Somatic mutations in collagens are associated with a distinct tumor environment and overall survival in gastric cancer.

BACKGROUND: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix. METHODS: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors. RESULTS: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors. CONCLUSIONS: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment.

Doege-Potter Syndrome with a Benign Solitary Fibrous Tumor: A Case Report and Literature Review.

Doege-Potter syndrome is a rare paraneoplastic syndrome that is often diagnosed incidentally during the workup of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia secondary to excessive production of partially processed IGF-II hormone from a solitary fibrous tumor (SFT). Often these tumors are intrathoracic, benign, and asymptomatic. Occasionally they present as a paraneoplastic event; hypertrophic osteoarthropathy in Pierre-Marie-Bamberger syndrome and hypoglycemia in Doege-Potter syndrome. The NAB2-STAT6 gene fusion is the hallmark of the SFT. Complete surgical resection of the tumor often results in resolution of symptoms and cure in most cases. Here we present the case of an 83-year-old non-diabetic female with recurrent syncopal events who was diagnosed with the Doege-Potter syndrome secondary to a SFT of pleura. Her tumor was positive for NAB2-STAT6 gene fusion on RT-PCR. Following the resection of the giant tumor mass, she became symptom-free within 24 h, and has remained asymptomatic at 4 months follow-up.

Drug and herbal/dietary supplements-induced liver injury: A tertiary care center experience.

BACKGROUND: Drug-induced liver injury (DILI) and herbal/dietary supplements (HDS) related liver injury present unique diagnostic challenges. Collaboration between the clinician and the pathologist is required for an accurate diagnosis and management. AIM: To report our experience on the clinical-pathological findings of hepatic injury caused by drugs/HDS. METHODS: A retrospective review of clinically proven cases of DILI/HDS who presented to our institution from January 1, 2013 to December 31, 2017 was performed. Slides were reviewed for histopathological patterns of injury and correlated with the causative agent. Out of 600 patients presenting with unexplained rise in liver enzymes undergoing biopsy, 107 were suspected to have DILI/HDS. Of these, 53 had a directly linked exposure to drug/herbal supplements. Fifteen patients were excluded for concurrent known liver disease. Thirty-eight patients with clinically proven DILI/HDS were finally included. RESULTS: Thirty-eight cases of DILI/HDS with a male:female of 1:1.5 and mean age of 51 ± 3 years were identified. DILI was identified in 84.2% cases while HDS injury in 15.8%. Acute hepatitis (42.1%) was the most common pattern of injury while granulomatous hepatitis (2.6%) was the least common. We found one case of acute-cholestasis due to rivaroxaban and two cases of cholestatic-hepatitis due to rizatriptan and trimethobenzamide-hydrochloride that, to the best of our knowledge, have not been previously reported. One case of steatohepatitis due to trimethoprim-sulfamethoxazole and three unusual cases of cholestatic-hepatitis with bile duct injury and steatosis due to dronedarone, C4-Extreme and hydroxycut, were also seen. Of our cohort, 81.6% of the patients fared well with discontinuation of drug and 18.4% underwent transplant; of which 42.9% were deceased. CONCLUSION: We describe the clinical findings, histopathological patterns of injury and clinical outcomes caused by drugs. In particular, we report a few previously unreported/ rarely observed clinical and histopathological patterns of hepatic injury.

A large inflammatory fibroid polyp of the rectum removed by transanal excision.

Inflammatory fibroid polyps (IFP) are rare benign lesions arising from the submucosa of the gastrointestinal tract, most commonly found in the stomach and small intestine. IFPs are very rarely found in the rectum, with only a few reported cases, and their presentation is quite varied. The patient is a 53 year old male who underwent routine screening colonoscopy, during which a lobular mass of the proximal rectum was discovered. The patient subsequently underwent an endoscopic ultrasound (EUS) with fine needle aspiration (FNA) biopsy. Pathology displayed scant spindle cells with benign glandular epithelium suspicious for a spindle cell neoplasm. The mass was excised transanally. The morphological and immunohistochemical findings supported the diagnosis of inflammatory fibroid polyp. Although this is not a malignant tumor, the treatment and surveillance guidelines have not been determined and there is no standard of care.

