Genes Behind Pancreatic Cancer

Pancreatic cancer is the third most common cause of cancer-related deaths in the United States, with over 43,000 deaths expected in 2017.1 While most pancreatic cancers are sporadic, approximately 10% of pancreatic cancers appear to have a familial component.2

pancreasabdomen

Familial Pancreatic Cancer (FPC) is defined as families that have > 2 affected individuals who are first-degree relatives of each other. FPC can also include families with > 3 affected individuals on the same side of the family, even if they are not first-degree relatives of each other.

Germline mutations in BRCA1, BRCA2, PALB2, ATM, p16, PRSS1, STK11, and the mismatch repair genes (Lynch syndrome) are associated with a significantly increased risk of pancreatic cancer; however, these genes have a low penetrance for pancreatic cancer, and often the family history is more notable for other cancers.

Despite what appears to be an autosomal dominant mechanism for inheritance, a genetic mutation leading to pancreatic cancer is found only 10% of seemingly hereditary cases.

Several large-volume centers have begun to study screening for pancreatic cancer in high-risk patients, and consensus-based guidelines have been published.3  Candidates for screening may include:

1) First-degree relative of an affected individual in a FPC family

2) First-degree relative of an affected individual in a family with > 2 pancreatic cancers

3) BRCA2, PALB2, p16, ATM, and mismatch repair gene mutation carriers with affected first-degree relatives

4)  BRCA2 mutation carriers with 2 affected relatives, even if no first-degree relative is affected

5) All Peutz-Jegher’s syndrome (STK11 mutation) patients regardless of their family history

6) All PRSS1 mutation carriers

Consensus guidelines recommend pancreatic cancer screening in high-risk individuals at age 50, with the exception being PRSS1 mutation carriers who start screening at age 40.

The goals of pancreatic cancer screening include:

1)  Detection and treatment of precancerous lesions (i.e., high grade multifocal pancreatic intraepithelial neoplasms, or high-grade dysplasia within an intraductal papillary mucinous neoplasm).

2) The detection and treatment of a T1N0M0 cancer.

3) Detection of any resectable pancreatic carcinoma.

Detection of these early pancreatic cancers or pre-malignant lesions is dependent on our ability to identify and screen high-risk individuals before the onset of symptoms.  Current tools for pancreatic cancer screening include Magnetic Resonance Imaging (MRI) with MR Cholangiography (MRCP) and endoscopic ultrasound (EUS.)

MRI has the benefit of being a non-invasive test, but is sometimes limited by the patient’s ability to lie still for the duration of the study. 

EUS is a more invasive examination which requires anesthesia, but offers an opportunity to sample any abnormalities that may be detected on examination.

Emerging data suggest that MRCP may be more effective in detecting cystic lesions of the pancreas, while EUS may be more sensitive to detect small solid lesions.4 Computer tomography (CT scan), abdominal ultrasound, and endoscopic retrograde cholangiopancreatography are not generally used in pancreatic cancer screening.

For further information on pancreatic cancer screening studies, or to arrange a consultation please visit  http://www.mountsinai.org/profiles/aimee-lucas or  http://labs.icahn.mssm.edu/lucas

Amiee Lucas, MD  Professor of Medicine – Gastroenterology  Mt. Sinai Hospital

References

1. Society AC. Cancer Facts & Figures 2017. Atlanta: American Cancer Society 2017.

2. Klein AP, Hruban RH, Brune KA, et al. Familial pancreatic cancer. Cancer J 2001;7:266-73.

3. Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2012.

4. Harinck F, Konings IC, Kluijt I, et al. A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals. Gut 2015.

Gastroenterology Fellowship: Journeys, Quests and Career Choices.

 

 

scope in hand-gi-05

The NYSGE is a nationally renowned gastrointestinal society, but a huge driving force for our successful society are the fellows in training working at our various institutions. There are 539 total members in NYSGE, and 227 of them are fellows and residents in training. Although our fellows are strong clinicians and work tireless hours seeing patients, setting up carts, and performing emergency endoscopies in the middle of the night, they somehow find time to pursue academic interests and publish very interesting research.

