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Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m 2 intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9–9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9–10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786–1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. Pfizer.

Pancreatic cancer is one of the most lethal malignancies. Epidermal growth factor receptor (EGFR), HER3, Akt, and amphiregulin have been recognized as targets for pancreatic cancer therapy. Although gemcitabine + erlotinib has been the recommended chemotherapy for pancreatic cancer, the prognosis is extremely poor. The development of molecularly targeted therapies has been required for patients with pancreatic cancer. To assess the validation of amphiregulin as a target for pancreatic cancer therapy, we examined its expression in pancreatic cancer using real‐time PCR analyses and ELISA. We also measured the apoptotic cell rate using TUNEL assays. In addition, alterations in signaling pathways were detected by immunoblotting analyses. Treatment with gemcitabine, which reduced the cell viability and augmented the cell apoptotic rate, activated and subsequently attenuated ERK and EGFR signals. However, gemcitabine, paclitaxel, or cisplatin treatment enhanced the Akt activation, heterodimer formation of EGFR with HER3, and secretion of amphiregulin, indicating that the presence of gemcitabine promoted the activity of targeted molecules including amphiregulin, Akt, and HER3 for pancreatic cancer therapy. Combined treatment with an inhibitor for amphiregulin and gemcitabine, paclitaxel, or cisplatin induced synergistic antitumor effects, accompanied by the suppression of Akt and ERK activation. Blockade of amphiregulin suppressed the activities of EGFR, HER3, and Akt and the expression of amphiregulin itself. According to this evidence, combination chemotherapy of conventional anticancer drugs plus an inhibitor for amphiregulin would allow us to provide more favorable clinical outcomes for patients with pancreatic cancer. (Cancer Sci 2010; 101: 2351–2360)

Superior mesenteric artery syndrome (SMAS) is an intermittent or persistent passage obstruction that occurs in the third portion of the duodenum between the aorta and the superior mesenteric artery. After symptoms stabilize, the nutritional intake is started by ingesting a small amount. Recently, an energy-dense, low-volume nutritional food, Terumeal uplead® (Terumo Corporation, Tokyo, Japan) with an energy density of 4.0 kcal/mL, was launched. We report a case of a postoperative SMAS patient who was successfully treated using Terumeal uplead® through gastrostomy. An 83-year-old man who developed adhesive intestinal obstruction underwent right hemicolectomy, lysis of adhesion, and partial small bowel resection. Gastric distension persisted after surgery; thus, gastrostomy was performed for decompression and enteral nutrition on the 21st postoperative day, and enteral feeding was started on the 23rd postoperative day. However, fluoroscopy showed obstruction in the third portion of the duodenum, which was considered to be SMAS. To reduce the administration volume, enteral nutrition was replaced with Terumeal uplead® from the 28th postoperative day (intermittent administration thrice a day, 300 mL, 1,200 kcal per day). From the 34th postoperative day, the gastrostomy tube was clamped for two hours after administration, and no drainage was observed. Oral intake was resumed from the 36th postoperative day, and it was used in combination with enteral nutrition. Three months later, the patient was discharged home and continued oral ingestion with occasional decompression from the gastrostomy tube. Thus, Terumeal uplead® may be useful during the conservative treatment of SMAS by initiation with small amounts.Superior mesenteric artery syndrome (SMAS) is an intermittent or persistent passage obstruction that occurs in the third portion of the duodenum between the aorta and the superior mesenteric artery. After symptoms stabilize, the nutritional intake is started by ingesting a small amount. Recently, an energy-dense, low-volume nutritional food, Terumeal uplead® (Terumo Corporation, Tokyo, Japan) with an energy density of 4.0 kcal/mL, was launched. We report a case of a postoperative SMAS patient who was successfully treated using Terumeal uplead® through gastrostomy. An 83-year-old man who developed adhesive intestinal obstruction underwent right hemicolectomy, lysis of adhesion, and partial small bowel resection. Gastric distension persisted after surgery; thus, gastrostomy was performed for decompression and enteral nutrition on the 21st postoperative day, and enteral feeding was started on the 23rd postoperative day. However, fluoroscopy showed obstruction in the third portion of the duodenum, which was considered to be SMAS. To reduce the administration volume, enteral nutrition was replaced with Terumeal uplead® from the 28th postoperative day (intermittent administration thrice a day, 300 mL, 1,200 kcal per day). From the 34th postoperative day, the gastrostomy tube was clamped for two hours after administration, and no drainage was observed. Oral intake was resumed from the 36th postoperative day, and it was used in combination with enteral nutrition. Three months later, the patient was discharged home and continued oral ingestion with occasional decompression from the gastrostomy tube. Thus, Terumeal uplead® may be useful during the conservative treatment of SMAS by initiation with small amounts.

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two‐step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m2 (i.v. days 1, 8, 15) in a 28‐day cycle in the first step, and efficacy and safety in the second step. The primary end‐point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment‐related death occurred. While interstitial lung disease‐like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1‐year survival rate and median progression‐free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients. (Cancer Sci 2011; 102: 425–431)

We aimed to determine the cumulative rate of diabetes mellitus (DM) and the risk factors for DM in patients with chronic pancreatitis (CP) in Japan. We conducted a follow-up survey of CP in 2002 in patients registered as having CP in 1994, and confirmed 656 patients to be checked in regard to the survey items concerning diabetes. We analyzed the cumulative rate of DM and the risk factors for DM over an 8-year follow up period. In 1994, 35.1% of 656 CP patients had DM, and the incidence of diabetes had increased to 50.4% in 2002. Of 418 patients without diabetes in 1994, 28.9% (121/418) were newly diagnosed with DM in 2002. Alcoholic CP was the most common type of CP in patients with newly developed diabetes, accounting for 67.8%. The incidence of DM was highest in those with alcoholic CP (34.3%) followed by idiopathic CP (23.0%). The risk of diabetes increased 1.32-fold after the onset of pancreatic calcification. Of 121 patients with newly diagnosed DM in 2002, 37 (30.6%) had pancreatic stones in 1994 and 49 (40.5%) had a stone in 2002. The highest incidence of newly diagnosed DM was observed in patients with continuous alcoholic intake (40.9%). Patients treated with camostat mesilate developed DM less frequently than those without camostat mesilate. The present study showed that the incidence of DM in patients with CP increased with time. Of 418 CP patients without DM in 1994, 28.9% developed DM over a period of 8 years. Continuous alcoholic intake aggravated CP and increased the risk of DM in those with CP.

