Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin- and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed non-polypoid lesions. Seven (88%) showed multifocal GI disease, including five with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single-system), with the remaining 14 (36%) exhibiting multi-system disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multi-system LCH more frequently presented with GI symptoms (92%, P<0.001), non-colorectal GI site involvement (50%, P=0.02), multifocal GI lesions (43%, P=0.005), non-polypoid lesions (71%, P<0.001), infiltrative histologic growth pattern (78%, P=0.04), and persistent disease (57%, P<0.001). Adult multi-system LCH patients appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrate that adults with single-system LCH involving the GI tract have an excellent prognosis, while multi-system LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, non-colorectal GI involvement, multifocal GI disease, non-polypoid lesions, and infiltrative growth pattern.

Incidental findings during donor liver assessment: Single center experience.

Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental pathologic findings discovered during the pretransplant evaluation of liver donors in our Institution from 1/2010 to 12/2022. During this 13-year period 369 intraoperative consultations from 262 liver donors were performed. Of those cases, incidental findings were identified in 22 cases (5.9 %) from 19 donors (7.3 %); two donors had more than one lesion. The median age of this subset of patients was 53 years (range: 18-70) and females predominated (63 %). Sixteen of the donors had abnormal findings in the liver: 6 bile duct hamartoma (BDH), 5 hyalinized nodule with Histoplasma capsulatum, 5 focal nodular hyperplasia (FNH), 2 bile duct adenomas (BDA), 1 biliary cyst and 1 hemangioma. One donor had both FNH and a BDH. One BDH and 1 BDA case was misdiagnosed as malignancy during the frozen section evaluation. Three donors had extrahepatic pathologies: a pancreatic tail schwannoma, a low-grade appendiceal mucinous neoplasm, and a lymph node with metastatic endometrial endometrioid adenocarcinoma. Of the 19 livers, the final organ disposition was available for 9: 6 were transplanted (67 %) and 3 were discarded (33 %). Two of the 3 discarded organs were misdiagnosed BDH and BDA cases, and one was incorrectly reported as having 90 % microvesicular steatosis during the frozen assessment. We present the clinicopathologic characteristics of liver donors with incidental findings during the pre-transplant evaluation which could lead to unwarranted graft dismissal if misdiagnosed. Additionally, incidental fungal infections can have implications for immunosuppressive therapy and the decision to use or reject the graft.

Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury.

Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagy-related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury.

Transition Zone in Total Colonic Aganglionosis and Colorectal Hirschsprung's Disease Shows a Similar Trend of Mucosal Innervation: Image Processing and Analysis Study.

The aganglionic segment of bowel in Hirschsprung's disease (HD) varies in length. It is not clear whether total colonic aganglionosis (TCA) merely represents a long form of HD or a different phenotype of the disease. Animal model studies suggest that TCA may have a longer transition zone (TZ) than conventional colorectal HD. We compared mucosal innervation of TZ in 2 TCA cases and 10 conventional colorectal HD cases by quantifying calretinin-positive mucosal nerve fibers using image processing and analysis. One TCA was associated with esophageal atresia-tracheoesophageal fistula, the other with trisomy 21. The gradients of calretinin-stained pixel count increase per distance from the beginning of TZ (slope) for TCA were not significantly different from those for the conventional HD group. Given this observation, it is speculated that the length of TZ in TCA may fall within the range of and may not be much longer than conventional colorectal HD.

In a pilot study, reduced fatty acid desaturase 1 function was associated with nonalcoholic fatty liver disease and response to treatment in children.

