Retrospective Analyses of PD-L1, LAG-3, TIM-3, OX40L Expressions and MSI Status in Gastroenteropancreatic Neuroendocrine Neoplasms.

We investigated expressions of PD-L1, LAG-3, TIM-3, and OX40L as immune checkpoint proteins, and MSI (repetitive short-DNA-sequences due to defective DNA-repair system) status were analyzed with immunohistochemistry from tissue blocks. Of 83 patients, PD-L1 expression was observed in 18.1% (n = 15) of the patients. None of the patients exhibited LAG-3 expression. TIM-3 expression was 4.9% (n = 4), OX40L was 22.9% (n = 19), and 8.4% (n = 7) of the patients had MSI tumor. A low-to-intermediate positive correlation was observed between PD-L1 and TIM-3 expressions (rho: 0.333, p < 0.01). Although PD-L1 expression was higher in grade 3 NET/NEC, MSI status was prominent in grade 1/2 NET.

Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria.

AIMS: Hepatocellular adenoma (HCA) is an uncommon liver neoplasm, and studies of HCA subtypes have been primarily limited to France, the USA, and Japan. The aim of this study was to describe the clinicopathological features of HCA subtypes in Turkey. METHODS AND RESULTS: The resection specimens of 59 cases diagnosed as 'hepatocellular adenoma' collected from 15 institutions were reviewed to confirm the diagnosis and to classify them according to the current World Health Organization 2019 classification. Immunostaining for glutamine synthetase, liver fatty acid-binding protein, C-reactive protein, ß-catenin and reticulin was performed. Of the 59 cases, 48 (81%) were diagnosed as HCA. We identified 24 (50%) hepatocyte nuclear factor 1α (HNF1α)-inactivated HCAs, five (10%) inflammatory HCAs, 15 (32%) ß-catenin-activated HCAs, three (6%) ß-catenin-activated inflammatory HCAs, and one (2%) unclassified HCA. HCA patients were predominantly female (female/male ratio of 5:1); they had a median age of 34 years and a median tumour diameter of 60 mm. In the ß-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the ß-catenin-activated HCA group, three cases (6%) showed focal areas supportive of transition to HCA. The original diagnosis of HCA was changed to well-differentiated hepatocellular carcinoma in nine cases and to focal nodular hyperplasia in two cases. CONCLUSION: In our series, the major HCA subtype was HNF1α-inactivated HCA. We found a low incidence of inflammatory-type HCA. Our data also showed that ß-catenin-activated hepatocellular neoplasms, including cases with atypical histology, constituted a relatively high proportion of the cases. These findings are in contrast to those of most other studies of HCA subtypes.

Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway.

AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism, are aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 (AKR1B1HIGH) was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients. Using publicly available datasets and ex vivo gene expression analysis (n = 51, Ankara cohort), we have validated our previous in silico finding that AKR1B1HIGH was associated with worse overall survival (OS) compared with patients with low expression of AKR1B1 (AKR1B1LOW) samples. A combined signature of AKR1B1HIGH and AKR1B10LOW was significantly associated with worse recurrence-free survival (RFS) in microsatellite stable (MSS) patients and in patients with distal colon tumors as well as a higher mesenchymal signature when compared with AKR1B1LOW/AKR1B10HIGH tumors. When the patients were stratified according to consensus molecular subtypes (CMS), AKR1B1HIGH/AKR1B10LOW samples were primarily classified as CMS4 with predominantly mesenchymal characteristics while AKR1B1LOW/AKR1B10HIGH samples were primarily classified as CMS3 which is associated with metabolic deregulation. Reverse Phase Protein Array carried out using protein samples from the Ankara cohort indicated that AKR1B1HIGH/AKR1B10LOW tumors showed aberrant activation of metabolic pathways. Western blot analysis of AKR1B1HIGH/AKR1B10LOW colon cancer cell lines also suggested aberrant activation of nutrient-sensing pathways. Collectively, our data suggest that the AKR1B1HIGH/AKR1B10LOW signature may be predictive of poor prognosis, aberrant activation of metabolic pathways, and can be considered as a novel biomarker for colon cancer prognostication.

