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.

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment.

Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient's liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.

UNLABELLED: Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism. CONCLUSION: Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986).

Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage.

p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB-lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.

Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child.

BACKGROUND AND AIMS: Fibrinogen gene mutations can rarely result in hepatic fibrinogen storage disease (HFSD). Herein, we report on the first Turkish family carrying the mutation p.Arg375Trp (fibrinogen Aguadilla) in the γ-chain of the fibrinogen (FGG) gene. METHODS: Clinical, laboratory and histopathological findings of the patient were documented. Molecular study of fibrinogen gene was performed in the patient and her family members. RESULTS: The proband was 5 years old girl presenting with advanced liver fibrosis of unknown origin. The child had very low plasma levels of fibrinogen and hypobetalipoproteinemia. Immunomorphologic and electron microscopic studies showed selective and exclusive accumulation of fibrinogen within the endoplasmic reticulum in liver biopsy of the patient. Patient, mother, two sisters and one brother carried p.Arg375Trp mutation (fibrinogen Aguadilla) in FGG gene. The patient was treated with ursodeoxycholic acid and carbamazepine. After 3 months, carbamazepine was suspended upon family decision and unresponsiveness of carbamazepine. CONCLUSIONS: HFSD is characterized by hypofibrinogenemia and accumulation of abnormal fibrinogen within hepatocytes. In addition, hypofibrinogenemia is associated with hypobetalipoproteinemia in Aguadilla mutation.

Successful multimodal treatment for aggressive metastatic and recurrent fibrolamellar hepatocellular carcinoma in a child.

Fibrolamellar variant of hepatocellular carcinoma (FLHCC) does not have a favorable prognosis than conventional HCC, and there is no difference regarding the response to chemotherapy and the degree of surgical resectability. FLHCC commonly recurs after complete surgical resection, and there is a high rate of lymph node metastases. Herein, we report a 12-year-old girl with metastatic FLHCC with multiple recurrences aggressively treated with surgery, chemotherapy, and antiangiogenic agents. She is in complete remission after 4 years and 2 months after the diagnosis of metastatic FLHCC. The standard treatment of FLHCC is excision of the primary tumor and its metastases. Chemotherapy for FLHCC is controversial, and it has been suggested that cytoreductive chemotherapy was ineffective and adjuvant chemotherapy did not improve survival. Our patient with multiple recurrences was successfully treated with surgery, first-line chemotherapy with cisplatin and doxorubicin, second-line chemotherapy with 5-fluorouracil/interferon-α combination, and adjuvant antiangiogenic agents like cyclophosphamide and thalidomide. As FLHCC patients have no underlying liver disease, they can tolerate higher doses of chemotherapy compared with conventional HCC patients. We support the use of repeated aggressive surgery with adjuvant chemotherapy and antiangiogenic therapy, which provided complete remission in our patient with metastatic and recurrent FLHCC.

Comparison of the recommendation of international autoimmune hepatitis pathology group 2022 and the simplified criteria for autoimmune hepatitis 2008: A preliminary study.

Background and Aim: The histological diagnosis of autoimmune hepatitis (AIH) is challenging. A new consensus recommendation was provided by the International AIH Pathology Group to address the problems in the histological diagnosis. The purpose of this study is to compare the 2008 'simplified' criteria for AIH with the 'consensus recommendation' of 2022 in terms of diagnostic sensitivity. Materials and Methods: A retrospective analysis was conducted on pathological specimens of patients diagnosed with Autoimmune Hepatitis (AIH) between 2010 and 2022. Out of 188 patients enlisted, 88 were selected based on exclusion criteria. The specimens were examined by two experienced hepatopathologists and a resident pathologist. All specimens were analyzed using both the "simplified" criteria and the new consensus recommendations. Results: Out of a total of 78 patients, the 2022 consensus recommendations raised the diagnostic category of 16 patients (20.5%) to a higher level. Six patients who were previously diagnosed as "atypical" were now considered "possible AIH", while 10 patients with a "compatible" diagnosis were elevated to "likely AIH" category. No patients were found to fall into a lower diagnostic category according to the new recommendations. A significant difference in diagnostic sensitivity was observed between the 2008 criteria and the 2022 consensus report (p<0.001). Conclusion: The 2022 consensus recommendation may be more sensitive in the diagnosis of AIH in comparison to the 2008 'simplified' histological criteria. More studies are needed both for the validation of the sensitivity of the new consensus recommendation and for the determination of the specificity.