Helicobacter pylori Infection: An Update for the Internist in the Age of Increasing Global Antibiotic Resistance.

Helicobacter pylori infects approximately half the world's population and is especially prevalent in the developing world. H. pylori is an important cause of global ill health due to its known etiological role in peptic ulcer disease, dyspepsia, gastric cancer, lymphoma, and more recently, recognized in iron deficiency anemia and idiopathic thrombocytopenic purpura. Increased antibiotic usage worldwide has led to antibiotic resistance among many bacteria, including H. pylori, resulting in falling success rates of first-line anti-H. pylori therapies. Eradication failures are principally due to resistance to clarithromycin, levofloxacin, and metronidazole. Several new treatment options or modifications of established regimens are now recommended by updated practice guidelines for primary or secondary therapy. Because these updated recommendations were published in the gastroenterological literature, internists and primary care physicians, who commonly manage H. pylori, may be unaware of these advances. In this review, we outline the changing epidemiology of H. pylori, advise on diagnostic test selection for patients not undergoing endoscopy, and highlight current management options in this era of growing antibacterial resistance.

Effects of infection on post-transplant outcomes: living versus deceased donor liver transplants.

INTRODUCTION: Post-transplant infections have been studied widely but data on comparisons of deceased donor liver transplants (DDLT) and living donor liver transplants (LDLT), type and timings of infections, and their relations to outcomes are not explored. MATERIAL AND METHODS: We analysed data from 612 participants of the Adult-to-Adult Living Donor Liver Transplantation Study (A2ALL), a retrospective data set of LDLT and DDLT. We compared the type and timing of the first post-transplant infection in relation to transplant outcomes between the two groups. RESULTS: Out of 611 patients, 24.5% experienced the first post-transplant infection, the majority of which were bacterial (35.3%), followed by fungal (11%) and viral infections (4.2%). There was no significant difference in the rate, type or timing of infection between LDLT and DDLT. Patients with late (> 1 year) first infection were 1.8 times more likely to die (95% CI: 1.12-2.98, p = 0.015) and 9 times more likely to have graft failures (95% CI: 3.26-24.8, p < 0.001). DDLT recipients who experienced bacterial infection had a significantly lower survival rate compared to LDLT recipients (p < 0.001). CONCLUSIONS: Late infection is associated with lower survival in both DDLT and LDLT. Bacterial infection might be more detrimental for DDLT than LDLT. Late infection should be managed aggressively to improve outcomes.

Clinicopathologic and gene expression analysis of initial biopsies from patients with eosinophilic esophagitis refractory to therapy.

Some patients with eosinophilic esophagitis (EoE) do not respond to therapy. The clinicopathologic characteristics and gene expression profile at time of presentation could help predict response to therapy. Refractory EoE was defined as persistence of symptoms and biopsies with histologic features of EoE after 6 months of therapy with proton pump inhibitors and topical corticosteroids. Initial biopsies from refractory EoE patients (n=21), responder to therapy (n=8), patients who relapsed (n=6), and reflux controls (n=24) were studied. RNA was isolated from a subset of cases, and gene expression analysis of 285 genes involved in inflammation was performed using NanoString technology. There was no difference in the presenting symptoms among groups. The number of eosinophils/high-power field among nonresponders was higher (66±15) than responders (39±8; P<.0001) and similar to patients who relapsed (62±11). Six genes were expressed by at least 4-fold compared with reflux at a false discovery rate < 0.05, including overexpression of ALOX15, CCL26, FCER2, RTNLB, and RNASE2, and underexpression of DSG1. EoE patients refractory to therapy or who relapsed showed a trend toward higher ALOX15 expression compared with patients with good response to therapy (364.4- and 425-fold change, P=.097 and P=.07). RTNLB was significantly overexpressed in patients who were refractory to therapy versus those who responded favorably (10-fold versus 3-fold; P<.01). In conclusion, the number of eosinophils/high-power field in the initial biopsy inversely correlates with therapy response. Overexpression of RTNLB in refractory-to-therapy patients and overexpression of ALOX15 and CCL26 suggest that they are critical in the EoE pathogenesis.