Is Human Papillomavirus and Helicobacter pylori Related in Gastric Lesions?

BACKGROUND: Human papillomavirus (HPV), the causative agent of cervical cancer, is also suggested as a risk factor for gastric adenocarcinoma. Many infectious agents besides Helicobacter pylori have been associated with gastritis. The aim of this study was to investigate HPV DNA and genotyping HPV type 16 DNA in gastric adenocarcinoma and Helicobacter pylori gastritis cases. METHODS: A hundred and six gastric adenocarcinoma and Helicobacter pylori gastritis samples and 26 controls were included. After deparaffinization by xylene, DNA extraction was performed by the phenol-chloroform-isoamyl alcohol method and 106 samples were studied with a G6PDH control kit (Eurogentec, Seraing, Belgium). Fifty-three adenocarcinoma and 43 Helicobacter pylori samples were thought to have enough tissue and were studied for HPV DNA. HPV types other than 16 and HPV type 16 DNA were detected by Real Time PCR using the L1 region. Amplifications of MY09/11 products were done by GP5+/GP6+ primers and Cyanine-5 labeled HPV DNA and HPV 16 DNA specific probe in Light Cycler 2.0 (Roche Diagnostics, Germany) device. RESULTS: Among gastric adenocarcinoma and Helicobacter pylori gastritis samples, 20/53 (38%) and 18/43 (41.8%) were HPV DNA positive, respectively. Five (19.2%) of 26 controls were HPV DNA positive. CONCLUSIONS: Our 38% positive result in the gastric carcinoma group is in concordance with previous reports. This is the first study revealing the HPV-H. pylori relationship in gastritis cases and we concluded that with regard to the nearly three-fold higher HPV DNA (41.8%) in gastritis cases compared to controls, Helicobacter pylori positive cases should also be evaluated in favor of HPV in the gastritis group.

Clinical and histological features of idiosyncratic liver injury: Dilemma in diagnosis of autoimmune hepatitis.

AIM: Drug-induced liver injury (DILI) is becoming a worldwide problem with its still unexplained properties. METHODS: The data of patients who were diagnosed with DILI between January 2008 and December 2013 were assessed. RESULTS: Five patients had been diagnosed with intrinsic and 82 patients with idiosyncratic DILI. The most common causative agents were antimicrobial drugs. The most common injury pattern was hepatocellular. When patients with bilirubin levels of more than 5 mg/dL were divided into two groups according to receiving steroid therapy (n = 11) or not (n = 40), there was not any significant difference according to their clinical results (P > 0.05). Five of the idiosyncratic DILI patients were diagnosed with drug-induced autoimmune hepatitis (DI-AIH). In histopathological examination, hepatic rosette formation and emperipolesis were observed to be more common among patients with DI-AIH when compared with ones without (P < 0.05). Interestingly, in the remaining patients with DILI (n = 77), three of them were diagnosed with classic autoimmune hepatitis during long-term follow up (range, 11-51 months). CONCLUSION: The most common causes were antimicrobials, but any agents that have not been defined to cause DILI can induce DILI. The efficacy of steroids in DILI has not been observed but all deaths were observed in the steroid-free group. The association of DILI and AIH was observed in two different types in terms of diagnosis in our study. The first association was DI-AIH. The second one is the classical AIH which developed in three patients after a few months following spontaneous recovery of DILI.

Is Gastric Xanthelasma an Alarming Endoscopic Marker for Advanced Atrophic Gastritis and Intestinal Metaplasia?

