Alopecia Areata

Alopecia Areata

Psychiatric disorders – Anxiety, personality disorders, depression, and paranoid disorders
Stressful life events inthe 6 months before onset
Alopecia areata canbe classified according to its pattern, as follows:
Reticular – Hair loss ismore extensive andthe patches coalesce
Ophiasis – Hair loss is localized tothe sides and lower backofthe scalp
Sisaipho (ophiasis spelled backwards) – Hair loss spares the sides andbackofthe head
Alopecia totalis – 100% hair loss onthe scalp
Alopecia universalis – Complete loss of hair onall hair-bearing areas
Nail involvement, predominantly ofthe fingernails, isfoundin 6.8-49.4% of patients, most commonly in severe cases. Pitting isthemost common; other reported abnormalities have included trachyonychia, Beau lines, onychorrhexis, onychomadesis, koilonychias, leukonychia, and red lunulae
See Clinical Presentation formore detail.
Diagnosis usually canbemadeon clinical grounds. A scalp biopsy seldom is needed, butitcanbe helpful whenthe clinical diagnosis is less certain.
See Workup formore detail.
Treatment isnot mandatory, becausethe condition is benign, and spontaneous remissions and recurrences are common. Treatment canbe topical or systemic. [ 1 ]
Corticosteroids
Intralesional corticosteroid therapy is usually recommended for alopecia areata with less than 50% involvement. Administration isas follows:
Injections are administered intradermally usinga 3-mL syringe anda 30-gauge needle
Triamcinolone acetonide (Kenalog) isusedmost commonly; concentrations vary from 2.5-10 mg/mL
The lowest concentration isusedonthe face
A concentration of 5 mg/mL is usually sufficient onthe scalp
Less than 0.1 mL is injected per site, and injections are spread outto cover the affected areas (approximately 1 cm between injection sites)
Injections are administered every 4-6 weeks
Topical corticosteroid therapy canbe useful, especially in children who cannot tolerate injections. It is administered as follows:
Fluocinolone acetonide cream 0.2% (Synalar HP) twice daily or betamethasone dipropionate cream 0.05% (Diprosone) hasbeen used
For refractory alopecia totalis or alopecia universalis, 2.5 g of clobetasol propionate under occlusion witha plastic film 6 days/wk for 6 months helped a minority of patients
Treatment must be continued fora minimum of 3 months before regrowth canbe expected, and maintenance therapy often is necessary
Systemic corticosteroids (ie, prednisone) arenotan agent of choice for alopecia areata becauseofthe adverse effects associated withboth short- and long-term treatment. Some patients may experience initial benefit, butthe dose needed to maintain cosmetic growth is usually so high that adverse effects are inevitable, andmost patients relapse after discontinuation of therapy.
Immunotherapy
Topical immunotherapy [ 2 ] is defined asthe induction and periodic elicitation ofan allergic contact dermatitis by topical application of potent contact allergens
Commonly used agents include squaric acid dibutylester (SADBE) and diphencyprone (DPCP) [ 3 ]
Anthralin
Both short-contact and overnight treatments havebeen used
Anthralin concentrations varied from 0.2-1%
Minoxidil
Minoxidil appears tobe effective inthe treatment of extensive disease (50-99% hair loss) butisoflittle benefit in alopecia totalis or alopecia universalis
The 5% solution appears tobemore effective
No morethan 25 drops are applied twice per day regardless ofthe extent ofthe affected area
Initial regrowth canbe seen within 12 weeks, but continued application is needed to achieve cosmetically acceptable regrowth
Psoralen plus UV-A
Both systemic and topical PUVA therapies havebeen used
20-40 treatments usually are sufficient inmost cases
Most patients relapse within afew months (mean, 4-8 months) after treatment is stopped
Other agents
Topical cyclosporine has shown limited efficacy
Topical tacrolimus
Methotrexate, withor without systemic corticosteroids, has shown mixed results [ 4 , 5 ]
Cosmetic treatment
Dermatography hasbeenusedto camouflage the eyebrows of patients with alopecia areata; on average, 2-3 sessions lasting 1 hour eachwere required foreach patient
Hairpieces are useful for patients with extensive disease
See Treatment and Medication formore detail.
Alopecia areata isa recurrent nonscarring type of hair loss thatcan affect any hair-bearing area. Clinically, alopecia areata can manifest manydifferent patterns. Although medically benign, alopecia areata can cause tremendous emotional and psychosocial distress in affected patients andtheir families.
The exact pathophysiology of alopecia areata remains unknown. The most widely accepted hypothesis isthat alopecia areata isa T-cell–mediated autoimmune condition thatismost likely to occur in genetically predisposed individuals. [ 6 ]
Much evidence supports the hypothesis that alopecia areata isan autoimmune condition. The process appears tobe T-cell mediated, but antibodies directed to hair follicle structures alsohavebeenfoundwith increased frequency in alopecia areata patients compared withcontrol subjects. Using immunofluorescence, antibodies to anagen-phase hair follicles werefoundinasmanyas 90% of patients with alopecia areata compared with less than 37% ofcontrol subjects. The autoantibody response is heterogeneous and targets multiple structures ofthe anagen-phase hair follicle. The outer root sheath isthe structure targeted most frequently, followed bythe inner root sheath, the matrix, andthe hair shaft. Whether these antibodies play a direct role inthe pathogenesis or whether theyarean epiphenomenon isnot known.
Histologically, lesional biopsy findings of alopecia areata show a perifollicular lymphocytic infiltrate around anagen-phase hair follicles. The infiltrate consists mostly of T-helper cells and, toa lesser extent, T-suppressor cells. CD4 + and CD8 + lymphocytes likely play a prominent role becausethe depletion ofthese T-cell subtypes resultsin complete or partial regrowth of hair inthe Dundee experimental bald rat (DEBR) model of alopecia areata. The animals subsequently lose hair again once the T-cell population is replete. The fact thatnotall animals experience complete regrowth suggests thatother mechanisms likely are involved. Total numbers of circulating T lymphocytes havebeen reported atboth decreased and normal levels.
Studies in humans also reinforce the hypothesis of autoimmunity. Studies have shown that hair regrows when affected scalp is transplanted onto SCID (severe combined immunodeficiency) mice thatare devoid of immune cells. Autologous T lymphocytes isolated froman affected scalp were cultured with hair follicle homogenates and autologous antigen-presenting cells. Following initial regrowth, injection ofthe T lymphocytes intothe grafts resulted in loss of regrown hairs. Injections of autologous T lymphocytes thatwerenot cultured with follicle homogenates didnot trigger hair loss.
A similar experiment on nude (congenitally athymic) mice failed to trigger hair loss in regrown patches of alopecia areata after serum from affected patients was injected intravenously intothe mice. However, thesame study showed that mice injected with alopecia areata serum showed an increased deposition of immunoglobulin and complement in hair follicles ofboth grafted and nongrafted skin compared with mice injected withcontrol serum, which showed no deposition.
In addition, research has shown that alopecia areata canbe induced using transfer of grafts from alopecia areata–affected mice onto normal mice. Transfer of grafts from normal mice to alopecia areata–affected mice similarly resulted in hair loss inthe grafts.
Clinical evidence favoring autoimmunity suggests that alopecia areata is associated withother autoimmune conditions, themost significant ofwhichare thyroid diseases and vitiligo (see History). For instance, ina retrospective cross-sectional review of 2115 patients with alopecia areata who presented to academic medical centers in Boston overan 11-year period, comorbid autoimmune diagnoses included thyroid disease (14.6%), diabetes mellitus (11.1%), inflammatory bowel disease (6.3%), systemic lupus erythematosus (4.3%), rheumatoid arthritis(3.9%), and psoriasis and psoriatic arthritis (2.0%). Other comorbid conditions found included atopy (allergic rhinitis, asthma, and/or eczema; 38.2%), contact dermatitis andother eczema (35.9%), mental health problems (depression or anxiety; 25.5%), hyperlipidemia (24.5%), hypertension (21.9%), and GERD (17.3%). [ 7 , 8 ]
In conclusion, the beneficial effect of T-cell subtype depletion on hair growth, the detection of autoantibodies, the ability to transfer alopecia areata from affected animals to nonaffected animals, andthe induction of remission by grafting affected areas onto immunosuppressed animals are evidence in favor ofan autoimmune phenomenon. Certain factors within the hair follicles, and possibly inthe surrounding milieu, trigger an autoimmune reaction. Some evidence suggests a melanocytic target within the hair follicle. Adding or subtracting immunologic factors profoundly modifies the outcome of hair growth.
Many factors favor a genetic predisposition for alopecia areata. The frequency of positive family history for alopecia areata in affected patients hasbeen estimated tobe 10-20% compared with 1.7% incontrol subjects. [ 6 ] The incidence is higher in patients withmore severe disease (16-18%) compared with patients with localized alopecia areata (7-13%). Reports of alopecia areata occurring in twins alsoareof interest. No correlation hasbeenfound between the degree of involvement of alopecia areata andthe type of alopecia areata seen in relatives.
Several genes havebeen studied anda large amount of research has focused on human leukocyte antigen. Two studies demonstrated that human leukocyte antigen DQ3 (DQB1*03) wasfoundinmorethan 80% of patients with alopecia areata, which suggests thatitcanbea marker for general susceptibility to alopecia areata. The studies alsofoundthat human leukocyte antigen DQ7 (DQB1*0301) and human leukocyte antigen DR4 (DRB1*0401) were present significantly morein patients with alopecia totalis and alopecia universalis. [ 9 , 10 , 11 ]
Another gene of interest isthe interleukin 1 receptor antagonist gene, which may correlate with disease severity. Finally, the high association of Down syndrome with alopecia areata suggests involvement ofa gene located on chromosome 21.
In summary, genetic factors likely play an important role in determining susceptibility and disease severity. Alopecia areata is likely tobethe result of polygenic defects rather thana single gene defect. The role of environmental factors in initiating or triggering the condition is yet tobe determined.
Interleukin 1 and tumor necrosis factor were shown tobe potent inhibitors of hair growth in vitro. Subsequent microscopic examination ofthese cultured hair follicles showed morphologic changes similar tothose seen in alopecia areata.
Another areaof interest concerns the modification of perifollicular nerves. The fact that patients with alopecia areata occasionally report itching or pain on affected areas raises the possibility of alterations inthe peripheral nervous system. Circulating levels ofthe neuropeptide calcitonin gene-related peptide (CGRP) were decreased in 3 patients with alopecia areata compared withcontrol subjects. CGRP has multiple effects onthe immune system, including chemotaxis and inhibition of Langerhans cell antigen presentation and inhibition of mitogen-stimulated T-lymphocyte proliferation.
CGRP also increases vasodilatation and endothelial proliferation. Similar findings were reported inanother study, inwhich decreased cutaneous levels of substance P andof CGRP butnotof vasoactive intestinal polypeptide werefoundin scalp biopsy specimens. The study also noted a lower basal blood flow and greater vasodilatation following intradermal CGRP injection in patients with alopecia areata compared withcontrol subjects. More studies are needed to shed light onthe significance ofthese findings.
Other hypotheses havebeen proposed to explain the pathophysiology of alopecia areata, butmore evidence is needed to support them. Alopecia areata was believed to possibly havean infectious origin, butno microbial agent hasbeen isolated consistently in patients. Many efforts havebeenmadeto isolate cytomegalovirus, butmost studies havebeen negative. [ 12 ]
Prevalence inthe general population is 0.1-0.2%. The lifetime risk of developing alopecia areata is estimated tobe 1.7%. Alopecia areata is responsible for 0.7-3% of patients seen by dermatologists. [ 13 , 14 ]
All races are affected equally by alopecia areata; no increase in prevalence hasbeenfoundina particular ethnic group.
Data concerning the sex ratio for alopecia areata vary slightly inthe literature. In one study including 736 patients, a male-to-female ratio of 1:1 was reported. [ 15 ] In another study ona smaller numberof patients, a slight female preponderance was seen.
Alopecia areata can occur atany age from birth tothe late decades of life. Congenital cases havebeen reported. Peak incidence appears to occur from age 15-29 years. As manyas 44% of people with alopecia areata have onset at younger than 20 years. Onset in patients older than 40 years is seen in less than 30% of patients with alopecia areata.[#IntroductionMortalityMorbidity]
Alopecia areata isa benign condition andmost patients are asymptomatic; however, itcan cause emotional and psychosocial distress in affected individuals. Self-consciousness concerning personal appearance can become important. Openly addressing these issues with patients is important in helping them cope withthe condition.
The natural history of alopecia areata is unpredictable. Most patients haveonlyafew focal areas of alopecia, and spontaneous regrowth usually occurs within 1 year. Estimates indicate less than 10% of patients experience extensive alopecia and less than 1% have alopecia universalis. Patients with extensive long-standing conditions are less likely to experience significant long-lasting regrowth.
Adverse prognostic factors include nail abnormalities, atopy, onset ata young age, and severe forms of alopecia areata.
Patient education isa key factor in alopecia areata. Inform patients ofthe chronic relapsing nature of alopecia areata. Reassure patients thatthe condition is benign and does not threaten their general health.
Most patients try tofindan explanation about why thisis happening to them. Reassure these patients thattheyhave done nothing wrong andthatitisnottheir fault.
Inform patients that expectations regarding therapy shouldbe realistic.
Support groups areavailableinmany cities; itis strongly recommended that patients be urged to contact the National Alopecia Areata Foundation at 710 C St, Suite 11, San Rafael, CA 94901 or view the Web site.
Many patients are reluctant touse hairpieces ortakepartin support groups because, at first, these often are perceived as last-resort options. Take thetimeto discuss the options with patients becausetheyareof great benefit.
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Chantal Bolduc, MD, FRCPC Assistant Professor, Department of Dermatology, University of Montreal Faculty of Medicine; Physician, Innovaderm Research, Inc
Chantal Bolduc, MD, FRCPC isa member ofthe following medical societies: Canadian Dermatology Foundation
Disclosure: Nothing to disclose.
Harvey Lui, MD, FRCPC Professor and Head, Department of Dermatology and Skin Science, Vancouver General Hospital, University of British Columbia; Medical Director, The Skin Centre, Lions Laser Skin Centre and Psoriasis and Phototherapy Clinic, Vancouver General Hospital
Harvey Lui, MD, FRCPC isa member ofthe following medical societies: Canadian Medical Association , American Society for Photobiology , Photomedicine Society , European Academy of Dermatology and Venereology , National Psoriasis Foundation , Canadian Dermatology Association , College of Physicians and Surgeons of British Columbia , North American Hair Research Society , Canadian Dermatology Foundation , American Academy of Dermatology , American Society for Laser Medicine and Surgery
Disclosure: Received consulting fee from Astellas for review panel membership; Received consulting fee from Amgen/Wyeth for speaking and teaching; Received honoraria from LEO Pharma for speaking and teaching; Received grant/research funds from LEO Pharma for investigator; Received grant/research funds from Galderma for other.
Jerry Shapiro, MD, FRCPC Clinical Associate Professor, Department of Medicine, Division of Dermatology, University of British Columbia Faculty of Medicine, Canada
Disclosure: Nothing to disclose.
Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD isa member ofthe following medical societies: American Academy of Dermatology , Texas Medical Association , Association of Military Dermatologists , Texas Dermatological Society
Disclosure: Nothing to disclose.
Lester F Libow, MD Dermatopathologist, South Texas Dermatopathology Laboratory
Lester F Libow, MD isa member ofthe following medical societies: American Academy of Dermatology , American Society of Dermatopathology , Texas Medical Association
Disclosure: Nothing to disclose.
Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Dirk M Elston, MD isa member ofthe following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
Leonard Sperling, MD Chair, Professor, Department of Dermatology, Uniformed Services University ofthe Health Sciences
Leonard Sperling, MD isa member ofthe following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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Prostate Cancer