BACKGROUND: FADS1 gene encodes delta 5 desaturase, a rate-limiting enzyme in the metabolism of n-3 and n-6 polyunsaturated fatty acids (PUFAs). Minor alleles of FADS1 locus polymorphisms are associated with reduced FADS1 expression and intra-hepatic fat accumulation. However, the relationship between FADS1 expression and pediatric nonalcoholic fatty liver disease (NAFLD) risk remains to be explored. METHODS: We analyzed FADS1 transcription levels and their association with intra-hepatic fat and histology in children, and we performed pathway enrichment analysis on transcriptomic profiles associated with FADS1 polymorphisms. We also evaluated the weight of FADS1 alleles on the response to combined docosahexaenoic acid, choline, and vitamin E (DHA-CHO-VE) treatment. RESULTS: FADS1 mRNA level was significantly and inversely associated with intra-hepatic fat (p = 0.004), degree of steatosis (p = 0.03), fibrosis (p = 0.05), and NASH (p = 0.008) among pediatric livers. Transcriptomics demonstrated a significant enrichment of a number of pathways strongly related to NAFLD (e.g., liver damage, fibrosis, and hepatic stellate cell activation). Compared to children who are common allele homozygotes, children with FADS1 minor alleles had a greater reduction in steatosis, fibrosis, and NAFLD activity score after DHA-CHO-VE. CONCLUSION: This study suggests that decreased FADS1 expression may be associated with NAFLD in children but an increased response to DHA-CHO-VE.

Multivisceral transplant is a viable treatment option for patients with non-resectable intra-abdominal fibromatosis.

BACKGROUND: Intra-abdominal fibromatosis often involves the mesentery root which is non-resectable by conventional surgery. Multivisceral transplant (MVT), as a potential cure to non-resectable fibromatosis, has rarely been reported and the prognosis is unknown. METHODS: Six patients who underwent MVT for intra-abdominal fibromatosis were reviewed. Clinicopathological features, immunohistochemistry for ß-catenin, p53, and Ki67, and outcomes were evaluated. Appropriate data for comparative analysis were obtained from a cohort of 24 patients who underwent conventional resection for intra-abdominal fibromatosis. RESULTS: Among six MVT patients, four had familial adenomatous polyposis (FAP). Two patients had an initial intestinal transplantation, three had multiple prior surgeries, and two had adjuvant therapy. One patient died of hemorrhagic stroke shortly after MVT, and five patients (83%) survived with a median follow-up of 64 months. The 1-year and 5-year survival rates were 67% for all five patients. Two patients had recurrences after MVT and one of them had FAP. In comparison, six of 24 patients who underwent conventional surgery had FAP; six (25%) had recurrences and three had FAP. For FAP patients; the mean recurrence time was 13 months for MVT versus 6 months for conventional surgery. Ki67 proliferative index, ß-catenin, and p53 expression did not significantly correlate to recurrence. CONCLUSIONS: Multivisceral transplant (MVT) is a viable option for patients who have non-resectable intra-abdominal fibromatosis with promising surviving rates, although recurrence still occurs. Surgical margin, Ki67 proliferative index, ß-catenin, and p53 expression are not predicative for recurrence of fibromatosis.

The expression of TTF1, CDX2 and ISL1 in 74 poorly differentiated neuroendocrine carcinomas.

BACKGROUND: The expression profile of immunohistochemical markers of origin in poorly differentiated neuroendocrine carcinoma (PDNEC) is not well studied. MATERIALS AND METHODS: Seventy-four PDNECs from gastroenteropancreatic (GEP) organs and the lung, including 48 large cell NEC (LCNEC) and 26 small cell carcinomas (SmCC), were subject to immunohistochemical staining for CDX2, TTF1 and ISL1. The staining intensity (1 to 3) and percentage of positive tumor cells [0 (negative), 1 (<50%) and 2 (≥50%)] were assessed. The multiplicative index (maximum 6) was calculated and the average total score (aTS) was determined for each primary site and histologic subtype. RESULTS: In the 38 GEP and 36 lung PDNECs, CDX2, TTF1 and ISL1 staining was observed in 71% (aTS 2.8), 16% (aTS 0.4), 63% (aTS 1.9), and 22% (aTS 0.6), 72% (aTS 2.9) and 92% (aTS 3.8), respectively. GEP PDNECs showed a higher aTS for CDX2 and lower aTS for TTF1 and ISL1, compared to that of lung PDNECs (Student's t-test, p < 0.001). SmCC had a higher aTS for TTF1 and ISL1 (p < 0.001) and lower aTS for CDX2 (p < 0.002) than that of LCNEC. CONCLUSIONS: CDX2 and TTF1 demonstrate potential utility in suggesting the primary site of PDNEC. In addition, CDX2 may be useful in supporting the diagnosis of LCNEC in cases with overlapping or borderline morphology. Utility of ISL1 as an adjunctive diagnostic marker of SmCC remains to be studied.