BACKGROUND/AIM: The clinical significance of gastric xanthelasmas is unknown. We conducted a case-control study in order to evaluate whether gastric xanthelasma is an indicator of advanced atrophic gastritis and intestinal metaplasia. MATERIAL AND METHOD: The study was conducted among 1400 patients who underwent elective upper endoscopy. Patients with gastric xanthelasma and atrophy and/or intestinal metaplasia constituted the study group (n = 55). The control group involved patients with only atrophic gastritis and/or intestinal metaplasia (n = 50). Histopathologic findings of the groups including the distribution of atrophic gastritis and/or intestinal metaplasia, operative link on gastritis assessment score, operative link on gastritis intestinal metaplasia assessment (OLGIM) score, and presence of dysplasia and malignancy were compared. Subgroup analysis was performed in order to establish the relation between the characteristics (size, number, and localization) of xanthelasmas, atrophy, and intestinal metaplasia. RESULTS: Multifocal atrophic gastritis was significantly more common in patients with a gastric xanthelasma (41.8 vs. 26.0 %, p = 0.03). Patients with multiple xanthelasmas had a significantly higher rate of intestinal metaplasia (p = 0.02) and a higher OLGIM score (p = 0.02) compared to those with a single xanthelasma. Dysplasia was detected in 8 (14.5 %) patients with a xanthelasma and 4 (8.0 %) patients without a xanthelasma (p = 0.2). CONCLUSION: Gastric xanthelasma(s) is a warning endoscopic sign for the presence of multifocal atrophic gastritis and advanced intestinal metaplasia.

Comparison of mismatch repair and immune checkpoint protein profile with histopathological parameters in pancreatic, periampullary/ampullary, and choledochal adenocarcinomas.

BACKGROUND: Pancreatic, periampullary/ampullary, and choledochal adenocarcinomas are aggressive malignancies with a poor prognosis. Immune checkpoint blockade is a promising treatment option for several tumor types. H long terminal repeat-associating 2 (HHLA2), which is analogous to programmed death-ligand 1 (PD-L1), is a recently discovered member of the B7/cluster of differentiation 28 family and is expressed in many malignancies. AIM: To analyze the expression of HHLA2 and its association with the pathologic biomarkers that predict sensitivity to immunotherapy. METHODS: Ninety-two adenocarcinoma cases located in the pancreas, ampulla, and distal common bile duct were identified. This study assessed 106 pancreaticoduodenectomy and distal/total pancreatectomy samples that were delivered to Ankara City Hospital between 2019 and 2021. Immunohistochemistry was conducted to examine the expression of DNA mismatch repair (MMR), PD-L1, and HHLA2 proteins. RESULTS: Patients with high HHLA2 expression had a higher mean age than those with low expression. Low HHLA2 expression was associated with high perineural invasion. HHLA2 expression was low in pathological stage T3 (pT) 3 cases and high in pathological stage T1, T2, and T4 cases. There was no correlation between HHLA2 expression and the expression of MMR proteins and PD-L1. CONCLUSION: Evaluation of HHLA2 expression in microsatellite stable and PD-L1-negative tumors may be useful for predicting the response of individuals to immunotherapy and may serve as a novel therapeutic target for immunotherapy in advanced-stage disease.

Tigecycline-Associated Hepatic Steatosis After Liver Transplant: A Case Report.

Tigecycline is a parenteral glycycline antibiotic that is used to treat severe infections caused by susceptible organisms, butitis also associated with hepatotoxicity. We present 2 similar patients with hepatic steatosis possibly associated with early tigecycline after transplant. In the first case, a 61-year-old woman underwent liver transplant for acute severe hepatitis; 6 days posttransplant, because of nonroutine resistant fever, the patient received tigecycline combined with daptomycin. Retransplant was applied to the patient on day 12 posttransplant because of acute liver failure secondary to hepatic vein thrombosis. After retransplant, biochemical levels gradually increased, exceeding the upper limit of normal. In liver biopsy, the patient had macrovesicular steatosis in 70% to 80% ofthe parenchyma. In the second case, a 53-yearold woman underwent liver transplant for liver cirrhosis. Tigecycline was added to the treatment because of recurrent fever on day 6 after transplant, with treatment also comprising piperacillin-tazobactam and meropenem. On day 15 of the patient's tigecycline treatment, her liver function tests were elevated. In liver biopsy, the patient had 30% to 40% macrovesicular steatosis and canalicular cholestasis in the parenchyma, especially in zone 3. Reports of hepatic steatosis associated with early tigecycline after transplant are quite new to the literature.

