Types and Rates of COVID-19 Vaccination in Patients With Newly Diagnosed Microsatellite Stable and Instable Non-Metastatic Colon Cancer.

Introduction Microsatellite instable (deficient mismatch repair, dMMR) colon cancer is associated with hypermutability and immune infiltration-activation. COVID-19 vaccines stimulate immune-inflammation response. This study aimed to investigate the types and rates of COVID-19 vaccines in patients with newly diagnosed colon cancer and compare it according to the microsatellite status. Methods The study was a single-center case-control study. Patients diagnosed with colon cancer at least three months after the last COVID-19 vaccine (BNT162b2, CoronaVac) dose were included. Patients with dMMR and microsatellite stable (MSS) tumors were defined as cases and controls, respectively, between June 2021 and June 2023. Baseline characteristics and vaccine status between case-control groups were compared as univariable and multivariable. Inflammation markers were compared between MSS+CoronaVac and dMMR+BNT162b2 groups. Results A total of 76 patients were included. The BMI was higher in the MSS group (BMI>25 84.3% vs. 57.9%, p=0.00), and right-sided tumors were more common in the dMMR group (71% vs.46.4%, p=0.00). The dMMR group had a higher BNT162b2 vaccine history than the MSS group (86.8% vs. 63.2%, p=0.01), while there was no difference in CoronaVac history (p=0.32). Significant variables in univariable analysis (BMI, localization, and BNT162b2) were included in multivariable logistic regression. The BNT162b2 vaccine was significantly associated with dMMR status (OR: 6.39, 95% CI: 1.55-26.26, p=0.01). The dMMR+BNT162b2 group had higher median C-reactive protein (CRP) level (p=0.01), erythrocyte sedimentation rate (p=0.05), and lower lymphocyte/CRP ratio (p=0.04) than the MSS+CoronaVac group. Conclusion Immune infiltration in dMMR colon cancer may interact with COVID-19 vaccine-induced immune activation. Long-term clinical and preclinical studies are needed to confirm these findings.

Assessing hepatic steatosis by magnetic resonance in potential living liver donors.

PURPOSE: To determine the accuracy of magnetic resonance imaging-proton density fat fraction (MRI-PDFF) measurements for detecting liver fat content in potential living liver donors and to compare these results using liver biopsy findings. METHODS: A total of 139 living liver donors (men/women: 83/56) who underwent MRI between January 2017 and September 2021 were included in this analysis retrospectively. The PDFFs were measured using both MR spectroscopy (MRS) and chemical shift-based MRI (CS-MRI) for each donor in a blinded manner. RESULTS: Significant positive correlations were found between liver biopsy and MRS-PDFF and CS-MRI PDFF in terms of hepatic steatosis detection [r = 0.701, 95% confidence interval (CI): 0.604-0.798, r = 0.654, 95% CI: 0.544-0.765, P < 0.001, respectively). A weak level correlation was observed between liver biopsy, MRI methods, and vibration-controlled transient elastography attenuation parameters in 42 available donors. Based on receiver operating characteristic (ROC) analysis, MRS-PDFF and CS-MRI PDFF significantly distinguished >5% of histopathologically detected hepatic steatosis with an area under the ROC curve (AUC) of 0.837 ± 0.036 (P < 0.001, 95% CI: 0.766-0.907) and 0.810 ± 0.036 (P < 0.001, 95% CI: 0.739-0.881), respectively. The negative predictive values (NPVs) of MRS-PDFF and CS-MRI PDFF were 88.3% and 81.3%, respectively. In terms of distinguishing between clinically significant hepatic steatosis (≥10% on histopathology), the AUC of MRS-PDFF and CS-MRI were 0.871 ± 0.034 (P < 0.001 95% CI: 0.804-0.937) and 0.855 ± 0.036 (P < 0.001, 95% CI: 0.784-0.925), respectively. The NPVs of MRS-PDFF and CS-MRI were 99% and 92%, respectively. CONCLUSION: The methods of MRS-PDFF and CS-MRI PDFF provide a non-invasive and accurate approach for assessing hepatic steatosis in potential living liver donor candidates. These MRI PDFF techniques present a promising clinical advantage in the preoperative evaluation of living liver donors by eliminating the requirement for invasive procedures like liver biopsy.

