A prospective feasibility study of one-year administration of adjuvant S-1 therapy for resected biliary tract cancer in a multi-institutional trial (Tokyo Study Group for Biliary Cancer: TOSBIC01).

BACKGROUND: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial. METHODS: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS). RESULTS: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events. CONCLUSIONS: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing. TRIAL REGISTRATION: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347.

[Complete clinical and pathological response to mFOLFOX6 neoadjuvant chemotherapy in a case of advanced rectal cancer].

The patient was a 78-year-old woman with a chief complaint of abdominal bloating and constipation who was referred to us and was examined for an AV 12-15 cm, circumferential type 2 rectal cancer. The pathological diagnosis was adenocarcinoma (tub1+tub2). T4 and N2 were suspected based on the CT findings, and because the CEA value was high, the patient was treated with 7 courses of mFOLFOX6 neoadjuvant chemotherapy followed by salvage surgery(low anterior resection+D3). Examination of the surgical specimen revealed chronic inflammatory cell infiltration, including histiocytes accompanied by ulceration, and fibrosis was observed down to SS. No viable cancer cells were detected, and the tumor response was evaluated as a pathological CR. mFOLFOX6 appeared to be effective as neoadjuvant chemotherapy for advanced rectal cancer.

Successful treatment with laparoscopic surgery and sequential multikinase inhibitor therapy for hepatocellular carcinoma: A case report.

BACKGROUND: Hepatocellular carcinoma (HCC) with massive portal vein tumor thrombosis (PVTT) and distant metastasis is considered unresectable. However, due to recent developments in systemic chemotherapy, successful cases of conversion therapy for unresectable diseases have been reported. Herein, we report a successful multidisciplinary approach for treatment of multi-visceral recurrence with sequential multikinase inhibitor and laparoscopic surgery. CASE SUMMARY: A 63-year-old woman with chronic hepatitis B virus infection was diagnosed with HCC. Subsequently, she underwent two rounds of laparoscopic partial hepatectomy, laparoscopic left adrenalectomy, and transcatheter arterial chemoembolization plus sorafenib for recurrence. Four years after initial hepatectomy, she presented with a 43-mm mass in the spleen and tumor thrombus involving the main portal vein trunk with ascites. Her liver function was Child-Pugh B (8), and protein induced by vitamin K absence or antagonist II (PIVKA II) levels were elevated up to 46.291 mAU/mL. Since initial treatment with regorafenib for three months was unsuccessful, the patient was administered lenvatinib. Ten months post-treatment, there was no contrast enhancement of PVTT or splenic metastasis. Chemotherapy was discontinued due to severe diarrhea. Afterward, splenic metastasis became viable, and PIVKA II increased. Therefore, hand-assisted laparoscopic splenectomy was performed. She experienced no clinical recurrence 14 mo after resection. CONCLUSION: Conversion surgery after successful multikinase inhibitor treatment might be considered an effective treatment option for advanced HCC.

Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease.

BACKGROUND & AIMS: We applied a metabolome profiling approach to serum samples obtained from patients with different liver diseases, to discover noninvasive and reliable biomarkers for rapid-screening diagnosis of liver diseases. METHODS: Using capillary electrophoresis and liquid chromatography mass spectrometry, we analyzed low molecular weight metabolites in a total of 248 serum samples obtained from patients with nine types of liver disease and healthy controls. RESULTS: We found that γ-glutamyl dipeptides, which were biosynthesized through a reaction with γ-glutamylcysteine synthetase, were indicative of the production of reduced glutathione, and that measurement of their levels could distinguish among different liver diseases. Multiple logistic regression models facilitated the discrimination between specific and other liver diseases and yielded high areas under receiver-operating characteristic curves. The area under the curve values in training and independent validation data were 0.952 and 0.967 in healthy controls, 0.817 and 0.849 in drug-induced liver injury, 0.754 and 0.763 in asymptomatic hepatitis B virus infection, 0.820 and 0.762 in chronic hepatitis B, 0.972 and 0.895 in hepatitis C with persistently normal alanine transaminase, 0.917 and 0.707 in chronic hepatitis C, 0.803 and 0.993 in cirrhosis type C, and 0.762 and 0.803 in hepatocellular carcinoma, respectively. Several γ-glutamyl dipeptides also manifested potential for differentiating between nonalcoholic steatohepatitis and simple steatosis. CONCLUSIONS: γ-Glutamyl dipeptides are novel biomarkers for liver diseases, and varying levels of individual or groups of these peptides have the power to discriminate among different forms of hepatic disease.

Cystathionine beta-synthase as a carbon monoxide-sensitive regulator of bile excretion.

