9 Safe Apoquel Alternatives

<h1>9 Safe Apoquel Alternatives</h1>

9 Safe Apoquel Alternatives

9 Safe Apoquel Alternatives
By: Deva Khalsa VMD –
Reading Time: 14 minutes
Allergies in dogs have truly reached epidemic proportions. Most veterinarians keep over-vaccinating dogs (read on to find out why this is a problem) … and conventional allergy treatments only work to suppress the natural functioning of the immune system.
Because of this, the genetic tendency for allergies appears to be increasing. Generation after generation it gets worse for our dogs. Allergies have become so much worse; even some of the drugs that used to help, like steroids, don’t work well any more. We’ll talk more about steroids later.
What is that over-vaccination and the suppression of the immune system going to do in the future? The epidemic of allergies we see right now is due to these factors, and the situation is only getting worse. It’s high time that we make a brave attempt to alter this course of events.
We need some Apoquel® alternatives . And luckily, I’ve got them. But first…
Is It Really An Allergy?
An allergy is due to a misbehaving immune system . The immune system is reacting to something it shouldn’t be reacting to. Think of a person with peanut allergies. All his friends may be eating all kinds of peanut candies and peanut butter sandwiches, but he can’t touch them. Is the problem the peanuts or the immune system? That’s right, it’s the immune system. So how do conventional treatments handle this misbehaving immune system? By abolishing it. No matter what drug I mention below, it’s an immune system extinguisher.
Interestingly, food sensitivities and intolerances are actually 15 times more prevalent than bona-fide allergies. In fact, reactions to food lie at the base of the pyramid in the whole scheme of allergies. The environmental factors act as the straw that break the camel’s back.
Throwing A Wrench In The Works
Here’s the rub, as far as food sensitivities and intolerances go. The reaction takes from a week to a month to manifest itself. So you can feed your dog, let’s say lamb, and get no response between days 1 to 14 of feeding it. So you assume that lamb is just fine. When you finally do get a response on day 21, you have no idea what actually caused it.
The standard allergy tests that most vets use to find out what your dog is allergic to are only 15% accurate for foods . What that really means is that these tests are 85% inaccurate and you can’t trust them at all as far as foods go. The good news is that these tests are 85% accurate for environmental allergens. Yet if foods are the base of the allergic response, we really have to find out what foods are the culprits.
Testing For Allergies At Home
The NutriScan food sensitivity test is a saliva test done by Hemopet. You can visit the website and send the sample in yourself. It’s a reliable test for food sensitivities and intolerances. (Remember, this is what’s really happening.) The thing is, you may find your dog is allergic to an amazing number of foods and be at a loss about what to feed.
I recommend you repeat the test every 6 months as the foods your pet reacts to will change with time.
Find three different meals that agree with your dog and rotate on a three-day basis. This will prevent him from developing an allergy to the food.
There’s another problem with finding out exactly what’s causing the allergies. Foods have compounds in them called phenolics. Phenolics create the taste and smell in foods and other substances. They’re in vegetables, fruits, meats, poultry, fish and potatoes. One particularly notorious phenolic is named gallic acid and it’s in 70% of foods. The issue: tests don’t check for phenolic sensitivity.
Often owners of dogs with “allergies” finally find a food that agrees with their best friend. Joyfully, we run and put Fido on the food and feed it every day. Why not? He loves it and either the itching or diarrhea or both are handled when he is eating it. Here’s the problem. Feeding the same food day after day will almost guarantee that an immune reaction will develop.
Here’s a perfect example: vets snap on talc-powdered latex examination gloves many times a day. As time passes we become allergic to the talc. Give it a little more time and we become allergic to the latex. Folks who never use examination gloves will not get this allergy.
That’s why the best way to go is to find three different meals that agree with your dog and rotate on a three-day basis. This will prevent him from developing an allergy to the food.
A Little History Of Conventional Allergy Drugs
It used to be that steroids, such as prednisone, were dispensed too excessively. Veterinarians had little choice about what to use for dogs with allergies. Steroids worked because they suppressed the immune system so well. But, dogs would wind up drinking and urinating too much and losing their fur when taking these steroids. That’s why dogs were weaned off as soon as they were comfortable again. Of course the fix was only temporary. Within weeks or months most doggies would have to go back on another round of steroids. Lots of dogs had seasonal allergies so they would go on prednisone in, let’s say, just the spring and fall seasons. At least they were only on these immune-suppressing drugs for short stints.
Feeding the same food day after day will almost guarantee that an immune reaction will start.
But then, steroids like prednisone and dexamethasone simply stopped working well. Dogs would take it and it did little for the itch.
Just about this time, a drug called Atopica (cyclosporine) became available. Some veterinarians began using Atopica instead of steroids. Yet, the side effects of Atopica were considerably worse.
Cyclosporine was developed in Switzerland in the 70s. It was designed to prevent the rejection of organs in transplant patients. In order to do this, it had to knock the immune system to smithereens. Dogs were getting cancer (one of the many side effects of cyclosporine) because they were on this drug.
That’s why, when Apoquel came onto the market, it seemed to be a dream come true. There was no excessive drinking as with steroids. There were no apparent serious side effects as with cyclosporine. Dogs simply stopped itching and were, once again, comfortable in their own skin. Veterinarians loved it, as it worked well in just about every case. The dogs loved it because they stopped itching. Pharmaceutical companies and vets loved it because people had to buy it and refill it each month … for the dog’s entire life.
Dogs weren’t taking it for some short period in the spring or fall when they had their allergies. Once they started Apoquel, the dog would seem to need it forever. Once again, Apoquel doesn’t cure, but merely suppresses the allergic symptoms.
Apoquel works because it slays the kinases, which serve as the communicators in the body.
Unlike steroids, it’s very difficult to get dogs off Apoquel. When I treat a dog to eliminate her allergies, I reprogram her immune system. I occasionally have to put the patient on prednisone for a very short period. This is because the capacity for internal communication in the body is compromised. Apoquel destroys the communication system. There has to be an immune system in place in order to correct it.
How Does Apoquel Work?
Exactly how is Apoquel getting the immune suppression job done?
Apoquel works because it slays the kinases, which serve as the communicators in the body. Kinases coordinate absolutely everything in the body with one communicating to the other. Think of it just like a big happy Italian family. Kinases never stop communicating. One talks to another and that one talks to 100 more kinases and the body’s functions get organized.
Kinases are the repair and regeneration mechanism of the body. They are the communicators and communicate between cells.
They have enormous diversity. They play a critical role in cellular communication and signaling.
Kinases send signals and perform regulatory complex processes in cells.
Dogs who get Apoquel become dependent on it. Allergies are often even more severe when the owner tries to wean their dog off it.
Kinases actually activate stem cells. Stem cells are our dogs’ internal repair system. They divide essentially without limit to replenish other cells. Each new cell either remains a stem cell or becomes another type of cell with a specialized function. These could be muscle cells, red blood cells or brain cells.
Kinsases are used extensively to transmit signals and control complex processes in cells. Up to 518 different kinases have been identified in humans.
Mutations in kinases that lead to a loss-of-function can cause cancer and disease .
The bottom line is that APOQUEL stops important kinases from functioning in your pet’s body. Apoquel obliterates several very important kinases to knock the immune system to smithereens.
And this particular allergy fix is addictive. Dogs who get Apoquel become dependent on it. Allergies are often even more severe when the owner tries to wean their dog off it. It’s a winning situation for the pharmaceutical companies as they get to sell this drug for a dog’s lifetime …
… until they develop cancer. One of the kinases Apoquel snuffs out is the one that searches for cancer cells.
Note: The drug Cytopoint was developed because it neutralizes only one kinase. That said, the communication between kinases is interdependent on many different kinases communicating. So the safety of Cytopoint remains in question.
