A case of unresectable combined hepatocellular and cholangiocarcinoma treated with atezolizumab plus bevacizumab.

An 81-year-old man initially underwent right hepatic lobectomy for liver cancer and was pathologically diagnosed with combined hepatocellular and cholangiocarcinoma (CHC). At 13 months after resection, multiple lymph node metastases were observed. We started atezolizumab plus bevacizumab (Atez/Bev), achieving a 7.5-month progression-free survival. Atez/Bev might exhibit efficacy for CHC patients.

Chronic Infection with Hepatitis C Virus Subtype 1g in a Japanese Patient Successfully Treated with Glecaprevir/Pibrentasvir.

A 66-year-old man, who had undergone plasma exchange 30 years previously in Egypt for the treatment of falciparum malaria, was referred to our hospital for treatment of chronic hepatitis C (HCV). An analysis of the 655-nucleotide 5'-untranslated region-core region sequence revealed infection with HCV subtype 1g. A phylogenetic analysis of the full-length HCV genome confirmed that the patient's HCV was subtype 1g, which was the first case identified in Japan. Although his HCV possessed several naturally occurring resistance-associated substitutions in the nonstructural (NS) 3 and NS5A regions, he was successfully treated by combination therapy with glecaprevir/pibrentasvir.

Impact of Pemafibrate in Patients with Hypertriglyceridemia and Metabolic Dysfunction-associated Fatty Liver Disease Pathologically Diagnosed with Non-alcoholic Steatohepatitis: A Retrospective, Single-arm Study.

Objective The therapeutic effect of pemafibrate on metabolic dysfunction-associated fatty liver disease (MAFLD) remains unknown. This retrospective, single-arm study investigated the efficacy and safety of pemafibrate in MAFLD patients with hypertriglyceridemia. Methods A total of 10 patients who received pemafibrate (oral, 0.1 mg, twice a day) at Gunma Saiseikai Maebashi Hospital between September 2018 and September 2019 were included. All patients underwent a liver biopsy, and the disease grade and stage were pathologically assessed based on the FLIP algorithm. Results The median age was 66.0 (53.8-74.8) years old, and 5 patients (50.0%) were men. All patients were diagnosed with non-alcoholic steatohepatitis (NASH). The fasting and non-fasting triglyceride (TG) levels were 175 (149-247) mg/dL and 228 (169-335) mg/dL, respectively. The AST and ALT values at 6 months were significantly lower than at baseline [AST: 28.0 (22.0-33.8) U/L vs. 43.5 (24.0-55.0) U/L, p=0.008, ALT: 23.0 (14.8-26.5) U/L vs. 51.5 (23.0-65.3) U/L, p=0.005, respectively], especially in NASH patients with significant activity and advanced fibrosis (p=0.040 and 0.014, respectively). Fasting TG levels were significantly lower and HDL-C levels significantly higher at 6 months than at baseline (p=0.005 and 0.032, respectively). At six months, FIB-4, the aspartate aminotransferase-to-platelet ratio index, and the macrophage galactose-specific lectin-2 binding protein glycosylation isomer level were significantly improved compared with baseline (p=0.041, 0.005 and 0.005, respectively). Treatment-related adverse events were not observed. Conclusion Pemafibrate treatment may be safe and effective for MAFLD patients with hypertriglyceridemia.

Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma.

Patients with extrahepatic cholangiocarcinoma (EHCC) have a poor prognosis; postoperative survival depends on cancer progression and therapeutic resistance. The mechanism of EHCC progression needs to be clarified to identify ways to improve disease prognosis. Stathmin1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes and chemoresistance in various cancers. Recently, STMN1 was reported to interact with p27, an inhibitor of cyclin-dependent kinase complexes. Eighty EHCC cases were studied using immunohistochemistry and clinical pathology to determine the correlation between STMN1 and p27 expression; RNA interference to analyze the function of STMN1 in an EHCC cell line was also used. Cytoplasmic STMN1 expression correlated with venous invasion (P = 0.0021) and nuclear p27 underexpression (P = 0.0011). Patients in the high-STMN1-expression group were associated with shorter recurrence-free survival and overall survival than those in the low-expression group. An in vitro protein-binding assay revealed that cytoplasmic STMN1 bound to p27 in the cytoplasm, but not in the nucleus of EHCC cells. Moreover, p27 accumulated in EHCC cells after STMN1 suppression. STMN1 knockdown inhibited proliferation and increased the sensitivity of EHCC cells to paclitaxel. STMN1 contributes to a poor prognosis and cancer progression in EHCC patients. Understanding the regulation of p27 by STMN1 could provide new insights for overcoming therapeutic resistance in EHCC.

