JOHNS HOPKINS InsıdeTract SPRING 2017

NEWS FROM THE JOHNS HOPKINS DIVISION OF AND

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In this colocalization of a specimen taken from a patient with ileal Crohn’s disease, a green stain in image 1 illuminates zinc transporter genes within the instestinal crypt cells. Image 2 shows the cells’ teal-stained nuclei. Image 3 overlays the other two images and highlights in red a special type of crypt cell. “This tells us that the zinc transporter is present in some of the immune cells in the epithelia of both the terminal illium and the small bowel,” says researcher Joanna Melia, “and that there is even more of it in the presence of inflammation.” Unlocking the Genetic Mysteries of IBD oanna Melia’s patients with inflammatory bowel disease all ask her the same thing. “WE STILL DON’T UNDERSTAND WHAT “Every single one of them wants to know HAPPENS WHEN THIS GENE IS MUTATED, BUT Jwhat they should and shouldn’t eat,” she says. WE KNOW ZINC IS VERY IMPORTANT TO “Which seems reasonable, right? But there’s very little information on dietary recommendations for IMMUNITY AND GUT HEALTH.” patients” with Crohn’s disease and ulcerative . —JOANNA MELIA Her research is driven by a desire to give those patients some answers. Melia, a gastroenterologist and researcher, says some patients tell her that certain foods trigger episodes while others report diet has no affect on or too little immune response in patients with IBD. the microbiome. their symptoms. Either can lead to intestinal inflammation. “There seems to be some competition among For example, for a long time, IBD patients were “Historically, we have divided up inflammatory the host and organisms in the gut for these encouraged to avoid foods containing fiber. “Now bowel disease into only two disease conditions, micronutrients in IBD,” she says. “For instance, the pendulum is swinging the other way,” she says. Crohn’s disease and ,” says Melia. we and our collaborators have found that the “Newer studies say that fiber is good. So it’s really a “But there are likely many subtypes driven by many microorganisms in the intestines of patients with moving target.” different processes.” Crohn’s disease have more zinc transporters than the To better understand one aspect of diet and IBD, Using enteroids grown from intestinal tissue ones in healthy people.” Melia is researching a zinc transporting gene that samples, Melia and other Johns Hopkins researchers The role of diet in shaping the microbiome is has a mutation associated with increased risk of study intestinal transporters. undeniable, Melia says. But exactly what effects Crohn’s disease. The mutation has also turned up in She says that many of her Johns Hopkins various foods produce remains elusive. Still, she research of several other diseases, including obesity colleagues have produced important work in IBD believes there is hope to unlocking the puzzles of and schizophrenia, and it might hold clues to how genetics and in the area of dietary trace minerals, IBD, diet and the microbiome. micronutrients in the gut affect disease. such as copper, iron and zinc. Melia sees herself “We really want to learn how we can harness “We still don’t understand what happens when working in that tradition. micronutrients to improve gut health. I think we have this gene is mutated,” she says. “But we know zinc is Melia’s research also focuses on how new laboratory tools to begin to study these questions very important to immunity and gut health.” micronutrients, required by both humans and in new ways, and it is my hope we can provide more Melia says that it may produce either too much the microorganisms present in the gut, shape answers for patients,” she says. n DIRECTOR’S COLUMN GASTROPARESIS Myotomy Offers Relieffor Some Gastroparesis Patients