Diagnostic potential of serum direct markers and non-invasive fibrosis models in patients with chronic hepatitis B.

AIM: Liver biopsy is recommended in the majority of patients with chronic viral hepatitis for fibrosis evaluation. Because of the disadvantages of liver biopsy, many studies related to non-invasive biomarkers and scores have been performed. In this study, we aimed to assess the diagnostic value of serum direct markers and non-invasive fibrosis models to predict liver fibrosis in the treatment-naive chronic hepatitis B (CHB) patients and to compare their diagnostic performance. METHODS: This study included 58 patients with a diagnosis of CHB virus infection and 30 healthy controls. Hyaluronic acid, tissue inhibitor of matrix metalloproteinase 1 and amino-terminal propeptide of type III procollagen were measured by enzyme-linked immunosorbent assay; and the Original European Liver Fibrosis panel, the Enhanced Liver Fibrosis (ELF) panel, PP score, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 indexes were calculated using the formulas taken from previous publications. Fibrosis stage was determined using Ishak's scoring system. RESULTS: The fibrosis stages identified upon liver biopsy was F0 in 12 patients (20.7%), F1-2 in 36 (62.1%) and F3-5 in 10 (17.2%). The diagnostic value of all the non-invasive indices was low to detect mild fibrosis. We demonstrated that the diagnostic accuracy of HA is the best for predicting fibrosis of F3 or more (area under the receiver-operator curve, 0.902). In our study, the results from a combination of tests showed that ELF and APRI had the highest diagnostic value sensitivity of 90%, specificity of 100%, positive predictive value of 100% and negative predictive value of 96.4% for detection of fibrosis of F3 or more. CONCLUSION: In CHB patients, combination of ELF and APRI has a better diagnostic value in predicting fibrosis of F3 or more.

Colonic lymphoid nodular hyperplasia in childhood: causes of familial Mediterranean fever need extra attention.

OBJECTIVES: The clinical importance and etiology of colonic lymphoid nodular hyperplasia (LNH) are not clear. It has been considered a response to some antigenic stimuli. Although food allergies, infections, inflammatory bowel diseases, and immunodeficiencies may be listed in the etiology of colonic LNH, the etiology has remained unclear in many cases. This study investigated the etiology of colonic LNH and its relation to familial Mediterranean fever (FMF) in children. FMF as an etiologic factor for colonic LNH has not been reported before in the literature. METHODS: Medical files of patients who underwent colonoscopy between 2007 and 2011 were examined retrospectively. Demographic features, presenting symptoms, colonoscopy indications, colonoscopic findings, and final diagnoses of patients were evaluated. According to etiologies, patients with colonic LNH were divided into 2 groups: group A consisted of patients with FMF and group B consisted of diseases other than FMF. RESULTS: A total of 311 patients were included in the study. Forty (12.6%) patients had isolated colonic LNH. In 23 (57.5%) patients, isolated LNH was observed in some colonic segments and total colonic LNH was noted in 17 (42.5%) patients. FMF was the etiologic factor in 6 (15%) patients. Thirty-four patients (85%) had etiologic factors other than FMF. We did not find any etiologic factor for LNH in 3.53% (11/311) of patients. CONCLUSIONS: FMF may be an etiologic factor for colonic LNH in children besides food allergies, infections, inflammatory bowel diseases, and immunodeficiencies.

Serum liver fatty acid binding protein shows good correlation with liver histology in NASH.

