Carlene L. Chun

SINGLE-FRACTION STEREOTACTIC BODY RADIATION THERAPY AND SEQUENTIAL GEMCITABINE FOR THE TREATMENT OF LOCALLY ADVANCED PANCREATIC CANCER

PURPOSE This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year. CONCLUSION Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT.

Evaluation and management of patients with symptoms after anti-reflux surgery.

Over the past two decades, there has been an increase in the number of anti-reflux operations being performed. This is mostly due to the use of laparoscopic techniques, the increasing prevalence of gastroesophageal reflux disease (GERD) in the population, and the increasing unwillingness of patients to take acid suppressive medications for life. Laparoscopic fundoplication is now widely available in both academic and community hospitals, has a limited length of stay and postoperative recovery time, and is associated with excellent outcomes in carefully selected patients. Although the operation has low mortality and postoperative morbidity, it is associated with late postoperative complications, such as gas bloat syndrome, dysphagia, diarrhea, and recurrent GERD symptoms. This review summarizes the diagnostic evaluation and appropriate management of such postoperative complications. If a reoperation is needed, it should be performed by experienced foregut surgeons.

Tube to Freedom: Use of a Venting Jejunostomy in a Patient with Chronic Intestinal Pseudo-Obstruction

A 71-year-old Caucasian female with a longstanding history of digestive issues presented with acute abdominal pain, nausea, vomiting, bloating, and constipation. She reported her severe, intermittent epigastric pain, nausea and vomiting were triggered by both eating and drinking. Notably on the morning of admission, she had her first bowel movement in 7 days characterized as hard, followed by black, watery stool. No bright red blood was noted. Despite a long history of chronic abdominal pain, this episode was not relieved with her usual doses of oral hydromorphone and lorazepam. She denied fevers, chills, or dyspnea. Her gastrointestinal symptoms began 16 years prior to presentation when she was diagnosed with bowel obstruction secondary to a sigmoid volvulus. This was immediately addressed with a laparotomy and a left colectomy. Interestingly, during the operation she was found to have organoaxial malrotation. In the following years she continued to have recurrent symptoms consistent with bowel obstruction, and 3 years prior to presentation she underwent a near-total colectomy and ileo-rectal anastomosis because of colonic inertia and megacolon. Her past medical history was also significant for esophagitis, gastritis, gastric ulceration, and severe erosive duodenitis thought to be secondary to risedronate use. There was no history of diabetes, autoimmune diseases, or malignancy. She lived at home with her supportive husband and enjoyed a healthy lifestyle as a national level bowler. She maintained a healthy, unrestricted diet and took oral hydromorphone 1 mg qid and lorazepam 0.5 mg tid as needed for chronic abdominal pain, in addition to vitamin D, calcium, and ibandronate infusions. She had been a smoker but did not drink alcohol. Her family history was unremarkable. A further review of systems was otherwise unremarkable. Her physical examination on presentation was only significant for a frail appearance and hypoactive bowel sounds. On initial assessment CBC and chemistry panels only revealed mild hypokalemia. An abdominal CT showed airfilled dilated loops of small bowel suggestive of prior bowel obstruction (Fig. 1). An upper endoscopy revealed distal esophagitis and gastro-duodenitis. A gastroduodenal motility study showed evidence of intestinal neuropathy and myopathy. Bacterial overgrowth testing was negative. Over the following months, and despite institution of a full liquid diet and osmotic laxatives, the patient continued to complain of nausea and vomiting in addition to persistent severe abdominal pain and abdominal distention despite resolution of her constipation. Follow-up abdominal X-rays revealed an adynamic ileus pattern with a dilated, almost paralyzed small bowel. Her abdominal pain was now unbearable despite narcotics, and she was willing to pursue any avenue that might offer her some relief. For this reason, the decision was made to proceed with an endoscopicallyplaced venting gastrostomy in hopes that gastrointestinal decompression might help to alleviate her abdominal pain. C. Chun (&) G. Triadafilopoulos Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA e-mail: carlene@stanford.edu