Very-early-onset Inflammatory Bowel Disease in an Infant with a Partial RIPK1 Deletion.

The monogenic causes of very-early-onset inflammatory bowel disease (VEO-IBD) have been defined by genetic studies, which were usually related to primary immunodeficiencies. Receptor-interacting serine/threonine-protein kinase-1 (RIPK1) protein is an important signalling molecule in inflammation and cell death pathways. Its deficiency may lead to various clinical features linked to immunodeficiency and/or inflammation, including IBD. Here, we discuss an infant with malnutrition, VEO-IBD, recurrent infections and polyathritis who has a homozygous partial deletion in RIPK1 gene.

Exploring the connection between microsatellite instability and inflammatory indicators in cancers.

Aim: This study aimed to investigate the association between microsatellite instability (MSI) status and inflammatory indicators in patients with cancer. Patients & methods: A total of 204 patients with various cancer diagnoses, including 102 with MSI-high (MSI-H) and 102 with microsatellite stable tumors, were enrolled. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), C-reactive protein (CRP)-to-albumin ratio and systemic immune-inflammation index were evaluated. Results: In microsatellite stable patients, NLR, LMR, PLR and systemic immune-inflammation index were significantly linked to worse survival in univariate analysis, and having a LMR ≤2.6 negatively affected survival in multivariate analysis, although these indicators did not affect the survival of MSI-H patients. Conclusion: The impact of chronic inflammation on survival varies with MSI status. Further research is needed for targeted therapies in different tumors.

A combination of non-invasive tests for the detection of significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease is not superior to magnetic resonance elastography alone.

OBJECTIVES: The aims of the present study were to investigate a combination of magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE) or MRE and fibrosis score 4 (FIB-4) in the detection of significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Between November 5, 2021, and March 4, 2022, a total of 119 consecutive patients with MASLD were included. Liver stiffness was measured using liver biopsy, MRE, VCTE, and FIB-4. Data were collected from outpatient visit charts. Significant fibrosis was defined as ≥ stage 2 fibrosis. RESULTS: All 119 MASLD patients were Caucasian, and their median age was 55 years. MRE, VCTE, and FIB-4 demonstrated significant accuracy in the detection of significant fibrosis with an area under the ROC curve (AUC) of 0.848 ± 0.036 (p < 0.001), 0.632 ± 0.052 (p = 0.012), and 0.664 ± 0.051 (p = 0.001), respectively. However, the diagnostic performance of MRE was superior compared to that of VCTE (AUC difference: 0.216 ± 0.053, p < 0.001) and FIB-4 (AUC difference: 0.184 ± 0.058, p = 0.001). With logistic regression analysis, it was determined that when compared to MRE alone, a combination of MRE and TE (p = 0.880) or MRE and FIB-4 (p = 0.455) were not superior for detecting significant fibrosis. CONCLUSIONS: MRE alone is an accurate and non-invasive method for the identification of MASLD patients with significant fibrosis. CLINICAL RELEVANCE STATEMENT: Magnetic resonance elastography alone accurately detects significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. KEY POINTS: • In routine clinical practice, several non-invasive biochemical-based biomarkers and imaging methods are widely used to assess liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. • Magnetic resonance elastography (MRE) is more accurate than vibration-controlled transient elastography (VCTE) or fibrosis score 4 (FIB-4) for assessing liver fibrosis and identifying significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. • The combination of MRE and VCTE or MRE and FIB-4 was not superior to MRE alone.

Not all enteropathies are coeliac disease! Report of an infant with microvillus inclusion disease.