BACKGROUND/AIMS: Simple, reproducible and non-invasive tests that can be used to determine the severity of non-alcoholic steatohepatitis (NASH) are needed. Liver-type fatty acid binding protein (L-FABP) plays a key role in the fatty acid metabolism of the liver. We aimed to determine whether serum L-FABP levels in patients with NASH were different from those in healthy controls, and if so, whether this was associated with the degree of fibrosis, steatosis and inflammatory activity. METHODOLOGY: Forty-seven patients with histologically confirmed NASH and 41 healthy controls were included in the study. Serum L-FABP levels were measured in all participants. RESULTS: Mean L-FABP levels were significantly higher in patients with NASH compared to the control group (2703.19±1603.47 vs. 1684.58±860.19, p<0.001). Serum L-FABP levels showed a significant positive correlation with NAS score (p=0.03, r=0.312), the degree of fibrosis (p=0.02, r=0.324) and inflammation (p=0.03, r=0.312), BMI (p=0.05, r=0.303), serum ALT (p=0.01, r=0.28), AST (p=0.04, r=0.315), and triglyceride levels (p=0.03, r=0.328). CONCLUSIONS: Serum L-FABP levels are elevated in NASH and this elevation is positively correlated with the degree of fibrosis and inflammation. L-FABP levels may aid as a non-invasive marker in determining the severity of fibrosis and inflammation in patients with NASH.

Oxidized Regenerated Cellulose can be a Cause of False Tumor Recurrence on PET/CT in Patients with Lung Cancer Treated Surgically.

Objectives: Regular follow-up of patients with lung cancer treated surgically is crucial to detect local recurrence or distant metastasis of the tumor. Postoperative follow-ups are performed with thorax computed tomography (CT) and, if necessary, positron emission tomography (PET)/CT. Sometimes, inflammatory tissue reactions due to the materials used during the surgery for hemostasis may cause the appearance of tumor recurrence in imaging modalities. In this study, we presented that oxidized regenerated cellulose (ORC) used intraoperatively may cause false tumor recurrence on PET/CT. Methods: The records of patients who had local tumor recurrence after lung cancer surgery was reviewed retrospectively. Inclusion criteria were the presence of local recurrence of cancer on PET/CT, specification of using ORC in the surgical notes, and histopathological diagnosis of the recurrence site of tumor was reported as a foreign body reaction. Data of patients were collected according to age, gender, surgery performed, adjuvant therapy status, resolution status and time ORC, and standard uptake value of 18F-fluorodeoxyglucose on PET/CT. Results: Eleven patients (1 female, 10 males) who met the criteria were included in the study. The median age was 64. Histopathological results of all patients were reported as foreign body reactions. The median detection time of PET/CT positivity after surgery was 139 days (range: 52-208 days). False tumor recurrence was resolved in 8 patients (72.7%) in their control radiological examinations and median resolution time was 334 days (range: 222-762 days). The median maximum standard uptake value of the lesions was 6.2 (1.7-11) on the PET/CT. Conclusion: ORC used intraoperatively in patients undergoing surgery for lung cancer may cause false tumor recurrence in imaging modalities in postsurgical follow-ups. When tumor recurrence is suspected in the follow-up of these patients, histopathological confirmation is necessary to prevent unnecessary operations and treatments.

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.

TASL Practice Guidance on the Clinical Assessment and Management of Patients with Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease and is significantly associated with obesity, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. NAFLD has become the most prevalent chronic liver disease in Western countries, and the proportion of NAFLD-related cirrhosis among patients on liver transplantation waiting lists has increased. In light of the accumulated data about NAFLD, and to provide a common approach with multi-disciplines dealing with the subject, it has become necessary to create new guidance for diagnosing and treating NAFLD. This guidance was prepared following an interdisciplinary study under the leadership of the Turkish Association for the Study of the Liver (TASL), Fatty Liver Special Interest Group. This new TASL Guidance is a practical application guide on NAFLD and was prepared to standardize the clinical approach to diagnosing and treating NAFLD patients. This guidance reflects many advances in the field of NAFLD. The proposals in this guidance are meant to aid decision-making in clinical practice. The guidance is primarily intended for gastroenterology, endocrinology, metabolism diseases, cardiology, internal medicine, pediatric specialists, and family medicine specialists.