Prevalence of sessile serrated adenoma/polyp in hyperplastic-appearing diminutive rectosigmoid polyps.

BACKGROUND AND AIMS: The American Society for Gastrointestinal Endoscopy recommends that distal colon hyperplastic lesions can be left in place without resection if adenomatous histology can be excluded with >90% negative predictive value. However, some lesions could be sessile serrated adenomas/polyps (SSA/Ps), which is also precancerous. The aim of this study was to describe the prevalence of SSA/Ps in hyperplastic-appearing diminutive rectosigmoid polyps. METHODS: We prospectively placed 513 consecutive diminutive rectosigmoid polyps that appeared hyperplastic to an expert endoscopist in individual bottles for pathologic. Each polyp was examined by 3 expert GI pathologists. RESULTS: The prevalence of SSA/P in the study polyps ranged from .6% to 2.1%. The lowest negative predictive value found by the endoscopist for the combination of adenomas plus SSA/Ps was 96.7%. CONCLUSIONS: The prevalence of SSA/Ps in diminutive rectosigmoid hyperplastic-appearing polyps is very low. These results support the safety and feasibility of a "do not resect" policy for diminutive hyperplastic-appearing rectosigmoid polyps.

Updated incidence rates and risk factors of esophageal cancer in Nan'ao Island, a coastal high-risk area in southern China.

Esophageal cancer (EC) is one of the most common cancers in China. The purpose of this study was to investigate the updated incidence rates and risk factors of EC in Nan'ao Island, where the EC incidence rate was chronically the highest in southern China. To calculate the annual incidence rate, data on 338 EC cases from Nan'ao Cancer Registry system diagnosed during 2005-2011 were collected. A case-control study was conducted to explore the EC risk factors. One hundred twenty-five alive EC patients diagnosed during 2005-2011 and 250 controls were enrolled into the case-control study. A pre-test questionnaire on demography, dietary factors, drinking water treatment, and behavioral factors was applied to collect information of all participants. The average EC incidence rates during 2005-2011 were 66.09/105, 94.62/105, 36.83/105 for both genders, males and females, respectively, in Nan'ao Island. The EC incidence rate in males was 2.40- to 4.55-fold higher than that in females in the period from 2006 to 2011 (P < 0.05). Considering the onset age, males tend to be much younger than females and reached peak incidence rate at a younger age (P < 0.05). Drinking water treatment by filter (odds ratio [OR] = 0.28, 95% confidence interval [95% CI] = 0.13-0.58) and fruit consumption (OR = 0.55, 95% CI = 0.32-0.94) reduced the risk for EC. On the contrary, the pickled vegetables consumption (OR = 2.64, 95% CI = 1.46-4.76) and liquor drinking (OR = 2.32, 95% CI = 1.21-4.44) increased the risk for EC. These results may be of importance for future research on EC etiology and prevention strategies.

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen.

Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.

EUS-guided liver biopsy for parenchymal disease: a comparison of diagnostic yield between two core biopsy needles.

