Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. PATIENTS AND METHODS: From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety. RESULTS: Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001). CONCLUSIONS: Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Randomized clinical trial of external stent drainage of the pancreatic duct to reduce postoperative pancreatic fistula after pancreaticojejunostomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains one of the most common causes of morbidity following pancreaticoduodenectomy (PD). This randomized trial examined whether external stent drainage of the pancreatic duct decreases the rate of POPF after PD and subsequent pancreaticojejunostomy (PJ). METHODS: Consecutive patients who underwent PD with subsequent construction of a duct-to-mucosa PJ were randomized into a stented and a non-stented group. The primary outcome was the incidence of clinically relevant POPF. Secondary outcomes were morbidity and mortality rates, and hospital stay. RESULTS: Of 114 PD procedures, 93 were suitable for inclusion in the study after informed consent. The rate of clinically relevant POPF was significantly lower in the stented group than in the non-stented group: three of 47 (6 per cent) versus ten of 46 (22 per cent) (P = 0·040). Among patients with a dilated duct, rates of POPF were similar in both groups. Among patients with a non-dilated duct, clinically relevant POPF was significantly less common in the stented group than in the non-stented group: two of 21 (10 per cent) versus eight of 20 (40 per cent) (P = 0·033). No significant differences in morbidity or mortality were observed. Univariable analysis identified body mass index (BMI), pancreatic cancer,pancreatic texture, pancreatic duct size and duct stenting as risk factors related to clinically relevant POPF. Multivariable analysis taking these five factors into account identified high BMI (risk ratio(RR) 11·45; P = 0·008), non-dilated duct (RR 5·33; P = 0·046) and no stent (RR 10·38; P = 0·004) as significant risk factors. CONCLUSION: External duct stenting reduced the risk of clinically relevant POPF after PD and subsequent duct-to-mucosa PJ.

p53 Homologue p63 represses epidermal growth factor receptor expression.

Tumor suppressor p53 has been shown to transactivate epidermal growth factor receptor (EGFR) expression through binding to a putative p53 responsive element in the EGFR promoter between nucleotides -265 and -239 (EGFRp53RE). Isotypes of p63 gene products, recently identified as p53 relatives, have a similar function to transactivate several p53 target gene promoters. However, our results indicate that TAp63gamma has a very low ability to bind to the EGFRp53RE and surprisingly represses both basal EGFR promoter activity and endogenous EGFR expression. Transient transfection assays show that the EGFR promoter region between -348 and -293, containing two Sp1 sites, is crucial for the repression of the EGFR expression by TAp63gamma. Mutations in these Sp1 sites in the reporter constructs result in loss of the TAp63gamma repression effect. We further show that TAp63gamma directly interacts with Sp1 by immunoprecipitation analysis and that TAp63gamma impairs Sp1 binding to the target DNA site in electrophoretic mobility shift assays. These results suggest that TAp63gamma is involved in the regulation of the EGFR gene expression through interactions with basal transcription factors.

[Possible inhibitory mechanism of liver regeneration through non-parenchymal cells after combined hepatectomy and pancreatectomy].

BACKGROUND: Recently, simultaneous hepatectomy (Hx) and pancreaticoduodenectomy have been performed in the treatment of biliary tract cancer. Postoperative hepatic failure is a common and potentially fatal complication. The aim of this study was to examine the reduced rate of liver regeneration after 70% Hx alone or in combination with 70% pancreatectomy (HPx). MATERIALS AND METHODS: Male Sprague-Dawley rats underwent Hx or combined Hx and Px. The ratio of liver-body weight, labeling index of hepatocytes in vivo, and DNA synthesis of hepatocytes and/or Kupffer cells in primary culture were analyzed. RESULTS: The ratio of liver-body weight in HPx rats was found to be significantly lower than that in Hx rats from 12 hours to 72 hours after surgery. There was no difference in blood glucose or ALT levels between the two groups. An inhibitory effect on DNA synthesis was observed in cocultured hepatocytes and Kupffer cells when portal plasma obtained one hour after surgery was added. We further observed that conditioned medium of Kupffer cells stimulated by portal plasma obtained one hour after HPx inhibited DNA synthesis by hepatocytes. This effect was abolished after incubation at 56 degrees C for 30 min. CONCLUSIONS: These results clearly indicate the existence of a growth inhibitory factor in portal serum after HPx. This heat-labile growth inhibitory factor was released from Kupffer cells stimulated by portal plasma after HPx and appears to act on hepatocytes in a paracrine manner.