Rare hepatocellular carcinoma presentation: Hepatoportal sclerosis.

Hepatoportal sclerosis (HPS) is an idiopathic non-cirrhotic portal hypertension (INCPH) characterized by hypersplenism, portal hypertension, and splenomegaly. Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Non-cirrhotic portal hypertension is an extremely rare cause of HCC. A 36-year-old woman was referred to our hospital with esophageal varices. All serologic tests for etiology were negative. Serum ceruloplasmin and serum Ig A-M-G were normal. In the follow-up, two liver lesions were identified on a triple-phase computer. The lesions had arterial enhancement but no washout in the venous phase. In the magnetic resonance imaging examination, differentiation in favor of HCC was considered at one of the lessions. Radiofrequency ablation therapy was first applied to a patient who had no signs of metastasis. Within 2 months, the patient underwent a living donor liver transplant. In explant pathology, well-differentiated HCC and HPS were considered the cause of non-cirrhotic portal hypertension. The patient has been followed without relapse for 3 years. The development of HCC in INCPH patients is still debatable. Despite the presence of liver cell atypia and pleomorphism in nodular regenerative hyperplasia liver specimens, a causal link between HCC and INCPH is yet to be established.

A Novel Gene List Identifies Tumors with a Stromal-Mesenchymal Phenotype and Worse Prognosis in Gastric Cancer.

BACKGROUND: Molecular biomarkers that predict disease progression can help identify tumor subtypes and shape treatment plans. In this study, we aimed to identify robust biomarkers of prognosis in gastric cancer based on transcriptomic data obtained from primary gastric tumors. METHODS: Microarray, RNA sequencing, and single-cell RNA sequencing-based gene expression data from gastric tumors were obtained from public databases. Freshly frozen gastric tumors (n = 42) and matched FFPE (formalin-fixed, paraffin-embedded) (n = 40) tissues from a Turkish gastric cancer cohort were used for quantitative real-time PCR and immunohistochemistry-based assessments of gene expression, respectively. RESULTS: A novel list of 20 prognostic genes was identified and used for the classification of gastric tumors into two major tumor subgroups with differential stromal gene expression ("Stromal-UP" (SU) and "Stromal-DOWN" (SD)). The SU group had a more mesenchymal profile with an enrichment of extracellular matrix-related gene sets and a poor prognosis compared to the SD group. Expression of the genes within the signature correlated with the expression of mesenchymal markers ex vivo. A higher stromal content in FFPE tissues was associated with shorter overall survival. CONCLUSIONS: A stroma-rich, mesenchymal subgroup among gastric tumors identifies an unfavorable clinical outcome in all cohorts tested.

Stereotactic body radioablation therapy as an immediate and early term antiarrhythmic palliative therapeutic choice in patients with refractory ventricular tachycardia.

BACKGROUND: Stereotactic body radioablation therapy (SBRT) has recently been introduced with the ability to provide ablative energy noninvasively to arrhythmogenic substrate while reducing damage to normal cardiac tissue nearby and minimizing patients' procedural risk. There is still debate regarding whether SBRT has a predominant effect in the early or late period after the procedure. We sought to assess the time course of SBRT's efficacy as well as the value of using a blanking period following a SBRT session. METHODS: Eight patients (mean age 58 ± 14 years) underwent eight SBRT sessions for refractory ventricular tachycardia (VT). SBRT was given using a linear accelerator device with a total dose of 25 Gy to the targeted area. RESULTS: During a median follow-up of 8 months, all patients demonstrated VT recurrences; however, implantable cardioverter-defibrillator (ICD) and anti-tachycardia pacing therapies were significantly reduced with SBRT (8.46 to 0.83/per month, p = 0.047; 18.50 to 3.29/per month, p = 0.036, respectively). While analyzing the temporal SBRT outcomes, the 2 weeks to 3 months period demonstrated the most favorable outcomes. After 6 months, one patient was ICD therapy-free and the remaining patients demonstrated VT episodes. CONCLUSIONS: Our findings showed that the SBRT was associated with a marked reduction in the burden of VT and ICD interventions especially during first 3 months. Although SBRT does not seem to succeed complete termination of VT in long-term period, our findings support the strategy that SBRT can be utilized for immediate antiarrhythmic palliation in critically ill patients with otherwise untreatable refractory VT and electrical storm.