In the past year there have been countless abstracts, papers, and publications involving our fellows. Although there are a multitude of publications, a selected listing here includes Anoop Appannagari, AET at Stony Brook, who published an interesting case in Gastrointestinal Endoscopy titled “Two endoscopic resection methods for the removal of an over the scope clip.” Lionel D’Souza, the BI-Mount Sinai AET recently published a case in ACG Case Reports Journal titled “A rare case of isolated pancreatic Tuberculosis.” Sunil Amin, AET of Columbia, helped publish the abstract titled “Longer time interval between ERCP and surgery associated with improved survival in pancreatic cancer patients” at ACG this past year. Nikhil Kumta (formerly the AET at Cornell) and Ming Ming Xu, the current AET at Cornell, who with other co-authors recently published a video in Endoscopy titled, “Submucosal tunneling endoscopic resection of a symptomatic leiomyoma in the proximal esophagus” which was also presented at the David B. Falkenstein Fellow’s Night. Shailja Shah, Mount Sinai Fellow won the distinguished poster award for her research in Ulcerative Colitis and the winner of the Peter Stevens Endoscopic Video Forum went to Sam Seroya of BI-Mount Sinai, both presented at this year’s Annual Dinner.

These extracurricular academic pursuits by our fellows are beneficial as they expand the knowledge and frontiers of Gastroenterology, but they also benefit the applicants as they are truly important markers of dedication, hard work, and persistence which are essential when applying for jobs. The light at the end of the tunnel comes quickly for many fellows, and after years of college, medical school, residency, and then fellowship come to a close, the real world rears its head come winter and spring for all of our senior fellows.

Job hunting can be a daunting task, and below are anonymous selected quotes of recently graduated fellows in the NY area to advise the current graduating fellows:

  • “The job search can be one of the most daunting tasks for any young physician finishing training. After having our career paths determined for us though the match process for the past 6 or 7 years, we are suddenly faced with the complete freedom to explore any type of practice setting in any location. This can be both amazing and terrifying. The first and most important step is to be honest with yourself about the situation that will be best for you and your family.”
  • “Use the interview to understand each practice model’s unique benefits and risks.”
  • “Ask around!  Discuss the position with your program director and people you trust.  Try to reach out to physicians who may have been recently hired by the practice you are interviewing for, or possibly who have left that practice in recent years.  Why did they decide to join that group?  Why did they leave?”
  • “Do not sell yourself short!  While you may not have experience outside of training, remember that the employers are seeking to fill the position.  They want YOU.”
  • “Have an attorney review your contract for loopholes.  Everything is negotiable.  If the terms are not equitable, continue to push for change so that they are.  You do not want to sign something that you will regret signing later on.
  • “Be flexible to an extent.  Some groups have specific needs and may ask if you would be willing to meet that need (reading capsules, learning nutrition/TPN, etc).  Consider these as these may still be good opportunities, but of course don’t sacrifice your goals/interests and settle on something you hate doing just to get the job.”
  • “Look at the dynamics and culture of the group (academic or private), could you see yourself fraternizing with these people for several years?  Are you proud to call them your colleagues?  Remember that these people will – for better or worse- represent the practice and take care of your patients when you’re on vacation, in the hospital, on call, etc.”
  • “Get a sense of the local admitting hospitals and ancillary services. Having an awful pathology department or radiologist will ultimately hurt your practice.”

 

Demetrios Tzimas, M.D.
Assistant Professor of Medicine
Advanced and Therapeutic Endoscopy Service – Director of Medical School GI Pathophysiology
Division of Gastroenterology and Hepatology  – Stony Brook University School of Medicine

Controversies in GERD Management

Gastroesophageal reflux disease, or GERD, is defined by the Montreal Classification as “a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.” This characterization has always been intentionally broad, as symptoms of GERD can vary widely in patients, and the frequency of symptoms does not necessarily correlate with the quantity of reflux in an individual patient. To further complicate matters, only certain patients have long-term esophageal injury from GERD. Progression of GERD to Barrett’s esophagus and even esophageal adenocarcinoma can occur, but the majority of patients with GERD do not develop these long-term sequelae. In patients without concerning esophageal injury, and accumulating data on the potential risks of long-term proton pump inhibitor (PPI) therapy, how are we to think long-term about their reflux disease? If the symptoms are not able to be managed with dietary and lifestyle changes alone, should we now be considering alternative medical and procedural therapies in more of our patients?

To have a chance to answer these questions, I believe it is vital to step back and ask: why does my patient have GERD? Sometimes, the answer is obvious: it could be a recent dietary change or weight gain, or a clear anatomic process at the esophagogastric junction (EGJ) such as a hiatal hernia. However, if the cause is not obvious, further evaluation of the mechanisms of GERD in a patient can be important. The attention and interest in the pathophysiology of GERD has been increasing in recent years. For example:

-Without a hiatal hernia, traditionally it has been unclear whether a low pressure lower esophageal sphincter (LES) may have a role in contributing to worsening GERD. In addition, with the advent of high-resolution esophageal manometry studies, other LES metrics, one being the “EGJ contractility integral,” are being deciphered to study the EGJ comprehensively. Still other technology, with impedance planimetry, is being studied to assess the compliance of the LES in patients with GERD.  