<h1>Prostate Cancer</h1>

Prostate Cancer

Immunotherapy/vaccine and other targeted therapies Bone-directed therapy (bisphosphonates and denosumab) Radiopharmaceuticals (radioactive substances used as drugs ) Research techniques including high-intensity focused ultrasound (HIFU) and others Observation and active surveillance
These two options are not the same. Both observation and active surveillance therapies share in common the decision up front to hold on treatment of the cancer and to follow the cancer periodically to determine if there is progression. Observation involves monitoring the course of the prostate cancer with the goal of treating the cancer with palliative care for the development of symptoms or changes in physical examination or PSA that suggest that symptoms will develop soon. Observation treatment is not trying to cure the cancer, rather to treat symptoms of cancer progression. Thus, observation treatment is preferred for men with low-risk prostate cancer and with a life expectancy of less than 10 years.
Active surveillance involves actively monitoring the course of the prostate cancer with the intent to intervene, with the intention to cure if the cancer appears to be progressing. Active surveillance is preferred for men with very low risk prostate cancer and a life expectancy of < 20 years. Cancer progression may have occurred if a repeat biopsy shows a high Gleason score (Gleason 4 or 5) or if cancer is found in a greater number of the biopsies or a greater extent of the core compared to prior biopsy.
The NCCN guidelines for prostate cancer (version 2.2017) note the following for active surveillance for prostate cancer: The PSA test should be obtained no more than every six months unless clinical changes support more frequent testing. A DRE should be performed no more than every 12 months unless clinical changes support more frequent examination. A repeat prostate biopsy should be done within six months if the initial biopsy removed less than 10 cores or the examination findings were not consistent with the biopsy results. A repeat biopsy should be considered as frequently as every year to assess for progression of the cancer. If one's life expectancy is less than 10 years, then repeat biopsy is not needed. If the PSA is rising and biopsy is negative, consider multiparametric MRI.
Active surveillance has advantages and disadvantages: From an advantage standpoint, it avoids unnecessary treatment and possible side effects of such treatments. Disadvantages of active surveillance include the risk of missed opportunity for cure, although the risk of this is very low if you are followed regularly, and the need for periodic prostate biopsies and the side effects of prostate biopsy.
Observation has advantages and disadvantages. From an advantage standpoint, observation avoids/delays the possible side effects of treatment. There is, however, the risk of troubles urinating ( urinary retention ) or bone fractures occurring before treatment is started.
As reported in the journal European Urology , Dr. Lu-Yao and colleagues performed a population-based cohort study that included 31,137 Medicare patients 65 years of age and older diagnosed with localized prostate cancer in 1992-2009 who initially received conservative management (no surgery, radiotherapy, cryotherapy, or androgen -deprivation therapy) who were followed until death or Dec. 31, 2009 (for prostate cancer specific mortality), and Dec. 31, 2011, for overall mortality and found that the 15-year outcomes with conservative management of newly diagnosed T1c Gleason 5-7 prostate cancer for men 65 years of age and older were excellent (15-year risk of prostate cancer specific mortality of 5.7%), whereas in men with T1c Gleason 8-10 prostate cancer there was a significant risk of prostatic cancer risk mortality (22%). Surgery for prostate cancer
The removal of the entire prostate gland and the urethra that runs through the prostate and the attached seminal vesicles is referred to as a radical prostatectomy. A variety of approaches are available for performing this procedure. The type of approach may vary with your surgeon's preference, your physique, and medical conditions. Traditionally, radical prostatectomy was performed through an incision that extended from below the belly button (umbilicus) down to the pubic bone or through an incision underneath the scrotum (perineal approach). In an effort to decrease the morbidity of the procedure, laparoscopic approaches to performing a radical prostatectomy were developed. The use of the robot to perform the laparoscopic radical prostatectomy, robotic-assisted radical prostatectomy, is currently the most common method to perform a radical prostatectomy. Compared to open radical prostatectomy, robotic assisted laparoscopic radical prostatectomy is associated with less postoperative discomfort and sooner return to full activity, as well as less intraoperative blood loss with comparable outcomes regarding urinary continence, erectile function. Radical prostatectomy is an appropriate treatment option for those individuals with clinically localized prostate cancer that can be removed completely surgically and who have a life expectancy of 10 or more years and have no medical contraindications to surgery.
In some men, a pelvic lymph node dissection may be recommended depending on the Gleason score, PSA, and radiologic findings. This involves removing lymph nodes in the pelvis that are common sites for prostate cancer to spread. This may be performed at the time of the radical prostatectomy or rarely as a separate procedure prior to definitive therapy.
Side effects of radical prostatectomy may have a significant impact on quality of life. Thus, it is essential that you discuss with your surgeon prior to the surgery the risk of such side effects occurring, as well as treatments that can occur after surgery to treat such sides effects.
Erectile dysfunction is a side effect of radical prostatectomy. The risk of developing erectile dysfunction varies with your age, erectile function status prior to surgery, and the need to remove one, both, or neither of the pelvic nerve bundles during the radical prostatectomy. The pelvic nerve bundles lie on either side of the prostate, just outside the capsule or outer edge of the prostate. The pelvic nerve bundles are involved in the erectile process, the ability to have an erection. Impotence — or the inability to have and sustain an erection of a quality sufficient for successful intercourse — can occur after radical prostatectomy due to trauma, damage, or removal of the pelvic nerve bundles. Nerve-sparing radical prostatectomy can be performed in select individuals with lower risk prostate cancer. Even after nerve-sparing radical prostatectomy, one may experience transient erectile troubles related to reversible trauma to the nerves during surgery. Specialists treating erectile dysfunction may recommend penile rehabilitation therapy in hopes of helping the nerves recover their function better and faster after radical prostatectomy.
Urinary incontinence is another risk after radical prostatectomy. The radical prostatectomy involves the removal of a portion of the urethra, which passes through the prostate gland. During the procedure, the urethra is sewn back to the bladder. When the prostate gland is removed, there may be some trauma to the sphincter around the urethra, which helps prevent leakage of urine. As with the risk of erectile troubles, the risk of incontinence may vary with your continence status prior to surgery, whether or not you have had prior surgery on the prostate (transurethral prostatectomy [TURP]) and the function of your sphincter muscle prior to surgery.
Both erectile dysfunction and urinary incontinence are treatable conditions. The treatment for either may involve medical and/or surgical therapies. You should discuss such risks and the treatment of these with your surgeon prior to surgery.
Other risks of radical prostatectomy include infection, bleeding, discomfort, and blood clots (deep venous thrombosis [ DVT ]) and rarely death. To help prevent a DVT , you may be asked to wear special compression devices on your legs or be administered a blood thinner.
Radical prostatectomy is rarely performed as a salvage procedure after other primary therapy, such as radiation therapy, has failed. The risk of complications, such as, erectile dysfunction, incontinence, bleeding, and stricture, are greater with salvage therapy. Radiation therapy
Radiation therapy as with surgical therapy is a potentially curative treatment that uses radiation to kill cancer cells. Radiation therapy can be performed via external beam therapy (EBRT) or the placement of radioactive seeds into the prostate (prostate brachytherapy). EBRT
An X-ray machine uses a low energy radiation beam to take a picture of a portion of the body. Radiation therapy machines put out high energy beams that can be focused very precisely to deliver treatment to a site. The radiation does not "burn out" the cancer, but damages the cells' DNA, which causes the cancer cells to die. This process can take some time to occur after the radiation treatments have been given.
The radiation passes directly through the tissues in EBRT. Radiation treatment used today delivers very little energy to normal tissues. It just passes through. Most of the energy is able to be focused and delivered directly to the area of the prostate gland containing cancer. This process minimizes damage to healthy tissue.
EBRT can be administered in a variety of different ways including 3-D CRT, IMRT, and others. EBRT is classically administered in brief daily treatments, 5 days a week over several weeks. While the radiation does not remain in the body with this approach, the effect of the daily fractions is cumulative. Newer forms of EBRT using machines called CyberKnife allow the treatment to be completed in shorter periods of time.
A recently popular technique of EBRT is called proton beam radiation, which can theoretically more closely focus on the area being treated. Proton beam radiation therapy is more expensive. Its side effects presently appear similar to those discussed for standard radiation therapy, except for an increased incidence of gastrointestinal side effects with Proton beam radiation. Studies comparing the effectiveness and overall results of conventional radiation therapy versus proton beam therapy have not been completed yet.
Radiation therapy to the prostate gland by external beam technique may cause fatigue and bladder and/or rectal irritation. One may experience frequency of urination or stools and blood in the urine or stools. These effects are usually temporary but may recur or persist long after treatments are finished. Radiation damage to adjacent tissues can cause skin irritation and local hair loss . Delayed onset of impotence can occur after radiation therapy due to its effect on normal tissues, including nerves adjacent to the prostate. Radiation therapy may be given alone or in combination with hormonal therapy, which can also shrink up the prostate gland, thereby reducing the size of the radiation area or field that needs to be treated. The NCCN guidelines recommend that patients with high-risk and very-high-risk prostate cancer receive neoadjuvant/concomitant/adjuvant hormone therapy (androgen deprivation therapy [ADT]) for a total of two to three years if the overall health of the patient permits and that patients with intermediate-risk prostate cancer be considered for four to six months of neoadjuvant/concomitant/adjuvant hormone therapy (ADT). Pelvic lymph node radiation may be considered for high-risk and very high-risk prostate cancer patients. Patients with low-risk prostate cancers should not receive ADT or lymph node radiation.
EBRT is appropriate for men who are candidates for radical prostatectomy but do not wish to undergo the surgery or who are not ideal surgical candidates.
EBRT may also be used to treat recurrent prostate cancer localized to the prostate bed (where the prostate was before it was removed surgically). It is also used to treat bone metastases (spread of the prostate cancer to the bone) to reduce pain or if the cancer is pressing on important structures, including the spinal cord.
Brachytherapy refers to the use of radiation sources — sometimes referred to as seeds — placed into the prostate gland. Brachytherapy may be done with what is called low-dose rate (LDR) or high-dose rated (HDR) technique. In LDR brachytherapy, types of radioactive seeds, which only briefly put out a form of radiation that does not travel very far through tissues, are permanently implanted in the prostate gland. High-dose rate (HDR) brachytherapy involves the temporary placement of different types of seeds or sources that give off higher amounts of more penetrating radiation. These seeds administer higher doses of radiation for longer periods of time and cannot be left in the body. Such sources are placed in the prostate gland through surgically implanted tubes. These HDR sources are removed along with the tubes in a couple of days. In LDR brachytherapy, the seeds are placed in the operating room using image guidance to ensure the seeds go into the right places — 40-100 seeds may be placed. With LDR, you can go home shortly after you wake up after the procedure. In HDR, you must stay at the hospital for a few days. If the prostate gland is large, hormonal treatment (ADT) may be used to shrink the gland before the brachytherapy is done. Brachytherapy may also be combined with external beam radiation therapy to further increase the dose of radiation therapy given to the prostate gland.
Brachytherapy can cause some blood in the urine or semen. It can cause a feeling similar to constipation due to the swelling of the prostate gland. One can also experience transient troubles urinating, called urinary retention, related to swelling of the prostate gland, that may require short-term catheter placement. It can also make you feel that you want to move your bowels more often. There may be some long-term problems with irritation of the rectum, difficulty urinating due to scar tissue formation, and even delayed-onset impotence .