he National Institutes "These were patients whose spastic lower esophageal sphincter of Health estimates that condition was debilitating," muscles have difficulty swallowing, as many as 5 million Khashab says. and food stays undigested in the TAmericans live with The endoscopist slides a stent esophagus. A myotomy of that gastroparesis. Johns Hopkins past the and deploys it muscle brought many patients relief, gastroenterologist Mouen Khashab into the pyloric valve, holding the prompting Khashab to wonder if cites a 2008 American Journal of valve open and allowing nutrition gastroparesis patients might enjoy Gastroenterology study stating that to begin its journey through the similar benefits. Innovating for Others diagnoses of gastroparesis have intestines. Khashab says the stent "It's a sphincter muscle in a increased by more than 150 percent was successful more often than different place," he says. "Instead We’re proud of—and humbled by—our in the past 20 years. not, but that he never meant it as a of at the bottom of the esophagus, reputation for world-class research at the "It's becoming more common," permanent solution. it's at the bottom of the stomach. I Johns Hopkins University School of Medicine. he says. "We don't know why it's on "Stents migrate," he says. thought it might work." For 127 years, our institution has led such a steep rise." "Mucosa grows over them. There Khashab did a study on the advancements in the science of medicine. What's more, Khashab says are all sorts of reasons why it wasn't procedure and found that, in many But underlying our relentless pursuit of medical knowledge is a fundamental drive: there's no reliable medication or permanent." cases, myotomy did indeed relieve to help alleviate human suffering through the treatment for the condition, in Meanwhile, Khashab and other gastroparesis symptoms. He notes treatment of illness and disease. which the stomach cannot empty Johns Hopkins endoscopists (continued on back cover) This edition of Inside Tract showcases just properly, causing , were frequently a few of the ways that we do what we’ve and . Ultimately, performing another dedicated our lives to—blending rigorous patients with persistent or chronic procedure for science with the compassionate care of patients. gastroparesis can suffer dehydration patients with The conditions you'll read about in this and . achalasia. That issue are among today’s most widespread "No one has found a specific procedure, and pernicious: inflammatory bowel disease, cause," explains Khashab, "and the called peroral gastroparesis, , obesity and, of course, only medication for it has a black- endoscopic cancer. Though the conditions are common, our box warning for significant side myotomy teams’ approaches are often anything but. effects." (POEM), Saowanee Ngamruengphong, for example, Khashab has developed an involves spent last summer in Tokyo, studying advanced endoscopic procedure that snips the cutting the therapeutic endoscopy techniques for gastric pyloric sphincter to treat certain lower esophageal cancer. There, she learned from some of the sufferers of gastroparesis. He is sphincter muscle world’s foremost experts in the field, and she encouraged by the early results. to relieve brings this expertise, scarcely available in the In 2012, he and several Johns that prevent it U.S., to our patients most in need. Hopkins colleagues began testing a from opening and Mouen Khashab says that about Mouen Khashab continues to advance metallic mesh stent to treat patients closing properly. two thirds of his patients who surgery-sparing, endoscopic solutions for have had pyloric myotomy report with severe, refractory gastroparesis. Patients with conditions of the GI tract. In this issue, we no more gastroparesis symptoms. delve into his efforts centered on the ubiquitous condition refractory gastroparesis. Equally innovative, Joanna Melia's research “IT'S A SPHINCTER MUSCLE IN A DIFFERENT into the genetics of IBD mines the origins of PLACE. I THOUGHT IT MIGHT WORK..” Crohn's disease and ulcerative colitis—teasing out clues that may one day lead to advanced —MOUEN KHASHAB treatments. And Ashish Nimgaonkar and colleagues are engineering a pill—based on prior research focused on —that may eliminate diabetes symptoms in patients who take it before meals. It is truly an honor to work with such colleagues—physicians and scientists who strive GASTRIC CANCER every day to improve the health and lives of our patients and people throughout the world. Should you have questions for me, anyone in this issue, or other members of our division, The Cutting Edge of Endoscopic Resection please don’t hesitate to contact us. Johns Hopkins among the few U.S. centers to offer innovative procedure Tony Kalloo, Director Division of Gastroenterology and Hepatology ooking at results from high-definition scopes, foremost facility for innovative endoscopic removal of Johns Hopkins University School of Medicine enhanced imaging, endoscopic ultrasound and gastric cancers. other advanced diagnostic tools, Johns Hopkins’ Gastric cancer is far less common in North Explore Our Online Resource for multidisciplinary teams work together on America than in Eastern Asia, which sees 50 percent Physicians: Clinical Connection L personalized care plans for patients with gastric cancer. of all new cases worldwide each year. The Japanese Connect with Johns Hopkins health care Most times, when resection is necessary, common center's faculty teaches the latest endoscopic resection professionals about the latest clinical endoscopic mucosal resection (EMR) is sufficient. techniques annually to only a few physicians from innovations and advances in patient care. But when patients require something more complex, around the world. gastroenterologist Saowanee Ngamruengphong and Ngamruengphong spent her time there learning Register for your free membership to colleagues offer other options. endoscopic submucosal dissection (ESD), as well as access videos, articles, clinical trials and For 10 weeks last summer, she studied advanced detection, evaluation and treatment of all kinds of early much more. endoscopic early-cancer removal techniques at the luminal cancers and precancers. Visit www.hopkinsmedicine.org/ place where they perform the procedures several times She says that EMR, the most common approach in clinicalconnection. a day: Tokyo’s National Cancer Center, the world’s the U.S., is not always the appropriate one for complex,