-There is a body of literature suggesting that the LES may shorten over time, and this decreasing LES length may be a surrogate for progression of GERD. Here too, esophageal manometry may be beneficial in determining the primary underlying cause of GERD.

-Transient LES relaxations have been a known mechanism of GERD for many years. However, the majority of evidence suggests that the quantity of these relaxations may not be the most significant factor, and GERD patients instead will likely reflux more when the relaxations occur. Thus, the physiology of the proximal stomach may have a function in GERD, and indeed an “acid pocket” has been described at the EGJ from which reflux can originate after a meal. The location of this reservoir may vary amongst patients.

There are many potential mechanisms for GERD, and these are but a few that have received recent attention. Work to decipher the major etiologies of GERD in patients is encouraging, and eventually we can hope for different “phenotypes” of GERD patients based on mechanisms.

Importantly, we know that an overall balance of symptom triggers (causticity of gastric contents, volume of reflux) and symptom modulators (ability to clear reflux, tissue sensitivity) exist to create the condition of GERD. There are a variety of technologies now that attempt to quantify reflux in patients and correlate that reflux to particular symptoms (wireless pH as well as catheter-based pH and impedance-pH testing), and even focus on the chronicity of reflux in an individual patient (mucosal impedance testing). Further study of these technologies is expected to improve our categorization of GERD patients. Lastly, our options for treating GERD continue to widen, at the same time there is increasing physician and patient concern over long-term potential adverse consequences of PPIs. There are several modern procedural options for treating GERD, with both endoscopic and laparoscopic approaches emerging in recent years.

So how should I treat my patient with GERD on long-term PPI? My approach has always been: if there is no clear indication for indefinite PPI, the goal should be to decipher if there is a therapeutic option that will allow the patient to stop it. This may be a dietary, medical, endoscopic, or surgical approach. Thinking long-term about GERD coincides with considering its mechanisms. In the current landscape, a meticulous individualized approach to care, with a concise discussion on the risks and benefits of both medical and procedural therapies for GERD, is warranted.

As we improve our ability to categorize and “phenotype” patients with GERD, as well as use our motility, pH, and impedance technologies to assess GERD in individual patients, carefully done studies should allow us to develop appropriate diagnostic and treatment algorithms. Certainly, not every patient with GERD will be expected to improve with an LES augmentation procedure, but the goal will be to answer: which patients should get which procedure? As of now, we know that the patients that do best with LES surgery are also the patients who respond best to PPI. We have to do better than that. In the coming years, I expect that we will.

 

Abraham Khan, M.D.

Director, Center for Esophageal Disease

NYU Langone Medical Center

 

Fecal Microbiota Transplantation: Beyond the treatment of Recurrent Clostridium Difficile

Do your patients ask you a lot of strange questions? Since I’ve begun doing fecal transplants (FMT), here are some of the typical questions I’ve been getting:

• “Is the FMT donor fat?”
• “Was the FMT donor breastfed?”
• “I have two great FMT donors and don’t want to hurt anybody’s feelings. Could you mix their stools?”
• “How do you extract the stool from the FMT donor?”
• “What if it doesn’t agree with my own poop?”

Image result for free fecal transplant image

Today, FMT has one approved use: the treatment of recurrent Clostridium Difficile colitis. For that use, the success rates are extremely high. Of all the things we prescribe as doctors, this is one we can feel unambiguously proud of. It’s fast, effective, and inexpensive. This is no small matter: about 30,000 Americans die every year of Clostridium Difficile . Millions of dollars are spent treating this infection, which can be devastating. One can administer FMT though the upper GI tract or directly into the colon. Since Clostridium Difficile colitis affects the colon, today most gastroenterologists administer it via colonoscopy.

As a result of this success, now some patients will try anything to convince you that they need a fecal transplant to cure a whole host of maladies. Others will refuse one even when they have been debilitated by years of infectious colitis and multiple hospital admissions.

But will there be other clinical uses for fecal transplant?

To do justice to this question, it is important first to consider the topic of the microbiome. Recently, FMT has inspired the medical community to look at this “newly discovered organ” we had been ignoring for so long. The “organ” is our microbiota: an enormous number of cells living in an organized dynamic ecosystem and playing so many roles in virtually every aspect of our health and disease. Our gut microbes interact with each other and with us, the host. We have coevolved and developed a mutually beneficial relationship: we provide them with food and shelter and they help with our nutrition, our ability to fight infections, our metabolism, and even our neurologic development. Their study is particularly fascinating because it brings together medicine, ecology, and evolution.

