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Genetic backgrounds of patients with pulmonary arterial hypertension (PAH) were not fully investigated. A variant of c.14429G > A (p.Arg4810Lys) in the ring finger protein 213 gene (RNF213) was recently identified as a risk allele for poor treatment response and poor clinical prognosis in patients with PAH. However, the molecular mechanisms of the RNF213 p.Arg4810Lys variant in development of PAH are unknown. We investigated the underlying molecular mechanisms of RNF213-associated vasculopathy using an in vivo mouse model. RNF213+/p.Arg4828Lys mice, harboring the heterozygous RNF213 p.Arg4828Lys variant corresponding to the p.Arg4810Lys variant in humans, were created using the CRISPR-Cas9 system to recapitulate the genetic status of PAH patients. RNF213+/p.Arg4828Lys mice had a significant elevation of the right ventricular systolic pressure, hypertrophy of the right ventricle, and increased thickness of the pulmonary arterial medial wall compared with wild-type mice after 3 months of exposure to a hypoxic environment. C-X-C motif chemokine ligand 12 (CXCL12), a C-X-C chemokine receptor type 4 (CXCR4) ligand, was significantly elevated in the lungs of RNF213+/p.Arg4828Lys mice, and PAH was ameliorated by the administration of a CXCR4 antagonist. CXCL12-CXCR4 is an angiogenic chemokine axis, and immunohistochemistry demonstrated an increase in CXCR4 in vimentin-positive spindle-shaped cells in adventitia and interstitial lesions in RNF213+/p.Arg4828Lys mice and lung specimens from severe PAH patients with the RNF213 p.Arg4810Lys variant. We confirmed a cause-and-effect relationship between the RNF213 p.Arg4810Lys variant and PAH via the CXCL12-CXCR4 pathway. The findings in this study suggest that targeting this pathway might be a novel therapeutic strategy for RNF213-associated vasculopathy. [ABSTRACT FROM AUTHOR]

This article discusses a rare case of a gastric mesenchymal tumor with gastroblastoma-like features. The tumor was found in a 25-year-old Japanese woman who presented with hematemesis and severe anemia. The tumor displayed a biphasic morphology with both spindle cell and epithelioid cell proliferation. Molecular analysis revealed a PTCH1::GLI2 fusion, which is a recurrent event in rare gastric mesenchymal neoplasms resembling gastroblastoma. The authors highlight the diagnostic challenge in distinguishing between gastroblastoma and other gastric mesenchymal neoplasms with similar features. Further studies are needed to better understand the relationship between these tumors and establish them as distinct entities. [Extracted from the article]

Purpose: We examined the microsatellite instability of duodenal tumors to evaluate their molecular features associated with the adenoma–carcinoma sequence. Methods: Fifty-two non-ampullary duodenal epithelial tumors collected by endoscopic mucosal resection or surgical resection were studied. When a tumor had two or more dysplasia grades, the highest grade was considered. Representative areas were macro-dissected and subjected to a microsatellite instability analysis and immunohistochemical staining. Results: The 52 tumors were classified as either adenoma with low-grade dysplasia (n = 18), adenoma with high-grade dysplasia (n = 20), or adenocarcinomas (n = 14). Among these, 3 adenocarcinoma cases showed microsatellite instability and the remaining 49 tumors showed microsatellite stability. Of the 14 adenocarcinoma cases, 3 contained both high-grade dysplasia and adenocarcinoma components, and 11 contained only the adenocarcinoma component. Interestingly, all three adenocarcinoma + high-grade dysplasia cases were microsatellite instability-high in both the adenocarcinoma and high-grade dysplasia components. Immunohistochemical staining of mismatch repair proteins showed mismatch repair deficiency in three microsatellite instability-high adenocarcinoma + high-grade dysplasia cases. Conclusions: Only adenocarcinoma cases with high-grade dysplasia components were microsatellite instability-high (in both the adenocarcinoma and high-grade dysplasia components). This suggests that microsatellite instability in the high-grade dysplasia component of duodenal adenoma is associated with progression to adenocarcinoma. [ABSTRACT FROM AUTHOR]