Preventing Allergies In The Future
When there were fewer vets on the planet, vaccines were given to puppies and not repeated on a yearly basis. Vets had plenty of business and didn’t need to send out annual reminder cards. These old-fashioned vets were doing it right. One puppy shot for distemper and parvovirus after 18 weeks is GOOD FOR LIFE.
Of course now your vet will probably try to convince you to pay out for other vaccines. Leptospirosis, Lyme, kennel cough and canine flu vaccines – this list goes on. Just don’t buy into the hype . The first three are bacteria. Vaccines against bacteria have to be given at least 2 to 3 times a year to be effective. And the kennel cough vaccine? It doesn’t even prevent the disease: it simply lessens the severity.
The thing is, these unnecessary vaccinations and the suppressive treatments have an effect. Dogs with allergies are being treated with drugs that suppress the immune system … drugs that screw up the inter-body communication. What kind of offspring will these dogs give birth to?
Dogs have 10 times more mast cells on their skin than people do. If we were built like a dog, we’d be itching our behinds and inner thighs during ragweed season.
How many allergic dogs will we have in the next 10 years? Will the percentage double? I personally think it will go up, not twice, but at least 10 times.
So what’s the first thing I want you to know about allergies? You shouldn’t, and I cannot stress this enough, over-vaccinate. Minimize toxins and minimize vaccines . I’ve specialized in treating dogs with allergies for 40 years. And I create a non-allergic dog using natural methods. But I’ve seen allergies return right after dogs are vaccinated again. Dog gets better. Dog isn’t itching for years. Dog gets vaccinated and it all starts up again.
Preparation For Dogs On Apoquel
As Benjamin Franklin said, “An ounce of prevention is worth a pound of cure.” This certainly applies to doggy allergies.
If you’re reading this blog, your dog may be on Apoquel already. I’ve got to warn you about what happens when you stop the Apoquel. Oftentimes, the itching that established the need for Apoquel will now be much worse. With steroids (prednisone), you’d just stop them and then it would take a while for the itching to come back.
It’s not so with Apoquel. The itching often comes back with a vengeance . I suggest that you have a natural substance at the ready (you’ll find these below). Don’t stop and wait to see what happens. You will, most likely, need something within a day or so of stopping the drug.
Allergies Can Be Complicated By Other Issues
Allergies do not, only or always, exist as an island in themselves.
Other problems can occur, either alone or in addition to allergies. And these problems can cause itching.
Something like sarcoptic mange (scabies) can look just like allergies. This is particularly true if the owner is doting and cares very well for the dog. In veterinary school, we’re taught the classical picture of scabies is a dog with crusts on the edges of his ears. I can say, with certainty, that I almost never see a case of scabies that looks like that. What I see are dogs who stop and itch when they’re doing something interesting. Sometimes the owners can have red bumps, particularly if they sleep with a dog who has it. It’s hard to diagnose with routine skin scrapings as the mite lives really deep in the skin. The best way to know if your dog has scabies is to treat it with Ivermectin. After the second dose (not the first) the itching will dramatically decrease. If your breed cannot tolerate Ivermectin you can use Revolution to treat it.
Dogs with allergies are being treated with drugs that suppress the immune system … drugs that screw up the inter-body communication.
Another complication is malasezzia. Malassezia is a yeast that normally lives on a dog’s skin and when it overgrows – boy is it itchy! I cannot stress this enough. Some dogs just have the yeast and treating it with an enzyme shampoo will help. But dogs with allergies tend to get inflamed skin and so the yeast has a super opportunity to overgrow. The itching of the allergy and of the yeast both combine to create a very, very itchy dog.
There’s still more. Dogs with allergies can often get a secondary bacterial infection, so you have to watch for that. A secondary bacterial infection is not uncommon in dogs on Apoquel. Demodex infections – a mite that grows in immune compromised dogs – also occurs.
In some cases, you’re treating for a myriad of problems at once. Allergies, insensitivities, intolerances, malasezzia yeast and secondary bacterial infection can all be common.
What can we do for dogs with allergies? Are there any alternatives to Apoquel? The answer to that question is a resounding yes.
Apoquel Alternatives
There are important Apoquel alternatives out there. I always prefer an allergy elimination therapy . Who wants to give natural itch relieving products, change dog food constantly, or read labels with a magnifying glass? You can change foods till the cows come home but you can’t avoid every blade of grass and every pollen or mold. Allergy elimination therapy is a simpler solution.
Stuff to do to avoid the allergic reactions:
Feed a rotating diet . Use a novel protein , which is a protein that your dog has never had before. Use novel ingredients. Try feeding rabbit based food as rabbit has one rare phenolic and contains no gallic acid. Get an air purifier for your home. Nip the itch in the bud with a topical product that works to calm the area in which it starts. Test Vitamin D3 levels . 75% of dogs fed commercial food are D3 deficient. Vitamin D levels have found to be very important when it comes to allergies. Here are some things you can use help the itch.
Remember – many allergic dogs are allergic seasonally. You can give these products during the common allergy seasons in dogs, the spring and fall. Another important point is that it’s difficult to get dogs off of Apoquel, so you need something on hand.
Chinese Herbs : Zhu Dan Tablets from Seven Forests can help with the itch. Give:
½ pill to 1 pill twice a day for a smaller dog 1 pill two to three times a day for a medium dog 2 pills two or three times a day for a large dog I recommend giving these with a meal.
Histoplex by Biotics Research. Give:
A small dog can get ½ pill twice a day Medium dog 1 pill twice a day A large dog can have up to 3 pills twice a day while 2 pills twice a day usually suffices. Betathyme – a naturally formed steroid that can help to stop that itch. Follow the directions on the label.
Atronex by Standard Process – is a very nice product that helps to curb the itch. Like Betathyme, follow the directions on the label.
Topical Solutions
Dogs have ten times more mast cells on their skin than people do. If we were built like a dog, we’d be itching our behinds and inner thighs during ragweed season. And, just like with people, your dog’s itching makes things worse. Itching increases the intensity of the itching because it activates more mast cells. When your mother told you that the more you itched that mosquito bite, the more it would itch, she was spot on!
What I’m trying to say with all this is that if you can nip the first itchy spot in the bud, you’re way ahead of the game. Itching begets itching and if we can handle the first set of itches we may be able to win the battle.
Derma Drops by Spa Diggety Dog – get these on the spot fast Zymox spray on or crème formula for hotspots Baking Soda – make a poultice and slurry it on the area NuStock – a dependable product to nip itching in the bud Allergy Elimination
While topical solutions win the battle, allergy elimination wins the war. That’s because it can correct the immune system’s perception of the item as an allergen. This turns the allergic dog into the non-allergic dog.
Allergy Elimination techniques began with Nambudripad’s Allergy Elimination Technique (NAET). Forty years of experience taught me that pet owners may easily do a similar program in the comfort of their own home.
My years of experience have allowed me to untangle and decode the basic items that pets need to be treated for. Allergy elimination techniques will naturally reboot, harmonize and revitalize your pet’s inappropriate immune system responses. It corrects the immune system so it behaves correctly and doesn’t overreact.
Some pets will need a direct consultation to assess and go over long term skin problems. For dogs with a less complicated history, they can often be helped with an at home kit.
For dogs with allergies and the owners watching them itch, Apoquel looked like a miracle. Unfortunately, it turned out to be anything but. The negative effects of this drug (as well as the others used to treat allergies) are now well known. Thankfully these Apoquel alternatives are things you can try to mitigate the risks and keep your dog safe and allergy free.
Deva Khalsa VMD
Since beginning her holistically oriented veterinary practice over 25 years ago, Dr Deva Khalsa has been incorporating homeopathy, acupuncture, Chinese herbs and nutritional advice into her practice. She also offers her unique Allergy Elimination 4 Pet technique to naturally reboot your pet’s inappropriate immune system responses. She’s the author of Dr Khalsa’s Natural Dog, now in its second edition. Visit her online at doctordeva.com

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The Sunshine Vitamin!

