Aparna Repaka

A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis

BACKGROUND Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights. RESULTS A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03). CONCLUSIONS Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.).

GCN5 is a required cofactor for a ubiquitin ligase that targets NF-κB/RelA

The transcription factor NF-kappaB is a critical regulator of inflammatory and cell survival signals. Proteasomal degradation of NF-kappaB subunits plays an important role in the termination of NF-kappaB activity, and at least one of the identified ubiquitin ligases is a multimeric complex containing Copper Metabolism Murr1 Domain 1 (COMMD1) and Cul2. We report here that GCN5, a histone acetyltransferase, associates with COMMD1 and other components of the ligase, promotes RelA ubiquitination, and represses kappaB-dependent transcription. In this role, the acetyltransferase activity of GCN5 is not required. Interestingly, GCN5 binds more avidly to RelA after phosphorylation on Ser 468, an event that is dependent on IKK activity. Consistent with this, we find that both GCN5 and the IkappaB Kinase (IKK) complex promote RelA degradation. Collectively, the data indicate that GCN5 participates in the ubiquitination process as an accessory factor for a ubiquitin ligase, where it provides a novel link between phosphorylation and ubiquitination.

Crohn’s Disease in an African-American Population

Objective:African-Americans have been underrepresented in most large Crohns disease (CD) trials. This study was undertaken to assess the course and character of CD in African-Americans in comparison with whites. Methods:We retrospectively compared the course and character of CD in African-American and white patients at 3 Atlanta hospitals. Ninety-nine patients (55 African-American, 44 whites) were enrolled. Telephone interviews and chart reviews were used to identify disease location, presence of fistulae and perirectal disease, surgical history, and medication use. Patients with ulcerative colitis or indeterminant colitis, and all non-African-Americans or whites, were excluded. Results:The numbers of male and female patients were similar (50 and 49). Overall, men comprised 54% of white patients and 47% of African-American patients. There were no significant differences in the setting in which CD were diagnosed, number of flares per year, or duration of symptoms before diagnosis. White patients were more likely to seek care for their CD in a clinic setting, both their primary care physicians (1.31 versus 0.21 visits/yr, P < 0.001) and their gastroenterologists (3.2 versus 2.3 visits/yr, P = 0.03). Small bowel (SB) disease was present more frequently in white patients, 84% versus 65% (P = 0.03), and SB resection was more common in this group, 59% versus 16% (P < 0.01). Colonic disease was more common in African-American patients, 89% versus 63% (P = 0.002). Perirectal fistulae were more frequent in African-American patients, 58% versus 22% (P < 0.001) white patients were more likely to report complete compliance with medical therapy, 77% versus 49% (P = 0.004). African-American patients more frequently discontinued medical therapy because they “felt better” (27% versus 9%, P = 0.02). Medication usage, including immunosuppressants, was similar in both groups, except that white patients were more likely to receive multiple doses of infliximab (34% versus 11%, P = 0.005). Both groups felt equally informed about CD, but white patients felt that their disease was under good control a greater percentage of the time, 71% versus 58% (P = 0.04). Conclusions:These data lend credence to the suggestion that the nature of CD may be different in African-Americans compared with whites. However, despite this apparent difference in disease manifestation, the contribution of socioeconomic factors, access to health care, and understanding of the disease likely play a role as well.

Ipilimumab administration in patients with advanced melanoma and hepatitis B and C.