Forkhead box protein C2 contributes to invasion and metastasis of extrahepatic cholangiocarcinoma, resulting in a poor prognosis.

Extrahepatic cholangiocarcinoma (EHCC) is a cancer with a poor prognosis, and the postoperative survival of patients depends on the existence of invasion and metastasis. The epithelial-to-mesenchymal transition (EMT) is an important step in EHCC invasion and metastasis. Forkhead box protein C2 (FOXC2) is a transcription factor that has been reported to induce the EMT. Therefore we examined the correlation between FOXC2 expression and clinical pathological factors, and analysed the function of FOXC2. The expression of FOXC2 in 77 EHCC cases was investigated by immunohistochemical staining, and the relationship between FOXC2 expression and clinicopathological factor was assessed. Knockdown by small interfering RNA (siRNA) was performed to determine the roles of FOXC2 in EHCC cell line. FOXC2 expression correlated with lymph node metastasis (P = 0.0205). Patients in the high FOXC2 expression group had a poorer prognosis than the patients in the low FOXC2 expression group. Moreover, FOXC2 knockdown inhibited cell motility and invasion, and decreased the expression of EMT markers (N-cadherin, and matrix metalloproteinase (MMP) -2) and Angiopietin-2 (Ang-2). The EMT inducer FOXC2 contributes to a poor prognosis and cancer progression. FOXC2 may be a promising molecular target for regulating EHCC metastasis.

Mixed ductal-endocrine carcinoma of the pancreas occurring as a double cancer: report of a case.

We present a successfully treated case of mixed ductal-endocrine carcinoma of the pancreas complicated by right renal cell carcinoma. The patient had no symptoms, and laboratory data were close to the normal range. Enhanced computed tomography demonstrated a marked enhanced tumor, which appeared to be an endocrine tumor, at the pancreas uncus. We performed pyrolus-preserving pancreaticoduodenectomy, regional lymph node resection, and right nephrectomy. Histologically and immunohistochemically, the pancreas tumor had both a ductal (exocrine) and an endocrine component. The renal tumor was a typical clear cell carcinoma. A diagnosis of synchronous double cancer was made. As demonstrated in previously published reports, this type of mixed tumor has malignant potential for invasive ductal carcinoma. We propose that mixed ductal-endocrine carcinoma of the pancreas should be treated by surgical resection with a sufficient surgical margin and regional lymph node resection to improve the patient's prognosis.

An individual with gastric schwannoma with pathologically malignant potential surviving two years after laparoscopy-assisted partial gastrectomy.

Schwannomas are a kind of neurogenic tumor. They are generally benign and originate primarily from the central and peripheral nerve. They rarely develop in the gastrointestinal tract: gastric schwannomas make up 0.2% of gastric neoplasms. A malignant gastric schwannoma is a comparatively rare tumor, a few cases have been reported until now. We present the case of a 34-year-old male patient diagnosed during medical examination. The patient was treated with surgical resection, and 2 years passed without recurrence.

Novel large-scale deletion (whole exon 7) in the ABCC2 gene in a patient with the Dubin-Johnson syndrome.

The Dubin-Johnson syndrome (DJS) is an inherited liver disorder characterized by conjugated hyperbilirubinemia and caused by ABCC2 gene mutations resulting in deficiency of multidrug resistance associated-protein 2 (MRP2) function. A 76-year-old woman with serious jaundice was referred to our hospital. She was clinically diagnosed with DJS with hepatic congestion, due to constrictive pericarditis. We analyzed all exons and exon-intron junctions of the ABCC2 gene by DNA sequencing and identified a new large-scale deletion, 1008 bp, including the whole exon 7, as homozygosity. Some mutations in the ABCC2 gene associated with splicing errors have been reported in intronic regions; however, this is a new type of large-scale deletion detectable in the genomic DNA sequence. Severe hyperbilirubinemia is rare in patients with constrictive pericarditis and this case suggests that MRP2 may play a crucial role in compensating for the serum bilirubin in congestive hepatopathy.

