Primary Yolk Sac Tumor of the Liver: A Rare Cause of Bile Duct Obstruction.

Primary yolk sac tumor (YST) of the liver is an extremely rare extragonadal germ cell tumor. Here, we present a case of a young man who developed primary YST of the liver which metastasized to periductal lymph nodes causing bile duct obstruction. A 32-year-old male was referred from an outside hospital for evaluation of painless jaundice. Initial investigation showed common bile duct compression from periductal lymph nodes. Inital biopsy results were concerning for adenocarcinoma. The patient was ultimately diganosed with primary YST of the liver. He was then started on a curative-intent chemotherapy regimen of bleomycin, etoposide, and cisplatin. This case highlights the importance of keeping the primary YST of the liver on the differential diagnosis as initial staining patterns are similar to adenocarcinoma which has a very different management.

Structured training program on confocal laser endomicroscopy for pancreatic cystic lesions: a multicenter prospective study among early-career endosonographers (with video).

BACKGROUND AND AIMS: Data on how to teach endosonographers needle-based confocal laser endomicroscopy (nCLE)-guided histologic diagnosis of pancreatic cystic lesions (PCLs) are limited. Hence, we developed and tested a structured educational program to train early-career endosonographers in nCLE-guided diagnosis of PCLs. METHODS: Twenty-one early-career nCLE-naïve endosonographers watched a teaching module outlining nCLE criteria for diagnosing PCLs. Participants then reviewed 80 high-yield nCLE videos, recorded diagnoses, and received expert feedback (phase 1). Observers were then randomized to a refresher feedback session or self-learning at 4 weeks. Eight weeks after training, participants independently assessed the same 80 nCLE videos without feedback and provided histologic predictions (phase 2). Diagnostic performance of nCLE to differentiate mucinous versus nonmucinous PCLs and to diagnose specific subtypes were analyzed using histopathology as the criterion standard. Learning curves were determined using cumulative sum analysis. RESULTS: Accuracy and diagnostic confidence for differentiating mucinous versus nonmucinous PCLs improved as endosonographers progressed through nCLE videos in phase 1 (P < .001). Similar trends were observed with the diagnosis of PCL subtypes. Most participants achieved competency interpreting nCLE, requiring a median of 38 assessments (range, 9-67). During phase 2, participants independently differentiated PCLs with high accuracy (89%), high confidence (83%), and substantial interobserver agreement (κ = .63). Accuracy for nCLE-guided PCL subtype diagnoses ranged from 82% to 96%. The learned nCLE skills did not deteriorate at 8 weeks and were not impacted by a refresher session. CONCLUSIONS: We developed a practical, effective, and durable educational intervention to train early-career endosonographers in nCLE-guided diagnosis of PCLs.

Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.

BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

Incidence of Recurrent NASH-Related Allograft Cirrhosis.

BACKGROUND: Cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is projected to become the leading indication for liver transplantation (LT) in the USA in the next decade. The long-term implications of post-LT NASH, specifically on the development of allograft cirrhosis, are not well known. METHODS: A retrospective cohort of patients at a single large center undergoing LT for NASH from 2000 to 2015 was identified using a prospectively collected database. A total of 226 patients undergoing LT for NASH were identified. Mean follow-up for the cohort was 7 years. Seventy-five percent of patients underwent at least one liver biopsy post-LT. RESULTS: Eighty-one patients (36%) developed recurrence of biopsy-proven NASH. Fifteen patients developed bridging fibrosis but only four patients (1.8%) progressed to recurrent NASH cirrhosis at a mean of 9 years post-LT. Body mass index at the time of LT was statistically higher in the NASH allograft cirrhosis group. Recurrent disease was less common and less severe in those transplanted with black donors. All four patients with recurrent NASH cirrhosis developed evidence of portal hypertension, but all remained alive at follow-up. CONCLUSION: Although recurrent NASH following LT is common, the development of allograft cirrhosis is rare. These findings are useful when counseling patients and important to consider during their post-LT care.