Primary enteropathies of infancy comprise of epithelial defects including microvillus inclusion disease, tufting enteropathy, and enteroendocrine cell dysgenesis and autoimmune enteropathies. The diseases in this group cause severe chronic (>2-3 weeks) diarrhoea starting in the first weeks of life and resulting in failure to thrive in the infant. Duodenal biopsies show moderate villous shortening together with crypt hyperplasia which are the main features causing resemblance to coeliac disease. We, hereby, report a term-born male infant of consanguineous parents. His two siblings died during infancy. He developed watery, urine-like diarrhea on the 3rd day of his life. On the postnatal 6th day he weighed 2750 grams, became dehydrated and had metabolic acidosis. Upper GI endoscopy performed on the postnatal 20th day appeared normal. Light microscopic examination of the duodenal biopsy showed moderate villous blunting, with mildly increased inflammatory cells in the lamina propria or and intraepithelial lymphocytosis. Enterocytes at the villous tips showed an irregular vacuolated appearance in the apical cytoplasm with patchy absence of the brush border demonstared by PAS and CD10. Electron microscopy revealed intracytoplasmic inclusions that were lined by intact microvilli in the apical cytoplasm of enterocytes. As he was dependent on TPN and aggressive intravenous fluid replacement he was hospitalized throughout his life. He died when he was 3 years and 4 months old. Paediatric coeliac disease is in the differential diagnosis of primary enteropathies of childhood. The differentiation lies on duodenal biopsy interpretation together with genetic analysis to detect the underlying genetic defect in childhood enteropathies.

Relationship Between ABO Blood Group and Microsatellite Instability in Colorectal Cancer: A Retrospective Single-Center Study.

PURPOSE: Colorectal cancer (CRC) is the second most common cancer in both women and men. Microsatellite instability-high (MSI-H) CRC is a molecular subgroup and has distinct clinical and pathologic features from microsatellite stable (MSS) CRC. Studies have suggested an association between hereditary antigens in ABO blood group system and the risk of developing various cancers but the relationship between blood groups and MSI-H CRC has not been investigated. This study aimed to investigate this relationship and its possible effect on clinicopathological features in patients with CRC. METHODS: This is a retrospective cross-sectional single-center study including pathology-confirmed CRC patients. Demographic and clinicopathological features, blood groups, and microsatellite status were examined among two groups. Microsatellite instability was examined by immunohistochemistry (IHC) in pathology specimen. RESULTS: A total of 144 patients, 72 patients with MSI-H CRC and 72 patients with MSS CRC, were included in the study. Among all patients, median age was 61.7 ± 12.9 (range 27-89) and 57.6% were male. MSI-H and MSS groups were similar in terms of age, gender distribution, and comorbidities. Patients with MSI-H CRC had significantly common O-blood group than control group (44.4% vs 18.1%, p: 0.001). In multivariate analysis, O-blood group was 4.2 times more common in the MSI-H patient group (95% CI: 1.514-11.819, p: 0.006). Also patients with MSI-H CRC were found to have significantly more right-sided, high-grade tumors and early-stage disease. CONCLUSIONS: MSI-H CRC is an important subgroup in colon cancer with different molecular and clinicopathological features. It was observed that O-blood group was 4.2 times more common in MSI-H CRC. We believe that clarifying the relationship between microsatellite instability and O-blood group and its possible genetic and epigenetic mechanisms in larger studies will enable us to better understand tumor behavior and prognosis, also affect our treatment choices of these patient groups.

Patterns and Grading of Gastrointestinal Graft-Versus-Host Disease: A Clinicopathologic Correlation Study.