The NCCN guidelines version 2.2017 indicate that brachytherapy can be used as a single therapy (monotherapy) in patients with low-risk cancers and select individuals with low-volume intermediate risk cancers. Intermediate-risk prostate cancers can be treated by a combination of brachytherapy and EBRT +/- four to six months of neoadjuvant, concomitant/adjuvant ADT.
High-risk patients can be treated with a combination of EBRT and brachytherapy +/- two to three years of neoadjuvant/concomitant/adjuvant ADT.
Patients with a very large prostate or very small prostate, those with symptoms of bladder outlet obstruction, or who have had a previous transurethral resection of the prostate (TURP) are more difficult to treat and have a greater risk of side effects.
Brachytherapy can be used as a salvage therapy for recurrent/persistent prostate cancer after external beam radiation therapy (EBRT). The risk of side effects is increased when used as a salvage therapy. Focal therapy
Focal therapy involves ablation of the prostate cancer within the prostate with preservation of the surrounding healthy tissue. A number of focal therapies are being investigated, and a comparison of the efficacy of each of these therapies cannot be made given the limited data on many of these therapies. Focal therapies being investigated include cryotherapy, high-intensity focused ultrasound, laser ablation, photodynamic therapy , irreversible electroporation, radiofrequency ablation , and focal brachytherapy. As many of these are considered experimental, only cryotherapy will be briefly reviewed. Cryotherapy (cryosurgery, cryoablation)
Cryotherapy is a minimally invasive therapy that damages tissue by local freezing.
Cryotherapy is most frequently used as a salvage treatment after failure of radiation therapy. As an outpatient, hollow needles are placed into the prostate through the perineum (the space between the scrotal sac and the anus) under image guidance. A gas is passed through the needles to freeze the prostate. Warm liquid is passed through the urethra at the same time to protect it. The needles are removed after the procedure. While potentially effective for local control of cancer in the prostate gland, the side effects can be significant and include pain and the inability to urinate. Potential long-term effects include tissue damage in needle-insertion areas, impotence, and incontinence. Cryotherapy is not currently recommend as a primary treatment for management of prostate cancer. Hormonal therapy
Prostate cancer is highly sensitive to and dependent on the level of the male hormone testosterone, which drives the growth of prostate cancer cells in all but the very high-grade or poorly-differentiated forms of prostate cancer. Testosterone belongs to a family of hormones called androgens, and today front-line hormonal therapy for advanced and metastatic prostate cancer is called androgen deprivation therapy (ADT).
In the past, this was accomplished by surgical castration called bilateral orchiectomy. In that procedure, the testes were both removed. Today, doctors can block the function of the testes in a controllable and most often reversible fashion with drugs that prevent the production of testosterone (medical castration). These agents can result in shrinkage of the prostate gland, can stop prostate cancer cells from growing for up to several years, and can relieve pain caused by prostate cancer that has spread or metastasized into the bones by shrinking the cancer. The use of ADT does not produce a cure. Over time, the prostate cancer cells will develop an ability to grow despite the lack of hormones (castrate resistance). Another form of hormonal therapy is the use of androgen receptor blockers; these medications prevent testosterone from attaching (binding) to the prostate cancer cell and being absorbed into the cell where it can help the cell survive and grow.
Hormonal treatment today is primarily used in the treatment of locally advanced and metastatic prostate cancer. It may be used in conjunction with primary curative therapies (surgical and radiation based) to shrink the cancer/prostate to increase the likelihood of cure of the treatment, neoadjuvant therapy, and with radiation therapy for several years after treatment (adjuvant therapy). However, the primary role of ADT is in the treatment of widespread or metastatic prostate cancer. While it is not a curative treatment in that setting, it can both reduce symptoms and slow down the growth of the prostate cancer to prolong life.
Today medicines used to block testosterone production by the testes include: LH-RH agonists : Leuprolide ( Lupron ), goserelin ( Zoladex ), histrelin ( Supprelin LA ), and triptorelin ( Trelstar ) are examples of these mediations. These are either given by injection into the muscle or under the skin at varying intervals of at least one month or longer. LH-RH antagonists : Degarelix (Firmagon) is a monthly injection that is given under the skin.
Medications that block the action of testosterone include the androgen receptor blockers Flutamide (Eulexin), bicalutamide (Casodex), nilutamide (Nilandron), and an even more effective form called enzalutamide (Xtandi) : Xtandi is recommended for use only in individuals with castrate-resistant prostate cancer (prostate cancer that is refractory to traditional ADT), including those with and without metastases. Xtandi is different than the other androgen receptor blockers in that it has three mechanisms of action: (1) It prevents androgens (testosterone) from binding to the androgen receptor, (2) it prevents the androgen receptor from moving into the central area (nucleus) of the cell, and (3) it prevents binding of the androgen receptor to DNA and stimulating growth. The most common side effects of Xtandi include fatigue , back pain , decreased appetite , constipation , arthralgia , diarrhea , hot flush , upper respiratory tract infection , swelling of the legs, shortness of breath with exertion, headache , hypertension , dizziness , and weight loss . Less commonly, seizures and posterior reversible encephalopathy syndrome characterized by seizure , headache , lethargy, confusion, and blindness may occur. A newer androgen receptor blocker with a similar mechanism of action as Xtandi, apalutamide (Erleada), is indicated for use in men with nonmetastatic castrate resistant prostate cancer.
Both surgical and medical castration result in impotence. They also can cause hot flashes , fatigue, anemia , and thinning of the bones ( osteoporosis ) over time. These drugs may be given individually or combined with an androgen receptor blocker in what is called a combined androgen blockade.
Other hormonal treatment options include: Estrogen : This female hormone has been utilized in the treatment of prostate cancer as it also results in medical castration. Its mechanism of action remains under study, and its association with a high risk of heart attack and blood clots when used in high doses has diminished the frequency of its use, particularly in front-line therapy. Other side effects include breast enlargement/pain ( gynecomastia ). Estrogen and related drugs may still have a role in the treatment of metastatic prostate cancer in select individuals. Adrenal androgen synthesis inhibitors : The adrenal glands, a pair of small glands that are located above the kidneys, also produce a small amount of testosterone. Individuals on traditional ADT have testicular production of testosterone suppressed but still may have testosterone production from the adrenal glands. In individuals on ADT who have continued growth of the prostate cancer (rising PSA), the use of adrenal androgen synthesis inhibitors may be useful. This group includes a drug called ketoconazole , which was primarily developed to treat fungal infections , but has shown to be effective in the treatment of prostate cancer. More recently, an agent called abiraterone acetate (Zytiga) has been developed. It has a similar effect on androgen synthesis, but it is more powerful than an older agent called ketoconazole ( Nizoral ) and has fewer side effects. The use of Zytiga in combination with prednisone is considered in individuals failing traditional ADT and individuals who have castrate-resistant prostate cancer (failed first-line ADT). More common side effects of Zytiga include fatigue, back or joint discomfort, peripheral edema , diarrhea , nausea , constipation , and low potassium levels. Blood pressure , liver tests , potassium, and phosphate levels should be monitored regularly when initially using Zytiga. Steroids : These agents including prednisone may have beneficial hormonal effects in prostate cancer, including slowing the production of androgen by the adrenal glands. They often make the patient feel better, but have many side effects including inducing or worsening diabetes , fluid retention, cataract formation, weight gain , and osteoporosis . Agents that block the conversion of testosterone to its active metabolite : Finasteride ( Proscar ) and dutasteride ( Avodart ) are not approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer, however, they have been used (off-label) in treating prostate cancer by preventing the conversion of testosterone to its active metabolite called DHT (dihydrotestosterone). These drugs are frequently utilized for the symptoms of prostate enlargement in men without prostate cancer and appear to reduce the risk of development of prostate cancer. Their side effects are limited. They are used in combination with other agents to optimize androgen blockade. As these medications are not currently approved for use in men with prostate cancer, consult with your physician and insurance provider to ensure that their use is medically appropriate and will be covered. Chemotherapy
Chemotherapy or " chemo " for prostate cancer involves the use of medications either in pill form or by injection into the veins, which can kill or at least slow the growth of metastatic prostate cancer cells. It does not presently have a role in the treatment of early stage prostate cancer except as part of clinical trials /research studies. The use of chemotherapy in metastatic prostate cancer is presently not a potentially curative treatment, but it can relieve symptoms of prostate cancer, and can prolong life. It is usually used in the setting of CRPC, castration- (medical or surgical) resistant prostate cancer.
Chemotherapy drugs work in many different ways. These drugs may damage the DNA of the cancer cells or disrupt the cells ability to divide (mitosis). These effects can cause cells to die. Not all prostate cancer cells may be sensitive to these drugs, but some may be. A tumor (a mass of cancer cells) will shrink if more cells are killed and removed than continue to grow and divide. As many normal tissues in the body also undergo the same patterns of growth and mitosis, these drugs have numerous side effects due to their effects on normal tissues.
Active chemotherapy drugs for the treatment of prostate cancer today include: Taxotere ( Docetaxel ) — first-line chemotherapy option Carbazitaxel (Jevtana) — option in individuals who have failed docetaxel Mitoxantrone ( Novantrone )
Although traditionally recommended for men with castrate-resistant prostate cancer, the NCCN recommended the use of docetaxel in combination with ADT and EBRT in men with high- and very-high-risk localized prostate cancer.
When these types of drugs are given to patients with prostate cancer they can help reduce pain and shrink tumors. Patients who respond to these drugs often live longer than those who do not respond. Immunotherapy/vaccine therapy
The immune system works by trying to very specifically target infections or to attack and kill cells which are either cancerous or are not our own. The immune system attempts to eliminate these invading problems using antibodies and cells called T-lymphocytes; in cases of cancer the immune system still struggles to control the problem for many reasons. The cancer seems often to either depress or overwhelm the immune system. Immune therapies (immunotherapy) attempt to boost the capability of our immune system.
Provenge (Sipuleucel-T) is a form of immunotherapy, a vaccine therapy, used to treat prostate cancer that has metastasized. It is appropriate in patients whose cancer is no longer responding to hormonal therapy but who are asymptomatic or minimally symptomatic. These patients may be showing a rise in PSA level after previous hormonal treatment has kept the PSA down for a long time.
Provenge therapy involves taking some of your own blood cells and growing them outside the body in the presence of a substance that is specific for prostate cancer. The cells are then given back to you by infusing them into the bloodstream. These cells can attack prostate cancer cells, and can help program other blood cells to do the same. Such treatment causes few side effects, including mild to moderate chills , fever , and headache , and can prolong survival by several months. Bone-targeted therapy
Bone health is an essential component of prostate cancer treatment. Both the disease itself, as well as the treatment of the disease with androgen deprivation therapy, can have a significant impact on bone health. Several bone-targeted therapies have been approved. Bisphosphonates
The bisphosphonates are a group of drugs used to treat several conditions people can get including osteopenia and osteoporosis . They also can lower elevated blood levels of calcium in people with cancer. They work by affecting cells in the bones called osteoclasts, which work to remove bone. These drugs encourage the death of the osteoclasts. In prostate cancer they impact the course of skeletal-related events including reducing pain in the bones, and delaying the progression of bone metastases associated problems including the appearance of fractures (breaks in bones). While the bisphosphonates can affect the growth of prostate cells in the laboratory, they are presently not considered a targeted or direct-acting drug like a chemotherapy or hormonal treatment. They have also not been shown to prevent the appearance of bone metastases in prostate cancer patients. Nonetheless, they are an important part of the treatment of prostate cancer patients with bone metastases.