"Oligoastrocytoma" disappeared as of the revised fourth edition of the World Health Organization Classification of Tumours of the Central Nervous System, except where appended with "not otherwise specified (NOS)". However, histopathological and genetic backgrounds of cases with dual features of astrocytoma/oligodendroglioma have been sparsely reported. We encountered a 54-year-old man with right frontal glioma comprising two distinct parts on imaging and histopathological examination: grade 4 astrocytoma with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q; and oligodendroglioma with IDH1-R132H, intact ATRX, p53-negativity and partially deleted 1p/19q. At recurrence, histopathology showed low-grade mixed astrocytic and oligodendroglial features: the former with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q and the latter showing IDH1-R132H, intact ATRX, p53-negativity and 1p/19q codeletion. At second recurrence, histopathology was astrocytoma grade 4 with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q. Notably, 1p/19q codeletion was acquired at recurrence and CDKN2A was deleted at second recurrence. These findings suggest insights into tumorigenesis: (1) gliomas with two distinct lineages might mix to produce "oligoastrocytoma"; and (2) 1p/19q codeletion and CDKN2A deletion might be acquired during chemo-radiotherapy. Ultimately, astrocytic and oligodendroglial clones might co-exist developmentally or these two lineages might share a common cell-of-origin, with IDH1-R132H as the shared molecular feature. [ABSTRACT FROM AUTHOR]

The current World Health Organization classification of diffuse astrocytic and oligodendroglial tumors requires the examination of isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations. Conventional analysis tools, including Sanger DNA sequencing or pyrosequencing, fail in detecting these variants of low frequency owing to their limited sensitivity. Digital polymerase chain reaction (dPCR) is a recently developed, highly sensitive, and precise quantitative rare variant assay. This study aimed to establish a robust limit of quantitation of the dPCR assay to detect a small fraction of IDH1 R132H mutation. The dPCR assays with serially diluted IDH1 R132H constructs detected 0.05% or more of mutant IDH1 R132H in samples containing mutant DNA. The measured target/total value of the experiments was proportional to the dilution factors and was almost equal to the actual frequencies of the mutant alleles. Based on the average target/total values, together with a twofold standard deviation of the normal DNA, a limit of quantitation of 0.25% was set to secure a safe margin to judge the mutation status of the IDH1 R132H dPCR assay. In clinical settings, detecting IDH1 R132H using dPCR assays can validate ambiguous immunohistochemistry results even when conventional DNA sequencing cannot detect the mutation and assure diagnostic quality. [ABSTRACT FROM AUTHOR]

Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 108 pfu (low dose) or 1 × 109 pfu (set dose), twice to identical coordinates within 5–14 days. Thirteen patients completed treatment (low dose, n = 3; set dose, n = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7–34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for "immunoprogression" characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development. G47Δ is a third-generation, triple-mutated oncolytic HSV-1 that has demonstrated anti-tumor efficacy in preclinical studies. Here the authors report the results of a phase I/II study of G47Δ in patients with recurrent or progressive glioblastoma. [ABSTRACT FROM AUTHOR]

Brain metastasis post-curative gastrectomy for early-stage gastric cancer is extremely rare. We present herein, a case of solitary brain metastasis that developed 4 years post-curative surgery for early-stage gastric cancer. A 60-year-old man had early-stage gastric cancer 4 years prior to presentation and underwent laparoscopy-assisted distal gastrectomy with lymph node dissection. The pathological TNM classification was T1b (submucosal) N0M0. He underwent scheduled examinations and had no recurrence. 4 years postoperatively, he presented to the emergency department with sudden onset of nausea, vomiting, and inability to speak clearly. Brain computed tomography revealed a 17-mm nodule in the right cerebral hemisphere and midline shift. The tumor could not be radically resected for anatomical reasons, and incisional biopsy was performed for histological examination. Histological examination confirmed the diagnosis of a poorly differentiated adenocarcinoma from the previous gastric cancer. Gamma knife radiosurgery and chemotherapy were scheduled. 28 months after brain metastasis, multiple liver and lung metastases appeared. The patient died 30 months after developing brain metastasis. Brain metastasis may occur during long-term follow-up even after curative resection of early-stage gastric cancer. In patients with a history of gastric cancer and neurological symptoms, brain metastasis should be considered. [ABSTRACT FROM AUTHOR]