BACKGROUND: The present study investigated gastrointestinal involvement patterns of acute graft-versus-host disease and assessed the correlation of pathologic severity with clinical grading. METHODS: Pathology reports of gastrointestinal (GI) endoscopic biopsies taken from 164 post-hematopoietic stem cell transplant patients with at least 1 endoscopic gastrointestinal biopsy diagnosed as "consistent with acute graft-versus-host disease" between 2005 and 2019 were retrieved from the automated hospital database. Endoscopic, pathologic and clinical gradings were performed using Freiburg criteria, Lerner and modified Seattle-Glucksberg grading systems, respectively. RESULTS: The majority of the patients (n = 140, 85.4%) were investigated with more than one biopsy from various gastrointestinal sites with a total of 479 biopsies: 44 (9.2%) esophagus, 90 (18.8%) stomach, 91 (19.0%) duodenum, 20 (4.2%) terminal ileum, 32 (6.7%) right colon, 87 (18.2%) left colon and, 115 (23.9%) rectum. Overall, lower gastrointestinal (n = 118/126, 93.6%) and upper gastrointestinal (n = 91/97, 93.8%) involvements were similar (P = .3). While the most severely affected site was duodenum (P = .021) in upper gastrointestinal, pathologic grades were similar in lower gastrointestinal sites, though more severe than upper gastrointestinal (P = .003). Pathologic grading had a low positive correlation with both clinical (r = 0.308, P = .001) and endoscopic grading (coefficient: 0.261, P = .003). CONCLUSION: Considering the similar graft-versus-host disease frequency of upper and lower gastrointestinal tract, distal colon evaluation with rectosigmoidoscopy seems to be a practical approach in patients with suspected gastrointestinal graft-versus-host disease. As it was positively correlated with both endoscopic and clinical grade, pathologic grading should be performed in these patients to assess gastrointestinal involvement patterns.

Non-invasive fibrosis markers for assessment of liver fibrosis in chronic hepatitis delta.

Assessment of liver fibrosis by non-invasive means is clinically important. Studies in chronic hepatitis delta (CHD) are scarce. We evaluated the performance of eight serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), age-platelet index (API), AST-to platelet-ratio-index (APRI), Goteborg University Cirrhosis Index (GUCI), Lok index, cirrhosis discriminant score (CDS) and Hui score] in CHD and chronic hepatitis B (CHB). Liver stiffness was assessed by transient elastography (TE) in CHD. The ability of fibrosis markers to detect significant fibrosis and cirrhosis were evaluated in 202 CHB and 108 CHD patients using published and new cut-offs through receiver operating characteristics (ROC) analysis. The latter was also applied to obtain cut-offs for TE. APRI, Fib-4, API and Hui score were assessed for significant fibrosis, and APRI, GUCI, Lok index, CDS and AAR for cirrhosis determination. Fibrosis markers displayed weak performance in CHB for significant fibrosis with area under ROC (AUROC) curves between 0.62 and 0.71. They did slightly better for CHD. TE displayed an AUROC of 0.92 and performed better than serum fibrosis markers (p < 0.05 for fibrosis markers). For cirrhosis determination, CDS and Lok Index displayed an AUROC of 088 and 0.89 in CHB and GUCI, Lok index and APRI displayed AUROCs around 0.90 in CHD. TE displayed the best AUROC (0.95). Hence TE is superior to serum fibrosis markers for diagnosing significant liver fibrosis and cirrhosis. GUCI, Lok index and APRI displayed a reasonable performance in CHD, which needs further confirmation.