Introduction Infection with hepatitis B (HBV) and/or C (HCV) represents a challenge for oncologists in treating patients with advanced cancers. Administration of chemotherapy may reactivate HBV and/or HCV, potentially causing severe hepatitis, hepatic decompensation, and even death. Patients and physicians must therefore balance the benefits of disease control with the risks of viral reactivation after systemic therapy. Postchemotherapy HBV reactivation has been reported particularly in patients with lymphoma or patients who receive treatment with rituximab, corticosteroids, anthracyclines, or bone marrow transplantation, a phenomenon that can be reduced by prophylactic antivirals such as lamivudine, entecavir, or tenofovir. Although reports of hepatitis from HCV reactivation exist, the incidence seems to be less frequent. The advent of new targeted therapies that may cause therapy-induced hepatitis reactivation and immunotherapies with unclear effects on viral replication and host immune status introduce even more complexity in treatment planning for these patients. Ipilimumab, a recombinant human immunoglobulin G1 monoclonal antibody that results in increased T-cell activation and proliferation by blocking the inhibitory action of the negative T-cell regulator cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), was the first agent to demonstrate a survival advantage in the treatment of advanced melanoma in a randomized study. This first-in-class drug has a unique adverse effect profile, with its activity manifesting as immune-related events that include enterocolitis, hepatitis, dermatitis, and endocrinopathies. Immune-mediated hepatitis occurred in 2% to 9% of patients in studies of ipilimumab, and 31.6% of patients experienced grade 3 to 4 immune-mediated hepatitis when ipilimumab was combined with dacarbazine. Recommendations for ipilimumab use include monitoring hepatic function tests before each dose, with initiation of corticosteroids for liver function tests (LFTs) and/or total bilirubin of grade 3 or higher that are unrelated to disease progression. Although chemotherapy may have immunosuppressive effects, the effects of ipilimumab in patients with hepatitis are less clear. Polymorphisms of CTLA-4 have been associated with chronic hepatitis B and C infection. CD8 T cells from humans with chronic HBV showed an increased propensity to express CTLA-4 that correlated with viral load and elevated levels of the proapoptotic protein Bim, which is thought to cause depletion of HBV-specific CD8 T-cell responses. Indeed, CTLA-4 blockade in cynomolgus macaques enhanced antibody response to hepatitis B surface antigen. The CTLA-4 pathway is also implicated in virus-specific T-cell exhaustion in patients with HCV. The mechanisms behind these events require further elucidation but imply an existing link between CTLA-4 activity and hepatic viral pathogenesis that could possibly be exploited for therapeutic benefit. Limited, if any, published data exist regarding the safety of ipilimumab in patients with HBV and HCV infection. Such patients were excluded from clinical trials of ipilimumab; therefore, information must be gained through postmarketing experience. Here we describe two patients, one with HBV and one with HCV, who were treated with ipilimumab for metastatic melanoma.

Immediate unprepared hydroflush colonoscopy for severe lower GI bleeding: a feasibility study

BACKGROUND Urgent colonoscopy is not always the preferred initial intervention in severe lower GI bleeding because of the need for a large volume of oral bowel preparation, the time required for administering the preparation, and concern regarding adequate visualization. OBJECTIVE To evaluate the feasibility, safety, and outcomes of immediate unprepared hydroflush colonoscopy for severe lower GI bleeding. DESIGN Prospective feasibility study of immediate colonoscopy after tap-water enema without oral bowel preparation, aided by water-jet pumps and mechanical suction devices in patients admitted to the intensive care unit with a primary diagnosis of severe lower GI bleeding. SETTING Tertiary referral center. MAIN OUTCOME MEASUREMENTS Primary outcome measurement was the percentage of colonoscopies in which the preparation permitted satisfactory evaluation of the entire length of the colon suspected to contain the source of bleeding. Secondary outcome measurements were visualization of a definite source of bleeding, length of hospital and intensive care unit (ICU) stays, rebleeding rates, and transfusion requirements. RESULTS Thirteen procedures were performed in 12 patients. Complete colonoscopy to the cecum was performed in 9 of 13 patients (69.2%). However, endoscopic visualization was thought to be adequate for definitive or presumptive identification of the source of bleeding in all procedures, with no colonoscopy repeated because of inadequate preparation. A definite source of bleeding was identified in 5 of 13 procedures (38.5%). The median length of ICU stay was 1.5 days; of hospital stay, 4.3 days. Recurrent bleeding during the same hospitalization, requiring repeated endoscopy, surgery, or angiotherapy, was seen in 3 of 12 patients (25%). LIMITATIONS Uncontrolled feasibility study of selected patients. CONCLUSION Immediate unprepared hydroflush colonoscopy in patients with severe lower GI bleeding is feasible with the hydroflush technique.