Association of Dietary Habits with Severity of Acute Pancreatitis.

BACKGROUND: The effect of diet on risk of acute pancreatitis (AP) has been suggested by prior studies, but the association of dietary habits with severity of AP has not been previously evaluated. OBJECTIVE: The objective of the study was to assess differences in reported dietary habits in patients with severe AP compared with those with mild or moderate AP. METHODS: A prospectively maintained cohort of patients with AP was utilized. A brief questionnaire on dietary habits was implemented. Dietary habits were categorized based on the overall type of diet, fruit/vegetable servings, fat content, dairy consumption, dessert/sweets consumption, and fluid intake. Patients were grouped into mild/moderate and severe AP. Multivariate analysis was used to determine whether dietary habits have an independent association with AP severity. RESULTS: 407 patients with AP were studied. Mean patient age was 51 y, and 202 (50%) were men. 29% of patients were smokers and 46% actively consumed alcohol. 225 patients had mild AP, 103 moderate AP, and 79 developed severe AP. The 3 groups were comparable in race, body mass index, etiology of AP, and comorbidities. Dietary factors were overall comparable between the groups except for diet type: subjects with severe AP had a higher percentage of consuming a meat-rich diet (84%) than patients with mild AP (72%) and moderate AP (67%) (P = 0.04). Based on multivariable logistic regression, the OR of developing severe AP was 2.5 (95% CI: 1.24-5.32, P = 0.01) between patients who eat a meat-rich diet and those who consume a vegetable-based diet. CONCLUSIONS: A meat-rich diet is independently associated with the development of persistent organ failure (severe disease) in patients with AP. These findings require further evaluation and could be useful for patient counseling, risk stratification, and disease prevention. This study is registered at clinicaltrials.gov as NCT03075605.

Rectal Trumpet-Associated Hemorrhage in the Intensive Care Unit: A Quality Improvement Initiative.

The rectal trumpet (RT) is a nasopharyngeal airway device that is inserted into the rectum for management of fecal incontinence. No published data exist on adverse events caused by the use of an RT. The purpose of this quality improvement project was to determine the rate of RT-associated hemorrhage among patients treated with an RT in our transplant intensive care unit (TICU). This quality improvement initiative and retrospective medical record review included all patients (N = 3933) cared for in a single specialty intensive care unit at a tertiary academic medical center between January 1, 2014, and May 31, 2016. We estimate that approximately 400 patients were treated with an RT. We found 3 possible and 9 probable cases of RT-associated hemorrhage, resulting in an estimated incident rate of 3% among RT-treated patients. All of these patients underwent invasive procedures for hemostasis. They received a mean of 4.9 units of packed red blood cell transfusions, and 9 experienced hypotension. Eight out of the 9 probable RT-associated hemorrhage patients experienced hemorrhage only after greater than 7 days of treatment with an RT. Following this initiative, RT use was banned in our TICU. The use of RTs can cause hemorrhage with clinically significant consequences.

The assessment and management of pain in cirrhosis.

PURPOSE OF REVIEW: The treatment of pain in patients with cirrhosis is complicated by unpredictable hepatic drug metabolism and a higher risk of adverse drug reactions. We aimed to conduct a scoping review regarding pain management in cirrhosis. RECENT FINDINGS: Despite the high prevalence of pain in patients with cirrhosis, there is little literature to guide the management of pain in this population. Complex pain syndromes and disease-specific pain etiologies exist are common in patients with cirrhosis. There are numerous contraindications and limitations when considering pharmacotherapy for analgesia in cirrhosis, specifically with non-steroidal anti-inflammatory drugs (NSAIDS) and opioid medications. Non-pharmacologic therapies for pain have not been specifically assessed in this population. SUMMARY: As with other populations, a multi-dimensional treatment approach to pain with a focus on physical, behavioral, procedural and pharmacologic treatment is recommended when caring for patients with cirrhosis and pain. However, more research is needed to evaluate opioid-sparing and non-pharmacologic analgesia in this population.

