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.

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.

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.

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.

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.

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.

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.

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.

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.

[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.

Support adapter for radiofrequency ablation probe: experimental study.

BACKGROUND: The purpose of the present study was to experimentally evaluate a new support adapter, which was created in order to insure a more complete contact between the ablation probe and a beating heart. METHODS: Support sleeve adapters for the Cobra Cooled probe were fashioned using a semi-rigid plastic. Forty epicardial radiofrequency ablation (RFA) lesions were created on both atria under the condition of a beating heart in six pigs weighing 26-30 kg. A Cobra Cooled surgical probe was used with continuous internal irrigation of a saline solution (500 mL/h). The ablation temperature was fixed at 80 degrees C and the duration of the RFA in each case was 20, 30 and 60 s. RESULTS: A support adapter ensured a more complete epicardial contact between the probe and a beating heart. An RFA probe supported by the adapter delivered greater power to the tissue. The histopathological transmural coagulation was obtained in 82% and 72% in RFA lesions with and without the adaptor, respectively. CONCLUSION: A new adapter was effective in the epicardial RFA under the condition of a beating heart.

Ampullary carcinoma associated with protein-losing gastropathy due to diffuse varioliform gastritis.

Protein-losing gastropathy due to diffuse varioliform gastritis is a rare condition, and its occurrence accompanying ampullary carcinoma is particularly rare. We report here a case of ampullary carcinoma accompanied with protein-losing gastroenteropathy due to diffuse varioliform gastritis. A 39-year-old Japanese woman was admitted to our hospital because of general fatigue and generalized edema. Her total protein level was 3.1g/dL, with an albumin level of 1.4g/dL, and hemoglobin level of 6.9g/dL. Upper gastrointestinal endoscopic examination showed diffuse varioliform gastritis and carcinoma of the papilla of Vater. A diagnosis of protein-losing gastropathy was made based on the results of scintigraphy using technetium 99m-labeled human albumin. Continuous bleeding from ampullary carcinoma caused anemia and deteriorated hypoproteinemia. Pancreaticoduodenectomy was performed for ampullary carcinoma prior to Helicobacter pylori eradication. The tumor was a papillary adenocarcinoma, which had invaded the lamina muscularis propria over the sphincter of Oddi; the resected stomach revealed typical hyperplastic lymphocytic gastritis. H. pylori were detected on microscopic analysis. Scintigraphy after surgery showed no accumulation of the tracer in the bowel. Anemia, hypoalbuminemia and diffuse varioliform gastritis are improved 6 months after surgery and H. pylori eradication, and the patient is currently free from disease.

Alcoholic chronic pancreatitis with simultaneous multiple severe complications--extrahepatic portal obliteration, obstructive jaundice and duodenal stricture.

The major complications of chronic pancreatitis are malabsorption, diabetes mellitus, pancreatic calcification and pseudocysts. Sinistral portal hypertension due to splenic vein thrombosis, obstructive jaundice and duodenal stricture have also been reported as complications of chronic pancreatitis. However, a case having all these three complications at the same time is relatively rare. We present a case of chronic alcoholic pancreatitis complicated with simultaneous multiple severe complications. Although biliary drainage is usually a useful treatment for reducing the bilirubin level in the patients with obstructive jaundice, jaundice was hardly improved by the percutaneous transhepatic cholangio-drainage (PTCD) in this case. We discussed the cause of the failure in reducing the jaundice and reviewed the previous reports of complications of pancreatitis.

Mucosa-associated lymphoid tissue lymphoma of the extrahepatic bile duct.

Mucosa-associated lymphoid tissue lymphoma of the extrahepatic bile duct has not yet been reported. Much more common than this is secondary involvement of the extrahepatic bile duct in cases of disseminated lymphoma. A 59-year-old man manifesting jaundice was referred to our hospital. PTC revealed an extrahepatic bile duct stenosis from the hilum to the lower part of the choledochus. On the operative specimen, we examined L26/CD20, Bcl-2, UCHL-1/CD45RO, cyclin D1 and p53. Histologically, follicular colonization, centrocyte-like cells and lymphoepithelial lesion was observed. Tumor cells were positive for L26/CD20 and Bcl-2 and were negative for intracytoplasmic immunoglobulins, UCHL-1/CD45RO, cyclin D1 and p53. Pathological diagnosis was mucosa-associated lymphoid tissue lymphoma of the extrahepatic bile duct. The authors present herein the first case of mucosa-associated lymphoid tissue lymphoma of the extrahepatic bile duct. It was very difficult to distinguish from hilar cholangiocarcinoma clinically. Only incomplete stenosis of the bile duct and 18-F fluoro-2-deoxyglucose positron emission tomography (FDG-PET) could suggest this unusual clinical entity.

Epicardial radiofrequency ablation on a beating heart: an experimental study.

PURPOSE: The effect of epicardial radiofrequency ablation (RFA) during normal heart beating was experimentally studied in order to establish safe and effective procedures for RFA. METHODS: Seven pigs weighing approximately 30 to 50 kg were used in this study. Fifty-one epicardial RFA lesions were created on both atria using a Cobra Cooled probe with continuous internal irrigation of a saline solution. The ablation temperature was fixed at 80 degrees C and the duration of the RFA in each case was 20, 30, 60 and 120 seconds. RESULTS: There was significant positive correlation between the right and left atria in wall thickness. Transmural coagulation was obtained in 69% of the total specimens, which decreased according to the increase of wall thickness especially over 3 mm. Transmural coagulation was seen in 64% of the specimens after RFA of less than 30 seconds, and 86% after ablation of >or=60 seconds. Occurence of 90% or deeper coagulation was higher in the right atrium than in the left one (97% vs. 78%). Right atrial rupture occurred in a region of 1 mm in thickness after ablation of 60 seconds. CONCLUSION: Further technical improvements associated with new instruments are indispensable to complete epicardial RFA procedures on a beating heart.

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.