The Relationship Between Plexin C1 Overexpression and Survival in Hepatocellular Carcinoma: a Turkish Oncology Group (TOG) Study.

PURPOSE: Plexin C1 is a transmembrane receptor and plexin C1 overexpression might have role in carcinogenesis. Hepatocellular carcinoma (HCC) has poor prognosis because of its aggressive behavior and limited treatment options, especially in advanced stage. We recently documented that Plexin C1 was overexpressed in HCC. We aimed to evaluate the prognostic significance of Plexin C1 overexpression in HCC in the present study. METHODS: Plexin C1 overexpression was evaluated immunohistochemically on paraffin-embedded blocks of the HCC patients. Plexin C1 immunohistochemical staining was scored. Plexin C1 overexpression staining intensity and prevalence were used for plexin scale staining evaluation and plexin scores were estimated according this staining scale. Plexin C1 score and its association with survival and clinicopathological features was assessed. RESULTS: Sixty-seven HCC patients with adequate tissue for pathological evaluation were included. Median age was 63 years with male predominance (male to female ratio was 4.75 (n 57/12). Well-differentiated HCC (53.7%) patients had higher plexin C1 overexpression (p < 0.05). Median OS was 22.1 months. Patients with lower plexin C1 score (< 12) had shorter OS (17.5 vs 30.1 months, p = 0.036). Neutrophil count, GGT, and PNR (platelet/neutrophil ratio) had prognostic significance (p = 0.047, p = 0.018, and p = 0.045). CONCLUSION: Plexin C1 overexpression is inversely correlated with grade in HCC. The patients with lower rate of Plexin C1 overexpression have worse survival outcome. It might be a prognostic factor in HCC.

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.

Granulomatous hepatitis, perihepatic lymphadenopathies, and autoantibody positivity: an unusual association in a child with hepatitis C.

A 10-year-old boy with hepatitis C had granulomatous hepatitis (GH) at initial liver biopsy. He also had enlarged perihepatic lymph nodes and smooth muscle antibody (SMA) positivity. GH is a rare finding in hepatitis C virus (HCV) infection. Our patient is special since GH secondary to HCV infection was associated with both autoantibodies and multiple intraabdominal lymphadenopathies. After interferon (IFN) and ribavirin therapy, HCV RNA became negative, along with the resolution of hepatic granulomas (HG), lymphadenopathies, and SMA positivity. Although early virologic response was not achieved under IFN treatment, the therapy period was extended, contrary to routine practice, and resulted in a delayed response. We conclude that the usage of IFN for longer periods in GH-associated HCV infection might be promising.

Cyclooxygenase-2 expression: does it have a probable role in tumorigenesis mechanisms of renal cell carcinoma?

OBJECTIVES: The purpose of this study was to evaluate the correlation between the levels of cyclooxygenase-2 (COX-2) expression with clinicopathologic features and determine the impact on prognosis in patients with renal cell carcinoma (RCC). METHODS: Expression of COX-2 was evaluated immunohistochemically in RCC tissues from 62 patients who underwent radical nephrectomy between 1996 and 2004. Percentage of COX-2 staining was scored as 0 (negative), 1 (1-24%), 2 (25-49%), 3 (50-74%), and 4 (75-100%). Immunohistochemical COX-2 staining score (ISS) was defined as summation of intensity and percentage of COX-2 staining. RESULTS: Twenty-seven patients (43.5%) with a median follow-up of 47.8 (25-115) months stained positively for COX-2. COX-2 expression was positive in 37.1%, 50%, and 66.7% of patients with stages 1, 2, and 3, respectively (P = 0.46). Correlation between ISS and pathological stage was statistically significant (P = 0.005). Multivariate regression analysis revealed no clinicopathologic parameter as independent predictors of progression. Kaplan-Meier analysis revealed statistically significant different survival rates in tumor stage, grade, and ISS. CONCLUSION: Although COX-2 expression is not an independent predictor of progression in patients with RCC, patients with higher ISS values have significantly shorter progression-free survival rates. These results might be important to the clinician because positive COX-2 expression of a certain RCC might necessitate early adjuvant systemic therapy to delay the progression of RCC. For this reason, there is a need for innovative, prospective, and randomized studies in patients with positive COX-2 expression that will display the impact of systemic therapies in these patients.