<h1>The Sunshine Vitamin!</h1>

The Sunshine Vitamin!

April 3, 2019
VITAMIN D3!
Vitamins are extremely important for proper functioning of various body systems. Vitamin D3 plays a very crucial role in proper functioning of bones and joints. Deficiency of this vitamin is quite common but can be identified and managed easily. Read on to know more about its functions, causes of deficiency, symptoms and management.
Function: Vitamin D3 is essential for the absorption of calcium from the food that is consumed. A decrease in the amount of vitamin D3 leads to poor calcium absorption, resulting in thin, soft, brittle bones.
Some of the possible causes of vitamin D3 deficiency (and ways to manage them) are listed below: Reduced intake: People with a strict vegan diet may be consuming reduced amounts of this important chemical. Most natural food sources are animal based including fish, fish oils, fortified milk, egg yolks and beef liver. Limited sun exposure: People who spend a lot of time indoors are likely to have this deficiency. People who wear sunscreen constantly, wear long robes for religious reasons, live in the polar areas; upper/lower hemispheres are all prone to vitamin D3 deficiency. Darker complexion: The body’s ability to make vitamin D3 when exposed to the sun is reduced if there is more melanin in the skin. Obesity: Vitamin D is extracted from the blood by fat cells and people with BMI of more than 30 have a vitamin deficiency.
Symptoms: While some people may go completely asymptomatic with this condition, others could develop significant symptoms. Bone pain and aches: When there is less calcium getting incorporated into the bones, pains and aches leading to fatigue are common. Depression: The areas of the brain that regulate mood contain vitamin D receptors, and low levels of this vitamin can lead to depression. They are also at higher risk of developing cognitive conditions like schizophrenia, Alzheimer’s and dementia. Gut problems: Vitamin D is fat soluble and in people with stomach conditions like Crohn’s or IBD, the gut functioning is altered and so vitamin D absorption is reduced. Increased risk of heart disease: Both the risk of developing heart disease and the severity of the disease went up considerably when there is vitamin D deficiency. This is given their role in controlling inflammation and improving immune function. Lesser chances of surviving cancer: In patients with colorectal cancer, lymphoma, and breast cancer, increasing vitamin D levels improved cancer prognosis by 4%. The chances of developing prostate cancer also increased in patients with vitamin D3 deficiency.
Management: Providing the required amounts of vitamin D3 through diet and supplements is the best way to manage this. Very few foods in nature contain vitamin D. The flesh of fatty fish (such as salmon, tuna, and mackerel) and fish liver oils are among the best sources. Small amounts of vitamin D are found in beef liver, cheese, and egg yolks. Vitamin D in these foods is primarily in the form of vitamin D3 and its metabolite 25(OH)D3. Some mushrooms provide vitamin D2 in variable amounts. Mushrooms with enhanced levels of vitamin D2 from being exposed to ultraviolet light under controlled conditions are also available.
Health Risks from Excessive Vitamin D
Vitamin D toxicity can cause non-specific symptoms such as anorexia, weight loss, polyuria and heart arrhythmias. More seriously, it can also raise blood levels of calcium which leads to vascular and tissue calcification, with subsequent damage to the heart, blood vessels, and kidneys. The use of supplements of both calcium (1,000 mg/day) and vitamin D (400 IU) by postmenopausal women was associated with a 17% increase in the risk of kidney stones over 7 years in the Women’s Health Initiative. A serum 25(OH)D concentration consistently >500 nmol/L (>200 ng/mL) is considered to be potentially toxic.
Excessive sun exposure does not result in vitamin D toxicity because the sustained heat on the skin is thought to photo-degrade pre-vitamin D3 and vitamin D3 as it is formed. In addition, thermal activation of pre-vitamin D3 in the skin gives rise to various non-vitamin D forms that limit formation of vitamin D3 itself. Some vitamin D3 is also converted to non-active forms. Intakes of vitamin D from food that are high enough to cause toxicity are very unlikely. Toxicity is much more likely to occur from high intakes of dietary supplements containing vitamin D.
Long-term intakes above the UL(Upper Limit) increase the risk of adverse health effects. Most reports suggest a toxicity threshold for vitamin D of 10,000 to 40,000 IU/day and serum 25(OH)D levels of 500–600 nmol/L (200–240 ng/mL). While symptoms of toxicity are unlikely at daily intakes below 10,000 IU/day, the FNB pointed to emerging science from national survey data, observational studies, and clinical trials suggesting that even lower vitamin D intakes and serum 25(OH)D levels might have adverse health effects over time. The FNB concluded that serum 25(OH)D levels above approximately 125–150 nmol/L (50–60 ng/mL) should be avoided, as even lower serum levels (approximately 75–120 nmol/L or 30–48 ng/mL) are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly .
The FNB committee cited research which found that vitamin D intakes of 5,000 IU/day achieved serum 25(OH)D concentrations between 100–150 nmol/L (40–60 ng/mL), but no greater. Applying an uncertainty factor of 20% to this intake value gave a UL of 4,000 IU which the FNB applied to children aged 9 and older and adults, with corresponding lower amounts for younger children. Interactions with Medications
Vitamin D supplements have the potential to interact with several types of medications. A few examples are provided below. Individuals taking these medications on a regular basis should discuss vitamin D intakes with their healthcare providers. Steroids
Corticosteroid medications such as prednisone, often prescribed to reduce inflammation, can reduce calcium absorption and impair vitamin D metabolism. These effects can further contribute to the loss of bone and the development of osteoporosis associated with their long-term use. Other medications
Both the weight-loss drug orlistat and the cholesterol-lowering drug cholestyramine can reduce the absorption of vitamin D and other fat-soluble vitamins. Both phenobarbital and phenytoin, used to prevent and control epileptic seizures, increase the hepatic metabolism of vitamin D to inactive compounds and reduce calcium absorption. By, N.B. Harini M.Sc(Clinical Nutrition)., RD., Certified Diabetes Educator. Related

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Pembrolizumab With Chemotherapy in Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung Neuroendocrine Carcinoma

<h1>Pembrolizumab With Chemotherapy in Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung Neuroendocrine Carcinoma</h1>

Pembrolizumab With Chemotherapy in Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung Neuroendocrine Carcinoma