Cameron Ulcers: You Will Find Only What You Seek

An obese 71-year-old Caucasian woman presented for evaluation a 2-year history of severe, unexplained iron deficiency anemia and recurrent melena. She was first diagnosed with iron deficiency anemia four years prior to presentation and was treated aggressively with oral and intravenous (IV) iron supplementation. During this time, she underwent several procedures at three different hospitals in an attempt to discover a cause of her anemia, including four upper endoscopies, three colonoscopies, a capsule endoscopy, an abdominal ultrasound, a technetium-99-tagged red blood cell scan and multiple chest X-rays. She also received more than 16 blood transfusions and over six IV infusions of iron for recurrent anemia. Despite these clinical and endoscopic evaluations, a definitive source of her gastrointestinal bleeding remained elusive. As a result, her hemoglobin levels continued to remain low, despite aggressive iron and blood replacement therapies (Fig. 1). In November 2010, the patient presented to our gastroenterology clinic for another opinion. Her past medical history was otherwise significant for nonalcoholic steatohepatitis, hypertension previously controlled with amlodipine, lisinopril and metoprolol, and bilateral pulmonary emboli that had resolved after IV heparin, IV tissue plasminogen activator and oral warfarin therapy. Subsequently, an unfixed inferior vena cava filter was placed. She was cytomegalovirus-positive and heterozygous for Leiden Factor V mutation. Her past surgical history was unremarkable. She was a retired physician-scientist, who lived alone and walked daily for exercise. She denied any alcohol, tobacco or drug use. Her father had died of a ruptured aortic aneurysm at age 51. On review of systems, she acknowledged muscle weakness, dizziness, severe fatigue and excessive thirst. She also reported difficulty swallowing liquids as well as solids, monthly vomiting, intermittent melena, occasional mild hemorrhoidal bleeding, and rare fecal incontinence. She denied any changes in appetite, heartburn, abdominal pain, early postprandial fullness, or constipation. On physical examination, her blood pressure was 198/87 and her pulse was 103 beats per minute. Otherwise, her examination was only remarkable for an obese abdomen and a resolving hematoma on her posterior right flank. There was no evidence of overt or occult gastrointestinal bleeding, jaundice, hepatosplenomegaly, or palpable lower extremity edema. Prior studies had failed to identify a source of her bleeding but had repeatedly noted a large sliding hiatal hernia, which we later characterized via barium esophagram as a large, unobstructed, type III hernia with 50% of the stomach displaced above the diaphragm (Fig. 2). Repeat upper endoscopy demonstrated a large hiatal hernia with fluid retention in the pouch, and a 1.5-cm Cameron ulcer at the diaphragmatic hiatus without stigmata of recent hemorrhage (Fig. 3). Esophageal, gastric and duodenal biopsies were normal, and there was no evidence of Helicobacter pylori infection. Esophageal manometry demonstrated normotensive upper and lower esophageal sphincters with normal esophageal body peristalsis. An C. L. Chun G. Triadafilopoulos (&) Division of Gastroenterology, Stanford University School of Medicine, Stanford, CA, USA e-mail: vagt@stanford.edu