Trimethylation of histone H3 at lysine 27 (H3K27me3) acts as a transcriptional repressor of target genes. Recent immunohistochemical studies have reported a loss of H3K27me3 modification in diffuse (especially 1p/19q-codeleted) gliomas. However, we did not observe H3K27me3 loss in diffuse gliomas using routine immunostaining conditions for the detection of H3K27me3 loss in malignant peripheral nerve sheath tumors (MPNSTs). Therefore, we conducted immunohistochemical analysis of surgically resected specimens to understand the differences in the H3K27me3 status in MPNSTs and diffuse gliomas and evaluate the diagnostic utility of H3K27me3 immunohistochemistry. Staining with a standard 1:200 dilution of the C36B11 antibody showed a complete loss of H3K27me3 in 5 out of 11 MPNSTs, whereas most diffuse gliomas (149/151, 98.7%) showed diffuse immunoreactivity. At a 1:2000 antibody dilution, 12.6% (19/151) of the diffuse gliomas showed H3K27me3 loss, which was significantly associated with 1p/19q codeletion (P < 0.001). H3K27me3 loss predicted 1p/19q codeletion in IDH-mutant gliomas with lower sensitivity (56.2%) and higher specificity (100%) than ATRX retention or p53 negative result. In conclusion, reduction in H3K27me3 levels was associated with 1p/19q codeletion in diffuse gliomas; however, the extent of reduction differed from that in MPNSTs, and the results depended on the immunostaining conditions. [ABSTRACT FROM AUTHOR]

Purpose: Well-differentiated liposarcoma, the most common subtype of liposarcoma, should be discriminated from benign lipoma. However, features on sonography for discriminating these two types of tumor have not been fully investigated. The present study was therefore aimed at clarifying differences in sonographic findings between well-differentiated liposarcoma and lipoma. Methods: The study population comprised 23 cases of well-differentiated liposarcoma and 181 cases of lipoma. We investigated differences in sonographic appearance and pathological findings between the two types of tumor. Results: Well-differentiated liposarcoma tended to develop more frequently in older patients and in the lower extremities including the gluteal region, compared with lipoma. Concerning sonographic findings, both tumors exhibited well-defined margins and heterogeneous internal echogenicity, including typical tiny striated hyperechoic lines. Well-differentiated liposarcoma was characterized by a higher frequency of the following findings compared with lipoma: (1) deep location, (2) irregular shape, (3) large diameter, (4) hyperechogenicity compared to surrounding tissue, and (5) presence of vascularity on Doppler sonography (p < 0.01 each). Notably, hyperechogenicity corresponded to the intermingled sclerosing component within the adipocytic component when sonographic findings were compared with those of pathology. Conclusion: The present study suggests that several sonographic findings including hyperechogenicity and presence of vascularity might be key features for discriminating well-differentiated liposarcoma from lipoma. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are characterized by the accumulation of excess hepatic fat. However, in the progression from NASH to cirrhosis, hepatic fat is often lost. Our aim was to elucidate the mechanism underlying hepatic fat loss during NASH progression.Methods: Liver biopsies were performed at The University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD and 14 patients with cryptogenic cirrhosis who were not being treated with any diabetes or dyslipidemia drugs. Among them, 70 patients underwent liver biopsy after an overnight fast, and 90 patients were biopsied 5 h after an oral glucose tolerance test. Expression differences in genes encoding several fatty acid metabolism-related factors were examined and correlated with hepatic histological changes based on NAFLD activity scores. Prospective patient follow-up continued until June 2018.Results: The level of fatty acid transport protein 5 (FATP5), which is associated with free fatty acid intake, was significantly and inversely correlated with features of histological progression, including ballooning and fibrosis. This was confirmed by immunohistochemical analysis. Transcript levels of genes encoding fatty acid metabolism-related proteins were comparable between NASH with severe fibrosis and cryptogenic cirrhosis. Furthermore, a prospective cohort study demonstrated that low FATP5 expression was the most significant risk factor for hepatic fat loss.Conclusions: Decreased hepatic FATP5 expression in NAFLD is linked to histological progression, and may be associated with hepatic fat loss during NASH progression to cirrhosis. [ABSTRACT FROM AUTHOR]

Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes. Our aim was to investigate the relationship between NAFLD and impaired glucose metabolism in terms of insulin receptor substrate 1 and 2 (IRS1 and IRS2) expression in the liver.Methods: Liver biopsy was performed at the University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD who were not being treated with any diabetes or dyslipidemia drugs. Among them, 63 underwent liver biopsy after an overnight fast, and 83 at 5 h after an oral glucose tolerance test (OGTT). Differences in messenger RNA (mRNA) levels of several glucose metabolism-related factors were determined and correlated with hepatic histological changes assessed by NAFLD activity score. We prospectively followed up with the patients until May 2017.Results: Hepatic necroinflammation was significantly correlated with serum insulin levels and inversely correlated with IRS1 mRNA levels. In specimens obtained after an OGTT, hepatic necroinflammation and IRS1 expression correlated significantly with both peripheral and hepatic insulin resistance. We also found that hepatic β-catenin and glucokinase mRNA levels were elevated in patients undergoing liver biopsy after an OGTT, especially in those with less hepatic necroinflammation and a lower degree of fibrosis. A prospective cohort study showed that ballooning is the most significant risk factor for developing diabetes.Conclusions: The decreased hepatic expression of IRS1 and β-catenin in NAFLD is linked to histological progression such as ballooning, and might lead to diabetes as a result of impaired glucose metabolism. [ABSTRACT FROM AUTHOR]

A 72-year-old woman with advanced ascending colon cancer and an intraductal papillary mucinous neoplasm (IPMN) of the pancreatic head was treated by right hemicolectomy (RHC) and pylorus-preserving pancreaticoduodenectomy (PpPD). Adjuvant chemotherapy was not administered. Multimodal examinations at 5 months after surgery detected a solitary metastatic liver tumor derived from cancer of the ascending colon. Liver resection proceeded at 7 months after the first surgery. A pathological study of a surgical specimen of the liver identified a necrotic nodule that did not contain viable tumor cells. However, an immunohistological study of the hepatic mass indicated metastasis derived from cancer of the ascending colon. These findings were consistent with total necrosis of a liver metastasis of colorectal cancer. The mechanism of spontaneous regression of tumors remains unexplained. In our case, pancreaticoduodenectomy was performed at the same time as right hemicolectomy, which involved a risk of continuous biliary infection after biliary tract reconstruction. A host immune response to chronic biliary tract infection might have been involved in the spontaneous regression of liver metastasis. Spontaneous regression of colorectal liver metastasis is rare, and the mechanism remains unknown. This needs to be investigated in more tissues from patients who have experienced this phenomenon. [ABSTRACT FROM AUTHOR]

Objectives: To determine if texture analysis of non-contrast-enhanced CT (NECT) images is able to predict nonalcoholic steatohepatitis (NASH).Methods: NECT images from 88 patients who underwent a liver biopsy for the diagnosis of suspected NASH were assessed and texture feature parameters were obtained without and with filtration. The patient population was divided into a predictive learning dataset and a validation dataset, and further divided into groups according to the prediction of liver fibrosis as assessed by hyaluronic acid levels. The reference standard was the histological result of a liver biopsy. A predictive model for NASH was developed using parameters derived from the learning dataset that demonstrated areas under the receiver operating characteristic curve (AUC) of >0.65. The resulting model was then applied to the validation dataset.Results: In patients without suspected fibrosis, the texture parameter mean without filter and skewness with a 2-mm filter were selected for the NASH prediction model. The AUC of the predictive model for the validation dataset was 0.94 and the accuracy was 94%. In patients with suspicion of fibrosis, the mean without filtration and kurtosis with a 4-mm filter were selected for the NASH prediction model. The AUC for the validation dataset was 0.60 and the accuracy was 42%.Conclusions: In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH.Key Points: • In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH. • The mean without filtration and skewness with a 2-mm filter were modest predictors of NASH in patients without suspicion of liver fibrosis. • Hepatic fibrosis masks the characteristic texture features of NASH. [ABSTRACT FROM AUTHOR]