You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Pembrolizumab With Chemotherapy in Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung Neuroendocrine Carcinoma The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT03901378 Recruitment Status : Not yet recruiting First Posted : April 3, 2019 Last Update Posted : April 3, 2019 Information provided by (Responsible Party): Robert Ramirez, Ochsner Health System Study Details Study Description Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Brief Summary: The purpose of this study is to test the efficacy, safety, and tolerability of the combination of chemotherapy treatment, which could be either Cisplatin or carbonplatin and etoposide, and the research study drug, Pembrolizumab (also known as MK-3475) in patients with high grade neuroendocrine carcinomas of the gastroenteropancreatic system or lung who are chemotherapy naïve. The chemotherapy treatment you receive will be either Cisplatin or carbonplatin and etoposide. the participant’s doctor will discuss this choice with you and determined which chemotherapy treatment is best for you. Condition or disease Neuroendocrine Carcinoma Large Cell Neuroendocrine Carcinoma of the Lung High Grade Neuroendocrine Carcinoma, Any Site Drug: Pembrolizumab Phase 2 Detailed Description: Combination chemotherapy is the mainstay of treatment for patients with high grade GEPNETs and neuroendocrine carcinomas of the lung. This study will utilize pembrolizumab, a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus blocks a protective mechanism of cancer cells and thereby allows the immune system to destroy them, in combination with chemotherapy. Combination chemotherapy and pembrolizumab was recently FDA approved and ongoing trials are utilizing this or similar combination with preliminary data demonstrating a promising safety profile. Study Design Go to
Layout table for study information Study Type : Treatment Official Title: A Phase II Trial of Pembrolizumab in Combination With Cisplatin or Carboplatin and Etoposide in Chemotherapy naïve Patients With Metastatic or Unresectable High Grade Gastroenteropancreatic or Lung (Excluding Small Cell) Neuroendocrine Carcinoma Estimated Study Start Date : Arms and Interventions Go to
Intervention/treatment Experimental: Single Arm Pembrolizumab 200mg IV day 1 with Carboplatin AUC 6 IV day 1 or Cisplatin 80mg/m2 day 1 with etoposide 100mg/m2 days 1-3 of 21 day cycle. Repeat 4-6 cycles to be followed by maintenance Pembrolizumab 200mg IV day 1 every 21 days until progression or intolerance for up to 2 years. Drug: Pembrolizumab Intravenous administration of pembrolizumab in combination with cisplatin or carboplatin and etoposide in first line metastatic or unresectable high grade neuroendocrine carcinoma: Outcome Measures Go to Progression Free Survial [ Time Frame: 1 year ] Assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Secondary Outcome Measures : Combination therapy will be safe and tolerable compared to historical controls [ Time Frame: Continuous from the signing of the informed consent to 28 days after last study treatment ] Collection of any adverse evernt Eligibility Criteria Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Layout table for eligibility information Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: Be willing and able to provide written informed consent/assent for the trial. Be 18 years of age on day of signing informed consent. Must have cytologically or histologically proven high grade neuroendocrine carcinoma of the gastroenteropancreatic system or large cell neuroendocrine carcinoma as defined by the 2010 WHO classification. a. GEPNETs need to have Ki-67 greater than 55%. Have metastatic or unresectable disease. No prior systemic chemotherapy or immunotherapy for metastatic disease allowed. Concurrent use of somatostatin analogs is allowed for symptom control. Life expectancy greater than 12 weeks. Have measurable disease based on RECIST 1.1. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor/PI. Have a performance status of 0 – 1 on the ECOG Performance Scale. Demonstrate adequate organ function. All screening labs should be performed within 10 days of treatment initiation. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. Exclusion Criteria: Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Has a known history of active TB (Bacillus Tuberculosis) Hypersensitivity to pembrolizumab or any of its excipients. Has had prior systemic anti-cancer therapy for metastatic or unresectable neuroendocrine tumors other than somatostatin analogs. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Has an active infection requiring systemic therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). Has a known history of Human Immunodeficiency Virus (HIV). Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed. Contacts and Locations Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03901378 Contacts Layout table for location contacts Contact: Sarah Nowak

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Systemic Lupus Erythematosus Autoimmune Disorder