Gallbladder dysmotility accelerates cholelithiasis. In turn, gallbladder dysmotility can occur secondary to inflammation and excess cholesterol accumulation in gallbladder smooth muscle. The present study was designed to determine how much gallbladder dysmotility contributes to gallstone formation as a primary cause and whether a sex difference exists in gallstone formation by comparing cholecystokinin-1 receptor gene-deficient [CCK-1R(-/-)] male and female mice. No sludge or gallstone formation was observed in mice at 6 months of age. The frequency of sludge and gallstone formation in mice at 12 and 24 months of age was slightly higher in female CCK-1R(-/-) mice than in males, but the difference was not significant. Gallbladder dysmotility may have accelerated sludge and gallstone formation, but its contribution was limited. A 12-month period was required to produce gallstones, and after the mice reached 12 months of age, further ageing did not increase the frequency of gallstones. The effect of sex did not reach a significant level.

Although cholecystokinin (CCK) has been shown to inhibit gastric emptying via CCK-A receptors (CCK-ARs), the role of CCK-B receptors (CCK-BRs) has not been verified. We examined whether gastric emptying of a nonnutrient liquid load was modified in CCK-AR, BR, and ARBR gene knockout mice. A liquid gastric load prepared with phenol red was administered via an orogastric tube (0.15 ml/mouse). The animals were killed by decapitation, and gastric emptying was estimated at 10 and 30 min after ingestion. The effects of the sulfated form of CCK-8 (CCK-8S) and of graded doses of atropine were examined. In addition, a proton pump inhibitor was administered to wild-type mice to examine the contribution of gastric acid to emptying. Gastric emptying was significantly enhanced in mice lacking CCK-BR, as compared with wild-type and CCK-AR(-/-) mice. CCK-8S inhibited gastric emptying in mice with CCK-AR, but not in mice without CCK-AR. A proton pump inhibitor did not affect gastric emptying. Atropine dose dependently inhibited gastric emptying in all genotypes. The thickness of smooth muscle was comparable for all genotypes. The gastric emptying of a nonnutrient liquid load was enhanced in mice without CCK-BR, although the precise mechanism is not known. Although cholecystokinin (CCK) has been shown to inhibit gastric emptying via CCK-A receptors (CCK-ARs), the role of CCK-B receptors (CCK-BRs) has not been verified. We examined whether gastric emptying of a nonnutrient liquid load was modified in CCK-AR, BR, and ARBR gene knockout mice.

The etiology of gallstone formation is multifactorial, and genetic factors are involved. The genetic variations of cholecystokinin A receptor (CCK-AR) in patients having gallstones and the molecular mechanisms of this polymorhpism were examined. The involvement of CCK-AR in gallstone formation was confirmed using CCK-AR gene knockout mice. CCK-AR gene expression was determined by Northern transfer analysis in gallbladders with or without gallstones. Genetic variations were determined by Southern blot and by direct sequencing. Molecular mechanisms in terms of the transcriptional activity and methylation status were examined. Finally, we investigated whether gallstone formation was enhanced in CCK-AR gene knockout mice. The gene expression of CCK-AR was significantly decreased in gallbladders with gallstones compared to those without gallstones. No genetic variations were detected in the coding region, but two sequence variations were detected in the promoter region in gallstone patients. However, no significant differences were found for the promoter activities of polymorphic promoter constructs. In contrast, less methylation in the promoter region was related to substantial expression of the CCK-AR gene. Gallstone formation was enhanced in CCK-AR gene knockout mice. The homozygote (GG/TT) polymorphism of the CCK-AR gene showed a significantly higher percentage of body fat. Deteriorating gallbladder contractions, possibly induced by alterations in the CCK-AR gene, as well as CCK-AR gene polymorphism, promoted gallstone formation.

A pilot phase II study showed S-1 monotherapy to be safe and active against biliary tract cancer (BTC). We, therefore, conducted a multicenter phase II study to evaluate the antitumor effect and safety of S-1 in previously untreated patients with advanced BTC. Eligible patients had pathologically proven, unresectable adenocarcinoma with no prior chemotherapy or radiotherapy. Patients received S-1 orally at 80 mg/m 2 total daily dose divided b.i.d. for 28 days followed by 14 days of rest. Of the 41 enrolled patients, 40 were assessable. The primary tumor sites were as follows: gallbladder ( n  = 20), extrahepatic bile duct ( n  = 15), and the ampulla of Vater ( n  = 5). One patient (2.5%) achieved a complete response, 13 patients (32.5%) had partial responses, 17 patients (42.5%) had no change, 7 patients (17.5%) had progressive disease, and 2 patients (5.0%) were not evaluable. The overall objective response rate was 35.0%. The median overall survival (median OS) was 9.4 months, and the median time to progression was 3.7 months. Grade 3 or 4 toxicities included fatigue (7.5%), anorexia (7.5%) and T-Bil elevation (7.5%). Significant antitumor activity combined with a mild toxicity profile was observed. This monotherapy warrants further evaluation in a randomized study.