BACKGROUND AND AIMS: EUS-guided biopsy of the liver has a variable diagnostic accuracy and specimen adequacy. A new core biopsy needle has been developed that may improve performance. The objective of this study was to compare the diagnostic yield of a new core biopsy needle with the previous standard needle. METHODS: In this cross-sectional study, consecutive patients who underwent EUS-guided core liver biopsy over a 7-year period for suspected parenchymal disease were prospectively evaluated. Between 2007 and 2011, all biopsies were performed with a 19-gauge Tru-cut biopsy needle (Quick-core [QC]), whereas a novel reverse bevel needle (PC) was used exclusively from 2011 to 2014. All specimens were examined by 1 of 3 experienced, blinded pathologists for the following: presence of visible core, aggregate specimen length, number of complete portal tracts, and specimen adequacy. RESULTS: A total of 75 patients (mean age 51 years, 51 female) underwent liver biopsy by using the QC (n = 45) or PC (n = 30) needle. The QC and PC groups had similar demographics, indications for EUS, indications for liver biopsy, and liver findings on EUS. Compared with those of the QC, biopsies with the PC required fewer passes (median 2 vs 3; P < .0001) but produced longer aggregate length (median 20 mm vs 9 mm; P < .0001) with more complete portal tracts (median 5 vs 2; P = .0003) and adequate specimens (P < .01). Two patients had abdominal pain after liver biopsy with the QC needle. CONCLUSIONS: Compared with the QC needle, EUS-guided core liver biopsy with the PC needle produced longer aggregate length, more complete portal tracts, and more adequate specimens despite fewer passes (Clinical trial registration number: NCT00586313.).

Histomorphological features and prognosis of colitis-associated colorectal cancer in patients with primary sclerosing cholangitis.

BACKGROUND: Histomorphology of colitis-associated colorectal cancer (CAC) in patients with primary sclerosing cholangitis (PSC) remains to be systemically characterized and prognosis in these patient needs to be further defined. AIM: To examine the impact of PSC on histomorphology and to assess prognosis of CAC-PSC patients. METHODS: A cohort of CAC patients were identified from the Pathology Database (1994-2010) at Cleveland Clinic; histomorphological features and other relevant data were collected by retrospective review of pathology slides and medical records. RESULTS: A total of 87 CAC patients were included, with 11 patients having PSC (the study group) and 76 patients without PSC (the control group). The overall median follow up was 6 (range: 0-20) years. The patients in the study group had a longer median duration of inflammatory bowel disease prior to CAC diagnosis (p = 0.046). In study group, seven (63.6%) patients had right-sided CAC (vs. 36.8% in the control group, p = 0.11). Background high-grade dysplasia was noted less (9.1% vs. 44.7%), while low-grade dysplasia was detected more in the study group (72.7% vs. 28.9%) (p = 0.02). All histomorphological features were comparable between groups. The overall survival (OS) and progression-free survival (PFS) showed no statistical difference between CAC patients with or without PSC. After excluding TNM stage IV patients, patients with PSC showed a trend toward shorter OS and PFS (p = 0.07 and p = 0.1). CONCLUSION: In CAC, histomorphology appeared to be independent of PSC. PSC is associated with a trend toward shorter OS and PFS in CAC patients with stage I-III diseases.

IgG4-related sclerosing cholangitis in the absence of autoimmune pancreatitis mimicking extrahepatic cholangiocarcinoma.