Always a Suspect: CMV in Ulcerative Colitis

In June 2011, a 60-year-old white woman with history of ulcerative colitis presented with severe bloody diarrhea, reporting up to 12 bowel movements per day, vomiting and fatigue. She had initially presented with painless diarrhea and urgency 14 years ago. After the initial colonoscopic and histologic diagnosis of ulcerative colitis, she was placed on tapering doses of steroids and eventually on 100 mg of 6-mercaptopurine (6-MP). Over the next 5 years, she was treated for intermittent flares of ulcerative colitis with oral steroids in addition to 6-MP. Colonoscopy performed for a flare 6 years ago revealed viral inclusions in the cecal and rectal biopsies, consistent with cytomegalovirus (CMV). Serum IgG and IgM levels were elevated at 50.1 and 3.1, respectively. She was treated with ganciclovir 900 mg for 6 weeks in addition to 6-MP and prednisone, with subsequent clearance of histologic CMV inclusions. Over the next 5 years, she had a total of six colitis flares which were treated with short courses of steroids. However, because of an episode of pancreatitis in October 2006, 6-MP was discontinued in favor of methotrexate 12.5 mg weekly. Infliximab infusions were included in her regimen in March 2011 and were continued every 8 weeks thereafter. Her past medical history was otherwise significant for hepatitis A, hypothyroidism, hyperlipidemia, sclerosing cholangitis (for which she was treated with ursodeoxycholic acid 900 mg orally daily) and Sjogren’s syndrome. She was a non-smoker and non-drinker and worked as a librarian. Upon presentation in June 2011, her physical examination revealed a pale woman with a soft, non-distended, non-tender abdomen with positive bowel sounds. She was re-started on 40 mg of prednisone with continuation of methotrexate and infliximab; severe diarrhea persisted. Colonoscopy revealed severe ulcerative colitis with several large nodules suggestive of ‘‘dysplasia-associated lesion or mass’’ (DALM) (Fig. 1). Biopsies revealed high-grade dysplastic epithelium in the sigmoid and rectal nodules (Fig. 2). Viral inclusion bodies specific to CMV were observed with conventional histology and with immunohistochemal stains (Fig. 3). Infliximab infusions were stopped in favor of ganciclovir 900 mg given orally twice daily for 6 weeks. After one week of therapy, bowel movements decreased to 5–6 per day, her fatigue improved, but her hematocrit decreased by 4 points to 28.8 %. Intravenous iron was initiated to treat iron deficiency. Ten days after stopping ganciclovir, her hematocrit normalized. Upon follow-up colonoscopy 4 months later, severe ulcerative colitis with more dysplastic nodular lesions in several locations were identified. Because of this, she underwent a laparascopically-assisted total proctocolectomy with an end-ileostomy. The specimen revealed welldifferentiated adenocarcinoma in the cecum and sigmoid colon. Sixty-two lymph nodes identified were negative. When seen at follow up 2 months post colectomy, she felt more energetic and had discontinued prednisone, infliximab and methotrexate. Ursodeoxycholic acid was continued as the treatment for her primary sclerosing cholangitis. S. Kommareddy C. L. Chun W. Rogers G. Triadafilopoulos El Camino Hospital, Mountain View, CA, USA

Holiday Pains: A Case of Radiation-Induced Mesenteric Ischemia

A 65-year-old Caucasian male with a history of metastatic testicular cancer treated with an orchiectomy, cobalt-radiation therapy, and chemotherapy 35 years prior, was referred for evaluation of a 4-year history of unexplained post-prandial abdominal pain and bloating. Five years prior to presentation, he had an epigastric bruit incidentally discovered on a routine physical examination, but he reported no abdominal pain at that time. A computer tomography angiography (CTA) scan revealed mild to moderate atherosclerotic disease, and a non-contrast CT scan showed vascular calcifications. Because of the lack of symptoms and minimal imaging findings, no further action was taken. His first episode of severe abdominal pain began 4 years prior to this presentation. Plain films showed dilated loops of small bowel with air-fluid levels suggestive of partial or early bowel obstruction. Asymptomatic 3 months later, a follow-up CT abdomen and pelvis showed near complete resolution of bowel dilation. Over the course of the next 3 years, the patient experienced multiple subclinical and clinical episodes of sudden abdominal pain occurring without warning approximately 90 min after large meals. The pain progressively increased in intensity and frequency while its time to resolution progressed from hours to days and the pain-free periods decreased. Each episode was typically followed by one to two loose bowel movements prior to pain relief. Interestingly, his severe episodes occurred while on vacation in New Zealand and while diving in Australia. Other than the bruit, physical examination, basic laboratory studies including a complete blood count, metabolic panel, inflammatory markers, thyroid function tests, Helicobacter pylori antigen testing, fecal tests, and a celiac panel were normal. Repeat upper endoscopies demonstrated non-specific findings ranging from antral atrophy to antral gastritis with telangiectasias and petechiae. Numerous abdominal imaging studies, including plain films, non-contrast CT scans, and upper gastrointestinal series were significant for small intestinal dilation, suggestive of early or partial bowel obstruction. All episodes spontaneously resolved on a liquid diet, without medical intervention. During this time, he also developed progressive bilateral lower extremity weakness and was diagnosed with early prostate cancer. After an extensive neurologic evaluation, including muscle and nerve conduction studies and spinal imaging, he was diagnosed with likely radiation-induced lumbosacral plexitis. In an effort to avoid additional radiation therapy, he underwent robotically-assisted radical prostatectomy to treat his prostate cancer. His past medical history was also significant for hypercholesterolemia, erectile dysfunction, intermittent urinary incontinence, gallstones, and a normal colonoscopy 9 years prior. There was no history of hypertension or diabetes. He had no known allergies and was taking atorvastatin 20 mg daily, sildenafil 50 mg as needed, and multivitamins. A retired businessman, he lived comfortably with his wife and enjoyed three glasses of wine each week matched C. L. Chun (&) G. Triadafilopoulos Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA e-mail: carlene@stanford.edu