Diagnosis and Treatment of Autoimmune Hepatitis: Questions, Answers, and Illustrative Cases: Endorsed by Autoimmune Liver Diseases Special Interest Group, Turkish Association for the Study of Liver.

Autoimmune hepatitis (AIH) is a rare, immune-mediated liver disease. It has a heterogeneous nature with varied clinical presentations. The management of patients with AIH is challenging in many ways. The main difficulties are inexperience due to the rarity of the disease, diagnostic confusion in controversial areas such as variant/overlap cases, acute presentations, the presence of non-alcoholic fatty liver disease or drug-induced liver injury features, and the long and complex course of treatment. Here, we provide a clear, concise, and visualized review regarding the diagnosis and treatment of AIH, including illustrative cases.

Is serum placental growth factor a prognostic marker for stage III colorectal cancer patients?

BACKGROUND/AIMS: To evaluate the clinical usefulness of serum placental growth factor (sPIGF) levels in stage III colorectal adenocarcinomas (CRC). METHODOLOGY: Serum PIGF were measured in 70 healthy controls and in 80 stage III CRC patients. Also the association between preoperative sPGF levels, clinicopathological features and patients survival were evaluated in stage III CRC patients. RESULTS: sPIGF levels in stage III CRC patients were significantly higher than those in controls. There was no significant association between sPIGF levels and clinicopathological features and sPIGF is not a prognostic factor for survival. Multivariate regression analysis showed the sPIGF levels (hazard ratio=3.28; 95% CI=1.10-9.5, p=0.032) to be significant independent factors for local recurrence. CONCLUSIONS: Serum PIGF levels in stage III CRC patients are significantly higher compared with normal controls and may be an indicator of local recurrence in stage III CRC patients.

A novel screening biomarker in gastric cancer: serum Dickkopf-1.

BACKGROUND/AIMS: Despite all the knowledge about gastric cancer, there is no prognostic biomarker which could be useful for early detection. Dickkopf-1 (DKK-1), a secreted protein, is known as a negative regulator of the Wnt signaling pathway. DKK-1 is reported to be over expressed in many malignant tissues. The purpose of this study was to elucidate the normal level of serum DKK-1 (sDKK-1) levels in healthy Turkish peoples and to investigate the clinical utility of sDKK-1 levels for gastric cancer screening. METHODOLOGY: Serum DKK-1 levels were measured in 69 healthy controls and in 60 gastric adenocarcinoma patients with ELISA and sDKK-1 levels were compared with clinicopathological features and outcomes in gastric cancer patients. RESULTS: Serum concentrations of DKK-1 in gastric adeno cancer patients were significantly higher than control patients (p<0.001). The optimal cut-off for sDKK-1 levels order to discriminate control group from gastric cancer patients was 25U/mL with sensitivity equal to 100% and specificity equal to 100%. CONCLUSIONS: Serum DKK-1 levels may be a potentially useful novel serologic marker for gastric cancers.

The role of mean platelet volume in the diagnosis of hepatocellular carcinoma in patients with chronic liver disease.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) has poor long-term prognosis so we need new diagnostic techniques and markers to detect HCC in the early phases. The aim of this study was to analyze the levels of serum mean platelet volume in HCC. METHODOLOGY: The clinical data of 230 subjects with normal, chronic hepatitis, cirrhosis and HCC were retrospectively analyzed at our hospital between January 2009 and December 2009. The levels of MPV were determined in patients with liver disease and compared between patient groups and with healthy persons. RESULTS: Serum MPV levels were significantly increased compared to the patients with chronic hepatitis, cirrhosis, and the control group (p<0.01). The cut-off value for MPV for the detection of HCC in cirrhotic patients was calculated as ≥9.2fl using ROC analysis [Sensitivity: 68.3%, specificity: 62.1%, AUC: 0.676 (0.580-0.773), p<0.001]. Additionally, serum MPV levels show higher sensitivity for diagnosis of HCC than AFP. An AFP of more than 7.4IU/mL and an MPV of ≥9.2fl, both put together, had a specificity of 95.2%, while when used separately, they have a sensitivity of 87.5%. CONCLUSIONS: MPV may be a potential or adjunctive marker of HCC in patients with chronic liver disease.