Characterization of the pancreas in vivo using EUS spectrum analysis with electronic array echoendoscopes

BACKGROUND Spectral analysis of the radiofrequency (RF) signals that underlie grayscale EUS images has been used to provide quantitative, objective information about tissue histology. OBJECTIVE Our purpose was to validate RF spectral analysis as a method to distinguish between chronic pancreatitis (CP) and pancreatic cancer (PC). DESIGN AND SETTING A prospective study of eligible patients was conducted to analyze the RF data obtained by using electronic array echoendoscopes. PATIENTS Pancreatic images were obtained by using electronic array echoendoscopes from 41 patients in a prospective study, including 15 patients with PC, 15 with CP, and 11 with a normal pancreas. MAIN OUTCOME MEASUREMENTS Midband fit, slope, intercept, correlation coefficient, and root mean square deviation from a linear regression of the calibrated power spectra were determined and compared among the groups. RESULTS Statistical analysis showed that significant differences were observable between groups for mean midband fit, intercept, and root mean square deviation (t test, P < .05). Discriminant analysis of these parameters was then performed to classify the data. For CP (n = 15) versus PC (n = 15), the same parameters provided 83% accuracy and an area under the curve of 0.83. LIMITATIONS Moderate sample size and spatial averaging inherent in the technique. CONCLUSIONS This study shows that mean spectral parameters of the backscattered signals obtained by using electronic array echoendoscopes can provide a noninvasive method to quantitatively discriminate between CP and PC.

Endoscopic management of Barrett esophagus

Endoscopy has a vital role in the diagnosis, screening, surveillance and treatment of Barrett esophagus. Over the past few decades, tremendous advances have been made in endoscopic technology, and the management of dysplasia and early cancer in Barrett esophagus has changed radically from being surgical to organ-sparing endoscopic therapy. Proper endoscopic techniques and systematic biopsy protocols improve dysplasia detection, and endoscopic surveillance improves outcomes in patients with Barrett esophagus and dysplasia. Endoscopic treatment can be tissue acquiring (as in endoscopic mucosal resection and endoscopic submucosal dissection) or ablative (as with photodynamic therapy, radiofrequency ablation and cryotherapy). Treatment is usually multimodal, combining endoscopic resection of visible lesions with one or more mucosal ablation techniques, followed by long-term surveillance. Such treatment is safe and effective. Shared decision-making between the patient and physician is important while considering treatment for dysplasia in Barrett esophagus. Issues such as durability of response, importance of subsquamous Barrett epithelium and the optimal management strategy in patients with low-grade dysplasia and nondysplastic Barrett esophagus need to be studied further. Development of safer wide-field resection techniques, which would effectively remove all Barrett esophagus and obviate the need for long-term surveillance, is needed.

A case of sumatriptan-induced intestinal ischemia.