Interleukin-10 induction after combined resection of liver and pancreas.

BACKGROUND/AIMS: Recently in Japan, combined resection of liver and pancreas is being performed in cases of advanced biliary neoplasms. As we previously reported, in the rat model of combined resection of the liver and pancreas, the potential for liver regeneration after this operation was decreased compared to that after hepatectomy only. Moreover, non-parenchymal cells play an important role in the production of inhibitory factors for liver regeneration. The anti-inflammatory cytokine IL-10, downregulates the release of TNF-alpha, and affects the progressive regeneration of the hepatic parenchyma. To investigate the role of IL-10 and TNF-alpha in hepatic regeneration in the rat, we measured the levels of IL-10 and TNF-alpha in the conditioned medium of non-parenchymal cells stimulated with portal plasma. We also investigated the concentration of IL-10 and TNF-alpha in the portal plasma after combined resection of the liver and pancreas. METHODOLOGY: Adult male Sprague-Dawley rats were used. Rats were divided into 3 groups: group I underwent 70% partial hepatectomy only (Hx), group II underwent 70% partial pancreatectomy only (Px) and in group III both procedures were used, Hx plus Px (HPx). Portal plasma was harvested at 1, 3, 6, 12 and 24 hours after surgery and was used to stimulate the culture medium of non-parenchymal cells. Cytokine concentrations in the plasma and in the conditioned medium were measured by ELISA. Northern blot analysis for IL-10 mRNA was performed on liver, pancreas, kidney, lung and spleen at 1, 3 and 6 hours after surgery. RESULTS: The level of IL-10 released by non-parenchymal cells stimulated with HPx portal plasma was 154.1 +/- 20.3 pg/mL and significantly higher than when stimulated with Hx portal plasma, which was 100.1 +/- 6.4 pg/mL (P < 0.05) during the first hour. Also, the level of TNF-alpha released by Kupffer cells stimulated with HPx portal plasma was 86.6 +/- 13.4 pg/mL, significantly less than when stimulated with Hx portal plasma, which was 138.7 +/- 15.1 pg/mL (P < 0.005) during the first hour. Furthermore, the plasma levels of IL-10 in the HPx group remained significantly higher than those of the other groups from 6 hours up to 12 hours. In northern blot analyses, higher IL-10 mRNA expression were detected in the spleen and moderately high levels in the liver at 1 and 3 hours after HPx, in contrast to those after Hx. CONCLUSIONS: IL-10 expression is induced in the spleen and liver remnant just after HPx. IL-10 released by the spleen and liver might downregulate TNF-alpha production, thereby inhibiting the liver regeneration.

Inhibition of glioma cells in vitro and in vivo using a recombinant adenoviral vector containing an astrocyte-specific promoter.

Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene in combination with the drug ganciclovir (GCV) is a promising approach for the treatment of cancer-inducing gliomas, a tumor with a poor prognosis. In an attempt to limit the toxic effects on normal tissues, we constructed a recombinant adenoviral vector, Adgfa2TK, in which the HSV-TK gene is driven by the promoter for the gene encoding glial fibrillary acidic protein, an intermediate filament protein expressed primarily in astrocytes. Infection by Adgfa2TK of a glial cell line (C6) and a non-glial cell line (MDA-MB-231) revealed markedly increased expression of HSV-TK in glial cells as determined by Western blot. In comparison, high HSV-TK protein levels were produced in both cell lines after infection with a control virus, AdCMVTK, in which the constitutive cytomegalovirus viral promoter was used to direct HSV-TK expression. Infection of two glial cell lines (C6, U251) and two non-glial cell lines (HepG2, MDA-MB-231) with Adgfa2TK followed by GCV treatment revealed high toxicity in glial cell lines (50% growth inhibitory concentration: <2 microg/mL of GCV) with little or no toxicity (50% growth inhibitory concentration: >75 microg/mL) in the non-glial cell lines. In vivo, injection of Adgfa2TK into C6 tumors grown in nude mice followed by intraperitoneal GCV treatment significantly repressed tumor growth compared with the controls. Adgfa2TK may be useful for directing expression of the HSV-TK gene to gliomas.