Systemic Lupus Erythematosus Autoimmune Disorder

Tuesday, April 2, 2019 Systemic Lupus Erythematosus Autoimmune Disorder Systemic Lupus Erythematosus Auto repellent DisorderAUTOIMMUNE DISORDERSThe tolerant system is an important system within the human clay that defends against unsoundness and internal malfunction. When there is an invader or a pathogen, the bodys immune system responds accordingly, usually ruining the pathogen before it potty infect the body and cause illness. The immune system alike aids identify malfunctioning cells and eliminates them before faulty desoxyribonucleic acid is replicated. autoimmune disorders continue when the immune system of a immenseanimous no monthlong identifies foreign versus self correctly. The immune system of a patient with an autoimmune disorder entrust beset the bodys cells or tissues causing ruin or death. (Lettre Rioux, 2008).autoimmune disorders arsehole be genetically predisposed, but erect because a patient is predisposed to a particular disorder does not mean they will necessarily experience it. Often times, autoimmune disorders occu r through a combination of genetic predispositions and environmental f transactionors. This means a patient may have a genetic predisposition for general lupus erythematosus but the disorder is triggered by an invading virus the patient encounters and precisely thereafter do they suffer from the symptoms of disseminated lupus erythematosus. There argon now 68 genetic precursors that argon linked to the development of autoimmune disorders, while in the past only about 15 had been set. Symptoms of autoimmune distempers vary depending on what part of the body the immune system is assail (Understanding Autoimmune Diseases, 2016) (Lettre Rioux, 2008). inwardly the immune system there argon several types of cells. B-cells and T-cells play rudimentary roles within the immune system and in autoimmune diseases. There are two types of T-cells, CD4 T- processer cells that identify an invader and make the antibody creating B-cells aware and CD8 cytotoxic T-cells which will destroy a pre viously encountered threat without stimulating the creation of antibodies by B-cells. CD4 T-cells are in any case known as regulatory T-cells (Treg cells). These Tregs play a role in preventing autoimmunity by maintaining the ability to identify self. When these cells no longer identify self properly or at all, an autoimmune disease occurs. When T-helper cells do not identify self-versus-foreign properly they stimulate B-cells to create antibodies to destroy the bodys tissues or cells, called autoantibodies, or the cytotoxic T-cells will destroy the tissue or cells of oneself. (Venes et al., 2005, pp. 132, 135, 203, 204) (Corthay, 2009) (Hampe, 2012).disseminated lupus erythematosus or Systemic Lupus Erythematosus is an autoimmune disease most ordinarily characterized by crossroads pain (arthralgia) and swelling (edema). systemic lupus erythematosus thunder mug also cause fatigue, mouth sores, sensitivity to sunlight, and butterfly rash crosswise the cheeks and odorize of the face, and hair loss. Other symptoms depend on where the body is being attacked by the immune system. For instance, if the immune system of a patient with disseminated lupus erythematosus is attacking the heart of the patient an additional symptom of arrhythmia may be experienced. (Systemic Lupus Erythematosus, 2016).Diagnosis of SLE can be difficult as it can be associated with varying symptoms. A runnel known as antinuclear antibody analyze (ANA) is use to help diagnose SLE. An antinuclear antibody is an antibody created by the patients immune system to attack the bodys tissues and cells. Some ANA tests are enzyme-linked immunosorbent assay (ELISA) and indirect florescent antibody (IFA). These tests examine how many antinuclear antibodies are present in a patients blood. ANA tests are used when the autoimmune disease may be affecting much than one area of the body this is called a systemic autoimmune disease. Because SLE is systemic, an ANA test helps confirm that SLE is the dia gnosis as opposed to rheumatoid arthritis. However, having a positive ANA test does not mean that a patient has SLE. SLE is often misdiagnosed as rheumatoid arthritis because they share common symptoms such as edema and arthralgia this is why doctors often use an assortment of early(a) tests to diagnose SLE, along with a physical exam as four of the eleven common symptoms of SLE must be present before a patient can be diagnosed. Some of those common symptoms were listed above butterfly rash across the face, occasion pain, sensitivity to sunlight, hair loss, fatigue, and edema. (Antinuclear Antibody, 2017)(Starkebaum, 2016)(Bocco, 2017).Systemic Lupus Erythematosus can be handle but not cured. Because it is an autoimmune disease, SLE is treated with immunosuppressives. Hydroxychloroquine (HCQ) is an immunosuppressant that slows down the immune system and its attack on the bodys tissues and cells. HCQ was originally used in the treatment of malaria and is known as a disease-modify ing anti-rheumatic drug (DMARD). It is recommended that patients diagnosed with SLE warmly start a HCQ regiment as this drug help prevent further dam mount from the disease process. HCQ is usually used in chorus with other pain relief drugs because HCQ itself does not provide immediate pain relief. NSAIDS (nonsteroidal anti-inflammatory drugs) are often used in reciprocal pain management for patients with SLE. Over time, HCQ will help relieve joint pain in SLE sufferers as well as help stop further damage to any other affected variety meat and joints. Corticosteroids are often also prescribed to those with SLE as joint pain is a prominent symptom of SLE. Corticosteroids mimic naturally produced conceptive anti-inflammatory substances within the body. However, treatments come with endangerment positionors. In rare cases, HQC can cause retinopathy retinopathy is when vision is altered or complete blindness occurs. Likewise, long term use of corticosteroids has adverse effects in cluding osteoporosis, hyperglycemia (high blood sugar), and cataracts. back breaker of corticosteroids are adjusted for long term use in patients with SLE to avoid these side effects and routine eye exams are do on those using HCQ to prevent retinopathy. (Plaquenil (hydroxychloroquine), 2014) (Bartels, 2016) (Mayo Clinic Staff, 2015).Systemic Lupus Erythematosus predominantly affects women. Research suggests this is due in part to oestrogen. For every one man diagnosed with SLE, there are nine to twenty women diagnosed. Within the population of women who are at risk for SLE, women who are not white are at a higher(prenominal) risk for SLE as well as women under the age of 15 and over the age of 45. The discrepancy in race may have to do with the fact that colored females have higher record levels of estrogen than do white females. Estrogen is thought to make women more susceptible to an autoimmune disease such as SLE because of its intracellular transcription ability to alter DNA . The effects of estrogen have also been studied holistically in association with the disease. Estrogen may encourage systemic inflammation in SLE and affect the severity of the disease and neat instances of it. Although estrogen has been identified as causing inflammation it has also been identified as prohibiting inflammation thus meaning estrogen can act oppositely as it does in SLE in terms of other autoimmune disease. The discrepancy between the genders cannot completely be accounted for primarily with estrogen levels, however. Sex hormones are not the only determining factor for autoimmune diseases, others include epigenetics, infections, genetics, and external environment. (Pierdominici Ortona, 2013, pp. 25-27) (Khan Ahmed, 2015) (Isherwood Witter, 2012)ReferencesAntinuclear Antibody (ANA). (2017, March 22). Retrieved March 23, 2017, from Lab Tests Online website https//labtestsonline.org/understanding/analytes/ana/ assay/test/Bartels, C. M. (2016, September 19). Systemi c Lupus Erythematosus (SLE) Treatment and Management (H. S. Diamond, Ed.). Retrieved March 23, 2017, from Medscape website http//emedicine.medscape.com/ name/332244-treatmentBocco, D. (2017, January 3). The Difference Between Lupus and RA (N. Carteron, Ed.). Retrieved March 23, 2017, from Healthline website http//www.healthline.com/health/lupus-and-raOverview1Corthay, A. (2009, June 27). How do regulatory T Cells Work? Retrieved March 22, 2017, from NCBI website https//www.ncbi.nlm.nih.gov/pmc/articles/PMC2784904/Hampe, C. S. (2012, September 23). B Cells in Autoimmune Diseases. Retrieved March 22, 2017, from Hindawi website https//www.hindawi.com/journals/scientifica/2012/215308/Hansen, M. S., Schuman, S. G. (2011, June). Hydroxychloroquine-Induced Retinal Toxicity. Retrieved March 23, 2017, from American Academy of Ophthamology website https//www.aao.org/eyenet/article/hydroxychloroquine-induced-retinal-toxicityIsherwood, D., Witter, J. (2012, July 16). Lupus fact sheet (B. Diam ond, Ed.). Retrieved March 24, 2017, from Womenshealth.gov website https//www.womenshealth.gov/publications/our-publications/fact-sheet/lupus.htmlKhan, D., Ahmed, S. A. (2015, December 3). The Immune System Is a essential Target for Estrogen Action Opposing Effects of Estrogen in Two Prototypical Autoimmune Diseases. Retrieved March 24, 2017, from NCBI website https//www.ncbi.nlm.nih.gov/pmc/articles/PMC4701921/Mayo Clinic Staff. (2015, November 26). Prednisone and other corticosteroids. Retrieved March 23, 2017, from Mayo Clinic website http//www.mayoclinic.org/steroids/art-20045692?pg=2Pierdominici, M., Ortona, E. (2013). Estrogen Impact on Autoimmunity blast and Progression the Paradigm of Systemic Lupus Erythematosus. International Trends in Immunity, 1(2), 24-34. Retrieved from http//researchpub.org/journal/iti/ amount/vol1-no2/vol1-no2-3.pdfPlaquenil (hydroxychloroquine). (2014, February 10). Retrieved March 23, 2017, from Netdoctor website http//www.netdoctor.co.uk/medici nes/aches-and-pains/a7356/plaquenil-hydroxychloroquine/Starkebaum, G. A. (2016, January 16). Systemic lupus erythematosus. Retrieved March 23, 2017, from MedlinePlus website https//medlineplus.gov/ency/article/000435.htmUnderstanding Autoimmune Diseases. (2016, March). Retrieved March 22, 2017, from National Institute of Arthritis and Musculoskeletal and Skin Diseases website https//www.niams.nih.gov/%5C/Health_Info/Autoimmune/default.aspVenes, D., Biderman, A., Adler, E., Fenton, B. G., Enright, A. D., Patwell, J., . . . Wight, A.-A. (Eds.). (2005). Tabers Cyclopedic medical checkup Dictionary (20th ed.). Philadelphia, PA F.A. Davis Company. Posted by

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Order Prednisone online saturday delivery – Buy Prednisone Using Visa

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Trial Shows Benefit in Using Prostate Cancer Drug Early

Trial Shows Benefit in Using Prostate Cancer Drug Early

The study of Zytiga from Johnson & Johnson also showed that it could pose a competitive threat to a rival drug, Provenge from Dendreon.

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New Epilepsy Tactic: Fight Inflammation

<h1>New Epilepsy Tactic: Fight Inflammation</h1>

New Epilepsy Tactic: Fight Inflammation

Some patients with epilepsy benefit from treatment with anti-inflammatory drugs, suggesting that brain inflammation plays a larger role in the disease than has been suspected.