Determining Subclinical Cardiovascular and Cardiac Diseases in Patients with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: The aims of the present study were to determine the subclinical coronary atherosclerosis and myocardial dysfunction in patients with non-alcoholic fatty liver disease, who were asymptomatic for cardiac disease. METHODS: A total of 61 non-alcoholic fatty liver disease patients were enrolled in the study. The 10-year probability of cardiovascular events was evaluated according to the pooled cohort equation risk score (atherosclerotic cardiovascular disease). The coronary artery calcium score was measured. Conventional echocardiographic examination was followed by 2- and 3-dimensional speckle tracking echocardiography. RESULTS: Patients with non-alcoholic steatohepatitis had significantly higher insulin resistance (P = .018), serum alanine aminotransferase (P = .002) and aspartate aminotransferase levels (P = .021), hepatic steatosis (P = .023), and fibrosis (P = .001) than non-alcoholic fatty liver disease patients. The mean Atherosclerotic Cardiovascular Disease score was 7.5% ± 6.9% and 37% of the patients had medium and high cardiovascular disease risk. Cardiovascular disease (>1) was found in 30% of the patients. Interestingly, 56% had significant and extended atherosclerotic plaques. Among the patients with moderate-to-high atherosclerotic cardiovascular disease scores, 63% had significant atherosclerotic plaques and 21% had extensive plaque burden. The presence of non-alcoholic steatohepatitis did not significantly affect cardiovascular risk. Non-alcoholic steatohepatitis was deleterious on left ventricle diastolic functions. Mean A velocity in non-alcoholic steatohepatitis patients was significantly increased compared to non-alcoholic fatty liver disease patients (87.0 ± 17.5 cm/s vs. 72.3 ± 13.6 cm/s, P = .002). Mean E/e' ratio was 8.1 ± 2.0. Submyocardial fibrosis detected had a slightly higher occurrence in non-alcoholic steatohepatitis patients than in non-alcoholic fatty liver disease patients (P = .530). CONCLUSION: The presence of non-alcoholic steatohepatitis did not significantly increase the risk of cardiovascular disease and subclinical myocardial dysfunction in asymptomatic patients for cardiac disease compared to non-alcoholic fatty liver disease patients.

The role of pericytes on the efficacy of bevacizumab in colorectal cancer.

BACKGROUND: Pericytes are mesenchymal cells surrounding capillary vessels and are known to play an essential role in tumor angiogenesis. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan and its release from pericytes and vascular smooth muscle cells is very important in tumor angiogenesis. Bevacizumab, which is a monoclonal antibody frequently used in the treatment of metastatic colorectal cancer, binds to the ligand of vascular endothelial growth factor A (VEGFA) and inhibits tumor angiogenesis. However, no reliable biomarker for predicting patients that will show a good response to this therapy has been established yet. In this study, we aimed to identify the significance of the presence of pericyte and VEGFA and CSPG4 expressions on the efficacy of Bevacizumab. METHODS: Fifty patients with metastatic or recurrent colorectal cancer who had been treated with Bevacizumab combined chemotherapy treatment were included in the study. The expressions of VEGFA and CSPG4 genes and also human ß-actin as the reference gene were examined using the quantitative real-time polymerase chain reaction method in the formalin-fixed paraffinembedded tumor tissues. For determining vascular and pericyte density in tumor tissue, immunohistochemical analysis was performed with CD31, alpha-smooth muscle actin, and CD34 antibodies. RESULTS: CSPG4 positive group had better objective response rate, as well as longer progression-free and overall survival than CSPG4 negative ones. Progression-free survival was significantly longer in VEGFA low group and CD31 low group. No significant correlation was found between CD34 positivity, SMA positivity, and progression-free and overall survival. DISCUSSION: Our results suggested that bevacizumab may be more effective in patients having less vascular density in the tumor tissue. But further studies are needed to support this finding.

Factors associated with the development of extrahepatic malignancy in patients with nonalcoholic fatty liver disease: a single-center longitudinal study.