A Retrospective Evaluation of the Epithelial Changes/Lesions and Neoplasms of the Gallbladder in Turkey and a Review of the Existing Sampling Methods: A Multicentre Study.

OBJECTIVE: As there is continuing disagreement among the observers on the differential diagnosis between the epithelial changes/lesions and neoplasms of the gallbladder, this multicentre study was planned in order to assess the rate of the epithelial gallbladder lesions in Turkey and to propose microscopy and macroscopy protocols. MATERIAL AND METHOD: With the participation of 22 institutions around Turkey that were included in the Hepato-Pancreato-Biliary Study Group, 89,324 cholecystectomy specimens sampled from 2003 to 2016 were retrospectively evaluated. The numbers of adenocarcinomas, dysplasias, intracholecystic neoplasms/adenomas, intestinal metaplasias and reactive atypia were identified with the review of pathology reports and the regional and countrywide incidence rates were presented in percentages. RESULTS: Epithelial changes/lesions were reported in 6% of cholecystectomy materials. Of these epithelial lesions, 7% were reported as adenocarcinoma, 0.9% as high-grade dysplasia, 4% as low-grade dysplasia, 7.8% as reactive/regenerative atypia, 1.7% as neoplastic polyp, and 15.6% as intestinal metaplasia. The remaining lesions (63%) primarily included non-neoplastic polypoids/hyperplastic lesions and antral/pyloric metaplasia. There were also differences between pathology laboratories. CONCLUSION: The major causes of the difference in reporting these epithelial changes/lesions and neoplasms include the differences related to the institute's oncological surgery frequency, sampling protocols, geographical dissimilarities, and differences in the diagnoses/interpretations of the pathologists. It seems that the diagnosis may change if new sections are taken from the specimen when any epithelial abnormality is seen during microscopic examination of the cholecystectomy materials.

Cholesteryl ester storage disease in a young child presenting as isolated hepatomegaly treated with simvastatin.

Cholesteryl ester storage disease (CESD) is an autosomal recessive disorder resulting from lysosomal acid lipase deficiency and is usually characterized by hepatomegaly and hyperlipidemia. This paper reports a two-year-old boy who had hepatosplenomegaly, hyperlipidemia and hypertransaminasemia determined incidentally. The liver biopsy sample was orange-yellow in appearance. Microscopically, microvesicular steatosis and birefringent crystals were seen in liver biopsy. The diagnosis of CESD was confirmed by the reduced human acid lipase activity in peripheral leukocytes. Simvastatin therapy was given and tolerated without side effects. Our patient is the youngest reported case in the literature treated with 3-hydroxy 3-methyl glutaryl (HMG) CoA reductase inhibitor.

Prevention of gentamicin induced ototoxicity by trimetazidine in animal model.

OBJECTIVE: To show the efficacy of intra-peritoneally administered trimetazidine to prevent gentamicin ototoxicity, which is still an important cause of profound deafness among children in different parts of the world. METHODS: Two groups of Swiss albino mice received daily intra-muscular injections of gentamicin for 30 days. One of the groups received trimetazidine intra peritoneally in addition to the gentamicin. Auditory thresholds of the animals were measured by evoked brain stem response at the beginning and the end of the study. Results were compared to the results of the control group, which received intra peritoneal saline injections. RESULTS: Both groups receiving gentamicin injections had significant auditory threshold shifts, but in the group receiving additional trimetazidine, the threshold shift was not statistically significant when compared to control group. Threshold shift in gentamicin group significantly differed from that of the control group (p=0.0001) and gentamicin+trimetazidine group (p=0.0001), on the other hand there was no statistically significant difference between control group and trimetazidine+gentamicin group (p=0.102). CONCLUSION: Gentamicin ototoxicity can be prevented by intra peritoneal trimetazidine injections in animal model. This treatment modality may be a mode of protection from gentamicin ototoxicity in children.