AIMS: IgG4-related sclerosing cholangitis in extrahepatic bile ducts in the absence of autoimmune pancreatitis (AIP) is rare and is poorly studied. Herein, we present the clinicopathological features of four cases of IgG4-related sclerosing cholangitis. METHODS AND RESULTS: The clinicopathological features of IgG4-related sclerosing cholangitis were compared with those of IgG4-related sclerosing cholangitis with AIP (n = 7), extrahepatic cholangiocarcinoma (n = 29), primary sclerosing cholangitis (n = 40), and secondary sclerosing cholangitis (n = 12). Several histomorphologic features distinguish IgG4-related sclerosing cholangitis, including a marked degree of bile duct injury, a higher percentage of lymphoid follicle formation, a higher percentage of perineuritis, and a more diffuse and dense lymphoplasmacytic infiltrate. All four cases of IgG4-related sclerosing cholangitis occurred exclusively in males. Of these cases, none had IgG4 serology checked preoperatively, and all had a preoperative diagnosis of extrahepatic cholangiocarcinoma. Clinical follow-up was available in 2 patients with a mean time of 11 months. Follow-up confirmed the benign course of the disease as the patients showed no evidence of relapse. IgG4-related conditions, including sclerosing cholecystitis and retroperitoneal fibrosis, were noted in three patients. CONCLUSIONS: IgG4-related sclerosing cholangitis in the absence of AIP presents as a distinct and under-recognized disease that mimics extrahepatic cholangiocarcinoma clinically. Awareness of this entity is essential to avoid erroneously diagnosing malignancy. The current threshold of 10 IgG4-positive plasma cells/high-power field (HPF) in the biopsy is not specific enough to exclude cholangiocarcinoma. Therefore, we suggest the diagnostic cut-off to be 50 IgG4-positive plasma cells/HPF in the biopsy.

Novel specific microRNA biomarkers in idiopathic inflammatory bowel disease unrelated to disease activity.

The diagnosis of idiopathic inflammatory bowel disease can be challenging. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate protein synthesis through post-transcriptional suppression. This study is to identify new miRNA markers in inflammatory bowel disease, and to examine whether miRNA biomarkers might assist in the diagnosis of inflammatory bowel disease. Illumina small RNA sequencing was performed on non-dysplastic fresh-frozen colonic mucosa samples of the distalmost colectomy tissue from 19 patients with inflammatory bowel disease (10 ulcerative colitis and 9 Crohn disease) and 18 patients with diverticular disease serving as controls. To determine differentially expressed miRNAs, the USeq software package identified 44 miRNAs with altered expression (fold change ≥ 2 and false discovery rate ≤ 0.10) compared with the controls. Among them, a panel of nine miRNAs was aberrantly expressed in both ulcerative colitis and Crohn disease. Validation assays performed using quantitative reverse transcription PCR (qRT-PCR) on additional frozen tissue from ulcerative colitis, Crohn disease, and control groups confirmed specific differential expression in inflammatory bowel disease for miR-31, miR-206, miR-424, and miR-146a (P<0.05). The expression of these four miRNAs was further evaluated on formalin-fixed, paraffin-embedded tissue of the distalmost colectomy mucosa from cohorts of diverticular disease controls (n=29), ulcerative colitis (n=36), Crohn disease (n=26), and the other diseases mimicking inflammatory bowel disease including infectious colitis (n=12) and chronic ischemic colitis (n=19), again confirming increased expression specific to inflammatory bowel disease (P<0.05). In summary, we demonstrate that miR-31, miR-206, miR-424, and miR-146a are novel specific biomarkers of inflammatory bowel disease. Furthermore, miR-31 is universally expressed in both ulcerative colitis and Crohn disease not only in fresh-frozen but also in formalin-fixed, paraffin-embedded tissues.

Fine needle aspiration of oncocytic variants of pancreatic neuroendocrine tumor: a report of three misdiagnosed cases.