Laparoscopic cholecystectomy, Calot's triangle, and variations in cystic arterial supply.

BACKGROUND: The extrahepatic biliary tree with the exact anatomic features of the arterial supply observed by laparoscopic means has not been described heretofore. Iatrogenic injuries of the extrahepatic biliary tree and neighboring blood vessels are not rare. Accidents involving vessels or the common bile duct during laparoscopic cholecystectomy, with or without choledocotomy, can be avoided by careful dissection of Calot's triangle and the hepatoduodenal ligament. METHODS: We performed 244 laparoscopic cholecystectomies over a 2-year period between January 1, 1995 and January 1, 1997. RESULTS: In 187 of 244 consecutive cases (76.6%), we found a typical arterial supply anteromedial to the cystic duct, near the sentinel cystic lymph node. In the other cases, there was an atypical arterial supply, and 27 of these cases (11.1%) had no cystic artery in Calot's triangle. A typical blood supply and accessory arteries were observed in 18 cases (7.4%). CONCLUSION: Young surgeons who are not yet familiar with the handling of an anatomically abnormal cystic blood supply need to be more aware of the precise anatomy of the extrahepatic biliary tree.

Kupffer cell-mediated inhibition of liver regeneration after combined hepatectomy and pancreatectomy.

Recently, simultaneous hepatectomy and pancreatoduodenectomy has been performed for the treatment of some biliary tract cancers in Japan. Postoperative hepatic failure is a common and potentially fatal complication. The aim of this study was to examine the reduction in the rate of liver regeneration after 70% hepatectomy (Hx) alone or in combination with 70% pancreatectomy (HPx). Male Sprague-Dawley rats underwent hepatectomy or simultaneous hepatectomy and pancreatectomy. The ratio of liver weight to body weight, the labeling index of hepatocytes in vivo, and DNA synthesis of the hepatocytes and/or Kupffer cells in primary culture were analyzed. The ratio of liver weight to body weight and the labeling index in HPx rat were found to be significantly lower than those values in Hx rats. There were no significant differences in plasma alanine aminotransferase levels between the two groups. The inhibitory effect on DNA synthesis was observed with coculture of hepatocytes and Kupffer cells when the portal plasma obtained 1 hour after operation was added. We further observed that the conditioned medium of Kupffer cells stimulated by the addition of the portal plasma that was obtained 1 hour after HPx inhibited DNA synthesis of hepatocytes. This effect was abolished after incubation at 56 degrees C for 30 minutes. These results strongly suggest the existence of a growth inhibitory factor in portal plasma after HPx. This heat-labile growth inhibitory factor was released from Kupffer cells and would appear to act on hepatocytes in a paracrine manner.

Simplified hepatic resection utilizing absorbable polyglycolic acid-based tape and other ligature apparatus.

Hepatic resection has been increasing in frequency in the management of metastatic or primary neoplasms of the liver. Although mortality for this procedure has steadily decreased, the associated morbidity remains high. Morbidity is mainly associated with operative time and blood loss, especially in jaundiced and cirrhotic patients. During hepatic resection, control of bleeding from various sources is the most important problem faced by surgeons. During conventional lobectomy, despite prior control of hepatic artery and portal vein to that lobe, bleeding still occurs from the opposite lobe or back flow from hepatic veins. We usually apply Pringle's maneuver for hemostasis, but consequently there is postoperative hepatic dysfunction. We have previously investigated methods for vascular occlusion at the site of liver resection. We developed a new absorbable polyglycolic acid-based tape (breadth, 3 mm; length, 70 cm) for use in hepatic mass ligation, as well as two types of ligature apparatus. Hemostasis was achieved with these devices, and all lobar, segmental, and non-anatomic resections were performed without prior control of the portal venous system, hepatic arterial inflow, and hepatic venous outflow before parenchymal resection. This significantly shortened the operative time, as well as decreasing the blood loss during hepatic resection, with consequent reduction of postoperative morbidity. The use of this absorbable tape may reduce the incidence of local infection, abscess formation, and septicemia.