Background: The necessity of histological analysis is increasing. A 19-gauge histology needle (PC19) in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has recently been developed and has shown high yields of tissue acquisition and histological diagnosis.Aims: To compare the histological diagnostic yield in single-pass EUS-FNA for solid lesions using PC19 and a standard 19-gauge needle (EC19).Patients and Methods: Consecutive patients with solid lesions were enrolled and underwent one pass with each of PC19 and EC19 for EUS-FNA with the randomized order of the needles. The primary endpoint was the histological diagnostic accuracy. The secondary endpoints were the feasibility, yield of histological core, cytological and overall diagnostic accuracies, and adverse events. Subgroup analysis was performed for the optimal situation with PC19.Results: Of the 115 patients, 110 underwent EUS-FNA and five were excluded. EUS-FNA was performed from the esophagus in four, stomach in 80, or duodenum in 26. The final diagnosis was malignancy in 100 and benign in 10. The feasibility was 98.2 and 97.3% with PC19 and EC19, respectively (p = 1.00). The rate of presence of a histological core and the histological, cytological, and overall diagnostic accuracies for PC19 versus EC19 were 84.6 versus 80.9% (p = 0.593), 83.6 versus 73.6% (p = 0.099), 63.6 versus 56.4% (p = 0.335), and 90.0 versus 79.1% (p = 0.039), respectively. PC19 was favored in the trans-esophageal/gastric approaches to obtain a histological diagnosis (p = 0.013). Adverse events were observed in four patients.Conclusion: Single-pass EUS-FNA with PC19 was feasible and showed significantly higher overall diagnostic accuracy and an increased tendency towards histological diagnostic accuracy, especially with trans-esophageal/gastric FNA. [ABSTRACT FROM AUTHOR]