BACKGROUND AND AIMS: The aim of the present study was to determine incident cases of extrahepatic malignancy in patients with nonalcoholic fatty liver disease (NAFLD) and to identify whether the factors are associated with cancer development. METHODS: Between 15 January 2001 and 14 March 2021, a total of 1365 patients had been diagnosed with NAFLD were enrolled in the study. RESULTS: The median follow-up period was 59.5 months. The mean age was 50.9 ± 10.9 years. The female gender was predominant (57%). During the follow-up period, 62 extrahepatic malignancies and 11 hepatocellular carcinomas were identified. Of all extrahepatic malignancies, 51 were solid organ malignancies and 11 were hematological malignancies. Female breast cancer was the most frequent (25.8%), followed by thyroid cancer (19.4%), lymphoma (12.9%), and lung cancer (9.7%). In univariate and multivariable analyses, after adjusting for age and sex, the presence of diabetes and high initial baseline gamma glutamyl transpeptidase (GGT) levels were significantly associated with the development of extrahepatic malignancies [hazard ratio (HR) = 1.82, 95% confidence interval (CI): 1.04-3.20, P = 0.036] and HR = 1.96, 95% CI: 1.14-3.38, P = 0.015, respectively). In 424 biopsy-proven NAFLD patients, the development of extrahepatic cancer was significantly associated with the severity of hepatic fibrosis (HR = 3.31, 95% CI: 1.36-8.07; P = 0.008). CONCLUSION: Extrahepatic malignancies are frequently seen in patients with NAFLD. Diabetes mellitus, high baseline GGT levels, and significant hepatic fibrosis are associated with the development of extrahepatic cancer in patients with NAFLD.

Histopathology of non-coeliac gluten sensitivity.

Diagnosis of non-coeliac gluten sensitivity (NCGS) remains still problematic due to the subjectiveness and lack of a specific biomarker. We aimed to compare NCGS duodenal mucosae with healthy individuals and Marsh type 1 coeliac disease (CD), to determine whether NCGS has characteristic histological features. A total of 44 healthy controls, 42 NCGS, and 44 type 1 CD patients were selected according to clinical, serological, and laboratory data. Duodenal biopsies were evaluated on H&E, CD, and CD117 for villus/crypt ratio, IEL counts/100 enterocytes, uneven distribution pattern with clusters of IELs in the villous epithelium, linear distribution of T lymphocytes in the basal lamina propria, and eosinophils and mast cells in the lamina propria. IEL counts were within normal range in controls (13 ± 7.65), normal or mildly increased in NCGS (24.7 ± 10.46), and increased in CD (58.79 ± 14.97) on CD3. The presence of uneven distribution pattern of IELs in the villous epithelium was significantly higher in NCGS (90.5%), in contrast to controls (27.3%) and CD (34.1%). The presence of linear distribution of T lymphocytes in the basal lamina propria (68.2%, 76.2%, 78.1%), eosinophil counts (6.85 ± 3.42, 6.21 ± 2.8, 7.62 ± 3.89), and mast cell counts (25.1 ± 5.1, 26 ± 2.9, 30.3 ± 4.4) was similar in controls, NCGS, and CD, respectively. In conclusion, duodenal mucosae in NCGS are characterized by preserved villous architecture, normal or mildly increased IELs with clusters, and eosinophils and mast cells within normal limits. We believe uneven distribution of IELs with clusters in the villous epithelium can be used as a supportive histopathological tool for NCGS in the right clinical setting.

Gastric and small intestinal traditional serrated adenomas: a detailed morphologic and immunohistochemical analysis.

BACKGROUND/AIMS: Traditional serrated adenomas (TSAs), despite their low incidence in colorectum, may originate in other parts of the gastrointestinal (GI) tract, including stomach and small intestine. Malignant transformation for upper GI TSAs has recently been reported in the literature. Here, we present a series of gastric and small intestinal TSAs with the aim to characterize their morphologic and immunophenotypic features as well as their neoplastic potential in a compartmental manner using digitalized images. MATERIALS AND METHODS: The study comprised 12 GI polyps with TSA features-5 gastric and 7 small intestinal. The extent of the characteristic features of TSA, including eosinophilic cells, ectopic crypt foci (ECF), slit-like serration, foveolar epithelium, goblet cells, together with dysplastic-carcinomatous foci were assessed on digitalized H-E images and were used as reference for immunohistochemical analysis. RESULTS: All polyps in the cohort contained eosinophilic cells as the most extensive morphologic feature followed by ECF and slit-like serration in decreasing order. Serrated dysplasia was more common in gastric polyps, which more frequently showed neoplastic progression compared with the intestinal ones. CK20 was the most widely expressed marker with a preference to eosinophilic cells while ECFs were mostly negative. Ki67 showed the opposite pattern of CK20. MUC6 and MUC2 were selectively expressed in the basal zone and goblet cells, respectively. CONCLUSION: Our results showed that the presence of eosinophilic cells with pencillate nuclei commonly accompanied by ECF and slit-like serration are the defining features of gastric and small intestinal TSAs. They frequently harbor neoplastic foci, particularly in gastric location where serrated dysplasia seems to be more common.

