BACKGROUND:Acute pancreatitis is one of the leading causes of mortality and morbidity. Most acute pancreatitis scoring systems have no pathophysiologic basis when evaluating severity. Such a limitation led to an interest in measuring intra-abdominal pressure (IAP) as a method to predict outcomes in patients with acute pancreatitis. AIMS:Investigate the predictive impact of intra-abdominal hypertension (IAH) on mortality and clinical outcomes in a patient hospitalized with severe acute pancreatitis. METHODS:We conducted a systematic search of the PubMed, Embase, and Cochrane databases from inception through November 2021 for studies evaluating the effect of IAH on acute pancreatitis. Relevant data were extracted and analyzed using STATA 17 software. A random-effects model was used for all variables. Publication bias was assessed using Egger's test. RESULTS:Fourteen studies investigating 1197 patients were included. Mortality, multiorgan dysfunction syndrome, pancreatic necrosis, renal, respiratory, and cardiovascular failure were more likely in the IAH group. However, infected necrosis and surgical intervention were not statistically significant between the two groups. After excluding abdominal compartment syndrome patients, mortality and respiratory failure were the only outcomes, which remained statistically significant. CONCLUSIONS:Patients admitted to the hospital with severe acute pancreatitis have higher odds for mortality, multiorgan dysfunction syndrome, renal, respiratory, and cardiovascular failure if they developed IAH. IAH remained a strong predictor of mortality and respiratory failure even in the absence of abdominal compartment syndrome. Therefore, the development of IAH is a strong predictor of mortality and poor clinical outcome in such a population.

Introduction: Iron deficiency anemia is a well-known presenting sign for gastrointestinal bleeding prompting upper and lower endoscopy. We present a 62-year-old male with ESRD on HD, COPD, CAD on DAPT with weakness, fatigue, and dyspnea for two weeks. Case Description/Methods: Labs revealed a hemoglobin of 5.6 with no abdominal pain or signs of bleeding. The patient was on clopidogrel and aspirin, but denied anticoagulant and NSAID use. Pre-transfusion Iron studies were performed and most consistent with anemia of chronic disease, but with element of iron deficiency: ferritin 275 tibc 239 iron 33 iron saturation 13.8% mcv 88. Patient was transfused 3 u prbc with improvement (9.2) and remained hemodynamically stable. CT without contrast demonstrated left hilar mass (4.8x4.0x6.1 cm). A lobular component of the mass was noted within and obstructing the proximal left upper lobe bronchus although aeration was preserved. Small, nodular pulmonary densities and nodal enlargement, left adrenal nodularity were also noted and suspicious for metastases. The stomach, small bowel, and colon were unremarkable. The liver demonstrated a 1.5cm hypoenhancement concerning for metastasis. No region of hemorrhage was noted. Given his significant anemia, DAPT use, and iron deficiency, gastroenterology was consulted for panendoscopy. Upon EGD, old and fresh blood were noted in the stomach. There were multiple large, umbilicated ulcers in the gastric body (greater and lesser curvatures) and cardia suspicious for metastases, sparing the antrum. The duodenum and esophagus were unremarkable. Pathology returned as metastatic melanoma. PET CT demonstrated increased uptake in the lungs, stomach, ileum, and right quadriceps. Biopsy of a soft tissue mass of the right thigh was consistent with metastatic melanoma. MRI of the brain revealed a metastatic lesion as well. Discussion: Our patient was diagnosed with metastatic melanoma of unknown primary by EGD findings. Unique to this case, the patient presented with anemia of chronic disease and iron deficiency without overt signs of GI bleeding. Melanoma metastasis found in the GI tract typically present in the liver or small bowel. While this patient’s lungs were involved, he had not presented clinically as such, despite his upper lobe bronchus being almost completely obstructed. Liver enzymes were not elevated despite suspected metastases. This patient presented in an atypical manner leading to melanoma diagnosis with first endoscopically noted metastases in his stomach.

Obeticholic acid (OCA) and elafibranor (ELA) are selective and potent agonists for the farnesoid X receptor (FXR) and dual peroxisome proliferator-activated receptor α/δ (PPAR-α/δ), respectively. Both agents have demonstrated clinical efficacy in nonalcoholic steatohepatitis (NASH). The present study used OCA and ELA to compare the effects of mono- and combination therapies on metabolic and histological endpoints in Lepob/ob mice with established diet-induced and biopsy-confirmed NASH (ob/ob-NASH). ob/ob-NASH mice were fed the AMLN diet high in trans-fat, fructose and cholesterol for 15 weeks, whereafter they received vehicle, OCA (30 mg/kg, PO, QD), ELA (3, 10 mg/kg, PO, QD), or combinations (OCA + ELA) for eight weeks. Within-subject comparisons were performed on histomorphometric changes, including fractional area of liver fat, galectin-3 and Col1a1. OCA and ELA monotherapies improved all quantitative histopathological parameters and OCA + ELA combinations exerted additive effects on metabolic and histological endpoints. In agreement with their different molecular mechanisms of action, OCA and ELA monotherapies elicited distinct hepatic gene expression profiles and their combination led to profound transcriptome changes associated with further improvements in lipid handling and insulin signaling, suppression of immune responses and reduced extracellular matrix formation. In conclusion, these findings provide preclinical proof-of-concept for combined FXR and PPAR-α/δ agonist-based therapies in NASH.