[An anaphylactic shock case after hepatic arterial infusion of zinostatin stimalamer suspension improved by anti-histaminics].

A 47-year-old man with hepatocellular carcinoma (HCC) at anterior and medical segment in the liver was treated with hepatic arterial infusion of Zinostatin Stimalamer-lipiodol suspension (SMANCS). After the 2nd infusion of SMANCS, the accumulation of lipiodol in the tumor was not good (Grade II), so additional administration was undertaken at five-weeks intervals. His systolic blood pressure immediately decreased from 120 to 60 mmHg, and he had numbness of hands, shaking chills, sweating, chest pain and numerous urticaria-like red exanthema. In spite of treatment by anti-shock agents such as steroid and catecholamines, these symptoms did not disappear, but antihistaminics greatly improved them without any serious side effects. Because of the remarkable effects of the antihistaminics and possibility of antibody production (IgE) after repeated infusions of high molecular SMANCS, this patient may have suffered anaphylactic shock caused by massive histamine release from mast cells.

[Bacteriological and clinical evaluation tazobactam/piperacillin in infectious diseases in surgical field].

We carried out bacteriological and clinical studies on tazobactam/piperacillin (TAZ/PIPC), a combination drug of piperacillin with the new beta-lactamase inhibitor tazobactam, in various infectious diseases in surgical field such as intra-abdominal infections (peritonitis and intra-abdominal abscess), hepatobiliary infections (cholecystitis, cholangitis and hepatic abscess) and secondary infections in wound, etc. The total number of cases treated with the combination drug was 164. Of these cases, 141 cases were assessable for clinical responses including 60 cases with intra-abdominal infections, 38 cases with hepatobiliary infections, and 43 cases with secondary infections. Clinical efficacy rates of the drug were 83.3% in cases with intra-abdominal infections, 86.8% in cases with hepatobiliary infections, and 95.3% in those with secondary infections, hence the overall efficacy rate was 87.9%. In the cases from which beta-lactamase producing strains were isolated, clinical efficacy rates were 84.8% in cases with intra-abdominal infections, 84.6% in those with hepatobiliary infections, and 96.2% in those with secondary infections, hence the overall efficacy rate was 88.9%. Bacteriological efficacy rates were 92.9% in cases with Gram-positive bacterial infections, 64.3% in those with Gram-negative bacterial infections, and 100% in those with anaerobic bacterial infections. Bacteriological efficacy rates were 84.2% in cases with single bacterial infections and 56.5% in those with multi-bacterial infections, and the overall bacteriological efficacy rate was 69.0%. In the cases of infections with beta-lactamase producing strains, bacteriological efficacy rates were 80.0% in cases with Gram-positive bacterial infections, 75.0% in those with Gram-negative bacterial infections, and 100% in those with anaerobic bacterial infections. They were 82.6% in cases with single bacterial infections and 57.9% in those with multi-bacterial infections; the overall bacteriological efficacy rate was 67.2%. The bacterial eradication rate was 79.9% against all the isolates, and it was 79.2% against beta-lactamase producing isolates. In addition, we compared the sensitivity distribution of the isolates to TAZ/PIPC with those to control drugs piperacillin (PIPC), cefotiam (CTM), ceftazidime (CAZ), sulbactam/cefoperazone (SBT/CPZ). The MIC50 and MIC90 values of TAZ/PIPC against all strains were 3.13 micrograms/ml and 50 micrograms/ml, respectively. MIC50 values show that TAZ/PIPC was two times less effective than CAZ and SBT/CPZ but four times more effective than CTM; furthermore, from the MIC90 values, TAZ/PIPC was four times more effective than PIPC, CTM and CAZ. The MIC50 and MIC90 values of TAZ/PIPC against beta-lactamase producing strains were 3.13 micrograms/ml and 50 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)