Duodenal bulb biopsy in the diagnostic work-up of coeliac disease.

Coeliac disease (CD) is an autoimmune enteropathy which can present with patchy mucosal lesions. The aim of the present study is to investigate the significance of duodenal bulb biopsy in the diagnostic work-up of CD in both pediatric and adult patients, and to highlight the key points for pathologists. D1 (duodenal bulb) and D2 (distal duodenum) biopsies of 153 newly diagnosed serology-positive CD patients were evaluated for villous/crypt ratio and intraepithelial lymphocyte (IEL) counts on CD3-stained slides and were classified according to Marsh. Mucosal pathology was patchy in 15% (13% only D1 and 2% only D2) of patients, and 85% of patients had diffuse mucosal pathology involving both D1 and D2 biopsies which showed concordant histology in 60% and discordant in 25% of the cases. Though majority of the patients (75%) with only D1 involvement were pediatric cases, no significant difference was found between pediatric and adult patients when all cases were considered (17 vs 14%). Our results clearly indicate that without D1 sampling, diagnosis of CD would have been missed in a significant number of cases (13%), thereby highlighting the importance of taking duodenal biopsies from multiple sites in the diagnostic work-up of CD. We, therefore, conclude that every biopsy piece from both D1 and D2 should be carefully evaluated for the whole spectrum of mucosal changes caused by gluten ingestion and classified using a scheme based on Marsh to allow recognition of mild lesions.

The Contribution of Additional Sampling in Cholecystectomy Materials: A Multicenter Prospective Study.

OBJECTIVE: Cholecystectomy materials are frequently encountered in routine practice. The aim of this study was to determine the true frequency of gallbladder lesions, the diagnostic consistency, and standardization of reports after macroscopic sampling and microscopic evaluation based on previously defined criteria. MATERIAL AND METHOD: 14 institutions participated in the study within the Hepato-Pancreato-Biliary Pathology Study Group. Routinely examined cholecystectomies within the last year were included in the study in these institutions. Additional sampling was performed according to the indications and criteria. The number of blocks and samples taken in the first macroscopic examination and the number of blocks and samples taken in the additional sampling were determined and the rate of diagnostic contribution of the additional examination was determined. RESULTS: A total of 5,244 cholecystectomy materials from 14 institutions were included in the study. Additional sampling was found to be necessary in 576 cases (10.98%) from all institutions. In the first macroscopic sampling, the mean of the numbers of samples was approximately 4 and the number of blocks was 2. The mean of the numbers of additional samples and blocks was approximately 8 and 4, respectively. The diagnosis was changed in 144 of the 576 new sampled cases while the remaining 432 stayed unaltered. CONCLUSION: In this study, it was observed that new sampling after the first microscopic examination of cholecystectomy materials contributed to the diagnosis. It was also shown that the necessity of having standard criteria for macroscopic and microscopic examination plays an important role in making the correct diagnosis.

The natural course of non-alcoholic fatty liver disease.