The most potent of the bisphosphonates is called zoledronic acid ( Zometa ). It is given intravenously. Its side effects are primarily reactions to the drug infusion. The dose of Zometa may need to be adjusted if the patient's blood tests show signs of deterioration in the function of the patient's kidneys. In addition, its use can predispose patients to serious dental conditions including what is called osteonecrosis of the jaw, which can result in breakdown of the bone of the jaw after dental extractions. It is advised that you see your dentist and have needed dental procedures performed prior to the start of a bisphosphonate. Monoclonal antibody therapy
Denosumab (Xgeva) is a monoclonal antibody agent that inhibits the work of osteoclasts in a manner different from bisphosphonates. The medication inhibits a protein that tells the osteoclasts to remove bone. This drug is useful as a treatment for all of the conditions for which bisphosphonates are used. Given as an injection under the skin at intervals, it has a better side effect profile than the bisphosphonates. It does not require dose adjustments if kidney function deteriorates. It can still cause osteonecrosis of the jaw to occur. It is considered an important new drug in the treatment of bone metastases in prostate cancer patients. In some studies it appears to be more effective than Zometa in delaying the initial onset of skeletal-related events in patients with bone metastases. Radiopharmaceuticals
The use of substances that are radioactive as a treatment for bone metastases has been tried for years. Strontium-89 and samarium-153 have been used in the past. They decrease pain in patients with prostate cancer with bone metastases but they do not prolong life; these medications lower levels of healthy blood cells in patients who receive them.
Recently a form of radium called Ra-223 ( Xofigo ) has been approved for use in prostate cancer patients with metastases to bone but not to other internal organs. Radium is like calcium and it migrates to bone where it acts locally. As an alpha emitter, radiation from radium does not travel far enough in the body to damage other healthy tissues. Unlike the bisphosphonates, the use of this agent reduces pain and can prolong survival. It is administered by an injection into a vein. It can cause nausea , diarrhea , and low blood counts. Castrate-resistant prostate cancer (CRPC) and metastatic castration-resistant prostate cancer (MCRPC)
A patient is noted to have metastatic castrate resistant prostate cancer if the individual has progressive prostate cancer with metastases while on ADT. The individual should have a serum testosterone level obtained to make sure that it is at castrate level ( 50 ng/dL, this would indicate that the source of the progression is inadequate androgen deprivation and alternative ADT should be considered. If the individual is determined to have a castrate level of testosterone on ADT with progression of disease (rising PSA) on ADT, the individual is considered to have metastatic castrate-resistant prostate cancer. If metastases are identified, then the individual has metastatic castration-resistant prostate cancer. Over the past several years, a number of therapies have been approved for the treatment of metastatic castrate-resistant prostate cancer, including a new androgen receptor blocker, chemotherapy, immunotherapy/vaccine therapy, as well as bone-directed therapies. Though each of these therapies have unique ways in which they work and different side effects, all have been demonstrated to prolong survival by approximately three to four months each. The sequencing of the various treatments (which should be used first) is not well defined at present. Sipuleucel-T, a vaccine immunotherapy, is the only agent that is specifically approved for use early on in the time frame before one has significant symptoms (asymptomatic or minimally symptomatic). Studies are ongoing to evaluate the best sequence of treatments. Research techniques
High-intensity focused ultrasound (HIFU) is an approach to therapy that is presently approved for use in Europe, and is under study in the U.S. It uses high intensity sound waves focused on the prostate gland to heat and thereby kill cancer cells. It should only be used as part of a research study (a clinical trial). The safety, side effects, and comparative effectiveness to surgery and radiation therapy must be established.
Clinical trials are research studies being conducted to evaluate new treatments for prostate cancer. These include approaches such as HIFU, as well as modifications of surgical and radiation techniques, and new drugs and immune therapy approaches. The National Comprehensive Cancer Network, a group assembled from the major comprehensive cancer centers of the U.S., considers that the best care of a cancer patient is afforded by their participation in a clinical trial. Patients with prostate cancer should always ask if there is a clinical trial option for them at any point in their therapy. Clinical trial participation assures you that your treatment has been considered by numerous cancer experts and is at least as good as a standard treatment that you may receive off of a clinical trial. In addition, the results of your treatment will be carefully analyzed in anonymous fashion, and results can be used to help others. Complementary and alternative care approaches
In addition to standard types of prostate cancer treatments, there are other approaches that patients may choose during their treatment for their disease.
Some of these treatments are called complementary treatments and may help with control of symptoms or problems the patient may be experiencing. Examples of these include acupuncture for pain control, yoga and meditation for relaxation, as well as guided imagery, aromatherapy, and other techniques. Tell your doctors about all treatment approaches you are engaged in. These approaches usually will be of no harm to you, and may be very beneficial. Knowing what you are doing may help your doctor to better understand and coordinate your treatments and medications. Herbal therapies have been demonstrated in the lab to affect prostate cancer cells, but in many cases, have not been proven to be clinically effective. PC-SPES is an herbal therapy that has been used in the past for prostate cancer. It was associated with an increased risk of blood clots. Thus, prior to taking this or other herbal therapies, discuss these therapies with your doctor.
Be very careful about alternative treatments. The vast majority of medical professionals keep up-to-date on the latest advances, or are willing to research them for patients when asked. No truly effective treatments are being withheld from patients, though alternative care providers often say they are in an attempt to sell patients on their types of treatment. Such alternative therapies can do harm to patients, and can interfere with conventional treatment. Alternative care providers can be reasonably said to be preying on the desperation of cancer patients.
If nutritional supplements are suggested in addition to conventional therapy by an alternative care professional, tell all your doctors what you are taking. Some nutritional substances can interfere with the effectiveness of some conventional cancer treatments. Some “natural” substances can be toxic and can result in side effects or problems your regular doctor may not recognize unless they know what you are taking.
Prostate cancer patients, like all cancer patients, are frightened. Discuss your anxiety and concerns with your primary care doctor, urologist, and radiation and medical oncologists. They have many ways to help. What is the prognosis for prostate cancer?
Staging evaluation is essential for the planning of treatment for prostate cancer. A basic staging evaluation includes the patient examination, blood tests, and the prostate biopsy including ultrasound images of the prostate. Further testing and calculations may be performed to best estimate a patient’s prognosis and help the doctor and patient decide upon treatment options. Prognosis refers to the likelihood that the cancer can be cured by treatment, and what the patient’s life expectancy is likely to be as a consequence of having had a prostate cancer diagnosis.
If a cancer is cured, your life expectancy is what it would have been had you never been diagnosed with prostate cancer. If the cancer cannot be cured due to it recurring in distant locations as metastases, or recurs either locally (where it started) or in an area no longer able to be treated in a curative manner, then estimates can be made of what is likely to be your survival based again on group statistics for people who have been in the same situation.
Nomograms are charts or computer-based tools that use complex math from analysis of many patients’ treatment results. They help to estimate the likelihood of a patient surviving free of recurrence after a treatment. They also can determine the likelihood of a cancer being found confined to the prostate, or spread beyond the prostate, or into the nearby lymph glands. Your doctor will likely input the data from your staging evaluation into a nomogram in order to best counsel you regarding your treatment options.
The prognosis for prostate cancer varies widely, and depends on many factors, including the age and health of the patient, the stage of the tumor when it was diagnosed, the aggressiveness of the tumor, and the cancer’s responsiveness to treatment, among other factors. The five-year survival rate for most men with local or regional prostate cancer is 100%. Ninety-eight percent are alive at 10 years. For men diagnosed with prostate cancer that has spread to other parts of the body, the five-year survival rate is 30%. Is it possible to prevent prostate cancer?
For a disease as common as prostate cancer, a condition which one man in six will be diagnosed with in their lifetime, the ideal approach is to prevent men from getting prostate cancer.
Two clinical trials referred to as the Prostate Cancer Prevention Trial (PCPT) and the subsequent Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial were conducted over the past two decades. These studies demonstrated that both finasteride and dutasteride (Propecia and Avodart), when used in men between 50 and 75 years of age, reduced the incidence of prostate cancer by 28% and 23% respectively as compared to similar men taking a placebo.
The reduction in the overall incidence of prostate cancer was significant. The use of these drugs and their FDA-approval for prevention has been slow to come in part because of the lingering concern over the high-grade prostate cancer risk. Men in these trials got less prostate cancer if treated with these drugs, but the prostate cancers that they did get were more often high-grade (had higher Gleason scores) and thus appeared to be at risk for behaving more aggressively. Men with a family history of prostate cancer or other high risk factors, and in fact any man, should discuss the use of these drugs for this purpose.
Trials have been conducted on several vitamins and nutritional supplements and naturally-occurring compounds in an attempt to prevent prostate cancer. Vitamin E and selenium were not effective in the prevention of prostate cancer in the SELECT trial. Vitamin E supplementation may have increased the incidence of prostate cancer. Lycopene was also ineffective as a preventive agent. Pomegranate juice had no meaningful impact on prostate cancer prevention. Green tea had some early results suggestive of a possible protective effect, and a larger trial is under way. Vitamin D and its derivatives have been studied in prostate cancer. There is no evidence that vitamin D protects against prostate cancer. The vitamin D derivative, calcitriol , has some therapeutic utility against this disease, and is still under study.
Prostate cancer is the most common cancer in men (after skin cancer ), and the second leading cause of death from cancer in men. The biology of prostate cancer is better understood today than it was in the past. The natural history of the disease and its staging have been well defined. There are numerous potentially curative approaches to prostate cancer treatment when the disease is localized. Treatment options also exist for prostate cancer that has spread. Ongoing research continues to search for treatments for metastatic prostate cancer. Coping with prostate cancer
The diagnosis of cancer can cause great anxiety to the individual and his family and friends. At times, one may have troubles coping with the diagnosis, the disease, and its treatment. Searching online for information may prove overwhelming also and may not be the best resource. Ask your physician or local hospital about local resources. Often, there are local prostate cancer support groups which may help you cope with your feelings and provide local resources for more knowledge. You may consider contacting one or more of the following organizations: US Prostate Cancer Foundation, American Urological Association Foundation, Centers for Disease Control and Prevention, American Cancer Society, and Patient Advocates for Advanced (Prostate) Cancer Treatment. The Internet has provided access to a number of sites focusing on prostate cancer treatment and outcomes. The National Cancer Institute and the National Comprehensive Cancer Network (NCCN) have patient information as well as the American Urological Association. Health Solutions From Our Sponsors