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Roles of Steroids in Preventing Esophageal Stricture after Endoscopic Resection

<h1>Roles of Steroids in Preventing Esophageal Stricture after Endoscopic Resection</h1>

Roles of Steroids in Preventing Esophageal Stricture after Endoscopic Resection

Yu Qiu 1,2 and Ruihua Shi 1,2
1 Medical School of Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, China 2 Department of Gastroenterology, Zhongda Hospital, Medical School of Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, China
Correspondence should be addressed to Ruihua Shi ;
Received 30 January 2019; Revised 20 February 2019; Accepted 7 March 2019; Published 1 April 2019
Academic Editor: Toshio Uraoka
Copyright © 2019 Yu Qiu and Ruihua Shi. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Background and Purposes . Endoscopic resection has been worldwide recognized as a treatment strategy for early esophageal lesions. The occurrence of esophageal stricture after endoscopic resection will reduce the quality of life of patients. This study will evaluate the efficacy and safety of steroids in the prevention of esophageal stricture after endoscopic resection and the influence of different steroid administration methods. Methods . In the relevant literature database, literature from 2008 to 2018 is retrieved by using preset keywords, the search results are carefully screened, and the conclusion of the literature is synthesized to form arguments and draw conclusions. Results . 73 articles met our requirements. Oral steroid administration, not prophylactic endoscopic balloon dilation alone, was effective in preventing esophagostenosis after esophagoscopic treatment and reducing the number of repeated endoscopic balloon dilations even after extensive endoscopic resection. Local steroid injection is useful and economy for preventing esophageal stricture, even though it may raise the risk of perforation during dilations. A wider range of circumferential mucosal defects is an independent predictor for stricture formation for patents given preventive steroid injections after endoscopic submucosal dissection. For complete circular mucosal defect, the further researches are essential to investigate the role of local steroid injection. The effect of other methods such as steroid gel, intravenous infusion of steroid, and novel steroid filling methods require more confirmation. Conclusions . Therefore, steroids play an irreplaceable role in preventing esophageal stricture after endoscopic resection. Oral and local injections of steroids are the two most acceptable methods and more prospective studies are needed to compare the effectiveness and safety of these two methods. 1. Introduction
Endoscopic resection has been worldwide recognized as a proper strategy for superficial esophageal dysplasia and carcinoma due to its feature of minimal invasion. As an alternative to esophagectomy, endoscopic mucosal resection (EMR) had been originally applied in the treatment for localized neoplasm, because of the better quality of life after surgery. Segmental circumcision of esophageal intima can successfully remove most of the stenosis lesions [ 1 , 2 ]. However, the operation of segmental circumcision is easy to cause the relapse of superficial esophageal cancer (SEC) [ 3 , 4 ]. In the past few years, focus of EMR has been gradually replaced by endoscopic submucosal dissection (ESD) for SEC. ESD allows the entire resection of the lesion regardless of its size and has a lower recurrence rate compared to EMR [ 5 ].
The incidence of esophageal stricture after endoscopic mucosal resection is rather high; patients often have to undergo radiofrequency ablation again to eliminate proliferative mucosa [ 6 ]. The definition of esophageal stenosis is a narrowing of the esophageal lumen found on endoscopy, which cannot be passed by a standard endoscope or is related to dysphagia [ 7 ]. The stricture rates after EMR are 1.3%-4.9% and 3%-11.6% for ESD [ 8 , 9 ], but the comparability of these rates is low, because the circular extent of the mucosal defect differs among the studies. Chikatoshi et al.’s research found that extensive defect of esophageal mucosa is one of the important predictors of esophageal stricture after ESD [ 10 ], which has been verified by many other authors [ 11 , 12 ]. In addition, Satoshi et al. added that T1A m2 histological depth was another important factor related to post-ESD esophageal stenosis [ 13 ].
The process of esophageal healing and stricture formation after endoscopic resection involves three stages: the first stage is an injury of epithelium, resulting in the damage of the barrier of the epithelial and making the submucosal layers exposed to food boluses, acid, or bile reflux and esophageal fungal or bacterial flora. The second stage is the activation of immune system [ 14 ] which is characterised by the hyperplasia of granulation tissue, including inflammatory cell infiltration and angiogenesis [ 15 ]. The third stage is scar tissue formation, which involves fibroblastic and myofibroblastic proliferation with the stimulation of cytokines like TNF-a, TGF-b1, IL-6, IL-1, IL-17A, PDGF, and so on [ 16 ].
Most post-ESD strictures are refractory and repeated endoscopic dilations are required [ 17 ]. Endoscopic dilation is effective for stricture of internal diameter after endoscopic esophageal mucosal dissection, but there is a high rate of recurrence [ 18 ]. Besides, repeated endoscopic balloon dilations (EBDs) would give rise to complications including perforation and bleeding [ 19 ]. It is reported that 7.1-9% of the patients suffer from perforation after repeated endoscopic dilation [ 20 ]. In recent years, there are many treatments for esophageal stricture after esophageal mucosal exfoliation, such as stents placement, botulinum toxin injection, oral tranilast, and local autologous cell transplantation. Numerous studies have shown good therapeutic effects, while more larger multicenters investigations are required. Therefore, prevention of esophageal stenosis after endoscopic resection is necessary for endoscopic therapy to develop.
Due to the double function of anti-inflammation, treatment of esophageal stricture by oral or local steroid injection has become the preferred option [ 21 ]. This review aims to evaluate the efficacy and safety of steroids in the prevention of esophageal stricture after endoscopic resection and evaluate the efficacy of steroids in different routes of administration. 2. Methods
We searched the relevant literature on PubMed and Web of Science (from 2008 to December 2018) that focused on steroid therapy for the prevention of esophageal stenosis after extensive endoscopic resections. The search terms included “esophageal stenosis or stricture” and “steroid” and animal studies were excluded from all literature. In addition, prevention was used as the criterion for research purposes, and treatment goals were excluded. As is seen from references, 73 articles eventually met our requirements. 2.1. Oral Steroid Method
Naoyuki et al. conducted a large number of clinical trials, which proved for the first time that oral steroids have a good therapeutic effect on esophageal stricture after esophageal mucosal stripping [ 22 ]. In the study, patients were given prednisolone 30 mg daily from the third day after ESD, and the dosage of prednisolone decreased by 5 mg per week until the end of the eighth week of the experiment. This study included 41 patients treated with ESD, whose circumference was more than three-quarters. The incidence of esophageal stricture in oral prednisolone group (5.3%) was significantly lower than that in pre-EBD group (31.8%, P=0.03). The average number of times requiring EBD treatment was 1.7 in the oral prednisolone group and 15.6 in the pre-EBD group (P < 0.0001). Later, Mikinori et al. [ 23 ] and Hiroki et al. [ 24 ] investigated oral steroid for prevention of esophageal stenosis by applying the Yamaguchi protocol with little change. It is worth mentioning that Hiroki et al. [ 24 ] paid attention to complete circumferential ESD, which showed that stenosis after ESD occurred in all patients. However, compared with EBD alone, the number of patients requiring EBD after steroid therapy was significantly reduced (13.8 versus 33.5, P < 0.001) and shorter than the period of physical rehabilitation (4.8 versus 14.2 months, P<0.005). Besides, some other investigations stated that oral corticosteroids can prevent esophageal stenosis after esophageal ESD [ 25 – 29 ]. Recently, in a survey conducted by Iizuka et al., 22 post-ESD patients requiring EBD treatment were included [ 25 ]. They investigated a modified oral steroid administration: in the first three weeks, 30 mg prednisolone was given orally every day, and the dosage of prednisolone was reduced by 5 mg every three weeks. The results showed that the esophageal stricture rate (36.4%) in the modified group was significantly lower than that in the original group (82%, P=0.04) after ESD compared with the traditional 8-week decreasing regimen. In the improved group, the number of patients requiring EBD treatment also decreased significantly (6.2 versus 19.4, P=0.023). Therefore, compared with previous methods, this improved administration is exciting in preventing esophageal stricture after endoscopic surgery.