Clinical outcomes of isolated renal failure compared to other forms of organ failure in patients with severe acute pancreatitis.

AIM: To assess differences in clinical outcomes of isolated renal failure (RF) compared to other forms of organ failure (OF) in patients with severe acute pancreatitis (SAP). METHODS: Using a prospectively maintained database of patients with acute pancreatitis admitted to a tertiary medical center between 2003 and 2016, those with evidence of persistent OF were classified to renal, respiratory, cardiovascular, or multi-organ (2 or more organs). Data regarding demographics, comorbidities, etiology of acute pancreatitis, and clinical outcomes were prospectively recorded. Differences in clinical outcomes after development of isolated RF in comparison to other forms of OF were determined using independent t and Mann-Whitney U tests for continues variables, and χ2 test for discrete variables. RESULTS: Among 500 patients with acute pancreatitis, 111 patients developed persistent OF: mean age was 54 years, and 75 (67.6%) were male. Forty-three patients had isolated OF: 17 (15.3%) renal, 25 (21.6%) respiratory, and 1 (0.9%) patient with cardiovascular failure. No differences in demographics, etiology of acute pancreatitis, systemic inflammatory response syndrome scores, or development of pancreatic necrosis were seen between patients with isolated RF vs isolated respiratory failure. Patients with isolated RF were less likely to require nutritional support (76.5% vs 96%, P = 0.001), ICU admission (58.8% vs 100%, P = 0.001), and had shorter mean ICU stay (2.4 d vs 15.7 d, P < 0.001), compared to isolated respiratory failure. None of the patients with isolated RF or isolated respiratory failure died. CONCLUSION: Among patients with SAP per the Revised Atlanta Classification, approximately 15% develop isolated RF. This subgroup seems to have a less protracted clinical course compared to other forms of OF. Isolated RF might be weighed less than isolated respiratory failure in risk predictive modeling of acute pancreatitis.

Chronic constipation: Update on management.

Managing chronic constipation involves identifying and treating secondary causes, instituting lifestyle changes, prescribing pharmacologic and nonpharmacologic therapies, and, occasionally, referring for surgery. Several new drugs have been approved, and others are in the pipeline.

Acute pancreatitis patient registry to examine novel therapies in clinical experience (APPRENTICE): an international, multicenter consortium for the study of acute pancreatitis.

BACKGROUND: We have established a multicenter international consortium to better understand the natural history of acute pancreatitis (AP) worldwide and to develop a platform for future randomized clinical trials. METHODS: The AP patient registry to examine novel therapies in clinical experience (APPRENTICE) was formed in July 2014. Detailed web-based questionnaires were then developed to prospectively capture information on demographics, etiology, pancreatitis history, comorbidities, risk factors, severity biomarkers, severity indices, health-care utilization, management strategies, and outcomes of AP patients. RESULTS: Between November 2015 and September 2016, a total of 20 sites (8 in the United States, 5 in Europe, 3 in South America, 2 in Mexico and 2 in India) prospectively enrolled 509 AP patients. All data were entered into the REDCap (Research Electronic Data Capture) database by participating centers and systematically reviewed by the coordinating site (University of Pittsburgh). The approaches and methodology are described in detail, along with an interim report on the demographic results. CONCLUSION: APPRENTICE, an international collaboration of tertiary AP centers throughout the world, has demonstrated the feasibility of building a large, prospective, multicenter patient registry to study AP. Analysis of the collected data may provide a greater understanding of AP and APPRENTICE will serve as a future platform for randomized clinical trials.