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Chef Sean Brock Puts Down the Bourbon and Begins a New Quest

<h1>Chef Sean Brock Puts Down the Bourbon and Begins a New Quest</h1>

Chef Sean Brock Puts Down the Bourbon and Begins a New Quest

This champion of Southern food has emerged from rehab with a determination to take on a kitchen culture of stress and excess.

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Dermatologic Manifestations of Graft Versus Host Disease

Dermatologic Manifestations of Graft Versus Host Disease

Scleroderma
Viral exanthem
Skin biopsy with routine hematoxylin and eosin staining isthe primary tool for evaluating skin eruptions in suspected graft versus host disease (GVHD). [ 28 ]
A grading system describes the histologic changes of acute GVHD as follows:
Grade 0 – Normal skin or changes not consistent with GVHD
Grade 1 – Basal vacuolization ofthe dermal-epidermal junction
Grade 2 – Basal vacuolization, necrotic epidermal cells, and lymphocytic infiltrate in superficial dermis, asinthe image below.
Grade 3 – Changes of grade 2 plus clefting atthe basement membrane
Grade 4 – Changes of grade 2 plus bullae formation
Chronic GVHD exhibits basement membrane changes similar tothoseof acute GVHD (eg, vacuolar changes, necrotic epidermal cells, presence of lymphocytes). In addition, chronic disease can result in features suchas thickened epidermis (acanthosis), thickened granular layer (hypergranulosis), thickened stratum corneum (hyperkeratosis), and rete ridges witha pointed or sawtooth appearance.
Horn et al reported thatthe lichen planus–like histologic changes (acanthosis, hypergranulosis, sawtooth rete ridges) believed to represent chronic GVHD occur before the 100th dayafter transplantation in approximately 15% of patients. In addition, lichen planus–like histologic changes, seen in either the acute or chronic clinical setting of GVHD, portend a poor patient prognosis. Several sequential biopsies are often needed becausethe rash evolves to establish the diagnosis; histologic changes during the early stage ofthe disease canbe nonspecific.
The best treatment for graft versus host disease (GVHD) is prevention. Prophylaxis for GVHD usually consists of methotrexate (MTX) withor without prednisone, cyclosporine, cyclophosphamide, or tacrolimus. Topical tacrolimus may be helpful for mucosal disease. [ 29 ] (However, Prot-Labarthe et al [ 30 ] noted toxic serum levels of tacrolimus after topical administration ofthe drug inan infant with severe cutaneous GVHD.)
Marrow T-cell depletion can substantially reduce the incidence and severity of acute GVHD, buttheseresultsare offset byan increase in graft failure and recurrent leukemia.
Once the diagnosis of GVHD is established, treatment consists of continuing theoriginal immunosuppressive agent and adding methylprednisolone. Chronic GVHD requires continued immunosuppressive therapy plus other modifying agents. Immune modalities suchas treatment with antibodies against the interleukin 2 receptor or antithymocyte globulin arenot beneficial in treating acute GVHD.
Halofuginone, a topically applied inhibitor of collagen type I synthesis, is beneficial in patients with sclerodermatous GVHD. Thalidomide hasbeenusedfor chronic GVHD with reported benefit, butthe high rate of adverse effects (including granulocytopenia) precludes its useinmany patients. [ 31 ]
Monoclonal antibodies directed either against activated T-cells (visilizumab, murine anti-CD147 monoclonal antibody [ABX-CBL]) or against cytokines (infliximab, etanercept) havehad promising preliminary results. [ 32 , 33 ] Large-scale studies evaluating their effectiveness arenot yet available.
Complex treatment of GVHD is sometimes stillthe standard in 2012, with topical agents, systemic agents, and physical modalities (eg, phototherapy, extracorporeal photopheresis) needed, andwiththe coordination ofmany types of physicians and providers working to help the patient. [ 34 ]
A 2013 report noted tofacitinib, a JAK inhibitor, reversed CD8 T-cell–mediated mucocutaneous GVHD ina mouse model. [ 35 ]
Topical tacrolimus can ameliorate GVHD. However, when applied under occlusion, systemic absorption, whichis toxic, can occur. [ 36 ]
Perfetti et al [ 37 ] and Flowers et al [ 38 ] found that extracorporeal photopheresis canbea treatment for steroid-refractory acute and chronic graft versus host disease (GVHD). Creamer et al [ 39 ] noted that eczematoid GVHD responded to psoralen plus UV-A (PUVA).
Patients who develop sclerodermatous changes of chronic GVHD may require surgical release ofa contracted joint. Patients who develop nonhealing ulcerations secondary to sclerodermatous GVHD may require wound debridement and skin grafting.
New techniques in transplantation might alter the findings in GVHD. Microtransplantation isa novel paradigm for parsing of GVHD and graft versus tumor. [ 40 ]
Narrowband UVB therapy (311 nm) canbea helpful treatment for GVHD. [ 41 ]
Patients recovering from bone marrow transplant are routinely hospitalized in specialized units for weeks afterthe procedure and continuously monitored forthe development of infectious complications secondary tothe immunosuppressed status. If the initial outcomes of bone marrow transplantations are successful, patients need close follow-up monitoring oftheir immunosuppressive regimens and primary tumor status.
Because patients usually require lifelong immunosuppressive therapy, long-term, continual monitoring is required. [ 42 ]
Subspecialists are often consulted forthe management of graft versus host disease (GVHD) and include the following:
Hematologist and oncologist – The most common indication for HCT remains hematologic malignancy; other indications include treatment of aplastic anemia and restoration of marrow after attempts at ablating solid tumors (most patients who receive HCT are treated primarily bythe hematologist or oncologist)
Dermatologist – A dermatologist may bethebest specialist to differentiate the various skin eruptions thatcan occur in patients whoare taking multiple medications andwhoareat risk for GVHD; skin biopsy remains the primary tool for differentiating the skin eruptions, anda dermatopathologist with clinical and dermatopathology training isthebest specialist for interpreting the results
Gastroenterologist – Patients with GVHD may have hepatic and gastrointestinal mucosal involvement; input from gastroenterologists is important in treating these complications
Physical medicine/rehabilitation specialist – Patients who develop chronic GVHD areat risk for joint contractures and pressure ulcerations
Transplantation medicine specialist and transplantation surgeon – Patients who receive solid organ transplants are treated bythese specialists; GVHD is rare, buthasbeen reported, in patients who receive solid organ transplants
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Brassat S, Fleury J, Camus M, Monégier du Sorbier C, Guillet G. Epidermolysa bullosa acquisita and graft-versus-host disease. Ann Dermatol Venereol . 2014 May. 141(5):369-73. [Medline] .
Kim TH, Lee HH, Chung SH. Hematocolpos asa complication of chronic graft-versus-host disease. Taiwan J Obstet Gynecol . June 2012. 51:292-3. [Medline] .
Jachiet M, de Masson A, Peffault de Latour R, Rybojad M, Robin M, Bourhis JH, et al. Skin ulcers related to chronic graft-versus-host disease: clinical findings and associated morbidity. Br J Dermatol . 2014 Jul. 171(1):63-8. [Medline] .
Finke J. [Chronic graft versus host disease (GvHD): causes, manifestation, diagnosis and treatment option]. Dtsch Med Wochenschr . 2012 Oct. 137(42):2166-70. [Medline] .
Inaba H, Hale G, Leung W, et al. Diagnostic challenge in recurrent skin rash after autologous bone marrow transplantation. J Pediatr Hematol Oncol . 2006 Aug. 28(8):525-8. [Medline] .
Fukuno K, Tomonari A, Takahashi S, et al. Varicella-zoster virus encephalitis ina patient undergoing unrelated cord blood transplantation for myelodysplastic syndrome-overt leukemia. Int J Hematol . 2006 Jul. 84(1):79-82. [Medline] .
Elhasid R, Krivoy N, Rowe JM, et al. Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer . 2010 Jul 29. [Medline] .
Aschan J, Carlens S, Hagglund H, Klaesson S, Mattsson J, Remberger M. Improved survival after bone marrow transplantation for early leukemia using busulfan-cyclophosphamide and individualized prophylaxis against graft-versus-host disease: a long-term follow-up. Clin Transplant . 1999 Dec. 13(6):512-9. [Medline] .
Zenz T, Ritgen M, Dreger P, et al. Autologous graft-versus-host disease-like syndrome afteran alemtuzumab-containing conditioning regimen and autologous stem cell transplantation for chronic lymphocytic leukemia. Blood . 2006 Sep 15. 108(6):2127-30. [Medline] .
Kuskonmaz B, Guçer S, Boztepe G, Cetin M, Uckan D. Atypical skin graft-vs.-host disease following bone marrow transplantation inan infant. Pediatr Transplant . 2007 Mar. 11(2):214-6. [Medline] .
Ozdemir E, Molldrem JJ. Hookworm infection of sigmoid colon masquerading as graft-versus-host disease inan allogeneic stem cell transplant recipient after donor lymphocyte infusion for refractory acute promyelocytic leukemia. Bone Marrow Transplant . 2006 Apr. 37(8):785-6. [Medline] .
Nakagiri T, Okumura M, Inoue M, et al. Thymoma-associated graft-versus-host disease-like erythroderma. J Thorac Oncol . 2007 Dec. 2(12):1130-2. [Medline] .
Vidal CI, Pollack M, Uliasz A, del Toro G, Emanuel PO. Cutaneous toxoplasmosis histologically mimicking graft-versus-host disease. Am J Dermatopathol . 2008 Oct. 30(5):492-3. [Medline] .
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Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol . 1996 Dec. 35(6):969-79. [Medline] .
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Okiyama N, Furumoto Y, Villarroel VA, et al. Reversal of CD8 T-Cell-Mediated Mucocutaneous Graft-Versus-Host-Like Disease bythe JAK Inhibitor Tofacitinib. J Invest Dermatol . 2013 Nov 8. [Medline] .
Olson KA, West K, McCarthy PL. Toxic tacrolimus levels after application of topical tacrolimus anduseof occlusive dressings intwo bone marrow transplant recipients with cutaneous graft-versus-host disease. Pharmacotherapy . 34(6). 2014 Jun:e60-4. [Medline] .
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Creamer D, Martyn-Simmons CL, Osborne G, et al. Eczematoid graft-vs-host disease: a novel form of chronic cutaneous graft-vs-host disease and its response to psoralen UV-A therapy. Arch Dermatol . 2007 Sep. 143(9):1157-62. [Medline] .
Spitzer TR. Microtransplantation: anew paradigm forthe separation of graft versus host disease and graft versus tumor?. J Clin Oncol . Nov 2012. 30:4051-2. [Medline] .
Iyama S, Murase K, Sato T, Hashimoto A, Tatekoshi A, Horiguchi H, et al. Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease bya mechanism involving in vivo expansion of CD4+CD25+Foxp3+ regulatory T cells. Int J Hematol . 2014 Apr. 99(4):471-6. [Medline] .
[Guideline] Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Sections 92-106: hematopoietic cell transplant. National Guideline Clearinghouse . 2006 Mar.
Noah S Scheinfeld, JD, MD, FAAD Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke’s Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice
Noah S Scheinfeld, JD, MD, FAAD isa member ofthe following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
Michael J Wells, MD, FAAD Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology
Michael J Wells, MD, FAAD isa member ofthe following medical societies: Alpha Omega Alpha , American Academy of Dermatology , American Medical Association , Texas Medical Association
Disclosure: Nothing to disclose.
Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School
Warren R Heymann, MD isa member ofthe following medical societies: American Academy of Dermatology , American Society of Dermatopathology , Society for Investigative Dermatology
Disclosure: Nothing to disclose.
Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Dirk M Elston, MD isa member ofthe following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Melanie K Kuechle, MD, tothe development and writing ofthe source article. Dermatologic Manifestations of Graft Versus Host Disease
Research & References of Dermatologic Manifestations of Graft Versus Host Disease|A&C Accounting And Tax Services