Esophageal granular cell tumor covered by intramucosal squamous cell carcinoma: report of a case.

We report a case of a granular cell tumor (GCT) covered by squamous cell carcinoma (SCC) in the esophagus. A 69-year-old Japanese man was admitted to our hospital for treatment of superficial esophageal cancer detected by upper gastrointestinal endoscopy. Endoscopic examination revealed a shallow ulcer in the esophagus, 28-32 cm from the incisor teeth. The pathological findings of a biopsy of the lesion were moderately differentiated SCC. Thus, we performed partial esophagectomy with two-field (thoraco-abdominal) lymph node dissection. Microscopic examination of the surgical specimen revealed intraepithelial SCC with minimal invasion, and a GCT, 3 x 1 mm in size, in the submucosa just beneath the SCC. Cytoplasmic granules in the GCT were positive for periodic acid-Schiff. Immunohistochemically, the GCT was strongly positive for S-100 protein. To our knowledge, this is the first published report of a GCT covered by SCC in the esophagus.

Lymphoplasmacytic infiltrate of regional lymph nodes in Kuttner's tumor (chronic sclerosing sialadenitis): a report of 3 cases.

Regional lymph nodes of Küttner's tumor from 3 patients showed reactive follicular hyperplasia and prominent interfollicular plasmacytosis. The patients were 71-, 57-, and 73-year-old Japanese men. The polytypic nature of plasma cells was demonstrated by immunohistochemistry. There were numerous IgG-positive plasma cells with scattered IgA-positive or IgM-positive plasma cells. IgG4-positive cells comprised 25% to 40% of IgG-positive plasma cells. Prominent polyclonal hyperimmunoglobulinemia was demonstrated on laboratory test in 2 cases examined. An elevated serum IgG4 level (16%) was also demonstrated in 1 patient. The present 3 cases indicated that regional lymph node of Küttner's tumor may show reactive follicular hyperplasia and prominent interfollicular plasmacytosis and should be differentiated from various benign and malignant lymphoproliferative disorders including systemic rheumatic disease, plasma cell type of Castleman disease, and lymph node involvement of marginal B-cell lymphoma of the mucosa-associated lymphoid tissue type showing prominent plasma cell differentiation.

Thymoma with ganglioneuroblastomatous component: case report.

A mediastinal tumor in a 49-year-old woman with myasthenia gravis is reported. The tumor was well-demarcated and located in the supero-anterior mediastinum. Microscopically, the tumor consisted of thymic and neuroblastic tumor components, the latter of which consisted of immature and maturing neuronal cells, abundant neuropils, and Schwannian stroma. The two components intermingled with each other inside the tumor capsule. The tumor was diagnosed as thymoma with a ganglioneuroblastomatous component. The coexistence of epithelial and neuronal tissues in the thymic neoplasm is extremely rare.

Small-cell carcinoma of the extrahepatic bile duct: a case report and review of the literature.

A small-cell carcinoma of the extrahepatic bile duct in a 69-year-old woman is herein reported. A tumor measuring approximately 3 cm in diameter was located at the confluence of the common bile duct, cystic duct, and common hepatic duct. Histopathologically, the tumor was small-cell neuroendocrine carcinoma without any gland formation or differentiation to squamous cell carcinoma. Tumor cells were immunoreactive for epithelial markers such as epithelial membrane antigen and cytokeratin and for the neuroendocrine markers such as neuron-specific enolase, chromogranin A, and synaptophysin. Although the carcinomas in more than half of the reported cases have been reported to be associated with well-to-moderately differentiated squamous or glandular components, seven cases, including our case, showed the carcinomas without squamous or glandular components. According to the review of 16 previously reported cases and our case of small-cell carcinoma of the extrahepatic bile ducts, there is no significant difference in the clinicopathological findings, namely, age, sex, site of carcinoma, and prognosis between the cases with or without squamous or glandular components. No CD34-positive multipotent adult progenitor cells, which might be the origin of the small-cell carcinoma, were detected in the bile duct epithelium in our case.

Up-regulation of a BCL9-related beta-catenin-binding protein, B9L, in different stages of sporadic colorectal adenoma.