We report the case of a 33-year-old Caucasian American man diagnosed with celiac disease in Japan. He presented to a community hospital because of chronic watery diarrhea and weight loss for 6 months. The laboratory data showed low serum albumin and serum cholesterol. A colonoscopy was normal. He was referred to our hospital for further work-up. Serum tissue transglutaminase immunoglobulin A (IgA) and endomysial antibody were positive. The HLA type was DQ2. Esophagogastroduodenoscopy (EGD) revealed nodular and mosaic-patterned mucosa from the bulb to the second part of the duodenum. The histopathological findings were consistent with Marsh type 3c of the modified Marsh classification for celiac disease. The patient was instructed to follow a gluten-free diet (GFD). Six months after the initiation of the GFD, his symptom and the levels of serum albumin and cholesterol were improved, and the serum tissue transglutaminase IgA and endomysial antibody became negative. However, EGD showed little improvement. Capsule endoscopy also revealed mosaic-patterned mucosa, nodular mucosa, and scalloping of the folds of the duodenum and proximal small intestine. There was no definite improvement in histopathological findings. Collectively, the GFD was effective in this patient with celiac disease, but it should be maintained to achieve endoscopic and histopathologic healing. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) presents as a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter is progressive, and its pathogenesis remains poorly understood. Recently, bile acid (BA) metabolism has become a therapeutic focus in NASH patients. The aim of the present study was to explore changes in bile acid metabolism in NAFLD patients in the context of disease progression.Methods: We prospectively enrolled patients with clinically suspected NAFLD. Patients taking ursodeoxycholic acid were excluded. The intrahepatic expression levels of genes associated with BA metabolism were determined by quantitative PCR and immunohistochemistry.Results: Seventy-eight patients (male:female = 49:29) histologically diagnosed with NAFLD were analyzed. The expression levels of farnesoid X receptor, liver receptor homolog 1, and small heterodimer partner, key proteins in BA synthesis, significantly decreased as the NAFLD activity score (NAS) increased in either males or females. The levels of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of BA synthesis, were not changed. Notably, the expression levels of a main export transporter, bile salt export pump (BSEP), significantly decreased as the NAS and the each NAS component increased in both genders. The decreases of BSEP levels were also observed by immunohistochemistry, particularly in areas with pronounced fatty changes in cases with high NAS.Conclusions: The expression levels of the BA export transporter BSEP were inversely correlated with NAS in NAFLD patients. Such down-regulation may cause excessive BA levels in hepatocytes, leading to cell injury. Our findings may afford new insights into the pathogenesis of NASH. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) with steatohepatitic features (steatohepatitic HCC, SH-HCC) is a histological subset of HCC, highly associated with metabolic disease and underlying steatohepatitis. Although it has distinct clinicopathologic characteristics, little is known about the immunophenotype or genetic characteristics of SH-HCC. We conducted an immunohistochemical analysis on a tissue microarray containing 197 HCCs (70 SH-HCCs and 127 conventional HCCs (C-HCCs)), focusing on proteins associated with genetic subtypes of HCC and those associated with non-alcoholic fatty liver disease (NAFLD) or NAFLD-associated HCC. We also investigated CTNNB1 mutations in 84 HCCs (31 SH-HCCs and 53 C-HCCs) to better characterize the SH-HCC. When compared to C-HCC, SH-HCC was characterized by a significantly lower incidence of nuclear accumulation of β-catenin (5.7 vs. 25.2 %, p < 0.001) and by a lower incidence of overexpression (H-score = 300) of glutamine synthetase (4.3 vs. 26.0 %, p < 0.001). Multivariate logistic regression analysis revealed that the low rate of nuclear β-catenin accumulation in SH-HCC was independent of background etiology, including underlying steatohepatitis (p < 0.001). In accordance with the immunohistochemical results, CTNNB1 mutations were less frequent in SH-HCC than C-HCC (3.1 vs. 20.8 %, p < 0.048). Other notable findings included the ubiquitous expression of sonic hedgehog ligand in typical SH-HCC (100 %) and the less frequent expression of progenitor markers, such as SALL4 and EpCAM, in SH-HCC. These results indicate that SH-HCC as a subtype is not only characterized by morphology but also by distinct phenotypic and genetic traits. [ABSTRACT FROM AUTHOR]

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis. Herein we report a case of a 49-year-old woman who developed bilateral knee pain. Imaging procedures revealed multiple long bone lesions and a well-defined 18F-fluorodeoxyglucose-avid mass in the left breast. The breast mass was resected, and an open biopsy was performed on the right femoral lesion. Both specimens revealed involvement by histiocytic infiltrates with features suggestive of ECD. The BRAF V600E mutation was detected by DNA sequencing and immunohistochemistry. [ABSTRACT FROM AUTHOR]

Background: Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear. Methods: In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence). Results: ICG fluorescence imaging enabled identification of 273 of 276 (99 %) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs ( P < 0.001). Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence. Conclusions: Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging. [ABSTRACT FROM AUTHOR]

Mucosa-associated lymphoid tissue (MALT) lymphoma usually arises from chronic inflammation. We herein report a case of small intestinal MALT lymphoma with protein-losing enteropathy (PLE). A 73-year-old woman presented with lower leg edema and severe hypoalbuminemia. She had a medical history of pylorus-preserving pancreaticoduodenectomy with Billroth II reconstruction. Oral and anal route double-balloon enteroscopies revealed irregular nodular mucosal lesions with erosion extending from the jejunum to terminal ileum. Histopathological evaluation of the biopsied mucosa showed proliferation of small-to-medium-sized lambda light chain-restricted B cells. Plasmacytic differentiation and lymphoepithelial lesions were present, leading to the diagnosis of MALT lymphoma. Tc-99m albumin scintigraphy indicated tracer exudation in the small bowel, suggesting the presence of PLE. Combination immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen improved both MALT lymphoma and PLE, whereas rituximab monotherapy was not successful. This case is considered to be common type of MALT lymphoma at an uncommon site and is distinct from immunoproliferative small intestinal disease (IPSID). To our knowledge, this is the first case of non-IPSID-type small intestinal MALT lymphoma complicated by PLE. Gastrointestinal reconstruction may be responsible for underlying chronic inflammation via small intestinal bacterial overgrowth. [ABSTRACT FROM AUTHOR]