Recurrence and survival rates of inflammatory bowel disease-associated colorectal cancer following postoperative chemotherapy: a comparative study.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC). Studies have shown tumorigenetic and histomorphological differences between IBD-associated CRC and non-IBD CRC, suggesting differences in tumor behavior and response to treatment. We aimed to compare tumor recurrence and survival rates following postoperative chemotherapy in CRC patients with and without IBD. METHODS: Search of the Cleveland Clinic's CRC database revealed 65 patients who had IBD-associated CRC and received postoperative adjuvant chemotherapy between 1994 and 2010. Twenty-one patients were excluded due to incomplete clinical data. Propensity score-matching based on age, surgery intent, CRC site, tumor grade, American Joint Committee on Cancer (AJCC) stage and T stage was used to match IBD and non-IBD patients (1:4). Competing risk and Cox regression models were used to analyze differences in disease-free survival and overall survival, respectively. RESULTS: Forty-four patients with IBD-associated CRC were matched to 176 patients with non-IBD CRC. Among IBD patients, 29 (66%) had ulcerative colitis, 14 (32%) had Crohn's disease, and one (2%) had indeterminate colitis. Mean IBD diagnosis age was 28.1 ± 14.5 years, and mean IBD duration at time of CRC treatment was 21.5 ± 12.6 years. Ten (23%) IBD patients had tumor recurrence compared with 34 (19%) non-IBD patients (P = .074). There was no significant difference in disease-free survival (hazard ratio [HR] = 0.60; 95% CI: 0.35-1.05; P = 0.074) or overall survival (HR = 0.87; 95% CI: 0.54-1.4; P = 0.58) between IBD and non-IBD patients. CONCLUSION: Patients with IBD-associated CRC have comparable rates of tumor recurrence and survival following postoperative chemotherapy as CRC patients without IBD. Prospective studies are needed to confirm these findings and guide therapeutic decisions.

Managing irritable bowel syndrome: The low-FODMAP diet.

A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) has been found to significantly reduce symptoms of irritable bowel syndrome (IBS). The diet is best implemented in two phases: initial strict elimination of foods high in FODMAPs, then gradual reintroduction based on symptoms. Further study of this diet's effect on intestinal microbiota is needed.

Acute Alcoholic Hepatitis, the Clinical Aspects.

Alcoholic hepatitis is an acute form of alcoholic liver disease with variable severity that develops in patients who usually have a history of prolonged and recent alcohol abuse. The diagnosis is clinical and depends on history, physical examination, and laboratory derangements. Liver biopsy is diagnostic but not universally performed, and noninvasive diagnostic modalities are under development. Scoring systems are used to assess severity of disease, predict mortality, and guide decisions for initiation of specific therapies. The natural history and long-term outcomes of alcoholic hepatitis, including recurrence, progression to cirrhosis, and mortality, vary and depend partly on abstinence from alcohol use.

Sonic hedgehog signaling in hepatocellular carcinoma: A pilot study.

Hedgehog signaling is involved in the pathogenesis of several tumor types; however, its role in hepatocellular carcinoma (HCC) has not been fully elucidated. Biomarkers that reflect tumor aggressiveness are of potential value in selecting HCC patients for liver transplantation (LT). The aim of the present study was to assess the tissue expression of sonic hedgehog (Shh) biomarkers in HCC and surrounding non-tumorous liver tissue, and to correlate this expression with HCC recurrence following LT. Patients who underwent LT for HCC at the Cleveland Clinic (Cleveland, OH, USA) between 2002 and 2006 were randomly selected for analysis. Tissue samples were retrieved from the explanted tumorous livers. Routine immunohistochemistry was used to detect three specific Shh pathway biomarkers: The ligand Shh, the receptor patched-1 (Ptch) and the transcription factor glioma-associated oncogene homolog 1 (Gli1). Computerized quantitative analysis was used to evaluate the expression levels of these markers in HCC and surrounding non-tumorous liver tissue. Analysis of variance was used to compare the differential tissue expression between patients with and those without HCC recurrence. A time-to-event analysis was performed to assess the association of hedgehog biomarker expression with the risk of HCC recurrence following LT. A total of 53 tissue specimens from 21 patients were analyzed. The mean patient age was 57±8 years and 86% of the patients were male. A total of 62% patients had hepatitis C virus infection, 14% had hepatitis B virus infection, 43% had alcoholic cirrhosis and 91% fulfilled the Milan criteria at the time of LT. The average follow-up time after LT was 36±15 months, during which 19% of the patients developed HCC recurrence and 29% died. Shh, Ptch and Gli1 were detected in the HCC tissues of all the patients. Ptch was overexpressed in HCC compared with the surrounding non-tumorous tissue. The statistical power of this study was unable to associate Shh pathway markers with HCC recurrence following LT. In a proof-of-concept study, we demonstrated tissue expression of three Shh biomarkers within HCC tumors, and also identified differences in Ptch expression between tumor and surrounding non-tumorous tissue. Further larger studies are required to assess the utility of these biomarkers in HCC.