Where is the acid coming from? Esophago-gastric fistula following laparoscopic nissen fundoplication.

A 61-year-old Caucasian female presented for evaluation of worsening retrosternal chest pain, heartburn, acid regurgitation, and dysphagia. She described a sensation of a bubble getting stuck in the bottom of her throat and chest after swallowing liquids. She also noted early satiety, belching, and nausea aggravated by greasy meals, weight loss, and frequent episodes of diarrhea. Three years prior, she had undergone a combined laparoscopic Nissen fundoplication, hiatal hernia repair, and cholecystectomy. Immediately after the operation, she experienced persistent nausea and vomiting, followed by recurrent reflux symptoms. Since a computed tomography scan obtained on the second post-operative day was unremarkable, she was reassured. She consulted a gastroenterologist due to progressive symptoms worsening over the ensuing 6 months. After a reportedly normal endoscopy, antisecretory drug therapy was started but failed to alleviate her symptoms. Over the next 30 months, her symptoms continued to worsen until she was evaluated in our unit. Her past medical and surgical histories were significant for overactive bladder, oral herpes, hypertension, hysterectomy, tubal ligation with subsequent reversal, carpal tunnel repair, and tendon repairs of both her hands. Having no known allergies, she was taking oxybutynin, acyclovir, lisinopril, and hydrochlorothiazide. Retired and living with her husband and daughter, she enjoyed gardening. She reported a 30-pack-year smoking history and denied alcohol and recreational drug use. Her family history was remarkable for Parkinson’s disease, breast cancer, and cholelithiasis. Further review of systems was unremarkable. Her physical exam was significant for a blood pressure 190/93 but was otherwise normal. Upper endoscopy revealed a fistula connecting her distal esophagus to her gastric cardia and a non-displaced but erythematous and tight fundoplication (Fig. 1a, b). The fistula was noted just proximal to the wrap, with an exit point at the level of the cardia, which was confirmed by a barium swallow that showed a 17-mm connection between the distal esophagus and the gastric fundus bypassing the lateral aspect of the wrap, consistent with an esophagogastric fistula (Fig. 1c). Esophageal manometry revealed a lower esophageal sphincter (LES) pressure of 23.3 mmHg (normal 10–30 mmHg) with a residual LES pressure of 17 mmHg and 40 % relaxation (normal [70 %) with swallowing, likely secondary to her prior fundoplication and consistent with an effective anti-reflux procedure. Nevertheless, an ambulatory pH study off anti-secretory medications revealed severe, mostly upright, pathologic acid reflux with a DeMeester score of 113.4 and a percentage fraction of time with a pH of \4.0 in the distal esophagus of 31.9 %. There was an excellent correlation between symptoms and acid events; the intra-gastric pH was normal when the patient was off protein-pump inhibitor therapy. C. L. Chun (&) Department of Internal Medicine, Oregon Health and Science University, Portland, OR, USA e-mail: chun@ohsu.edu