Claudin-18 (CLDN18), a tight junction protein specific to stomach and lung, is aberrantly expressed in preinvasive and invasive neoplasms of the pancreas. To investigate the significance of CLDN18 expression in biliary neoplasms, immunohistochemical analysis was performed. CLDN18 expression was frequently observed in the epithelial cells of extrahepatic bile duct carcinomas (90%, n = 99), intrahepatic intraductal papillary neoplasms of the bile duct (IPNBs, 100%, n = 11), and extrahepatic IPNBs (89%, n = 9), while it was less frequent in intrahepatic cholangiocarcinomas (ICCs, 43%, n = 83). Interestingly, CLDN18 expression was also frequently observed in precancerous lesions such as biliary intraepithelial neoplasias (78%, n = 18). Among ICCs, CLDN18-positive cases showed higher frequencies of periductal infiltrative growth, perineural invasion, and lymph node metastasis. Multivariable analysis demonstrated that positive CLDN18 expression was an independent risk factor for lymph node metastasis in ICCs. Furthermore, CLDN18 expression was associated with poor overall survival by univariable analysis, as well as lymph node metastasis. These results suggest that CLDN18 may play an important role in biliary carcinogenesis, and especially in ICCs, it is associated with aggressive behavior and serves as a useful marker for the classification of ICC. [ABSTRACT FROM AUTHOR]

We describe an unusual progression of astrocytoma into secondary glioblastoma exhibiting advanced neuronal immunophenotype. A tumor of the left frontal lobe of a 35-year-old man was diagnosed as astrocytoma. The tumor was treated by partial removal with postoperative chemoradiotherapy, followed by extensive removal of the residual regrowing tumor 5 month later. A secondary tumor was discovered and partially resected 8 years later, but the patient died 11 months following the operation due to extensive tumor progression showing subarachnoidal and intraventricular dissemination. The secondary tumor was small cell-predominant, highly proliferative tumor with an extremely high MIB-1 labeling index (80%). Unexpectedly, most of the tumor cells were positive for neuronal markers (synaptophysin and NeuN), but not for glial fibrillary acidic protein (GFAP). Retrospective examination of the original tumor revealed not only diffuse GFAP expression, but also neuronal marker expressions in small numbers of tumor cells that were hard to discriminate from the other cells on hematoxylin-eosin (HE) stain. This way of malignant progression of astrocytoma was quite unusual. Although the secondary tumor was classified as glioblastoma according to World Health Organization (WHO) classification (2000), it might be categorized into new variants of malignant glioneuronal tumors proposed recently. [ABSTRACT FROM AUTHOR]

Mixed neuronal-glial tumors of the central nervous system display a wide spectrum of differentiation. Among them, the papillary glioneuronal tumor (PGNT) is characterized by pseudopapillary structures composed of astroglial cells covering hyalinized vessels, and by neurocytic, ganglioid and ganglion cells. In addition, a “nonspecific” cell type, not similar to either astrocytes or neurocytes, has been recognized since the initial reports. Recently, minigemistocytic cells and a population immunostained by anti-Olig2 antibody have also been recognized in PGNT. Olig2 is a transcription factor that is specific for the cellular phenotype of oligodendrocytes. The aim of this study was to further investigate the histological diversity of PGNT. We examined six cases of PGNT, each of which showed Olig2 immunopositivity. Minigemistocytes were encountered in three cases at close proximity to the Olig2-positive area. Olig2-positive cells were negative for glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen by double immunostaining, and mainly occupied the interpapillary area laterally adjacent to the GFAP-positive cells. They had relatively small, round and vesicular nuclei, and were formerly regarded as neurocytic cells or nonspecific cellular elements. Fluorescence in situ hybridization targeting chromosome 1p failed to demonstrate any deletion. This study disclosed an additional cellular component of PGNT that is characterized by Olig2 positivity, suggestive of oligodendroglial phenotype, and the results also encourage us to investigate oligodendroglial participation in various glioneuronal tumors. [ABSTRACT FROM AUTHOR]