OBJECTIVES: An oncocytic variant of pancreatic neuroendocrine tumors (PanNET) is exceedingly rare. Here we report cytomorphological features of the oncocytic variant of PanNET and discuss how to avoid diagnostic pitfalls. STUDY DESIGN: A computerized search of our laboratory information system was performed over an 18-year period to identify all cytology and surgical pathology cases where a diagnosis of PanNET was made or considered in the differential diagnosis. Three cases of the oncocytic variant of PanNET were identified. RESULTS: Endoscopic ultrasound-guided fine needle aspiration (FNA) smears showed cohesive clusters of large atypical cells with abundant eosinophilic granular cytoplasm, anisonucleosis, nuclear enlargement and overlapping, prominent nucleoli, and a relatively smooth nuclear membrane. Nuclei were round to oval with finely granular chromatin. Additional features included rare isolated cells and glandular formation. Some of these morphological features, such as anisonucleosis, nuclear enlargement, and overlapping, prominent nucleoli, are also commonly seen in the pancreatic adenocarcinoma. All these cases were misclassified by FNA as adenocarcinoma (2 cases) or suspicious for carcinoma (1 case) and were histologically confirmed to be oncocytic variants of PanNET. CONCLUSIONS: Useful salient features of the oncocytic variant of PanNET include abundant eosinophilic granular cytoplasm, finely granular chromatin, and relatively smooth nuclear membrane. The awareness of this variant will help to avoid misdiagnosis.

Hürthle cell neoplasms diagnosed by fine needle aspiration are not associated with an increased risk of malignancy.

OBJECTIVES: The aim of this study is to determine the risk of neoplasm and malignancy in thyroid fine needle aspiration (FNA) diagnosed as atypia of undetermined significance with Hürthle cell change (AUS-H) or Hürthle cell neoplasm (HCN). STUDY DESIGN: A computerized search of our laboratory information system was performed to identify all thyroid FNA and correlating surgical pathology diagnoses including Hürthle cell or oncocyte in the diagnostic nomenclature. The risks of neoplasm and malignancy were calculated for AUS-H and HCN categories separately. RESULTS: For the 29 AUS-H cases, the follow-up histology demonstrated 15 benign lesions, 4 follicular adenomas, 7 Hürthle cell adenomas, 1 papillary microcarcinoma (PMC), 1 follicular carcinoma and 1 Hürthle cell carcinoma. For the 93 HCN cases, the follow-up histology demonstrated 28 benign lesions, 9 follicular adenomas, 32 Hürthle cell adenomas, 2 PMCs, 2 papillary thyroid carcinomas, 6 follicular carcinomas and 14 Hürthle cell carcinomas. CONCLUSIONS: The risks of neoplasm and malignancy were 62 and 7% for the AUS-H category and 73 and 24% for the HCN category, respectively. The risk of malignancy for the AUS-H patients is within the 5- to 15-percent range suggested by the Bethesda System for Reporting Thyroid Cytology and within the 15- to 30-percent range suggested for follicular neoplasms.

Clinical and Pathological Correlation in Concomitant Celiac Disease and Eosinophilic Esophagitis Suggests Separate Etiologies.

Introduction. Recently, an increased risk of celiac disease or eosinophilic esophagitis has been postulated among patients with either of these disorders, prompting some to suggest a common underlying mechanism, whereas others maintain that their co-existence is coincidental. Methods. We compared clinical and pathological features of 29 patients meeting criteria for both celiac disease and eosinophilic esophagitis to 26 celiac disease and 26 eosinophilic esophagitis controls to determine whether any distinguished study patients from controls. Results. Eight (28%) study patients presented with symptoms of both celiac disease and eosinophilic esophagitis, whereas 14 (48%) had celiac disease symptoms only and 5 had (17%) esophageal symptoms only. Study patients had similar autoimmune and atopic conditions seen in both control groups. Histological severity of disease, including Marsh II-III duodenal histology (study specimens: 87%; controls: 89%), mean peak esophageal eosinophil counts (study specimens: 55/400x field; controls: 80/400X field, P = .1), and presence of eosinophil microabscesses, scale crust, and subepithelial fibrosis were also similar to controls. Gluten-free diet resolved celiac disease-related symptoms (19 of 20, 95%) and histology (10 of 12, 83%), but not esophageal symptoms or eosinophilia in most study patients. Conclusion. Patients with concomitant celiac disease and eosinophilic esophagitis lack distinguishing features compared to controls with celiac disease or eosinophilic esophagitis alone. The occurrence of both disorders is likely coincidental in most cases.