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Catabasis Pharmaceuticals: My Long Thesis And Analysis – Catabasis Pharmaceuticals (NASDAQ:CATB)

<h1>Catabasis Pharmaceuticals: My Long Thesis And Analysis – Catabasis Pharmaceuticals (NASDAQ:CATB)</h1>

Catabasis Pharmaceuticals: My Long Thesis And Analysis – Catabasis Pharmaceuticals (NASDAQ:CATB)

Catabasis Pharmaceuticals (NASDAQ: CATB ) recently performed a 10 for 1 reverse stock-split “R/S”; which reduced the number of shares of common stock about 71M to approximately 7.1M. This puts CATB into the “low-float” category of stocks and can often attract day traders to a cause a “parabolic” move upwards with a subsequent sell-off, or “pump and dump.” However, if that occurs, the aftermath can often provide potential long-term investor a great chance to initiate or add to their position.
The recent success of its flagship program PolarisDMD for the treatment Duchenne Muscular Dystrophy “DMD” and the company’s continued development of its NF-kB inhibitor Edasalonexent have me looking for an entry point. Catabasis has been on my radar since September of 2017, but the low share price has always pushed me away due to the risk of being delisted by NASDAQ for trading under $1.00 for 30 consecutive days . Well, the latest R/S has remedied that for me and forced me to do a refresh of the company’s current status in terms of pipeline, platform technology, competition, potential market, ability to commercialize, patent protections, financials, and technical analysis. This analysis not only convinced me to consider a position but ultimately made me realize CATB could be an acquisition target in the future.
I will present my thesis on why I think CATB is a potential acquisition target and also provide potential downside risks that could prevent it.
Source: CATB
Company Overview Catabasis is a clinical-stage biopharmaceutical company dedicated on the discovery, development, and commercialization of novel therapeutics derived from its proprietary Safely Metabolized And Rationally Targeted linker, or branded as SMART LinkerSM, drug discovery platform. The company’s SMART Linker drug discovery platform facilitates it to discover product candidates that can concurrently modulate several targets in a disease. Catabasis product candidates influence pathways that are pivotal to diseases where efficacy may be enhanced by addressing multiple targets. Catabasis has implemented its SMART Linker drug discovery platform to construct an impressive pipeline of product candidates for rare diseases.
The company’s lead product candidate is Edasalonexent (formerly CAT-1004), which the company has confidence in its potential to be a disease-modifying therapy for all patients impacted by DMD, irrespective of the primary dystrophin mutation. Edasalonexent is an orally administered, nuclear factor kappa-light-chain-enhancer of activated B cells “NF-kB” inhibitor. The FDA has granted Edasalonexent orphan drug, fast track and rare pediatric disease designations for the treatment of DMD. What is more, the European Commission “EC” has granted orphan medicinal product designation to Edasalonexent for the treatment of DMD.
NF-kB and DMD Background DMD is a rare pediatric disorder involving progressive muscle degeneration that eventually leads to death. DMD is caused by various mutations in the dystrophin gene that causes a reduction of functional dystrophin in muscle fibers, which exposes muscle fibers to increased mechanical stress. Dystrophin is a protein that is embedded in the membrane of muscle cells and is vital to the stability of muscle fibers in skeletal , diaphragm, and cardiac muscle . When muscles contract or stretch the lack of normally functioning dystrophin causes facilitation of the NF-kB pathway, thus, stimulating inflammation in the muscles, beginning of muscle degeneration, and decreasing the ability of muscles to regrow. As the process continues connective and adipose tissues “fat” replace muscle fibers , resulting in inevitable muscle weakness.
DMD occurs almost exclusively in males, occurring in approximately 1 in 3,500 live male births . Based on this incidence rate, the company estimates that DMD affects a total of approximately 15,000 patients in the United States “U.S.” and approximately 19,000 patients in the European Union “EU”.
Children with DMD typically start to show symptoms of disease between the ages two and five, when they display a waddling gait, high incidence of falls, and showing difficulty rising off the floor. Progressive weakness then progresses to deterioration of function in the arms, legs and axial body. The weakness typically develops into contractures of the joints. By the age of eight, most DMD patients have a hard time climbing stairs and could lose their ability to walk between the ages ten and fourteen. Sadly, DMD patients also experience the weakening of their cardiac and respiratory muscles and often require ventilators in their late teens. This weakening of cardiac and respiratory muscles of DMD patients eventually results in death, typically in the patient’s mid-twenties.
What is NF-kB’s role in DMD? NF-kB has the ability to regulate skeletal muscle mass in chronic diseases such as DMD. Activated NF-kB promotes the degradation of specific muscle proteins, which leads to the facilitation of pro- inflammatory mediators such as cytokines, TNF-a, interleukin 6, or IL-6, IL-1b; chemokines, cell adhesion molecules, and MMP-9. Furthermore, NF-kB suppresses muscle stem cell differentiation that is a necessity for muscle regrow by preventing satellite stem cells from differentiating into myoblasts, which turn into muscle cells. What is more, facilitation of NF-kB has been reported in muscle tissues of DMD patients just before the emergence of other disease indications.
Source: CATB
Pipeline Overview The company’s pipeline weighs heavily on Edasalonexent and the DMD programs. Looking at the chart below (Figure 1), we can see the company is progressing through the regulatory pathway and is approaching critical points in development.
Figure 1: CATB Pipeline (Source: CATB )
In September 2018, the company initiated its PolarisDMD trial , a global Phase III trial for the treatment of DMD. The PolarisDMD trial is designed to assess the efficacy and safety of Edasalonexent, with top-line results anticipated in Q2 of 2020. PolarisDMD enrollment in the U.S. is estimated continue into 2019. The company has other sites in Canada, Australia, Israel, and Europe; which are also projected to start enrolling in early 2019.
Source: CATB
PolarisDMD anticipates enrolling roughly 125 patients between the ages of four and seven, irrespective of mutation type, who have not been on steroids for at a minimum of six months. Boys may be qualified to enroll in the trial if they are on a stable dose of Sarepta Therapeutics ( SRPT ) EXONDYS 51 , (eteplirsen), which is exon skipping therapy approved in the U.S. For DMD. The primary efficacy endpoint is a positive change in North Star Ambulatory Assessment “NSAA” score after 12 months of treatment with Edasalonexent compared to placebo.
Source: CATB
The company is testing secondary endpoints which include: timed function tests, growth assessments, and cardiac and bone health. Enrolled boys are being randomized in a 2:1 ratio with two boys receiving Edasalonexent for every boy that receives placebo. At the conclusion of the study, the company will offer the patients the opportunity to receive Edasalonexent in an open-label extension.
Source: CATB
The company’s MoveDMD Phase 1/2 trial enrolled ambulatory (walking) boys four to seven years old with a genetically confirmed diagnosis of DMD who were steroid-naive or had used steroids for no less than six months preceding the trial. Similar to PolarisDMD, patients enrolled in the trial were not restricted to any specific dystrophin mutations. The 31 patients in the trial had 26 different dystrophin mutations . In Phase I of the MoveDMD trial, CATB measured the safety, tolerability, and pharmacokinetics “PK” of Edasalonexent in 17 patients, after seven days of dosing, the company reported that the three doses of Edasalonexent were, by and large, were “well tolerated, no safety signals observed, and there were no serious adverse events and no drug discontinuations.” During the Phase II portion of the trial, the company evaluated the operations of Edasalonexent by means of magnetic resonance imaging “MRI, T2” as an initial biomarker at 12 weeks, and declared in January 2017 the MRI T2 at 12 weeks revealed lower leg muscles for the pooled Edasalonexent treatment groups compared to placebo did meet primary endpoints. However, the company detected “directionally positive results” in the 100/mg/kg/day Edasalonexent treatment group.
Source: CATB
In MoveDMD’s open-label extension trial , the company has observed preserved muscle function and consistent improvements in all four assessments of muscle function at 72 weeks. The measures were significant compared to the rates of change in the “control period” for boys preceding dosing of Edasalonexent. Furthermore, the company has reported positive changes in non-effort-based measures of muscle health, which the company believes supports the durability of Edasalonexent treatment effects. Most notably, researchers observed statistically significant progress in the rate of change in lower leg composite MRI T2 through 12, 24, 36 and 48 weeks on 100 mg/kg of Edasalonexent treatment compared to the off-treatment control period.
Source: CATB
Using magnetic resonance spectroscopy “MRS,” researchers and physicians can differentiate the qualified proportion of fat in muscle “fat fraction”; which is linked with functional ability in DMD patients. At 48 weeks, the company determined positive improvements in the MRS fat fraction rate in the Edasalonexent treated patients matched to the off-treatment control period. The company inspected both soleus and vastus lateralis leg muscles, which are strongly related with ambulatory function (walking). Furthermore, the company reported that the heart rate of the boys treated with Edasalonexent significantly decreased toward age-normative values over a year and a half period of Edasalonexent treatment. Typically, patients with DMD are tachycardic, even at rest and is often associated with the death of these patients.
Source: CATB
Similar to previous Edasalonexent studies, treatment continued is well tolerated with no safety signals detected in the MoveDMD trial. Boys treated with Edasalonexent continued to follow age-appropriate growth curves with age-appropriate increases in weight and height and overall body mass index trended down to age-normative values. Furthermore, the study reveals substantial reductions in muscle enzymes through 72 weeks, which is when it will have a positive impact on muscle health and supportive of a positive impact from the treatment with Edasalonexent.
Adding BMD and Cardiac Function to Edasalonexent
In addition to DMD, the company is also evaluating Edasalonexent for the potential treatment of Becker muscular dystrophy “BMD.” BMD is a rare disease like DMD, and patients with BMD display low levels of dystrophin attributable to mutations in the dystrophin gene. Using a similar method of action, Edasalonexent will inhibit NF-kB and will boost dystrophin production.
On November 13, 2018, we announced a collaboration with University of Texas Southwestern, to explore the potential of Edasalonexent to improve cardiac function in DMD and BMD. This is a one-year preclinical will study cardiomyopathy as the leading cause of mortality in DMD and BMD. Catabasis already has some preclinical and clinical data to support the potential for cardiac benefits with Edasalonexent in DMD and BMD patients. By starting this collaboration, I expect the company to ready to expand Edasalonexent to more specific DMD and BMD indications.
Source: CATB
CAT-5571 & CAT-4001
Along with Edasalonexent, the company is working on a pipeline of product candidates for treatments for other rare diseases. The company’s pipeline includes CAT-5571, for cystic fibrosis “CF.” The company’s CAT-4001 product candidate is being developed for neurodegenerative diseases such as amyotrophic lateral sclerosis “ALS” and Friedreich’s ataxia “FA.”
CAT-5571 is a SMART Linker conjugate that contains cysteamine, a molecule that is a degradation product of the amino acid cysteine, and DHA. CAT-5571 is intended to repair the body’s defense by activating autophagy , a mechanism for reprocessing cellular components and break down pathogens, which is diminished in CF patients.
CAT-4001 is a SMART Linker conjugate that the company designed to combine the potentially beneficial activities of monomethyl fumarate and DHA on the Nrf2 and NF-kB pathways. CAT-4001 is a small molecule that activates Nrf2, and inhibits NF-kB, two pathways that have been implicated in FA and ALS. Nrf2 is a gene transcription factor, a protein that works inside of cells to manipulate the expression of genes that control the body’s response to cellular stress and oxidative damage. The company’s original plan was to complete the IND for CAT-5571 and to advance CAT-5571 into a Phase I clinical trial in the second half of 2018 and report top-line results in 2019. However, we have yet to see this come to fruition and still remains pre-IND.
SMART Linker Drug Discovery Platform
The company’s SMART Linker drug discovery platform allows it to discover product candidates that can simultaneously modulate multiple biological targets in a disease. The company’s proprietary product candidates impact pathways that are pivotal to diseases where efficacy may be enhanced by a multi-target approach. The company’s aim is to leverage the growing body of knowledge associated with disease pathways and to rationally design orally bioavailable product candidates that simultaneously interact with multiple biological targets in a disease. Although other conjugate technologies exist, the company believes that their platform provides notable improvements over previous approaches to bioactive conjugation.
The company’s SMART Linker drug discovery platform includes a broad array of linkers that the company uses to engineer molecular series that can simultaneously modulate multiple biological targets in a disease. The linkers used in its drug discovery platform are small chemicals designed to join two separate bioactives into a single conjugate molecule, and some linkers are also bioactives. While in systemic circulation, SMART Linker conjugates are characteristically stable and inactive, theoretically reducing off-target toxicities and side-effects. These conjugates are designed to be cleaved by specific enzymes exclusively within cells in order to release the two bioactives inside the cells. By releasing the bioactive components of the conjugate molecule inside cells, the SMART Linker allows the bioactives to reach their targets more efficiently and potentially have greater efficacy than if the bioactives were dosed independently or in combination.
Edasalonexent FDA and EC Designations
The FDA has granted Edasalonexent orphan drug, fast track and rare pediatric disease designations for the treatment of DMD. In order for a product to be designated as an “orphan drug” by the FDA, it has to be intended to treat a rare disease or condition affecting fewer than 200,000 individuals in the US. The benefit of Edasalonexent getting this designation is the FDA will not approve another product for the same use or indication for seven years if it able to get FDA approval.
The FDA fast track designation allows an expedited development and review process of drugs intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. This will allow Catabasis to submit NDAs on a rolling basis, expedite the FDA review process, and enable more frequent communication with the FDA to discuss all aspects of clinical development. Furthermore, Edasalonexent is eligible for accelerated approval and priority review if it is able to meet certain criteria.