Colon perforation (CP) is still a critical complication after renal transplantation (RT), and idiopathic perforation is extremely rare. Here we describe a successfully treated case of idiopathic rectosigmoid perforation that occurred 7 years after RT. In our research this is the tenth reported case of idiopathic CP after RT and the second case that has occurred in the rectosigmoid. The patient was a 51-year-old Japanese male RT recipient still receiving immunosuppressive medication. He was admitted to the hospital for sudden onset of abdominal pain during defecation. Emergency laparotomy was performed 5 h after the onset, and a longitudinal 1.5 cm perforation with a clear margin was observed in the rectosigmoid, 8 cm above the peritoneal reflection. Hartmann’s operation was performed. Macroscopic and histological examination did not reveal any specific findings that may have caused perforation, so the case was diagnosed as idiopathic rectosigmoid perforation. [ABSTRACT FROM AUTHOR]

Metabolic disturbance of lipids is a hallmark of nonalcoholic fatty liver disease (NAFLD). In this study, we measured the serum levels of 15 acylcarnitine species of various carbon chain lengths from 2 to 18 in 241 patients with biopsy-proven NAFLD, including 23 patients with hepatocellular carcinoma (HCC), and analyzed the relationship between serum acylcarnitine profile and NAFLD status. Long-chain acylcarnitines AC14:1 and AC18:1 increased gradually with the progression of fibrosis and further increased in patients with HCC, whereas the middle-chain acylcarnitine AC5:0 exhibited the opposite trend. In particular, AC18:1, which we previously showed to possess a tumor promoting effect, was significantly elevated in patients with HCC compared to those without HCC. In addition, long-chain acylcarntines including AC18:1 were positively correlated with serum levels of inflammatory cytokines. Although none of the acylcarnitine species were independently associated with the presence of HCC, (AC16:0 + AC18:1)/AC2:0, an index for the diagnosis of carnitine palmitoyltransferase 2 (CPT2) deficiency, was independently associated with the presence of HCC after adjusting for age and liver fibrosis stage, likely reflecting the downregulation of CPT2 in HCC tissues. Thus, serum acylcarnitine profiles changed significantly according to the status of NAFLD, which may be implicated in the pathogenesis of NAFLD. [ABSTRACT FROM AUTHOR]

Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker. Endoplasmic reticulum (ER) stress has been proposed to play a role in metabolic diseases. Here, Sasako and colleagues identify stromal cell-derived factor 2 like 1 (Sdf2l1) as a regulator of the ER stress response to feeding in the liver, and suggest that its downregulation may promote diabetes and hepatic steatosis in humans. [ABSTRACT FROM AUTHOR]

Background: Long-term survival after resection of metastases from pancreatic ductal adenocarcinoma is rare.Case presentation: A 54-year-old man underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) with UICC staging pT3N1M0 followed by adjuvant chemotherapy with gemcitabine (GEM). Three years after radical resection of the primary tumor, a tiny nodule was found in the lower lobe of the left lung. Despite treatment with GEM, it increased gradually, but no other metastases were found. Eighteen months after the first indication of the nodule, wedge resection was performed. Pathological examination of the nodule indicated a metastatic tumor from PDAC. Pulmonary metastasectomy was again performed for lung oligometastases at 77 and 101 months after PD. The patient has been asymptomatic without tumor recurrence for 4 years since the last pulmonary resection.Conclusions: In PDAC, the treatment strategy for oligometastasis is controversial. However, a few cases of long-term survival after pulmonary metastasectomy for oligometastasis of PDAC have been reported. More such cases need to be studied to address this issue effectively. [ABSTRACT FROM AUTHOR]