Exacerbated ischemia-reperfusion injury in fatty livers is mediated by lipid peroxidation stress and ferroptosis.

BACKGROUND: Ischemia-reperfusion injury is a common problem in liver surgery and transplantation. Although ischemia-reperfusion injury is known to be more pronounced in fatty livers, the underlying mechanisms for this difference remain poorly understood. We hypothesized that ferroptosis plays a significant role in fatty liver ischemia-reperfusion injury due to increased lipid peroxidation in the presence of stored iron in the fatty liver. To test this hypothesis, the ferroptosis pathway was evaluated in a murine fatty liver ischemia-reperfusion injury model. METHODS: C57BL6 mice were fed with a normal diet or a high fat, high sucrose diet for 12 weeks. At 22 weeks of age, liver ischemia-reperfusion injury was induced through partial (70%) hepatic pedicle clamping for 60 minutes, followed by 24 hours of reperfusion before tissue harvest. Acyl-coenzyme A synthetase long-chain family member 4 and 4-hydroxynonenal were quantified in the liver tissues. In separate experiments, liproxstatin-1 or vehicle control was administered for 7 consecutive days before liver ischemia-reperfusion injury. RESULTS: Exacerbated ischemia-reperfusion injury was observed in the livers of high fat, high sucrose diet fed mice. High fat, high sucrose diet + ischemia-reperfusion injury (HDF+IRI) livers had a significantly greater abundance of acyl-coenzyme A synthetase long-chain family member 4 and 4-hydroxynonenal compared with normal diet + ischemia-reperfusion injury (ND+IRI) livers or sham fatty livers, which indicated an increase of ferroptosis. HFD fed animals receiving liproxstatin-1 injections had a significant reduction in serum aspartate transaminase and alanine transaminase after ischemia-reperfusion injury, consistent with attenuation of ischemia-reperfusion injury in the liver. CONCLUSION: Ferroptosis plays a significant role in ischemia-reperfusion injury in fatty livers. Inhibiting ferroptotic pathways in the liver may serve as a novel therapeutic strategy to protect the fatty liver in the setting of ischemia-reperfusion injury.

Clinical Significance and Prognostic Implications of Discontinuous Growth Pattern in Esophageal Adenocarcinoma: A Multi-Institutional Study.

The significance of discontinuous growth (DG) of the tumor to include tumor deposits and intramural metastasis in esophageal adenocarcinoma (EAC) is unclear. Esophagectomy specimens from 151 treatment-naïve and 121 treated patients with EAC were reviewed. DG was defined as discrete (≥2 mm away) tumor foci identified at the periphery of the main tumor in the submucosa, muscularis propria, and/or periadventitial tissue. Patients' demographics, clinicopathologic parameters, and oncologic outcomes were compared between tumors with DG versus without DG. DGs were identified in 16% of treatment-naïve and 29% of treated cases ( P =0.01). Age, gender, and tumor location were comparable in DG+ and DG- groups. For the treatment-naïve group, DG+ tumors were larger with higher tumor grade and stage and more frequent extranodal extension, lymphovascular/perineural invasion, and positive margin. Patients with treated tumors presented at higher disease stages with higher rates of recurrence and metastasis compared with treatment-naïve patients. In this group, DG was also associated with TNM stage and more frequent lymphovascular/perineural spread and positive margin, but not with tumor size, grade, or extranodal extension. In multivariate analysis, in all patients adjusted for tumor size, lymphovascular involvement, margin, T and N stage, metastasis, neoadjuvant therapy status, treatment year, and DG, DG was found to be an independent adverse predictor of survival outcomes in EAC. DG in EAC is associated with adverse clinicopathologic features and worse patient outcomes. DG should be considered throughout the entire clinicopathologic evaluation of treatment-naïve and treated tumors as well as in future staging systems.