The FDA’s rare pediatric disease designation gives it the potential to receive a priority review voucher if Edasalonexent is approved. However, the rare pediatric disease program is set to expire in September 2020, so Edasalonexent will not benefit for this in other indications.
In addition to the FDA, the EC has granted orphan medicinal product designation to Edasalonexent for the treatment of DMD. Similar to the FDA orphan drug designation, the orphan medicinal product typically leads to up to a ten-year period of market exclusivity if Edasalonexent is granted marketing authorization (approval) in the EU.
These designations are critical for Catabasis and Edasalonexent because they potentially allow a faster approval process and market exclusivity for an extended period of time. These benefits will save the company time and money but also help protect Edasalonexent from potential competitors past the average time-to-peak sales of 6 years (Figure 2).
Figure 2: Drug Launch Time-To-Peak Sales (Source Nature )
DMD Competition There are currently only two therapies approved in the US for the treatment of DMD. Sarepta Therapeutics’ ( SRPT ) drug EXONDYS 51, was approved by the FDA for the treatment of DMD for patients who have a confirmed mutation of the DMD gene that is responsive to exon 51 skipping. In addition, in February 2017, the FDA granted approval of PTC Therapeutics’ ( PTCT ) drug Emflaza , for the treatment of DMD in patients five years and older.
Source: SRPT
Although not previously approved for the treatment of DMD, corticosteroid therapy, including prednisone, is considered standard of care and is often prescribed to treat the inflammation underlying DMD and to delay loss of ambulation.
A number of companies are developing therapies to treat DMD in patients with specific mutations in the dystrophin gene. In addition to EXONDYS 51, Sarepta has two additional exon-skipping therapies for DMD in clinical development. These agents, SRP-4053 and SRP-4045, target skipping of exons 53 and 45, respectively. Other exon-skipping agents include:
Daiichi-Sankyo ( OTCPK:DSKYF ) – Exon 45 skipping candidate for DMD NS Pharma – exon 53 skipping candidate NS-065/NCNP-01. Wave Life Sciences Ltd. ( WVE ) – Exon 51 skipping candidate WVE-210201. Some other gene therapy companies include:
Solid Biosciences ( SLDB ) – SGT-001 Pfizer ( PFE ) – PF-06939926 Sarepta Therapeutics – GALGT2 In addition to exon-skipping therapies, other companies have alternative therapeutic approaches to the treatment of DMD in late-stage clinical development including Santhera ( OTCPK:SPHDF ), PTC Therapeutics, Italfarmaco S.p.A. , Akashi Therapeutics , Astellas Pharma (ALMPF), Capricor Therapeutics ( CAPR ), Cardero Therapeutics , Fibrogen ( FGEN ), and Reveragen .
PTC Therapeutics’ Emflaza is a corticosteroid indicated for the treatment of DMD in patients five years of age and older. Corticosteroids are often prescribed to treat the underlying inflammation in DMD and to postpone the loss of ambulation. In DMD patients, corticosteroids have established efficacy, which is assumed to be facilitated by reductions in activated NF-kB.
Source: PTCT
Conversely, corticosteroids primarily act through another pathway called the glucocorticoid receptor-mediated pathway and can create complications, including growth suppression, unwarranted weight gain, behavioral variations, decrease in bone strength and compromise of the immune system. Eventually, corticosteroids prompt chronic myopathy in many diseases through the initiation of muscle protein breakdown, which ultimately causes muscle damage. DMD patients treated with corticosteroids characteristically show an initial improvement in measures of muscle function but then recommence a progressive decline. Approximately half of DMD patients treated with steroids lose the ability to walk by age thirteen and the vast majority are in wheelchairs by age sixteen. Typically, DMD patients only live until their mid-twenties, even with the availability of corticosteroids.
Gene Therapy and Edasalonexent Being a gene disorder, it is obvious a gene therapy would be seen as the best route to ameliorate or cure DMD. Unfortunately, the large size of the gene is the cause for the elevated risk for mutations as compared to other genes. This makes this genetic disorder a bit more complicated and harder to pin down the exact exons to focus on. The mutations are typically categorized into out-of-frame mutations and in-frame mutations. The out-of-frame mutation disrupts the open reading frame “ORF” and prevents dystrophin from being expressed. Sometimes, the ORF is preserved despite the presence of a mutation, which is known as an in-frame mutation, culminating in a truncated yet functional dystrophin leading to a milder form of the disorder, called Becker muscular dystrophy “BMD”. BMD patients exhibit a later onset of the symptoms with slow progression and have a longer lifespan than DMD patients.
Variation in the severity of the disorder opened gateways to various therapeutics in order to ameliorate the severity to a milder phenotype, which is BMD. For example, patients exhibiting large deletions, sometimes encompassing almost half the gene, are associated with milder cases of BMD. Skipping the mutated exons and/or adjacent exons corrects the open reading frame “ORF”. Exon skipping therapy rescues the target protein using antisense oligonucleotides “AOS” by restoring the ORF.
The main aim of exon-skipping therapy is to slow down the progression of DMD by interfering with the splicing events thereby converting the severe symptoms to the milder ones as seen in BMD. This is the goal of Sarepta Therapeutics’ EXONDYS 51 AO called as a treatment for DMD. In 2016, the FDA conditionally approved this therapy, which targets exon 51 and is applicable for approximately 13% of patients. It is the targeting of exon 51 that could change DMD patient into BMD phenotype patient .
The therapeutic goal of these product candidates is to reduce disease severity and extend survival in those DMD patients who are candidates for therapy with these agents. Based on the prevalence of the specific mutations that EXONDYS 51 and ataluren are designed to address, they would be expected to be effective in an aggregate of approximately 26% of DMD patients. Catabasis believes that DMD patients, including those treated with these dystrophin-targeted therapies, will continue to require treatments to reduce muscle inflammation and degeneration and enhance muscle regeneration.
Edasalonexent Working Both Channels Based on the mechanism of action by which Edasalonexent suppresses NF-kB, the company believes that Edasalonexent has the massive potential to combine the reduction of inflammation and muscle degeneration with positive effects on muscle regeneration, which may allow patients to retain muscle function longer. In addition, the company believes that Edasalonexent can be an effective therapy for all DMD patients, regardless of the underlying mutation, and to provide significant benefit to patients, both as monotherapy and when used in combination with other therapies, including dystrophin-targeted therapies .
It is these attributes that make Edasalonexent a unique agent that could transform DMD treatment. Although gene therapy could eventually provide a universal treatment for DMD, at the moment, most DMD patients are still relying on corticosteroids to prolong their ambulatory capabilities. Edasalonexent is comprehensive and does not augment the efficacy of gene therapies.
In fact, back in September 2016, the company announced a pre-clinical joint research collaboration with Sarepta to explore a combination drug treatment approach for DMD. In the collaboration, Edasalonexent will be complementary to an exon-skipping treatment strategy. Although the company believes in Edasalonexent as a monotherapy, demonstrating safety and efficacy with a gene therapy will allow patients to remain on Edasalonexent even if they seek gene therapy.
What happens if gene therapy becomes universal for DMD? At the moment, gene therapy for DMD patients creates a BMD phenotype. A quick reminder, Catabasis is exploring Edasalonexent’s capability in BMD patients. Even if a DMD patient experiences a positive gene therapy, they will still need a product for their BMD phenotype… in steps Edasalonexent.
Intellectual Property Currently, Catabasis has six issued U.S. patents pertaining to the composition of matter and method of use claims directed to Edasalonexent. The other four patents affect CAT-5571 and the composition of matter and method of its use. The company expects these patents to expire between 2029 and 2030, not counting potential patent term extensions. On top of the U.S approved patents, CATB also has four U.S. patents pending applications. Into the bargain, the company has a strong ex-U.S. patent portfolio that includes over 70 issued foreign patents, and 19 pending foreign patent applications.
With regard to CAT-4001, Catabasis has two issued U.S. patents for CAT-4001 that relates to the composition of matter and method of use claims covering and also its use. Both of these patents are slated to expire in 2031. In addition, Catabasis has patents that have been granted in various countries and regions.
Financials At the end of Q3, Catabasis had about $43M in cash, cash equivalents and short-term investments (Figure 3). Catabasis believes it has enough cash to fund operations into the second quarter of 2020. The company paid off all principal and interest due to their creditors and currently has no debt.
Figure 3: Q3 Earning Report (Source CATB )
Downside Risks Catabasis has the standard downside hallmarks of most developmental biotech companies. Most notable are the financial requirements and regulatory risks of getting a product through the pipeline and commercialized. So far, Edasalonexent has had a smooth ride through the regulatory process and has multiple designations. However, if the company fails to properly manage a trial or regulatory submission, we can expect a delay and loss of market exclusivity, cash position, and overall potential profits.
The company currently has a healthy cash position in comparison to their expected cash burn. Nevertheless, as the company moves closer to commercialization it will require substantial increases in funds. The final phase III trials are long and require an extensive amount of patients and resources to finish. In addition, the commercialization process will require a manufacturing facility and hiring a sales force. Even though I expect the company to sign a contract manufacturer and sales force, we have to suspect a higher cash burn as Edasalonexent moves to the finish line. If Catabasis does not secure a commercial partner, we can expect a large fundraising event in the future and possible share dilution.
Why is CATB an Acquisition Target? When attempting to find acquisition targets in the biotech sector, I have a list of standards or criteria that need to be fulfilled in order to take a chance on the company being bought out. In this section, I have highlighted three of these criteria and how Catabasis checks them off.
Niche Product in an Underserved Population
Large biotech companies are always on the lookout for acquisition targets that have a unique niche in a particular population or field of medicine.
The larger company is able to sit back and wait till the smaller company has progressed through some or all of the regulatory pathway and has derisked their product. In addition, due to the cost of developing a drug or therapy being so high, the larger companies will rely on smaller companies to pick up the costs.
Catabasis is developing a niche drug in an underserved population. Although Edasalonexent still has a bit to go in the regulatory process, the product quickly moving through pathway due to multiple FDA and EC designations to expedite the process. If approved, Edasalonexent should have an instant impact on the market due to the lack of comparable products and market exclusivity. A larger company could be knocking on the door even before Edasalonexent receives regulatory approval.
Need for Cash
Although Catabasis is capable of fundraising and taking on debt, the final costs of commercialization and manufacturing will require a large number of finances. At the moment, the company has not made any commercialization deals or has signed any contracts for manufacturing. A larger company with commercial and manufacturing resources in place could seize the opportunity to offer a helping hand with of a buyout bid.
Clean Structure
When assessing a potential takeover target, the larger company will take a look at the corporate and financial structure of the company. A company with a limited amount warrants, preferred stock, and no debt is very attractive due to the potential of a clean deal. Catabasis has no warrants, bonds, elaborate partnership deals or contract, or debt. This would allow for a quick and straightforward deal with little chance of outside parties dictating the process or details.
Considering the points of above, I see Catabasis as a potential takeover target in the coming years as Edasalonexent gets closer and closer to its final regulatory processes. The company is structured for a clean acquisition deal, and Edasalonexent would be an instant addition to a larger company’s pipeline or product portfolio.
Is it a Buy Now? Regardless of a potential takeover bid, I find CATB to be a strong buy even at this point in its journey to be a commercial stage company. I believe current market cap of about $37M and its current price/book of ~1 tell me the stock is undervalued.
Figure 4: Valuation Summary (Source Seeking Alpha )
Even if we anticipate the company burning about $7M this quarter, the stock is still trading around a price/book of 1. The end of 2018 sell-off and low float R/S event has provided prospective value investors a great opportunity to buy at the holy grail P/B value of under 1. Furthermore, the company has enough cash to last till Q2 2020 and has no debt.
Considering these points, I find CATB to be a value buy at these trading levels.
Conclusion I will put CATB to be on my short list of acquisition targets for the next couple of years. Edasalonexent is potentially a game-changing product that should be effective for all DMD with a small number of adverse events. Not only has Edasalonexent demonstrated its ability to slow the progression of DMD but could also work in combination with other therapies. In addition, the company is targeting multiple indications for Edasalonexent in DMD and BMD. If approved, Catabasis will have multiple indications from one product.
The company has secured multiple FDA and EC designations that will expedite the regulatory process and provide market exclusivity. In addition, the company has a strong patent portfolio for Edasalonexent protecting the agent till 2029-2030.
Although I cannot predict if or when a deal would come to fruition, I can say the stock’s current market valuation has me searching for a good entry point. Looking at the daily chart (Figure 5), it appears I have to make up my decision sooner than later as the chart is starting to move out of its long-term downtrend.
Figure 5: CATB Daily (Source Trendspider )
I will use break above the 50-Day SMA to initiate my long position. I plan to buy and hold CATB for the long-term due to the potential of acquisition and the long-term prospects for Edasalonexent. Investors looking to initiate or add to their position should use technicals to manage their position.
Accurately forecasting the stock price in the near term is enigmatic. Considering this, I would like to stress caution that CATB is an extremely speculative stock. There is a risk that investors lose all or a substantial amount their investment. Although the upside of CATB is great, it is a long way from being free of risk.
Disclosure: I/we have no positions in any stocks mentioned, but may initiate a long position in CATB over the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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What Are Corticosteroids?