2 • JOHNS HOPKINS INSIDE TRACT • SPRING 2017 TO DISCUSS A CASE OR TO REFER A PATIENT, CALL 410-933-7495. DIABETES Bypassing Bypass Surgery Polymer-pill for weight loss may hold promise for patients with diabetes

Johns Hopkins gastroenterologist altogether," says Nimgaonkar. is on his way to reproducing a Because the barrier remains superficial and serendipitous byproduct of a gastric does not adhere to intestinal cells, the polymer Abypass using neither surgery nor dissipates within several hours; its remains are endoscopy. excreted by the patient. An hour or so before Gastroenterologist Ashish Nimgaonkar the next meal, the patient takes another pill. is engineering a pill that will mimic not only Because of diabetes' increasing prevalence, “REROUTING the weight loss effects but also the glycemic researchers and pharmaceutical companies FOOD PAST THE benefits of a gastric bypass procedure. have long pursued drugs and devices aimed at DUODENUM When patients first underwent gastric treating the disease. But side effects and spotty bypass surgery, the obvious benefit was results have derailed most efforts. DURING THE dramatic weight loss. But patients who One such study used a plastic tube as a DIGESTION happened to have enjoyed an bypass device. The tube did its job; diabetes PROCESS HAS A additional, unexpected outcome. was no longer a problem. But because of side TREMENDOUS "A few days after the surgery, they were effects—patients reported severe nausea and walking out of the hospital without a need some experienced systemic infection from the AND IMMEDIATE for insulin or diabetes medicine," says metal anchor that held the tube in place— EFFECT ON Nimgaonkar. as well as the device's 12-month GLYCEMIC Rerouting food past the duodenum during duration, it was never approved in the United CONTROL.” the digestion process has a tremendous and States. But Nimgaonkar says researchers —ASHISH immediate effect on glycemic control," he says. nevertheless learned from the data the tube Nimgaonkar along with his colleagues yielded. NIMGAONKAR gastroenterologist Jay Pasricha and "For us, it provided a great insight," he biomedical engineer Kevin Colbert are says. "The device worked. It just had some developing a pill that will deploy a polymer problems." that creates a barrier to the same part of the Nimgaonkar points out that both small intestine that is bypassed in gastric surgery and endoscopy present an bypass surgery, producing similar weight added cost when patients with diabetes loss and glycemic benefits as a surgical or require frequent visits to surgeons and endoscopic procedure. gastroenterologists. "It's still at a very early stage," he says. "GI physicians don't typically see "But we have shown that it works in animal diabetic patients," he says. "They go to models." endocrinologists or to their primary care Nimgaonkar and his team won a $500,000 doctors. When gastroenterologists do see prize for the pill’s concept in an international patients with diabetes, it's for other associated competition sponsored by a large multinational gastrointestinal conditions but it's not the main drug maker. They continue to engineer the pill purpose for the visit." to optimize the dose, properties and delivery While the pill doesn't cure diabetes, Radioactive dye shows system for the polymer. They will soon embark Nimgaonkar believes it could change how the polymer used by on clinical trials. the way it's treated in the future. Ashish Nimgaonkar coats The patient swallows the pill before a "As long as they take the pills, the duodenum, sealing it meal, and it activates upon contact with patients with diabetes should have off from food absorption n and the part of the the duodenum. This allows food to pass well-regulated blood sugar." digestive tract responsible untouched from the pylorus to the jejunum. for diabetes. "That way, we're able to avoid the

