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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Consensus Report on Diagnosis, Treatment and Prevention of Infective Endocarditis by Turkish Society of Cardiovascular Surgery (TSCVS), Turkish Society of Clinical Microbiology and Infectious Diseases (KLIMIK), Turkish Society of Cardiology (TSC), Turkish Society of Nuclear Medicine (TSNM), Turkish Society of Radiology (TSR), Turkish Dental Association (TDA) and Federation of Turkish Pathology Societies (TURKPATH) Cardiovascular System Study Group.

Infective endocarditis (IE) is rare, but associated with significant morbidity and mortality rates. Estimates of the incidence of IE in Turkey are compromised by the absence of population-based prospective studies. Due to the frequent presence of predisposing cardiac conditions and higher rates of nosocomial bacteremia in highrisk groups, the incidence of IE is expected to be higher in Turkey. Additionally, while IE generally affects older people in developed countries, it still affects young people in Turkey. In order to reduce the mortality and morbidity, it is critical to diagnose the IE to determine the causative agent and to start treatment rapidly. However, most of the patients cannot be diagnosed in their first visits, about half of them can be diagnosed after three months, and the disease often goes unnoticed. In patients diagnosed with IE, the rate of identification of causative organisms is significantly lower in Turkey than in developed countries. Furthermore, most of the centers do not perform some essential microbiological diagnostic tests as a routine practice. Some antimicrobials that are recommended as the first-line of treatment for IE, particularly antistaphylococcal penicillins, are not available in Turkey. These problems necessitate reviewing the epidemiological, laboratory, and clinical characteristics of IE in our country, as well as the current information about its diagnosis, treatment, and prevention together with local data. Physicians can follow patients with IE in many specialties. Diagnosis and treatment processes of IE should be standardized at every stage so that management of IE, a setting in which many physicians are involved, can always be in line with current recommendations. Study Group for Infective Endocarditis and Other Cardiovascular Infections of the Turkish Society of Clinical Microbiology and Infectious Diseases has called for collaboration of the relevant specialist organizations to establish a consensus report on the diagnosis, treatment, and prevention of IE in the light of current information and local data in Turkey.

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.

Symptomatic hepatic metastasis of insulinoma 15 years after pancreatic resection.

Malignant insulinomas are infrequent endocrine tumors with miscellaneous clinical courses. In this report, we present a rare case of insulinoma that recurred with solitary hepatic metastasis 15 years after the initial resection of the primary tumor from the pancreas. A 20-year-old woman first presented with the symptoms of hypoglycemia in 1996. The diagnosis of pancreatic insulinoma was confirmed by laboratory findings, and the initial surgery had been performed involving complete enucleation of the pancreatic mass. Histopathologically, the tumor was diagnosed as a benign adenoma. After 15 years, the patient experienced symptoms of hypoglycemia again, and laboratory findings and abdominal computed tomography identified a lesion in the liver. Intraoperative ultrasound did not show any lesion in the pancreas, and wedge resection was performed for the hepatic lesion. Postoperative blood glucose levels returned to normal. Histopathologic examination confirmed the diagnosis of liver metastasis of a neuroendocrine tumor. This is the longest interval between primary tumor and the metastasis reported in the literature, for insulinoma. Thus, it should be remembered that long-term follow-up is mandatory for the patients with insulinoma even after resection of the primary tumor. Resection is recommended when a metastatic lesion is observed.

The role of the PLR-NLR combination in the prediction of the presence of Helicobacter pylori and its associated complications.

BACKGROUND/AIM: The aim of this study was to investigate the role of the platelet-to-lymphocyte ratio (PLR)-neutrophil-to-lymphocyte ratio (NLR) combination, in the prediction of the presence of Helicobacter pylori (HP) and its associated complications in the gastrointestinal system. PATIENTS AND METHODS: In all, 1289 patients who underwent esophagogastroduodenoscopy and biopsy for HP were included in the study. RESULTS: The ratio of patients with moderate and severe chronic gastritis was higher in HP (+) group than HP (-) group. The ratio of patients with levels 1-3 atrophy and intestinal metaplasia was higher in HP (+) group. Compared with HP (-) group, HP (+) had higher PLR and NLR levels. The ratio of HP (+) patients was higher in high-risk group compared with low- and medium-risk groups. HP invasion stage, the intestinal metaplasia level, and the ratio of patients with atrophy level "3" were higher in high-risk group compared with low- and medium-risk groups. Regression analysis showed that the PLR-NLR combination was an independent risk factor for both HP presence and moderate and severe chronic gastritis. CONCLUSION: We found the PLR-NLR combination to be a good predictor of HP presence and gastrointestinal complications associated with HP.