UNLABELLED: Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine beta-synthase (CBS) that rate-limits transsulfuration pathway and H(2)S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H(2)S to stimulate HCO(3) (-)-dependent choleresis: these responses were attenuated by blocking HO or by donating H(2)S. Livers of heterozygous CBS knockout mice neither down-regulated H(2)S nor exhibited the choleresis while overproducing CO. In the mouse model of estradiol-induced cholestasis, CO overproduction by inducing HO-1 significantly improved the bile output through stimulating HCO(3) (-) excretion; such a choleretic response did not occur in the knockout mice. CONCLUSION: Results collected from metabolome analyses suggested that CBS serves as a CO-sensitive modulator of H(2)S to support biliary excretion, shedding light on a putative role of the enzyme for stress-elicited adaptive response against bile-dependent detoxification processes.

[A case showing a complete response by weekly paclitaxel associated with severe empyema and mediastinal abscess caused by reduction of a recurrent lung metastatic tumor originating from adenocarcinoma of the esophagogastric junction after primary operation].

The patient was a 57-year-old man who presented with cancer of the esophagogastric junction. He underwent total gastrectomy, lower esophagectomy, distal pancreatectomy and splenectomy with para-aortic lymphnode dissection by the transthoracoabdominal approach. He was given a daily dose of 100 mg of S-1 as adjuvant chemotherapy. About one year after the operation, lung metastasis was recognized by enhanced CT examination. He began weekly paclitaxel as second-line chemotherapy. Paclitaxel was infused once a week. About two weeks after the first infusion therapy, he was admitted to our hospital with fever and dyspnea. A chest enhanced CT revealed remarkable empyema and mediastinal abscess. Chest drainage and mediastinal drainage were performed.After one month of drainage, the empyema and mediastinal abscess had improved. The metastastic tumor of the lung disappeared at the time of discharge. CR has been maintained for more than a year without chemotherapy.This case suggests that remarkable reduction of the tumor induced by chemotherapy may have caused the empyema and mediastinal abscess.

Surgery for colloid carcinoma of the pancreas with portal vein tumor thrombus: a case report.

BACKGROUND: The portal vein is occasionally invaded by advanced malignant tumors in the pancreatic head region. However, pancreatic cancer rarely has portal vein tumor thrombi. We report a case of pancreatic cancer with a massive portal vein tumor thrombus undergoing pancreatoduodenectomy with combined resection of the portal vein. CASE PRESENTATION: A 71-year-old man visited a clinic with complaints of abdominal discomfort and vomiting. Gastroscopy showed a massive tumor in the duodenum. He was referred to our hospital for further examinations and treatment. The CT showed a low-density tumor with a maximum diameter of 10 cm located on the pancreas head. A tumor widely invaded the duodenum and had a 6-cm portal vein tumor thrombus. MRCP did not show obvious stenosis of the pancreatic duct due to tumor invasion. There were no findings suggesting distant metastases. Biopsy of the duodenum revealed adenocarcinoma. He was diagnosed with primary pancreatic cancer or duodenal cancer with portal vein tumor thrombus and underwent pancreatoduodectomy with resection and reconstruction of the portal vein. He suffered no postoperative complications and was discharged 2 months after surgery. The final histopathological diagnosis was pancreatic colloid carcinoma. He received adjuvant chemotherapy, but died 16 months after surgery. CONCLUSIONS: Colloid carcinoma of the pancreas is rare, and pancreatic carcinoma seldom forms a portal vein tumor thrombus. We experienced a very rare case of pancreatic colloid carcinoma with portal vein tumor thrombus and performed radical resection of the pancreas and portal vein.

[A Case of gastric endocrine cell carcinoma successfully treated by FU plus irinotecan(CPT-11)adjuvant therapy against recurrent metastases].

A case of gastric endocrine cell carcinoma successfully treated by FU (5-FU/UFT) +irinotecan (CPT-11) adjuvant therapy against recurrent metastases is reported with some discussion. A 69-year-old man was admitted to our hospital with severe anemia. He was diagnosed with advanced gastric cancer, T3N1H0P0M0, Stage IIIa. Total gastrectomy with pancreato-splenectomy with D2 lymph node dissection was done for curative resection. The pathological diagnosis was gastric endocrine cell carcinoma because Grimelius and Chromogranin A stained positive histologically. Seven months after operation, recurrent liver metastases with tumor embolism of the portal vein were revealed by enhanced CT examination. FU (5-FU/UFT) +CPT-11 was done as the first-line adjuvant chemotherapy. Metastatic lesion of the liver and portal vein tumor embolism was decreased. Tumor marker CA19-9 level was also decreased and within normal limits. This therapy was evaluated as a partial response (PR) in twelve months and the patient died three years and eight months after operation. Gastric endocrine cell carcinoma is known as a potentially highly malignant tumor. But in our case FU+CPT-11 controlled growth of the recurrent tumor. Based on this finding, we recommend adjuvant chemotherapy by FU+CPT-11 for gastric endocrine cell carcinoma.