INTRODUCTION: We report a case of colo-colic intussusception caused by sigmoid adenocarcinoma with concomitant incidental entero-enteric intussusception in a middle aged female. Intussusception in adults is a known rarity, but it is important to note that more than 60% of large bowel intussusceptions are caused by a neoplasm. CASE DESCRIPTION/METHODS: A 50 year old female presented with intermittent abdominal pain for 2 months, worsening with oral intake and associated with abdominal distension and obstipation. Computed tomography of the abdomen & pelvis showed two areas of intussuscepted bowel in the left upper quadrant. One was thought to be an incidental loop of the jejunum. The other representing the splenic flexure and was causing obstruction within the small and large bowel proximal to this lesion. With the diagnosis of intussusception, exploratory laparotomy was performed. A mass was palpated at the splenic flexure, and this was found to originate at the sigmoid colon, leading to left hemicolectomy and transverse colostomy. The histological diagnosis of the mass was well-differentiated adenocarcinoma stage IIIb. The patient later underwent adjuvant chemotherapy with Capecitabine plus Oxaliplatin. DISCUSSION: Large bowel intussusception can be due to benign, malignant, or idiopathic etiologies. As the incidence of intussusception in adults is low, surgical exploration is imperative.

Background and Aim The United Kingdom‐primary biliary cholangitis (UK‐PBC) and global primary biliary cholangitis group (GLOBE) prognostic models have been recently developed to predict long‐term outcomes in primary biliary cholangitis (PBC). However, these predictive scores have not yet been well evaluated in the U.S. population. Methods We retrospectively reviewed newly diagnosed PBC patients at the Cleveland Clinic between November 1998 and February 2017. Adverse events were defined as liver transplantation, liver‐related mortality, and all‐cause mortality. Transplant‐free survival (TFS) was estimated using the Kaplan–Meier method. Predictive performances of all prognostic models were evaluated using the C‐statistic. Results We identified 352 patients who used ursodeoxycholic acid therapy. Of them, 311 (88.4%) only had PBC, while 41 (11.6%) were diagnosed with PBC‐autoimmune hepatitis overlap. A total of 22 (6%), 47 (13%), and 55 (16%) patients had adverse events within 5, 10, and 15 years after diagnosis, respectively. In patients with PBC only, the C‐statistic in predicting 15‐year adverse events was 0.75 per GLOBE compared to 0.74 per UK‐PBC (P = 0.94), 0.73 per Rotterdam (P = 0.44), 0.66 per Barcelona (P = 0.004), 0.65 per Paris 1 (P = 0.005), 0.62 per Paris 2 (P < 0.0001), 0.60 per Toronto (P < 0.0001), and 0.60 per Mayo (P < 0.0001) scores. Median follow‐up was 9.2 years. Ten‐year TFS for patients who had optimal versus suboptimal treatment response was 92 versus 74% per Paris 1 (P < 0.0001), 95 versus 79% per Paris 2 (P = 0.0002), 93 versus 65% per Barcelona (P < 0.0001), and 96 versus 68% per Rotterdam (P < 0.0001) risk scores, respectively. Conclusion In our cohort of PBC patients, the UK‐PBC and GLOBE scores were both accurate and reasonably valid prognostic models in the U.S. population.

AIM:To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis (NASH).METHODS:The effects of INT-767 on histological features of NASH were assessed in two studies using Lepob/ob (ob/ob) NASH mice fed the AMLN diet (high fat with trans-fat, cholesterol and fructose). In a proof-of-concept study, Lepob/ob (ob/ob) NASH mice were first dosed with INT-767 (3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767 (3 and 10 mg/kg) to obeticholic acid (OCA) (10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57Bl/6 mice on standard chow. C57Bl/6 mice were orally dosed with INT-767 or OCA (1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS:INT-767 dose-dependently (3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation (assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study (16 wk), the FXR agonists OCA (10 and 30 mg/kg) and INT-767 (3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function.CONCLUSION:These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH.