Aberrant activation of Wnt signaling is a critical event in the development of human colorectal tumors. The aim of this study was to elucidate the role of B9L and its association with beta-catenin in each stage of the adenoma-carcinoma sequence of human colorectal tumorigenesis. We investigated the expression levels of B9L in sporadic colorectal adenomas and carcinomas, categorized according to the Vienna classification, using real-time quantitative polymerase chain reaction (RTQ-PCR) and immunohistochemical analysis. B9L was expressed in the nuclei of non-neoplastic colonic mucosa cells and was overexpressed in the nuclei of neoplasias and invasive carcinoma cells. Immunoreactivity to B9L protein was correlated with the progressive grades of colorectal neoplasias, as was the expression of B9L mRNA. A high level of immunoreactivity to nuclear B9L was present in 27% of low-grade neoplasias and in more than 50% of high-grade neoplasias and invasive carcinomas, whereas a high level of nuclear B9L immunoreactivity was not observed in any of the non-neoplastic mucosa samples. The expression of B9L was dramatically increased in low-grade neoplasias compared with that in non-neoplastic mucosa. B9L may play an important role in tumorigenesis induced by aberrant activation of Wnt signaling and may act as a key protein in the progressive dysplasia of adenoma.

Preoperative tegafur suppositories for resectable rectal cancer: phase II trial.

PURPOSE: Preoperative radiochemotherapy for rectal cancer causes a high rate of moderate-to-severe toxicities and is associated with only moderate survival benefits. A simpler, safer, and more convenient treatment would be preferable. Preoperative tegafur suppositories (1,500 mg/day) for at least 14 days were piloted. METHODS: A total of 129 patients with resectable rectal cancer were enrolled. The primary end points were pathologic response, adverse events, rate of sphincter-sparing surgery, recurrence, and survival. RESULTS: The total dose of tegafur ranged from 21 to 78 (mean, 32) g. The anal sphincter was preserved in 60.5 percent with microscopic no residual tumor (R0). The overall morbidity rate was 32 percent. Wound infection occurred in 13.2 percent of cases and anastomotic leakage in 9 percent of cases. Pathologic responses were observed in 70 percent of patients, with a complete necrosis occurring in 3.9 percent, two-thirds or more necrosis in 6.2 percent, one-third or more but less than two-thirds necrosis in 18.6 percent, and less than one-third necrosis in 41.9 percent. The mean total dose that patients showing complete or two-thirds or more necrosis received was 42.8 +/- 6.4 g (P = 0.01) compared with 31.6 +/- 1.2 g administered to patients showing less than two-thirds necrosis. Adverse events were observed in 15.6 percent of patients overall, and Grade III or IV events were observed in 2.3 percent of patients. During a median follow-up of 48 months, distant metastasis occurred in 14.7 percent of patients and local recurrence occurred in 6.2 percent of patients. The four-year, disease-free and overall survival rates were 67.6 and 80.1 percent, respectively. CONCLUSIONS: Preoperative tegafur suppositories are associated with low toxicity and may lead to anal sphincter-sparing surgery with acceptable postoperative complications and favorable local and distal control.

Immunohistochemical expression of 14-3-3 sigma protein in intraductal papillary-mucinous tumor and invasive ductal carcinoma of the pancreas.

BACKGROUND: 14-3-3 sigma (sigma) has been shown to be overexpressed in pancreatic cancers by a c-DNA microarray technique. However, the expression of 14-3-3 sigma in intraductal papillary-mucinous tumor (IPMT) of the pancreas remains unclear. MATERIALS AND METHODS: To evaluate the biological importance of 14-3-3 sigma expression in pancreatic carcinogenesis, immunohistochemistry for 14-3-3 sigma, CDX2, MUC1, MUC2, p53, p16 and Ki-67 was carried out on 33 IPMTs and the results were compared with those for 14 invasive ductal carcinomas (IDCs). RESULTS: The frequency of 14-3-3 sigma immunoreactivity was 70% and 100% in IPMT and IDC, respectively. The frequency of MUCI and Ki-67 immunoreactivity was significantly higher in IDC than IPMT. In IPMT, dark columnar cell types prevailed over clear columnar cell types in terms of the frequency of the Ki-67 labeling index. CONCLUSION: The overexpression of 14-3-3 sigma was confirmed in both IDC and IPMT. Therefore, this overexpression might occur in the early stages of pancreatic carcinogenesis. Moreover, IPMT composed of dark columnar cells might be a potentially more advanced form than that made up of clear columnar cells.