Hydrogen sulfide as an endogenous modulator of biliary bicarbonate excretion in the rat liver.

Cystathionine gamma-lyase (CSE) is an enzyme catalyzing cystathionine and cysteine to yield cysteine and hydrogen sulfide (H(2)S), respectively. This study aimed to examine if H(2)S generated from the enzyme could serve as an endogenous regulator of hepatobiliary function. Gas chromatographic analyses indicated that, among rat organs herein examined, liver constituted one of the greatest components of H(2)S generation in the body, at 100 mumol/g of tissue, comparable to that in kidney and 1.5-fold greater than that in brain, where roles of the gas in the regulation of neurotransmission were reported previously. At least half of the gas amount in the liver appeared to be derived from CSE, because blockade of the enzyme by propargylglycine suppressed it by 50%. Immunohistochemistry revealed that CSE occurs not only in hepatocytes, but also in bile duct. In livers in vivo, as well as in those perfused ex vivo, treatment with the CSE inhibitor induced choleresis by stimulating the basal excretion of bicarbonate in bile samples. Transportal supplementation of NaHS at 30 mumol/L, but not that of N-acetylcysteine as a cysteine donor, abolished these changes elicited by the CSE inhibitor in the perfused liver. The changes elicited by the CSE blockade did not coincide with alterations in hepatic vascular resistance, showing little involvement of vasodilatory effects of the gas in these events, if any. These results first provided evidence that H(2)S generated through CSE modulates biliary bicarbonate excretion and is thus a determinant of bile salt-independent bile formation in the rat liver.

Endoscopic biliary drainage as a bridging procedure to single-stage surgery for perforated choledochal cyst: a case report and review of the literature.

Choledochal cyst (CC)-a congenital anomaly of the bile duct-is rare. We report a 28-year-old woman complaining of epigastralgia who was transferred to our hospital. Physical examination revealed severe tenderness to abdominal palpation without symptoms of diffuse peritonitis. Urgent contrast-enhanced abdominal computed tomography indicated the dilated common bile duct (CBD) was perforated, with a presumed diagnosis of perforated CC. Endoscopic external biliary drainage was performed immediately as a bridging procedure to the definitive surgery. Additional evaluations confirmed a type IVa CC, according to Todani's classification, but no signs of malignancy. Twenty-two days after biliary drainage, laparotomy was performed. A large cystic mass was found in the CBD with a perforated scar on the right-side wall. Because inflammation around the pancreas head was too severe to perform cyst excision safely, the patient underwent subtotal stomach-preserving pancreatoduodenectomy. The postoperative course was uneventful, and the patient was discharged on the 29th postoperative day. Pathologic examination of a specimen showed no malignancy, and the patient has remained well during the 3-year follow-up. Our experience with this case suggests that definitive single-stage surgery for perforated CC in an adult can be performed safely owing to external biliary drainage as a bridging procedure, if manifestation of diffuse peritonitis is not evident.

Hypotaurine is an Energy-Saving Hepatoprotective Compound against Ischemia-Reperfusion Injury of the Rat Liver.

Metabolome analyses assisted by capillary electrophoresis-mass spectrometry (CE-MS) have allowed us to systematically grasp changes in small molecular metabolites under disease conditions. We applied CE-MS to mine out biomarkers in hepatic ischemia-reperfusion. Rat livers were exposed to ischemia by clamping of the portal inlet followed by reperfusion. Metabolomic profiling revealed that l contents of taurine in liver and plasma were significantly increased. Of interest is an elevation of hypotaurine, collectively suggesting significance of hypotaurine/taurine in post-ischemic responses. Considering the anti-oxidative capacity of hypotaurine, we examined if supplementation of the compound or its precursor amino acids could affect hepatocellular viability and contents of taurine in liver and plasma. Administration of hypotaurine, N-acetylcysteine or methionine upon reperfusion comparablly attenuated the post-ischemic hepatocellular injury but with different metabolomic profiling among groups: rats treated with methionine or N-acetylcysteine but not those treated with hypotaurine, exhibited significant elevation of hepatic lactate generation without notable recovery of the energy charge. Furthermore, the group treated with hypotaurine exhibited elevation of the plasma taurine, suggesting that the exogenously administered compound was utilized as an antioxidant. These results suggest that taurine serves as a surrogate marker for ischemia-reperfusion indicating effectiveness of hypotaurine as an energy-saving hepatoprotective amino acid.