Preoperative serum levels of soluble endoglin for prediction of recurrence in stage III colorectal cancer patients.

BACKGROUND: To evaluate the clinical usefulness of serum levels of soluble form of endoglin in stage III colorectal adenocarcinomas (CRC) patients for detection of recurrence. METHODS: The case-control study consisted of 80 stage III CRC patients who underwent surgery with curative intent and 70 age-and sex-matched healthy volunteers. Serum levels of soluble form of endoglin (sol-end) were measured in both groups. Also, predictive factors of recurrence were evaluated using multivariate analyses. RESULTS: Serum levels of sol-end in stage III CRC patients were significantly higher than those in controls. There was not a significant association between serum levels of sol-end and clinicopathological features in CRC patients. Multivariate regression analysis showed the LNR (hazard ratio, 2.54; 95% CI, 1.46-4.34; p < 0.001), to be significant independent factors to estimate local recurrence in stage III CRC patients. CONCLUSION: Preoperative serum levels of sol-end do not seem useful as a marker for detection of recurrence in stage III CRC patients.

An Unusual Diagnosis in a Single-Lung Transplant Recipient: Secondary Amyloidosis.

Silicosis, a progressive, fibrotic occupational lung disease with no known treatment, is an uncommon indication for lung transplant. There is a paucity of research on patients with silicosis who have received lung transplants. The long-term consequences of the native lung in patients with severe chronic silicosis who have had a single-lung transplant are also of interest. We present a case of amyloidosis in a patient who underwent a single-lung transplant for silicosis.

Extrapelvic intravenous uterine leiomyomatosis mimicing cardiac myxoma and deep vein thrombosis.

Extrapelvic intravenous uterine leiomyomatosis is a rare smooth muscle neoplasm. Uterine leiomyomatosis is a histologically benign pathology. Rarely, it can be confused with a cardiac mass. A 44-year-old female patient was admitted with increasing severity of pain and swelling in both legs for the past week. The patient was initially diagnosed with bilateral deep vein thrombosis. After further evaluation, we decided that the patient had cardiac myxoma. However, we intraoperatively observed that the lesion in the right atrium was arising from the inferior vena cava. In the final postoperative histopathological evaluation, the definite diagnosis was extrapelvic intravenous leiomyomatosis. The patient was discharged uneventfully following her second operation.

Deep learning-enabled assessment of cardiac allograft rejection from endomyocardial biopsies.

Endomyocardial biopsy (EMB) screening represents the standard of care for detecting allograft rejections after heart transplant. Manual interpretation of EMBs is affected by substantial interobserver and intraobserver variability, which often leads to inappropriate treatment with immunosuppressive drugs, unnecessary follow-up biopsies and poor transplant outcomes. Here we present a deep learning-based artificial intelligence (AI) system for automated assessment of gigapixel whole-slide images obtained from EMBs, which simultaneously addresses detection, subtyping and grading of allograft rejection. To assess model performance, we curated a large dataset from the United States, as well as independent test cohorts from Turkey and Switzerland, which includes large-scale variability across populations, sample preparations and slide scanning instrumentation. The model detects allograft rejection with an area under the receiver operating characteristic curve (AUC) of 0.962; assesses the cellular and antibody-mediated rejection type with AUCs of 0.958 and 0.874, respectively; detects Quilty B lesions, benign mimics of rejection, with an AUC of 0.939; and differentiates between low-grade and high-grade rejections with an AUC of 0.833. In a human reader study, the AI system showed non-inferior performance to conventional assessment and reduced interobserver variability and assessment time. This robust evaluation of cardiac allograft rejection paves the way for clinical trials to establish the efficacy of AI-assisted EMB assessment and its potential for improving heart transplant outcomes.