What Are Corticosteroids?

January 14, 2019 10:55am ET MORE Corticosteroids are often included in asthma medication to decrease inflammation and swelling in the airways. Credit: shutterstock
Corticosteroids are synthetic drugs that are used to treat a wide variety of disorders, including asthma, arthritis, skin conditions and autoimmune diseases. The drug mimics cortisol, a hormone that’s naturally produced by the adrenal glands in healthy people.
Cortisol, commonly called the “stress hormone,” is a steroid hormone (not to be confused with anabolic steroids, which are sometimes abused by athletes) that’s released in response to stress. It’s involved in a wide range of processes in the body, such as metabolism, inflammation, blood pressure regulation and bone formation, according to Johns Hopkins Medicine .
Corticosteroids work by decreasing inflammation and suppressing the immune system , according to Cleveland Clinic . Left untreated, excess inflammation can damage healthy tissue, as well as cause redness, swelling and pain.
The first use of corticosteroids dates back to 1948, when rheumatologists at the Mayo Clinic treated a patient who had debilitating rheumatoid arthritis , according to a 2010 article published in the journal Clinical Chemistry . The patient, who was treated with the then-experimental injectable drug, was able to walk out of the hospital after the third treatment and go on a 3-hour shopping spree, according to the author.
There are several types of corticosteroids, including cortisone, prednisone , dexamethasone, prednisolone, betamethasone and hydrocortisone. Cortisone was the first corticosteroid drug approved for use in the U.S., which happened in 1950, according to the U.S. National Institutes of Health . Corticosteroid benefits
Corticosteroids are often used as a anti-inflammatory medications and immune suppressants to treat arthritis, asthma, autoimmune diseases (including lupus and multiple sclerosis ), skin conditions (such as eczema and psoriasis ), some types of cancer (such as leukemia ), and the aftermath of organ transplant, according to the U.S. National Library of Medicine .
Depending on the specific treatment goal of the drug, it may be used orally, injected, inhaled or applied topically, according to the Mayo Clinic . Oral corticosteroids are typically used to treat and help control symptoms of chronic conditions, such as rheumatoid arthritis, by reducing inflammation throughout the body. Injected corticosteroids treat a specific location, such as inflammation or pain caused by tendinitis in a joint.
Corticosteroids are inhaled to treat asthma by reducing inflammation and swelling of the airways, and they can also help lower the risk or frequency of future attacks. Topical steroids are usually put into creams and ointments to treat and soothe skin conditions.
The immunosuppressive properties of corticosteroids are useful in treating diseases, such as lupus , in which the body’s immune system can’t properly distinguish between healthy cells and harmful ones. The drugs can also be beneficial in reducing the risk of rejection of a newly transplanted organ.
Corticosteroids are often used in conjunction with other treatments of lymphoid cancers, leukemia and tumors, where inflammation is a primary symptom, according to a 2016 article published in the journal Steroids . The corticosteroids prevent white blood cells from traveling to the site of inflammation, decreasing the swelling around tumors and the pressure on nerve endings to relieve pain, according to Chemocare . Corticosteroids are also prescribed to lessen the effects of chemotherapy symptoms such as nausea, vomiting and diminished appetite, although how the drugs work in those instances isn’t fully understood. Risks of corticosteroids
Although corticosteroids are effective medications, they can also have serious side effects.
For oral corticosteroids, these side effects may include glaucoma , fluid retention, high blood pressure and weight gain, according to the Mayo Clinic. There can even be psychological effects, including mood swings, confusion and behavior changes, the Mayo Clinic said. Taking the medication long term can also lead to cataracts, high blood sugar and diabetes , increased risk of infection from common bacteria and viruses , osteoporosis , suppressed adrenal-gland hormone production, and thin skin that has higher rates of bruising and slower wound healing.
When inhaled, corticosteroids may cause oral thrush (a fungal infection in the mouth) and hoarseness. These side effects are typically caused when some of the drug lingers in the mouth and throat after inhalation, instead of traveling to the lungs. The risk is typically minimized by rinsing and gargling with water, without swallowing, to clear any residual medication.
Application of topical steroids may lead to thin skin, red skin lesions and acne at the application site in some instances, according to the Mayo Clinic.
The side effects of injected corticosteroids may include temporary skin thinning, skin color loss and intense pain at the injection site, as well as facial flushing, insomnia and high blood sugar.
If a regiment of corticosteroids is prescribed by a doctor, there are ways to help minimize side effects. Patients should be sure to take the medication exactly as prescribed, eat a healthy diet with limit ed fat and salt and plenty of calcium and vitamin D , and exercise regularly to maintain strong bones and muscles, according to the University of Washington Orthopaedics and Sports Medicine .
Withdrawal symptoms may also occur if the medication is stopped suddenly or reduced too quickly. These can include muscle, bone and joint pain, nausea, weight loss and headache.
Long term use of corticosteroids may alter normal hormone production. For that reason, doctors may advise their patients to wear a medical bracelet or tag so that other medical professionals are aware of the patient’s’ corticosteroid use, and will alter treatment accordingly.
Additional resources: Learn more about the history of clinical research on corticosteroids from the National Institutes of Health. See the definition of corticosteroids and a list of inhaled corticosteroid medications from the American Academy of Allergy, Asthma and Immunology. Find out more about corticosteroids from the U.S. National Library of Medicine. You’d Also Like

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Fanconi’s anemia is a disease passed down through families (inherited) that mainly affects the bone marrow. It results in decreased production of all types of blood cells. Fanconi’s anemia is different from Fanconi syndrome, a rare kidney disorder…

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Swelling is the enlargement of organs, skin, or other body parts. It is caused by a buildup of fluid in the tissues. The extra fluid can lead to a rapid increase in weight over a short period of time (days to weeks). Swelling can occur all over th…

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Catabasis Pharmaceuticals: My Long Thesis And Analysis

<h1>Catabasis Pharmaceuticals: My Long Thesis And Analysis</h1>

Catabasis Pharmaceuticals: My Long Thesis And Analysis

Catabasis Pharmaceuticals has been on my speculative watchlist since September 2017 and now is on my potential acquisition target buy list. I present my thesis

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