To the Editor: Sumatriptan succinate, a serotonin-l (5hydroxytryptamine-1) receptor agonist, is an antimigraine drug that is reported to act by selectively constricting intracranial arteries. Recently, vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic, pulmonary, and coronary circulations. A series of eight cases of ischemic colitis in the setting of sumatriptan have been reported previously.1 We present a case report of focal segmental ischemia of the small bowel in the setting of migraine headaches in a patient treated with sumatriptan. A 20-year-old female patient was admitted to the hospital in June 2005 with severe abdominal pain, nausea, and vomiting. She had been having intermittent but worsening symptoms for 4 months before admission. She described her abdominal pain as dull, periumbilical, without radiation, with no relation to food or bowel movements. Patient denied diarrhea, constipation, melena, or hematochezia. She had a 20-pound weight loss over the past 4 months. Past medical history was significant for migraine headaches. She did not have any prior abdominal surgeries. She was taking Topiramate and Imitrex (sumatriptan). She denied any use of oral contraceptives. She denied smoking tobacco or drinking alcohol. Family history was significant for Crohn’s disease (maternal uncle). The patient disclosed that she had been using 50mg sumatriptan prn for migraine headaches. She reported that she consistently took sumatriptan for migraine headaches and that her abdominal complaints usually started approximately 24 h after her intake of sumatriptan. She had visited the ER for severe migraine the day before her symptoms became severe and was given sumatriptan. Physical examination was significant for mild periumbilical tenderness with no rebound. No masses were felt, and there were good bowel sounds. She was afebrile and her blood pressure and heart rate were within normal limits. Her serum chemistry values, including liver function tests, were within normal limits. Amylase was slightly elevated at 127 (30–110). Lipase was within normal limits. Hemogram showed leukocytosis with a white count of 12.7 thousand with 80% neutrophils. Hematocrit and platelet count were within normal limits. She had normal serum protein electrophoresis. ESR and CRP were within normal limits. Her stool was positive for occult blood. She had a KUB (plain abdominal film) film and a right upper quadrant ultrasound done, which were normal. She had an abdominal computed tomography (CT) scan, which showed thickening of terminal ileum suspicious for Crohn’s (Fig. 1). She had a small bowel follow-through that showed a focal edematous loop of small bowel in the left lower quadrant approximately 5 cm in length. She underwent a colonoscopy that showed mild erythema and nodularity of her terminal ileum. She had a capsule endoscopy and a small bowel magnetic resonance imaging, (MRI), both of which were normal. Her terminal ileal biopsies showed a normal villous pattern without ileitis. Serological markers for irritable bowel syndrome (IBD) including ASCA, OmpC IgA, and pANCA were negative. Due to her intractable symptoms, she was started on TPN and on IV antibiotics including ciprofloxacin and metronidazole, along with other supportive measures. Given her abdominal CT findings suspicious for Crohn’s, she was started on prednisone. She was seen at our clinic, where we diagnosed her symptoms to be secondary to sumatriptan use. We tapered her prednisone and advised her not to take any more sumatriptan. She remains symptom free since that time. Vascular insults to short segments of small bowel produce a broad spectrum of clinical features without the life-threatening complications that are associated with more extensive ischemia. The causes of focal segmental ischemia (FSI) of the small bowel include atheromatous emboli, strangulated hernias, immune complex disorders and vasculitis, blunt abdominal trauma, segmental

ASGE guideline for infection control during GI endoscopy

The Quality Assurance in Endoscopy Committee of the American Society for Gastrointestinal Endoscopy (ASGE) updated and revised this document, which was originally prepared by The Standards of Practice Committee of the ASGE and was published in 2008. In preparing this guideline, a search of the medical literature was performed by using PubMed, supplemented by accessing the related-articles feature of PubMed. Additional references were obtained from the bibliographies of the identified articles and from recommendations of expert consultants. When little or no data existed from welldesigned prospective trials, emphasis was given to results from large series and reports from recognized experts. Guidelines for appropriate use of endoscopy are based on a critical review of the available data and expert consensus at the time the guidelines are drafted. Further controlled clinical studies may be needed to clarify aspects of this guideline. This guideline may be revised as necessary to account for changes in technology, new data, or other aspects of clinical practice. This guideline is intended to be an educational tool to provide information that may assist endoscopists in delivering care to patients. This guideline is not a rule and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment. Clinical decisions in any particular case involve a complex analysis of the patient’s condition and available courses of action. Therefore, clinical considerations may lead an endoscopist to take a course of action that varies from these guidelines.

Lymph node characterization in vivo using endoscopic ultrasound spectrum analysis with electronic array echo endoscopes

Our purpose was to demonstrate the use of radiofrequency spectral analysis to distinguish between benign and malignant lymph nodes with data obtained using electronic array echo endoscopes, as we have done previously using mechanical echo endoscopes. In a prospective study, images were obtained from eight patients with benign-appearing lymph nodes and 11 with malignant lymph nodes, as verified by fine-needle aspiration. Midband fit, slope, intercept, correlation coefficient, and root-mean-square (RMS) deviation from a linear regression of the calibrated power spectra were determined and compared between the groups. Significant differences were observable for mean midband fit, intercept, and RMS deviation (t test P < 0.05). For benign (n = 16) vs. malignant (n = 12) lymph nodes, midband fit and RMS deviation provided classification with 89 % accuracy and area under receiver operating characteristic (ROC) curve of 0.95 based on linear discriminant analysis. We concluded that the mean spectral parameters of the backscattered signals from electronic array echo endoscopy can provide a noninvasive method to quantitatively discriminate between benign and malignant lymph nodes.