 25, no. 5, pp. 556–560, 2005. View at Publisher · View at Google Scholar · View at Scopus Y. Yonekawa and J. D. Wolfe, “Dexamethasone intravitreal implant: pharmacology and clinical update,” Retina Today , vol. 10, no. 9, pp. 54–58, 2015. View at Google Scholar S. T. Alshahrani, R. Dolz-Marco, R. Gallego-Pinazo, M. Diaz-Llopis, and J. F. Arevalo, “Intravitreal dexamethasone implant for the treatment of refractory macular edema in retinal vascular diseases,” Retina , vol. 36, no. 1, pp. 131–136, 2016. View at Publisher · View at Google Scholar · View at Scopus I. Zucchiatti, R. Lattanzio, G. Querques et al., “Intravitreal dexamethasone implant in patients with persistent diabetic macular edema,” Ophthalmologica , vol. 228, no. 2, pp. 117–122, 2012. View at Publisher · View at Google Scholar · View at Scopus D. Bellocq, J.-F. Korobelnik, C. Burillon et al., “Effectiveness and safety of dexamethasone implants for post-surgical macular oedema including Irvine-Gass syndrome: the EPISODIC study,” British Journal of Ophthalmology , vol. 99, no. 7, pp. 979–983, 2015. View at Publisher · View at Google Scholar · View at Scopus J. Kim, K. M. Rhee, S. J. Woo, Y. S. Yu, H. Chung, and K. H. Park, “Long-term temporal changes of macular thickness and visual outcome after vitrectomy for idiopathic epiretinal membrane,” American Journal of Ophthalmology , vol. 150, no. 5, pp. 701–709, 2010. View at Publisher · View at Google Scholar · View at Scopus J.-H. Ahn, H.-J. Park, J.-E. Lee, and B.-S. Oum, “Effect of intravitreal triamcinolone injection during vitrectomy for idiopathic epiretinal membrane,” Retina , vol. 32, no. 5, pp. 892–896, 2012. View at Publisher · View at Google Scholar · View at Scopus E. Mandelcorn, Y. Khan, L. Javorska, J. Cohen, D. Howarth, and M. Mandelcorn, “Idiopathic epiretinal membranes: cell type, growth factor expression, and fluorescein angiographic and retinal photographic correlations,” Canadian Journal of Ophthalmology , vol. 38, no. 6, pp. 457–463, 2003. View at Publisher · View at Google Scholar · View at Scopus C. Harada, Y. Mitamura, and T. Harada, “The role of cytokines and trophic factors in epiretinal membranes: involvement of signal transduction in glial cells,” Progress in Retinal and Eye Research , vol. 25, no. 2, pp. 149–164, 2006. View at Publisher · View at Google Scholar · View at Scopus S. A. Vinores, A. Amin, N. L. Derevjanik, W. R. Green, and P. A. Campochiaro, “Immunohistochemical localization of blood-retinal barrier breakdown sites associated with post-surgical macular oedema,” Histochemical Journal , vol. 26, no. 8, pp. 655–665, 1994. View at Publisher · View at Google Scholar · View at Scopus I. H. Leopold, “Nonsteroidal and steroidal anti-inflammatory agents,” in Surgical Pharmacology of the Eye , M. L. Sears and A. Tarkkanen, Eds., pp. 83–133, Raven, Norris, MT, USA, 1985. View at Google Scholar G. Pagano, A. Bruno, P. Cavallo-Perin, L. Cesco, and B. Imbimbo, “Glucose intolerance after short-term administration of corticosteroids in healthy subjects. Prednisone, deflazacort, and betamethasone,” Archives of Internal Medicine , vol. 149, no. 5, pp. 1098–1101, 1989. View at Publisher · View at Google Scholar B. H. B. Robinson, D. Mattingly, and C. L. Cope, “Adrenal function after prolonged corticosteroid therapy,” Bmj , vol. 1, no. 5292, pp. 1579–1584, 1962. View at Publisher · View at Google Scholar · View at Scopus K. G. Saag, “Glucocorticoid-induced osteoporosis,” Endocrinology and Metabolism Clinics of North America , vol. 32, no. 1, pp. 135–157, 2003. View at Publisher · View at Google Scholar · View at Scopus R. M. Stanbury and E. M. Graham, “Systemic corticosteroid therapy—side effects and their management,” British Journal of Ophthalmology , vol. 82, no. 6, pp. 704–708, 1998. View at Publisher · View at Google Scholar · View at Scopus O. Weijtens, F. A. Van Der Sluijs, R. C. Schoemaker et al., “Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection,” American Journal of Ophthalmology , vol. 123, no. 3, pp. 358–363, 1997. View at Publisher · View at Google Scholar · View at Scopus O. Weijtens, E. J. Feron, R. C. Schoemaker et al., “High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection,” American Journal of Ophthalmology , vol. 128, no. 2, pp. 192–197, 1999. View at Publisher · View at Google Scholar · View at Scopus O. Weijtens, R. C. Schoemaker, F. P. H. T. M. Romijn, A. F. Cohen, E. G. W. M. Lentjes, and J. C. van