Background and Aim: The present study aims to describe the characteristics and long-term clinical outcomes of patients with non-alcoholic fatty liver disease (NAFLD). Material and Methods: A total of 1308 individuals with NAFLD were seen in the Liver Diseases Outpatient Clinic. Diagnosis of NAFLD in each case was based on biochemical, radiological and histological criteria, when available. After diagnosis, all NAFLD patients were administered a conventional diet and exercise program. The median follow-up period was 55.3 months. Results: At the time of the diagnosis, the mean age was 50.8±11.3 years, and female gender was slightly predominant (51.4%). The median body mass index was 29.2±4.7 kg/m2: 39% were obese. Seventeen percent of the patients had diabetes mellitus, 53% insulin resistance, 60% hyperlipidemia, and 32% hypertension. Median serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase levels were 31 U/L (range: 10-248 U/L), 45 U/L (range: 10-285 U/L) and 41 (range: 8-1200 U/L), respectively. Liver biopsy was performed in 293 individuals. The median NAFLD activity score was 5.0, median hepatic steatosis 2, ballooning 1, lobular inflammation 1, portal inflammation 0, and fibrosis 0. Of note, 41.3% of the samples (121/293) revealed the presence of fibrosis and 31% of the samples (37/121) showed significant fibrosis. With multivariate analysis, diabetes and obesity were associated with the presence of significant fibrosis. Among them, 765 patients (M/F: 353/412, mean age: 51.0±10.9) had at least six months of follow-up. In this group, from baseline to the end of the follow-up period, a significant improvement in the serum AST and ALT levels was observed. Conclusion: NAFLD is a potentially progressive disease. Diabetes and obesity were associated with the presence of advanced fibrosis.

The role of PNPLA3 (rs738409) c>g variant on histological progression of non-alcoholic fatty liver disease.

Background and Aim: The present study aims to investigate the role of genetic variability of the PNPLA3 gene (adiponectin) in predisposition to non-alcoholic fatty liver disease (NAFLD) by comparing NAFLD patients to healthy controls and to investigate any impact of the PNPLA3 genetic variability on the natural course of the disease. Materials and Methods: This cohort consisted of 174 patients with biopsy-proven NAFLD and 151 healthy controls. DNA was extracted from peripheral blood and the rs738409 C>G single nucleotide polymorphism was assessed using PCR-DNA sequencing. Results: The frequency distribution of the GG genotype was significantly higher in NAFLD patients than in controls (p=0.01). In patients with NAFLD, the GG genotype was associated with lower platelet counts (p=0.001), the presence of steatohepatitis (p=0.04) and hepatic fibrosis (p=0.016). After adjustment for age, gender, obesity, and diabetes mellitus, the GG genotype was an independent predictor of significant hepatic fibrosis (adjusted odds ratio =3.031 p=0.012). From the baseline to sequential liver biopsies, the progression of NAS in NAFLD patients was slightly higher in the GG genotype than that of CC and GG genotypes (p=0.18). Conclusion: The PNPLA3 GG genotype is a predisposing factor for the development of hepatic steatosis in NAFLD patients and related to a more severe liver disease.

Allogeneic hematopoietic stem cell and liver transplantation in a young girl with dedicator of cytokinesis 8 protein deficiency.

DOCK8 deficiency is a rare inherited combined immunodeficiency, caused by mutations in the DOCK8 gene. We describe a case with DOCK8 deficiency associated with severe CLD in whom orthotopic LT was performed successfully after allogeneic HSCT. A 5 year-old girl with DOCK8 deficiency presented with mild direct hyperbilirubinemia and abnormal GGT level and without a previous history of jaundice. She had severe growth retardation, hepatosplenomegaly and generalized eczema. Progressive worsening of CLD was observed within 4 months. Investigations for etiology of liver disease were negative. Liver biopsy showed bridging necrosis, cholestasis and, cirrhosis. Recurrent immune hemolytic crisis and several viral infections developed in follow-up. She underwent whole cadaveric LT for end-stage liver disease (ESLD) 1 year after allogenic HSCT from a full matched related donor. The postoperative course was uneventful. The patient is alive with normal liver function and moderate skin graft versus host disease for 36 months after LT. In conclusion DOCK8 deficiency can be associated with severe CLD. Successful LT following HSCT is possible in patients with ESLD in DOCK8 deficiency. The timing of LT is challenging in patients requiring both HSCT and LT since conditioning regimens for HSCT can be highly hepatotoxic and the patients with suboptimal liver function can become decompensated during HSCT.