Current studies have fully confirmed the preventive and therapeutic effects of steroids on esophageal stricture after esophageal endometrectomy, but more studies are needed to determine the safest and most effective way of administration, dosage, and time of administration. As we can see from Table 1 , most investigations adopt 8-week therapy despite the differentiation of dose and interval. However, the total dose of prednisolone usually exceeds 1,000 mg in eight weeks and it has been reported that patients undergoing systemic steroid administration for 21 days or taking more than 700 mg prednisolone have a raised risk of infection [ 30 ]. Oliveira et al. confirmed that the use of high dose glucocorticoids would lead to serious complications such as gastrointestinal ulcer, elevated blood sugar, immunosuppression, osteoporosis, and even systemic infection [ 31 ]. For example, pneumocystis pneumonia (PCP) is caused by systemic immune suppression in some patients who take high doses of steroids for a long time. The mortality rate of PCP is very high [ 32 ]. Limper et al. suggested that steroids administration in doses greater than 20 mg for 1 month or longer should call for prophylaxis for PCP [ 33 ]. In addition, Tsukasa et al. reported an 85-year-old man who had almost completely resected the periphery of esophageal mucosa and used steroids to prevent esophageal stricture after surgery [ 34 ]. After six weeks’ steroid treatment with a total of 1120 mg prednisolone, he developed high fever and finally was diagnosed with infection of nocardiosis. These cases suggest the importance and necessity of preventing fatal infections in patients receiving systemic steroid treatment after endoscopic resection and it is necessary to reduce the amount and shorten the duration of systemic steroid therapy. Stuck et al. pointed out that the early application of steroids after esophageal mucosal resection is helpful to cut off the inflammation process as early as possible, and patients will get more benefits [ 35 ]. Hiroki et al.’s study compared the occurrence and progression of esophageal stricture after early and late steroid therapy for ESD [ 24 ]. In their study, three patients in EBD therapy alone group finally orally intake prednisolone after about 158 days due to the fact that they failed to responded to EBD therapy alone. Therefore, they added a subgroup analysis to compare these three additional patients with 10 original patients in the steroid plus EBD group. The results showed that the time needed for EBD in steroid + EBD group was significantly reduced (13.8 versus 46.0, P < 0.002), and the total EBD time was significantly shortened (4.8 versus 17.5, P<0.005). 3-7 days after injury is the key period for collagen deposition and fibrosis, which may be the main mechanism for the early benefit of steroid hormone application [ 36 ]. More studies with larger sample size comparing early and late oral steroid therapy are needed to confirm and further explain the results of the study and explore the mechanism of steroids exerting local anti-inflammatory and antifibrotic effects. To conclude, early oral steroid administration, with proper amount and duration, not preventive EBD alone, was effective in preventing esophageal stricture and avoiding EBD. Further larger scale of investigations are required before this therapeutic option can be widespread. Table 1: Clinical outcomes of oral steroid method of preventing esophageal stricture after endoscopic resection. 2.2. Local Steroid Injection
Holder et al. [ 37 , 38 ] took the lead in studying the effect of corticosteroid local injection therapy on benign esophageal stricture in dogs and children. Since then, its clinical application has gradually increased [ 39 – 41 ]. In recent years, local steroid injection therapy has been widely used to prevent the formation of stenosis after SEC [ 7 , 42 ]. Kouichi et al. had explored the healing process of local ulcers after ESD by injecting steroids into pigs’ esophagus [ 43 ]. After Satoru’s study, they used triamcinolone acetonide at doses and injection intervals [ 7 ]. What the conclusion they drew was that local steroid injection seemed to be effective to prevent the stricture after esophageal ESD, but as for the optimal injection technique, frequency, and dose of triamcinolone, it requires further people-based studies. As is shown in Table 2 , several prospective or retrospective studies have manifested that local steroid injection at the ulcer base significantly reduced esophageal stricture rate after endoscopic resection. Table 2: Clinical outcomes of local steroid injection of preventing esophageal stricture after endoscopic resection.
Satoru et al. [ 7 ] conducted the first study to manifest that endoscopic triamcinolone injection (ETI) leads to decreased stricture rate and numbers of EBD in patients undergoing ESD for SEC in 2011. Based on the knowledge that fibroblasts begin to proliferate 3 to 7 days after local trauma[ 36 ], they began ETI at this time point and injected steroid hormones into the site of ulcer. The results showed that when triamcinolone acetonide was injected into the shallow layer with equal interval of 2 mg, the total dose of triamcinolone acetonide was 18-62 mg; there were no significant complications such as delayed perforation and local abscess. Then Hanaoka et al. [ 44 ] conducted a prospective study on 30 patients with esophageal squamous cell carcinoma (ESCC) treated with EDS which had a periesophageal defect of more than 3/4, but not a whole-week defect. Compared with 29 patients without ETI treatment, the rate of esophageal stricture in the experimental group was significantly reduced (10% versus 66%, P<0.0001), and the number of patients requiring EBD treatment in the later stage was significantly reduced (0-2 versus 0-15, P<0.0001). One patient in study group suffered from a submucosal tear and another suffered from bleeding, which were both not direct results of EBD. In addition, for patients with whole circumferential mucosal defects after esophageal ESD, Takahashi et al. [ 45 ] conducted a randomized controlled trial and they found that ETI did not reduce the stricture rate, but decreased the mean times of dilatation sessions (from 12.5 to 6.1), indicating that, in some patients, local steroid injection prevented the rapid healing of esophageal ulcer. Similarly, the results of a single-center randomized controlled trial conducted by Mei-Dong Xu et al. [ 46 ] showed that local steroid hormone injection was effective in preventing stenosis in patients with peripheral esophageal defects less than half a week after ESD. Yasuaki et al.’s [ 47 ] propensity score matching analysis excluded steroid injection selection bias and other confusing factors. They used two LSI methods: one was to inject 80 mg triamcinolone acetonide (TA) immediately after ESD; the other was to inject 6.6 mg dexamethasone and Twi immediately after ESD. Stenosis was found in 1 of 12 lesions treated with TA (8.3%) and in 2 of 16 lesions treated with dexamethasone (12.5%) (p = 1.00). Their results also indicated that LSI is usefully limited to mucosal defects less than 3/4 of their esophageal circumference. Therefore, what on earth are the risk factors for stricture formation in patients who received ETI after esophageal ESD? Recently, a study by Yasuaki et al. [ 48 ] assessed the risk factors for preventing esophageal stricture by routine prophylactic steroid injection after ESD. They concluded that a wide mucosal defect (odds ratio: 2.42; 95% confidence interval: 1.01-5.80; P=0.048) was an independent predictor of stenosis. The cut-off value related to stenosis formation was 5/6 of the peripheral mucosal defect. Tendency analysis showed that the rate of esophageal stricture was increased in patients with circumference greater than 5/6, compared with those with less than 5/6 mucosal defects (odds ratio: 5.70; 95% confidence interval: 1. 61-20.18; P= 0.007).
