Eric U. Yee

Histology Grade Is Independently Associated With Relapse Risk in Patients With Ulcerative Colitis in Clinical Remission: A Prospective Study.

OBJECTIVES:Objective evidence of inflammation has been associated with the risk of relapse in patients with ulcerative colitis (UC) who are in clinical remission. We compared endoscopic and histologic grades for their ability to predict clinical relapse in this patient population.METHODS:Patients with UC in clinical remission were prospectively enrolled into an observational cohort. Baseline endoscopic scores (Mayo) and histological (Geboes) grades and blood markers were collected. All subjects were followed for 12 months and relapse determined using clinical indices.RESULTS:A total of 179 subjects were enrolled into the study and followed for 12 months. Clinical relapse occurred in 23%; 5% were hospitalized, and 2% underwent colectomy. In univariate analysis, the baseline Mayo endoscopy score and the Geboes histology grade were significantly associated with the later development of clinical relapse (P<0.001 for both), but only the histology grade remained significant in a multivariate model (P=0.006). The relative risk of clinical relapse was 3.5 (95% CI 1.9–6.4, P<0.0001) in subjects whose baseline Geboes grade was ≥3.1. The area under the curve was 0.73 for the Geboes histology grade to identify subjects at risk of future clinical relapse. Of the patients in clinical, endoscopic, and histological remission at baseline (n=82), only 7% had a clinical relapse over the subsequent 12 months.CONCLUSIONS:Histology grade has the strongest association with the risk of clinical relapse in patients with UC who are in clinical remission. Consideration should be given to including this end point in evaluating therapy for UC.

Severe Pazopanib-Induced Hepatotoxicity: Clinical and Histologic Course in Two Patients

Introduction Kidney cancer is the ninth most common cancer in the United States, with an estimated 60,920 new diagnoses in 2011. The vast majority of adult kidney neoplasms are renal cell carcinomas (RCCs). Although the majority of patients present with localized disease, 20% of patients present with advanced disease, and 20% to 30% of all patients subjected to a nephrectomy with curative intent develop distant recurrence. The clear-cell histologic subtype accounts for 75% to 80% of sporadic RCCs and is well known to be associated with high levels of angiogenic factors such as vascular endothelial growth factor (VEGF) through the downstream effects of Von-Hippel-Lindau tumor-suppressor inactivation. Since 2005, four anti-VEGF therapies (sorafenib, sunitinib, bevacizumab, and pazopanib) have been approved for treatment of patients with metastatic RCC. Pazopanib, which is the most recently approved drug, is an oral small molecule tyrosine kinase inhibitor that inhibits VEGF receptors 1, 2, and 3, c-kit, and platelet-derived growth factor receptors and . Pazopanib (Votrient; GlaxoSmithKline, London, United Kingdom) was approved by the US Food and Drug Administration in October 2009 on the basis of phase III data that showed a significant prolongation in progression-free survival relative to a placebo in patients with advanced RCC. Approval came with a black box warning about hepatotoxicity. In the phase III trial, the incidence of grade 3 to 4 ALT increase was 12%, and 53% of patients experienced some degree of hypertransaminasemia. A subsequent meta-analysis of all pazopanib-containing trials confirmed a 42% incidence of all-grade ALT increase and an 8.2% incidence of high-grade ALT increase. To our knowledge, there have been two hepatotoxicity-related deaths among the 977 patients (0.2%) described in published clinical literature. The incidence of grade 3 to 4 ALT increase from published sunitinib trials is 3%, although these data were not specifically recorded forsorafenibinpatientswithRCCs.Despitetheestablishedincidenceof hepatotoxicity there is little understanding of the underlying mechanism, and a histopathologic correlation is lacking. In this article, we report two cases of high grade (4 or 5) hepatotoxicity associated with pazopanib use in patients with metastatic RCC. To our knowledge, these are the first two case reports with accompanying liver-biopsy information.

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis, which is a chronic inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pretreated orally with vehicle or 5-PAHSA (10 mg/kg) and 9-PAHSA (5 mg/kg) once daily for 3 days, followed by 10 days of either 0% or 2% dextran sulfate sodium water with continued vehicle or PAHSA treatment. The colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4+ T cells from syngeneic mice were co-cultured to assess antigen presentation and T cell activation in response to LPS. PAHSA treatment prevented weight loss, improved colitis scores (stool consistency, hematochezia, and mouse appearance), and augmented intestinal crypt Paneth cell bactericidal potency via a mechanism that may involve GPR120. In vitro, PAHSAs attenuated dendritic cell activation and subsequent T cell proliferation and Th1 polarization. The anti-inflammatory effects of PAHSAs in vivo resulted in reduced colonic T cell activation and pro-inflammatory cytokine and chemokine expression. These anti-inflammatory effects appear to be partially GPR120-dependent. We conclude that PAHSA treatment regulates innate and adaptive immune responses to prevent mucosal damage and protect against colitis. Thus, PAHSAs may be a novel treatment for colitis and related inflammation-driven diseases.

Colorectal Cancer Screening in Inflammatory Bowel Disease

Patients with long-standing ulcerative colitis (UC) or Crohn’s colitis are at increased risk of developing colorectal cancer (CRC). Given that most cases of CRC are thought to arise from dysplasia, previous guidelines have recommended endoscopic surveillance with random biopsies obtained from all segments of the colon involved by endoscopic or microscopic inflammation. However, recent evidence has suggested that the majority of dysplastic lesions in patients with inflammatory disease (IBD) are visible, and data have been supportive of chromoendoscopy with targeted biopsies of visible lesions versus traditional random biopsies. This review article will discuss the risk of colon cancer in patients with IBD, as well as current recommendations for CRC screening and surveillance in patients with UC or Crohn’s colitis.

Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier

Purpose Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification. Experimental Design Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells. Results A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95% sensitivity and 89% specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94%, specificity = 89.6%) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion. Conclusions This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets.

Adenomas with high-grade dysplasia and early adenocarcinoma are more likely to be sessile in the proximal colon

Size and the sessile morphology of an adenoma may explain why colonoscopy is less effective in preventing proximal colonic cancer than distal cancers. We wanted to determine if advanced polypoid neoplasms (APNs, i.e. adenoma with high‐grade dysplasia or early adenocarcinoma) are more likely to be sessile and/or smaller in the proximal colon.

MR Enterography of the Ileoanal Pouch: Descriptive Radiologic Analysis With Endoscopic and Pathologic Correlation

OBJECTIVE The purpose of this study was to describe the MR enterography (MRE) appearance of inflammation of the ileoanal pouch after ileal pouch-anal anastomosis (IPAA) surgery and to correlate it with pouch endoscopic and histopathologic findings. MATERIALS AND METHODS All MRE studies performed between October 1, 2007, and September 30, 2013, for patients who had previously undergone IPAA (n = 54) were retrieved. After review of medical records, the patients who underwent MRE, pouch endoscopy, and biopsy within 90 days (14 men, 14 women; mean age, 42.2 years; range, 24-67 years) were selected for inclusion in the study. Two blinded MRI radiologists in consensus retrospectively evaluated MRE studies for multiple MRI features. Two MRI scores were then calculated: an active and a composite inflammation score. A gastroenterologist retrospectively reviewed the pouch endoscopic images, and a pathologist reviewed the slides; both of these investigators were blinded. Both MRI scores were correlated with the pouch endoscopic and histopathologic findings. RESULTS The composite MRI score had strong positive correlation with the endoscopic score (r = 0.61; p = 0.0005) but weak positive correlation with the histopathologic score (r = 0.31; p = 0.10, not statistically significant). The active inflammation MRI score had moderate positive correlation with the endoscopic score (r = 0.57; p = 0.0017) and weak positive correlation with the histopathologic score (r = 0.20; p = 0.31, not statistically significant). An MRI score ≥ 4 indicated the best results, with sensitivity of 86%, specificity of 79%, positive predictive value of 80%, negative predictive value of 85%, and accuracy of 82% for pouch inflammation. A positive likelihood ratio of 4.00 and negative likelihood ratio of 0.18 were obtained. CONCLUSION In patients who have undergone IPAA surgery, the MRE findings strongly correlate with the pouch endoscopic findings with high sensitivity and positive predictive value for pouch inflammation. Therefore, MRE is a useful noninvasive test performed without ionizing radiation that can be used to evaluate patients with clinical symptoms and possibly alleviate the need for endoscopy in a select patient population.

Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy

Pancreatic cancers are usually detected at an advanced stage and have poor prognosis. About one fifth of these arise from pancreatic cystic lesions. Yet not all lesions are precancerous, and imaging tools lack adequate accuracy for distinguishing precancerous from benign cysts. Therefore, decisions on surgical resection usually rely on endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Unfortunately, cyst fluid often contains few cells, and fluid chemical analysis lacks accuracy, resulting in dire consequences, including unnecessary pancreatic surgery for benign cysts and the development of cancer. Here, we report an optical spectroscopic technique, based on a spatial gating fibre-optic probe, that predicts the malignant potential of pancreatic cystic lesions during routine diagnostic EUS-FNA procedures. In a double-blind prospective study in 25 patients, with 14 cysts measured in vivo and 13 postoperatively, the technique achieved an overall accuracy of 95%, with a 95%confidence interval of 78–99%, in cysts with definitive diagnosis.

Lanthanum deposition from oral lanthanum carbonate in the upper gastrointestinal tract.

Lanthanum carbonate is used as an alternative to calcium‐based phosphate binders to manage hyperphosphataemia in patients with renal failure. The deposition of lanthanum within gastroduodenal mucosa of patients treated with the medication has been described, but given the relative novelty of this entity, the histiocytic deposits in the gastroduodenal mucosa can be confused with a variety of other processes, including infections and other drug‐induced forms of injury.

Multicystic biliary hamartoma: A report of a rare entity and a review of the literature

INTRODUCTION Multicystic biliary hamartoma is a rare liver tumor that was first described in 2005. Only nine cases are reported in the literature and all of them originate from Eastern patient populations, specifically Japan and Korea. PRESENTATION OF CASE Herein we report the occurrence of the tenth multicystic biliary hamartoma reported to date, arising in a Caucasian American woman initially presenting with abdominal pain. At 4.7 cm this is the second largest tumor reported to date and the only one arising in a Western patient population. DISCUSSION The patient underwent multimodality imaging and the tumor was biopsied preoperatively, but the diagnosis remained unclear. An extended right hepatectomy was performed for resection of her tumor, and the tumor was definitively diagnosed based on the surgically resected specimen. As all nine of the previously reported cases also underwent resection, the natural history of this lesion remains unknown. The lack of both recurrence and tumor spread in the previously reported cases indicates that this may be a benign lesion not requiring surgical resection unless symptomatic. CONCLUSION Multicystic biliary hamartoma is an extremely rare tumor. Increased awareness of the radiologic and pathologic features will likely lead to the diagnoses of further cases in both Western and Eastern populations and could potentially assist with preoperative diagnosis. The natural history and optimal management of this tumor remain uncertain.