Meurs, “Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate,” Ophthalmology , vol. 109, no. 10, pp. 1887–1891, 2002. View at Publisher · View at Google Scholar · View at Scopus B. Katzung, S. Masters, and A. Trevor, “Adrenocorticosteroids and adrenocortical antagonists,” in Basic and Clinical Pharmacology , pp. 592–607, Appleton & Lange, New York City, NY, USA, 12th edition, 1995. View at Google Scholar B. D. Kuppermann, L. C. Zacharias, and M. C. Kenney, “Steroid differentiation: the safety profile of various steroids on retinal cells in vitro and their implications for clinical use (an American Ophthalmological Society thesis),” Transactions of the American Ophthalmological Society , vol. 112, pp. 116–141, 2014. View at Google Scholar A. Thakur, R. Kadam, and U. B. Kompella, “Trabecular meshwork and lens partitioning of corticosteroids,” Archives of Ophthalmology , vol. 129, no. 7, pp. 914–920, 2011. View at Publisher · View at Google Scholar · View at Scopus D. Goldman, “Müller glial cell reprogramming and retina regeneration,” Nature Reviews Neuroscience , vol. 15, no. 7, pp. 431–442, 2014. View at Publisher · View at Google Scholar · View at Scopus K. Franze, J. Grosche, S. N. Skatchkov et al., “Muller cells are living optical fibers in the vertebrate retina,” Proceedings of the National Academy of Sciences , vol. 104, no. 20, pp. 8287–8292, 2007. View at Publisher · View at Google Scholar · View at Scopus A. Reichenbach and A. Bringmann, “New functions of Müller cells,” Glia , vol. 61, no. 5, pp. 651–678, 2013. View at Publisher · View at Google Scholar · View at Scopus E. Yamda, “Some structural features of the fovea centralis in the human retina,” Archives of Ophthalmology , vol. 82, no. 2, pp. 151–159, 1969. View at Google Scholar C. Furino, F. Boscia, N. Recchimurzo, C. Sborgia, and G. Alessio, “Intravitreal dexamethasone implant for refractory macular edema secondary to vitrectomy for macular pucker,” Retina , vol. 34, no. 8, pp. 1612–1616, 2014. View at Publisher · View at Google Scholar · View at Scopus L. S. Taney, C. R. Baumal, and J. S. Duker, “Sustained-release dexamethasone intravitreal implant for persistent macular edema after vitrectomy for epiretinal membrane,” Ophthalmic Surgery, Lasers and Imaging Retina , vol. 46, no. 2, pp. 224–228, 2015. View at Publisher · View at Google Scholar · View at Scopus Y. Yonekawa, D. A. Mammo, B. J. Thomas, J. D. Wolfe, and T. S. Hassan, “A comparison of intraoperative dexamethasone intravitreal implant and triamcinolone acetonide used during vitrectomy and epiretinal membrane peeling: a case control study,” Ophthalmic Surgery, Lasers and Imaging Retina , vol. 47, no. 3, pp. 232–237, 2016. View at Publisher · View at Google Scholar · View at Scopus L.-O. Hattenbach, C. Springer-Wanner, H. Hoerauf et al., “Intravitreal sustained-release steroid implants for the treatment of macular edema following surgical removal of epiretinal membranes,” Ophthalmologica , vol. 237, no. 4, pp. 232–237, 2017. View at Publisher · View at Google Scholar · View at Scopus G. Guidi, G. Casini, G. Ripandelli et al., “Residual intraretinal edema after 25-gauge vitrectomy and macular pucker removal: is intraoperative sustained-release dexamethasone a real treatment option?” Retina , vol. 38, no. 5, 2018. View at Publisher · View at Google Scholar · View at Scopus Follow Us

Read More…

So I was recently diagnosed with crohns And coliti

<h1>So I was recently diagnosed with crohns And coliti</h1>

So I was recently diagnosed with crohns And coliti

So I was recently diagnosed with crohns And colitis this year around August and I did a course of steroids prednisone, Ad-cal and Pentasa right after my camera and everything seemed to be going fine until I finished the course and was just taking two Pentasa a day. So on my follow up appointment I explain to them I was still getting pains, cramps and feeling like my stomachs full of air and bloated, but I never have an urge to just go and run to the toilet.
anyways I’ve been told and advised to take Azathioprine, because my inflammation is moderate to severe and if I don’t consider this I run the risk of a major operation or bowel cancer but I’m extremely worried about the side effect, cancer risk and everything else that goes with Azathioprine, I’ve been given 8 weeks to think because my blood tests will come back to say if I’m fit to do so, but ultimately I’m just here to see and ask if anyone has had any good or bad experiences with it.

Read More…