Methtrexate-associated lymphoproliferative disorders. A clinicopathological study of 13 Japanese cases.

We conducted clinicopathological and immunohistochemical analyses to investigate the prevalence of Epstein-Barr virus (EBV) among 13 cases with methotrexate (MTX)-associated lymphoproliferative disorder (LPD). The subjects of this study were four men and nine women ranging in age from 53 to 78 years (mean: 63 years). All 13 patients had received low dose MTX therapy for 1-13 years before the onset of LPD (mean: 5.8 years). LPDs were found at extranodal sites in six cases, and the disease stage was advanced in seven cases. The present study confirmed certain aspects of a previous observation made in the USA, including the following findings (i) the cases commonly showed diffuse large B-cell lymphomas (n=4) and Hodgkin lymphomas (HL) (n=3), (ii) EBV-encoded small RNA (EBER) + cells were identified in seven cases (60%), which is a much higher percentage than would be expected in lymphomas occurring in a general population, and (iii) three cases of polymorphous small lymphocytic or lymphoplasmacytic infiltrate achieved spontaneous remission of LPDs after MTX withdrawal. Of seven cases of EBER + in our series, three cases were PSLLPI, and two were HL. EBER + tumor cells were detected in only two (30%) of the seven cases with non-Hodgkin lymphomas. The present study suggests that EBV- associated non-Hodgkin lymphomas comprise only a portion of all non-Hodgkin lymphomas among MTX-associated LPDs.

Xanthogranulomatous cholangitis causing obstructive jaundice: a case report.

This article reports the case of a 34-year-old woman with xanthogranulomatous cholangitis who developed obstructive jaundice. Microscopically, the bile duct was surrounded and narrowed by a xanthogranulomatous lesion, but no xanthogranulomatous cholecystitis was seen. Although percutaneous cholangiograms done via the transhepatic biliary drainage showed smooth narrowing of the upper to middle bile duct, the cytology of bile was diagnosed as class V adenocarcinoma. Therefore, right extended hepatectomy and extrahepatic bile duct resection were performed. The differentiation of benign and malignant strictures at the hepatic hilum is often difficult. Xanthogranulomatous cholangitis is one possible diagnosis of a bile duct stricture. Precise review of all the preoperative information is required to make a correct diagnosis.

Spontaneous regression of hepatic inflammatory pseudotumor with primary biliary cirrhosis: case report and literature review.

Hepatic inflammatory pseudotumor (IPT) is a rare benign non-neoplastic lesion characterized by proliferating fibrous tissue infiltrated by inflammatory cells. The exact etiology of IPT remains unclear. Although the association of IPT with systemic inflammatory disorders has been well established, a specific relationship with cholangitis is distinctly rare. We report a case of spontaneous regression of hepatic IPT with primary biliary cirrhosis (PBC). To date, only two cases of IPT with PBC have been reported. In our case, however, IPT developed during the course of improvement of cholangitis of PBC induced by effective treatment, differing from two previously reported cases. Our case indicates that the development of IPT does not also relate to the activity of cholangitis and/or hyper gamma-globulinemia, since our case was confirmed radiologically to be free of IPT when biliary enzymes and immunoglobulins were much higher than the corresponding values on admission. Comparison of our case with the two previously reported cases suggests that IPT occurring with PBC does not represent the same disease entity or be a bystander for PBC.

[A recurrent endocrine cell cancer of the stomach showing almost complete remission after chemotherapy for 1 year].

We report a recurrent case of gastric endocrine cell cancer that showed a remarkable response to systemic chemotherapy. A 70-year-old male who underwent gastroscopy at our hospital showed a 0-IIa-like lesion, but no abnormal CT findings. He was diagnosed with gastric cancer, and underwent a proximal gastrectomy. The resected specimen showed endocrine cell cancer. The tumor was Grimelius-positive histologically and chromogranin A-and NSE-positive immunohistochemically. About 2 years after surgery, liver, lymph node, and bone metastases were detected. Systemic chemotherapy with TS-1 and CDDP was started, and the lesions progressed. Then, by approximately 1 year after CDDP and CPT-11 treatments, the recurrent lesions had diminished remarkably and were no longer seen on CT or FDG-PET.