To better understand the microbiota, we have used several tools that have allowed us to gather an enormous amount of information: more information than we can actually interpret. In a sense one could say that technology is ahead of science. Today, for example, we have the ability to sequence the genetic material of the organisms that live in the gut instead of culturing them.

We have observed that the microbiota of patients with IBS, IBD, metabolic syndrome, obesity, autoimmune diseases, and even autism is different from the “normal” microbiome, but association and causation are of course two different things.

Moreover, it has become clear that in order to understand the effects of the microbiota, we need to not only identify these microorganisms, but also measure the products of their metabolism. The mere presence of a particular microbe or a group of microbes may not be as important as what they are doing.

FMT has also helped to advance our understanding of the microbiome and its role: If for example a disease or a trait can be transmitted though FMT, that could support at least some role of the microbiota in causing that disease or trait.

But studying the effects of stool transplant is a lot more complicated than studying the effects of a regular drug. Even though stool (when used for FMT) is now considered a drug, there are many unknowns: dose, ideal route of administration, mechanism of action, etc. Also, each individual person’s stool is different, like a fingerprint. And it may therefore interact in a unique way with the recipient’s microbiota.

A few months ago we started to enroll patients in a multicenter study with doctors at Montefiore, Yale, and Concorde Medical Group to investigate the possible use of FMT in IBS-D (diarrhea predominant IBS).

IBS-D, especially when it is moderate to severe, can be a debilitating disease and very frustrating to treat. Most patients have typically tried conventional therapies like special diets, probiotics, antidiarrheals, antispasmodics, and sometimes antibiotics like rifaximin, which was recently approved for this use.

Why are there currently so many different conventional therapies prescribed for IBS? Likely this is because the pathogenesis of IBS is so little understood. Visceral hypersensitivity, low-grade inflammation, and dysbiosis have been thought to play a role.  Regarding dysbiosis, we know that there is an abnormal microbiota: the numbers of lactobacilli and bifidobacteria, for example, are lower in patients who suffer from IBS than in those who don’t. Also their microbiota seems to be less diverse. Replacing “good bacteria” is the idea behind the use of probiotics, which seem to help some patients. But why are they not sufficient to cure IBS in most patients? The answer is not clear today. Perhaps the numbers of bacteria that survive the passage through the GI tract are not sufficient. Or maybe in order to change that whole ecosystem that is our microbiota in a permanent way, one has to modify it more radically instead of just adding a few specific strains of bacteria.

Despite the unanswered questions about IBS-D, we hypothesize that IBS-D is a condition that occurs secondary to an altered microbiota in the small bowel. Therefore, instead of administering the FMT via colonoscopy as we would do for recurrent Clostridium Difficile colitis, we are using “poop capsules.” It’s a 6-month, randomized, placebo-controlled trial and at 3 months there is a crossover so by the end of the study 100% of the patients will have received the active drug.

Image result for free fecal transplant image

As doctors and investigators, we are eager to help our patients with this very debilitating disease. In the process, we also hope to learn more about the microbiota, its effects on our health, and how this new knowledge will lead to exciting new therapies.

To learn more about this trial, go to clinicaltrials.gov

Caterina Oneto, M.D. (@caterina_oneto) | Twitter

2016 NYSGE Annual Course

40th Annual New York Course
Four Decades at the Forefront of Endoscopy
December 15-16, 2016

Under the direction of expert faculty, this course is designed to improve endoscopic practice through live case presentations, video and hands-on demonstrations, didactic lectures including audience interaction and questions, and hands-on training using animal tissue models.

The course goals are to help participants improve their ability to accurately diagnose and effectively treat the spectrum of gastrointestinal diseases and disorders, enhance quality in all practice settings, embrace advances in healthcare delivery, payment systems, and healthcare information sharing; apply state-of-the-art technology in a cost-effective way, understand trends in interventional endoscopic and surgical procedures, and to foster an evidence-based approach to endoscopic decision-making for commonly encountered and controversial problems in gastroenterology.

As gastrointestinal endoscopy continues to experience a rapid expansion of knowledge and technological innovation, and advances in therapeutic endoscopy challenge or entirely replace certain purely diagnostic endoscopy techniques, the need for superior continuing education becomes increasingly important. This course will enable participants to attain and apply cutting edge information and evolving technological innovations to elevate practice levels and enhance patient care and treatment outcomes.

Learn more about the 40th  Annual Course held at the New York Marriott Marquis Hotel.