Diagnosis and Management of Alcoholic Liver Disease.

Alcohol is a leading cause of liver disease and is associated with significant morbidity and mortality. Several factors, including the amount and duration of alcohol consumption, affect the development and progression of alcoholic liver disease (ALD). ALD represents a spectrum of liver pathology ranging from fatty change to fibrosis to cirrhosis. Early diagnosis of ALD is important to encourage alcohol abstinence, minimize the progression of liver fibrosis, and manage cirrhosis-related complications including hepatocellular carcinoma. A number of questionnaires and laboratory tests are available to screen for alcohol intake. Liver biopsy remains the gold-standard diagnostic tool for ALD, but noninvasive accurate alternatives, including a number of biochemical tests as well as liver stiffness measurement, are increasingly being utilized in the evaluation of patients with suspected ALD. The management of ALD depends largely on complete abstinence from alcohol. Supportive care should focus on treating alcohol withdrawal and providing enteral nutrition while managing the complications of liver failure. Alcoholic hepatitis (AH) is a devastating acute form of ALD that requires early recognition and specialized tertiary medical care. Assessment of AH severity using defined scoring systems is important to allocate resources and initiate appropriate therapy. Corticosteroids or pentoxifylline are commonly used in treating AH but provide a limited survival benefit. Liver transplantation represents the ultimate therapy for patients with alcoholic cirrhosis, with most transplant centers mandating a 6 month period of abstinence from alcohol before listing. Early liver transplantation is also emerging as a therapeutic measure in specifically selected patients with severe AH. A number of novel targeted therapies for ALD are currently being evaluated in clinical trials.

Syndromic and sporadic inflammatory/hyperplastic small-bowel polyps: a comparative study.

BACKGROUND: Inflammatory/hyperplastic small-bowel polyps (SBPs) occur either sporadically or in patients with a polyposis syndrome; however, comparison between these two settings of the histological features of SBPs has not been reported and the etiology of sporadic inflammatory/hyperplastic SBPs remains unclear. METHOD: Twenty-eight cases of sporadic inflammatory/hyperplastic SBPs and nine cases of syndromic SBPs were retrieved from the Department of Anatomic Pathology at the Cleveland Clinic. Clinico-demographics and histological features were compared between the two groups. RESULTS: Patients with syndromic inflammatory/hyperplastic SBPs were younger (48 vs. 63 years; P = 0.007) and had higher rates of hemorrhagic telangiectasia (55.6% vs. 0%; P = 0.000), gastric polyps (87.5% vs. 21.4%; P = 0.001), and family history of colon cancer (62.5% vs. 11.1%; P = 0.014). Sporadic cases were more frequently associated with gastro-esophageal reflux (35.7% vs. 0%; P = 0.079) and anti-reflux medication use (55.6% vs. 11.1%; P = 0.026). Histologically, the syndromic SBPs were more often of pure intestinal type (45.4% vs. 3.8%; P = 0.005) and had prominent vessels (81.8% vs. 42.3%; P = 0.036). CONCLUSIONS: Patients with syndromic SBPs are younger and have higher rates of hemorrhagic telangiectasia, gastric polyps, and family history of colon cancer. Histologically, syndromic inflammatory/hyperplastic SBPs are more likely to be of pure intestinal type and to have prominent vessels.