Yoshiki et al. [ 49 ] stated that the boundary between esophageal submucosa and muscular layer was blurred and the muscular layer was partially ruptured after local steroid injection. Thereafter, Yoshiki’s team conducted a central retrospective study to assess the prognosis of patients with periesophageal mucosal defects more than three-quarters of the time after ESD. Their findings found that 43% of LSI patients had esophageal stricture, compared with 90% of nonpreventive patients, and only esophageal perforation occurred in LSI patients [ 50 ]. Yamashina et al. [ 51 ] reported the cases of delayed perforation caused by tissue damage caused by LSI. They believed that injection needles should be avoided to puncture the intrinsic muscles directly. Therefore, mild puncture of the residual submucosa should be performed without needling deeper. EBD should also be performed cautiously. Regarding the amount of steroids injected, studies from Yasuaki [ 52 ] showed that a single dose of 80 mg TA had sufficient protection against stenosis, although this dose was lower than previous studies. Finally, according to the statistical data of Furuhashi et al. [ 53 ], each case in LSI group used 60±28 mg of triamcinolone acetonide and the Japanese public insurance system proposed a reduction of $9330 in medical expenses. In conclusion, LSI is useful and economical in preventing esophageal stricture after ESD, although it may increase the risk of perforation during EBD. A wide mucosal defect was an independent predictor of stenosis after LSI and the cut-off value was 5/6 of the peripheral mucosal defect. For complete circular ESD, more prospective studies are needed to investigate the role of LSI. 2.3. Other Methods Using Steroids
In addition to oral intake and local injection, steroids can also be applied in other forms such as sterid gel, intravenous drip infusion, and TA filling method to prevent esophageal stricture after ESD. In 2013, Hirohito Mori et al. [ 54 ] reported an innovative method using combined steroid gel application and balloon dilatation to prevent esophageal strictures after ESD, compared with steroid injection. They drew a conclusion that steroid gel application is more effective than local injection in terms of prevention of esophageal stricture after ESD. However, the results of Hirohito Mori’s study which was questioned by Yang Fan et al. [ 55 ] have made great contributions in optimizing and expanding the design process, data analysis, and results study of the experiment in this direction. In addition, Satoshi et al. [ 56 ] reported intravenous steroid infusion for the first time in 2010 as a case report. A 61-year-old male patient with SEC underwent esophageal ESD examination and treatment. Multiple myeloma and multiple bone metastases were found during further treatment. Therefore, from the 9th day after ESD, 40 mg dexamethasone was orally administered daily for three consecutive days, a total of three courses of treatment. Subsequently, the patient received peripheral blood stem cell transplantation, which was successful. During follow-up, no significant esophageal stricture or typical symptoms were found in this patient. This study opens a new era of pulsed hormone therapy. In 2015, Nakamura et al. [ 57 ] prospectively studied the efficacy and safety of steroid pulse therapy in preventing esophageal stricture after ESD. Esophageal cancer was diagnosed. No serious life-threatening complications related to steroid pulse therapy have been found. The median interval between ESD and EBD was 18 days (15-21 days) and 2 days (1-6 days). Although the occurrence of esophageal stricture seems inevitable, pulsed steroid regimens can significantly reduce the frequency and overall time of EBD. Similarly, Nakamura et al. [ 58 , 59 ] conducted a prospective study of 11 patients in 2017 and found that pulsed steroid regimens were extremely safe. Unfortunately, no preventive effect on esophageal stricture was found. On this basis, they proposed a local esophageal tamponade therapy using triamcinolone acetonide (TA), which is to inject TA saline solution into the esophagus for a period of time, expecting the drug to penetrate evenly into the broader resected surface. The results showed that esophageal stricture was effectively controlled in all patients. Unfortunately, the results of large-scale data analysis are still lacking in this study. 3. Discussion
Wound healing is a process involving inflammation, hyperplasia, and remodeling, and scar formation is considered to be a part of wound healing. Collagen is the major fibrous connective tissue protein in scars [ 40 ]. In theory, steroids are the most suitable treatment agent for scar because they can inhibit inflammation response, collagen synthesis and fibroblast proliferation [ 60 ]. At present, oral or local steroid injection has become a common clinical treatment to prevent esophageal stricture after ESD. Compared with EBD, the treatment results are more economical and effective, and patients suffer less pain [ 51 ]. However, there are high-risk complications such as delayed ulcer healing, ulcer, or perforation caused by injection injury in LSI treatment. The oral steroid hormone pathway is not 100% safe. Severe complications such as immunosuppression, pulmonary infection, elevated blood sugar, osteoporosis, and mental disorders often occur. Tsukasa et al. reported a case of severe disseminated nocardiosis during oral steroid therapy [ 34 ]. Wang et al. made a meta-analysis with the objectives to evaluate the efficacy of steroids in preventing esophageal stricture after ESD and to conclude that LSI is superior to oral steroids in reducing EBD [ 61 ]. Recently, Yang et al. conducted another network meta-analysis to assess the efficacy and safety of different steroid applications in the prevention of esophageal stricture after endoscopic submucosal dissection [ 62 ]. Interestingly, they drew the conclusion that long-term oral steroid (at least 12-week period with more than 1470-mg prednisolone) might be the superior prevention for postoperative stricture with satisfying efficacy, comparing with preemptive EBD, median-term oral steroid, short-term oral steroid, and steroid injection therapy. However, it has been reported that patients undergoing systemic steroid administration for 21 days or taking more than 700 mg prednisolone have a raised risk of infection [ 30 ]. Therefore, more prospective comparative studies are needed to clarify the effectiveness and safety of oral steroid and local injection methods.
Multicenter prospective randomized controlled trials (JCOG1217) are currently comparing the efficacy of prophylactic oral steroids and LSI in the treatment of noncircular lesions [ 63 ]. Besides, Kawaguchi et al. [ 64 ] proposed a combined therapy called “sequential steroid therapy”, which means LSI of triamcinolone on the day of ESD followed by oral intake of prednisolone for the next few days. The effectiveness of this novel therapy requires confirmation by more prospective studies. According to a retrospective study conducted by Kadota et al. [ 65 ], stricture rates were assessed based on different widths of mucosal defects caused by ESD. Their findings confirm that prophylactic steroid use is effective in the treatment of esophageal stricture in patients with mucosal defect 7/8 weeks or more after ESD, but ineffective after full-week mucosal defect. Further investigations with larger sample size are required. In addition, more and more researchers take steroid therapy, either oral steroids or LSI, as a basic therapy for preventing esophageal stricture after ESD, combining with some other methods like stents insertion and polyglycolic acid sheets, which may have additive or synergistic effects. Nowadays, new methods for prevention and treatment of esophageal stricture after ESD have been widely studied, such as esophageal stent implantation, polyglycolic acid shielding, autologous oral epithelial cell transplantation, and so on. Many new methods have good results and broad prospects for clinical application, but large-scale studies are still needed to obtain more clinical data. 4. Conclusions
Steroids play an irreplaceable role in preventing stenosis after esophageal ESD. Its usage mainly includes oral steroid method, local steroid injection method, other methods such as steroid gel, intravenous infusion of steroid, and novel steroid filling methods. Currently the most widely accepted methods are oral steroid and LSI, and both of them have advantages and disadvantages; more researches are needed to compare the effectiveness and safety of these two methods. Early oral steroid administration, with proper amount and duration, not preventive EBD alone, was effective in preventing esophageal stricture and avoiding EBD. LSI is useful and economical in preventing esophageal stricture after ESD. A wide mucosal defect was an independent predictor of stenosis after LSI and the cut-off value was 5/6 of the peripheral mucosal defect. For complete circular ESD, more prospective studies are needed to investigate the role of LSI. Besides, a combination of these two methods, called sequential therapy, is a novel therapy requiring confirmation by more prospective studies. Last but not least, steroid therapy combining with other treatments like stents insertion and polyglycolic acid sheets may have additive or synergistic effects on the prevention of esophageal stricture after ESD. Conflicts of Interest
The authors declare that they have no conflicts of interest. Acknowledgments
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