The most common cause of death secondary to melanoma is widespread metastasis. Malignant melanomas appear to have a particular tendency of metastases to the gut. However, these metastases rarely involve the gastric mucosa of the stomach. We present a case of 68-year-old male with a past medical history of cutaneous melanoma 3 years prior treated with wide excision and no evidence of metastasis at the time, presented with complaints of a one-month history of nausea, dizziness, black stool and a 15-lb weight loss. Initial workup revealed a Hemoglobin 9.4 g/dl (reduced from his baseline of 14g/dl) and positive occult blood in the stool. Physical exam was benign otherwise. Given the presentation of anemia, melena and weight loss, the patient underwent esophagogastroduodenoscopy (EGD), which revealed diffuse mild gastropathy, three large ulcerative gastric polyps about 3-4 cm, and several smaller gastric polyps [Image 1]. Biopsy revealed metastatic gastric melanoma with staining positive for S100+, SOX 10+, MART1+, AMB45 +, and BRAF + [Image 2,3]. CT (Computed Tomography) of the chest and abdomen, revealed lesions affecting the lung and liver. The patient was diagnosed with Stage 4 metastatic melanoma. Chemo and radiation therapy were started, however, he was soon changed to hospice care and died within 4 months of diagnosis. Melanoma can metastasize to the gastrointestinal tract. Studies report up to 60% pathological involvement of the gastrointestinal tract in autopsies of patients with metastatic melanoma. However, rarely do these metastases involve the gastric mucosa of the stomach, only reaching clinical relevance in a median of 2% of patients with metastatic melanoma (range: 0.8-8.9%). Gastric manifestations are non-specific and may present as obstruction, gastrointestinal hemorrhage, anemia, weight loss, or abdominal pain. Non-specific pulmonary, hepatic, or GI symptoms in conjunction with the history of melanoma should raise the suspicion of metastases. Management includes surgical and non-surgical interventions, including, chemotherapy and palliative radiation therapy (XRT). Metastatic gastric melanoma should be considered when evaluating a patient with melanoma, especially in those who manifest with nonspecific GI symptoms. Identification of metastases early on can better guide therapeutic treatment recommendations and improve patient outcomes.2644_A Figure 1. Esophagogastroduodenoscopy (EGD) revealed diffuse mild gastropathy, th ree large ulcerative gastric polyps about 3-4 cm, and several smaller gastric polyps.2644_B Figure 2. Diffuse S100 + staining in the tumor cells supporting the diagnosis of melanoma.2644_C Figure 3. H&E stained section shows gastric mucosa being replaced by tumor. The tumor is growing in a diffuse fashion. It is comprised of cells with round, oval and spindled nuclei. There is a moderate amount of amphophilic to eosinophilic cytoplasm. Mitotic figures are easily identified.

Small cell lung carcinoma is a rapidly growing subtype of lung cancer typically presenting with pulmonary complaints. Rarely this carcinoma can spread to lymph nodes and cause esophageal dysphagia. This case presents a patient with small cell lung carcinoma discovered after an exhaustive workup for progressive dysphagia. A 65-year-old female with a past medical history of coronary artery disease, presented to the emergency department with a single episode of substernal non-radiating chest pain lasting several days that had resolved on arrival and a two month history of dysphagia recently progressing to solids. Past medical history was significant for diabetes mellitus type 2, hypertension, gastroesophageal reflux disease (GERD), and tobacco dependence. She had mild epigastric tenderness on palpation, without distention, rebound tenderness or guarding. A modified barium swallow showed contrast stasis in the mid-esophagus. A follow-up esophagogastroduodenoscopy (EGD) showed external compression of the proximal esophagus, without mucosal abnormalities. (Image 1) A subsequent computed tomography (CT) scan showed bulky hilar and mediastinal lymphadenopathy causing extrinsic compression of the esophagus, narrowing of the left upper lobe bronchi and to a lesser extent the left lower lobe bronchi. Transbronchial needle aspirations of the enlarged lymph nodes were obtained using an endobronchial ultrasound (EBUS), along with biopsies of the lung. (Image 2, 3). The morphologic and immunohistochemical findings from the lung and lymph node specimens were the same, confirming metastatic SCLC. Lung cancer is the leading cause of cancer deaths in the United States and the second most common cancer among both males and females. SCLC makes up 20% of all lung cancer cases and it is one of the most rapidly growing and most lethal subtypes. Dysphagia is an uncommon initial presenting symptom only seen in an estimated 1-2% of all lung cancer patients, and can be suggestive of mediastina metastases as seen in this case. Due to its rapid doubling time and aggressive behavior SCLC is often diagnosed as stage IV at initial presentation and many do not live past one year. This case is of particular significance as it highlights a rare presentation of a highly malignant carcinoma. Therefore, in smokers presenting with dysphagia, high suspicion and early detection is imperative to improve survival and quality of life.2960_A Figure 1 No Caption available.2960_B Figure 2 No Caption available.2960_C Figure 3 No Caption available.

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

Balagoni, Harika MD1; Devani, Kalpit MD1; Phemister, Jennifer MD2; Young, Mark F.2 Author Information