GASTRIC CANCER

precancerous tissue, as well as the area around it, then “IT'S VERY DELICATE. YOU NEED A HIGH-DEFINITION using a clip to isolate it. Ngamruengphong says she SCOPE, AND YOU USE AN ENDOSCOPIC KNIFE TO usually sutures the bottom of the gathered-up tissue SEPARATE THE MUSCLE FROM THE SUBMUCOSA.” and cuts just above the suture. Because the excision is already closed, there is very little bleeding and —SAOWANEE NGAMRUENGPHONG patients seldom require hospital admission. "We send the whole resected tissue to pathology, looking for clear margins," she says. She describes a recent procedure as typical. "The patient had a four-centimeter tumor large or difficult-to-reach dysplasia. This technique wall, taking great care against any perforations, in her colon. We removed it and sutured it," uses the endoscopic snare to resect lesions a piece at Ngamruengphong can excise tumors that have not Ngamruengphong says. "The patient went home after a time. entered the muscle layer. the procedure." "But with ESD, you can resect no matter the "It's very delicate," she says. "You need a high- Pathology found that the tissue was malignant. size," says Ngamruengphong. "And you can tell if it's definition scope. And you use an endoscopic knife to "But because we got the foci of cancer and the curative, which EMR cannot do." separate the muscle from the submucosa." margins were clear, all she requires now is follow-up ESD uses endoscopy to accomplish what, not For larger, more invasive cancers, monitoring for recurrence." long ago, could only be achieved with open surgery. Ngamruengphong performs full thickness By separating the intestinal lining from the muscle resection, which involves gathering up cancerous or (continued on back cover)

JOHNS HOPKINS INSIDE TRACT • SPRING 2017 • 3 The Cutting Edge of Endoscopic Resection Myotomy Offers Relief (continued from page 2) CONTACT INFORMATION (continued from page 3) that patients whose symptoms abated with the temporary Gastroenterology Central stent therapy were the best candidates for what he now Scheduling calls G-POEM, or gastric peroral endoscopic myotomy. 410-933-7495 "We knew that the cause of their gastroparesis was most The only number you need likely a spastic pyloric sphincter because, for a while, the to refer any patient to any stents worked for them," he explains. Johns Hopkins GI service Khashab has performed about 30 G-POEM procedures, which he describes as slightly more technically challenging Gastroenterology and Hepatology than POEM. Division Website "It's like going from driving a car to driving a truck," hopkinsmedicine.org/GI Endoscopic submucosal dissection for a rectal he says. "It's the same principle, but it requires a little tumor. The procedure allows Saowanee more skill." Hopkins Access Line (HAL) Ngamruengphong to resect the whole tumor Your 24/7 connection to Johns rather than snare it in pieces. He says the rate at which patients show significant improvement is roughly the same as the pyloric stent, about Hopkins full-time faculty members in Because she used the endoscopic knife rather 80 percent. The difference, of course, is that G-POEM any subspecialty 410-955-9444 or than the snare, she was able to remove the offers a better chance at permanent relief. 800-765-5447 whole tumor. Khashab can't say for sure if the patients' gastroparesis Online Referral Directory "In the past, that would have come out in is cured, since the procedure is only a few years old. But Find a Johns Hopkins physician about 20 pieces," Ngamruengphong says. "It for patients who have responded to the treatment, the by name, specialty and more at would have been impossible for pathologists to outlook is good. hopkinsmedicine.org/profiles tell us whether we got it all." n "About two-thirds of our patients who've experienced relief have reported no more gastroparesis symptoms." n

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Johns Hopkins Medicine Marketing and Communications 901 S. Bond St./Suite 550 Baltimore, MD 21231 Gastroenterology and Hepatology Anthony N. Kalloo, M.D., Editor Email: [email protected] Marketing and Communications Dalal Haldeman, Ph.D., M.B.A., Senior Vice President Patrick Smith, Writer Justin Kovalsky, Managing Editor Email: [email protected] Lori Kirkpatrick, Designer Keith Weller, Photographer © 2017 The Johns Hopkins University and The Johns Hopkins Health System Corporation. InsıdJOHNS HOPKINSeTract SPRING 201 7

NEWS FROM THE JOHNS HOPKINS DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY 1 2 3

Inside Unlocking Myotomy Offers Bypassing the Genetic Relief for Some Bypass Surgery Mysteries of IBD Gastroparesis Patients