Updated results from GEST study: a randomized, three-arm phase III study for advanced pancreatic cancer.

PURPOSE: The GEST study showed non-inferiority of S-1 but not superiority of gemcitabine plus S-1 (GS) to gemcitabine alone for overall survival with the data by the cut-off date of 31st July in 2010 for chemo-naïve patients with advanced pancreatic cancer. We considered it important to determine whether S-1 maintains non-inferiority after a long-term follow-up in the GEST study and to obtain a firm positive conclusion. In addition, it may be an interesting challenge to explore the efficacious profile of GS in the long-term follow-up study. Using the data from the follow-up period, background and efficacy in patients from Taiwan and Japan, as well as the rates of tumor shrinkage in locally advanced and metastatic patients (Waterfall plot) were also analyzed. METHODS: The results of the primary analysis were reconfirmed, and subset analysis of overall survival and progression-free survival was performed based on the overall survival data updated by the cut-off date of 31st July in 2011. RESULTS: The median follow-up period was 29.8 months, and 795 deaths occurred (95.6%). The median overall survival was 8.8 months for gemcitabine, 9.7 months for S-1 (hazard ratio [HR], 0.96; 97.5% confidence interval [CI], 0.79-1.17), and 9.9 months for GS (HR 0.91; 97.5% CI 0.75-1.11). In patients with performance status (PS) 0, the median overall survival was 9.8 months for gemcitabine, 10.9 months for S-1, and 10.5 months for GS. In patients with PS 1, the median overall survival was 6.2 months for gemcitabine, 6.3 months for S-1, and 9.6 months for GS. CONCLUSION: Our survey reconfirmed the non-inferiority of S-1 to gemcitabine and showed S-1 can be used as one of the standard treatment options for advanced pancreatic cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00498225.

Phase II trial of combination therapy of gemcitabine plus anti-angiogenic vaccination of elpamotide in patients with advanced or recurrent biliary tract cancer.

Background Elpamotide is an HLA-A*24:02-restricted epitope peptide of vascular endothelial growth factor receptor 2 (VEGFR-2) and induces cytotoxic T lymphocytes (CTLs) against VEGFR-2/KDR. Given the high expression of VEGFR-2 in biliary tract cancer, combination chemoimmunotherapy with elpamotide and gemcitabine holds promise as a new therapy. Patients and Methods Patients with unresectable advanced or recurrent biliary tract cancer were included in this single-arm phase II trial, with the primary endpoint of overall survival. Survival analysis was performed in comparison with historical control data. The patients concurrently received gemcitabine once a week for 3 weeks (the fourth week was skipped) and elpamotide once a week for 4 weeks. Results Fifty-five patients were registered, of which 54 received the regimen and were included in the full analysis set as well as the safety analysis set. Median survival was 10.1 months, which was longer than the historical control, and the 1-year survival rate was 44.4%. Of these patients, injection site reactions were observed in 64.8%, in whom median survival was significantly longer (14.8 months) compared to those with no injection site reactions (5.7 months). The response rate was 18.5%, and all who responded exhibited injection site reactions. Serious adverse reactions were observed in five patients (9%), and there were no treatment-related deaths. Conclusion Gemcitabine and elpamotide combination therapy was tolerable and had a moderate antitumor effect. For future development of therapies, it will be necessary to optimize the target population for which therapeutic effects could be expected.

Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study.

BACKGROUND AND STUDY AIMS: Despite the development of peroral video cholangioscopy (PVCS), no prospective multicenter studies have been undertaken to investigate the diagnostic accuracy of PVCS in biliary tract diseases. Therefore, the aim of this study was to clarify the accuracy of PVCS in evaluating biliary tract lesions. PATIENTS AND METHODS: This study was a prospective multicenter study at five tertiary referral centers in Japan and included 87 eligible patients with biliary tract diseases who underwent PVCS. The study evaluated the ability of PVCS to diagnose indeterminate biliary tract diseases, detect mucosal cancerous extension preoperatively in extrahepatic bile duct cancers, and predict adverse events. RESULTS: The use of PVCS appearance alone correctly distinguished benign from malignant indeterminate biliary lesions in 92.1 % of patients whereas biopsy alone was accurate in 85.7 %. In extrahepatic bile duct cancer, mucosal cancer extended histologically at least 20 mm in 34.7 % (17/49) of patients. The accuracy rate of PVCS to evaluate the presence or absence of mucosal cancerous extension by endoscopic retrograde cholangiography (ERC) alone, ERC with PVCS, and ERC with PVCS + biopsy were 73.5 %, 83.7 %, and 92.9 %, respectively. Adverse events were seen in 6.9 % of PVCS patients, but no serious complications were observed. CONCLUSION: PVCS enhanced the accurate diagnosis of biliary tract lesions by providing excellent resolution in combination with biopsy.

Endoscopic resection of benign tumors of the papilla of vater.

Most benign papillary tumors are adenomas which can potentially undergo the adenoma-carcinoma-sequence making complete removal mandatory for curative therapy. Endoscopic resection (papillectomy) of these lesions is being increasingly performed as a less traumatic alternative to surgery. Available data shows endoscopic papillectomy to be effective and safe in experienced hands with usually little morbidity and virtually no mortality. Success rates are around 80 % for lesions without intraductal involvement. Selected cases of limited distal intraductal involvement accessible after sphincterotomy may also be managed curatively by endoscopic resection. Endoscopic snare resection of entire lesions should be primarily regarded as a diagnostic procedure. It allows for an accurate histological diagnosis based on examination of the entire specimen rather than forceps biopsies and thus a reliable assessment of the need for surgical therapy. Subsequent surgery in operable patients is not precluded by previous endoscopic resection. Surgery is indicated in case of incomplete removal and if malignancy is present. The curative role of endoscopic papillectomy for early invasive carcinoma needs to be established. Histological features and individual risk for surgery are factors to be considered. Inoperable patients may still benefit from palliative endoscopic stenting. After endoscopic papillectomy has been completed, regular follow-up examinations including biopsies are warranted because of the risk of local recurrence. For benign looking papillary tumors, endoscopic papillectomy serves as a diagnostic tool and should be considered as first line procedure regardless of age. The following article details the approach to patients with benign papillary tumor and the technique of endoscopic papillectomy.

Percutaneous radiofrequency ablation for unresectable large hepatic tumours during hepatic blood flow occlusion in four patients.

AIM: To evaluate percutaneous radiofrequency (RF) ablation therapy for unresectable large hepatic tumours combined with regional interruption of hepatic blood flow, and to assess the safety and efficacy of this procedure. MATERIALS AND METHODS: Four patients with hepatic tumours were enrolled in this study. Patients were treated by a single session of RF ablation during occlusion of both hepatic artery and hepatic vein. Tumour size ranged from 45-57 mm (mean 50.2 mm). Initial therapeutic efficacy was evaluated with helical computed tomography (CT) performed within 9 days after the treatment. CT or magnetic resonance imaging (MRI) was performed every 2-3 months thereafter. RESULTS: The largest axis of coagulated lesions after the ablation was 50-60 mm (mean 56.5 mm) in diameter. The ablation therapy was considered complete in three patients; after a mean follow-up of 12.7 months, CT and MRI revealed complete destruction of their tumours. One patient required further treatment. No severe complications occurred. CONCLUSION: Although further studies are needed, in this limited clinical trial a local ablation area exceeding 50 mm in diameter was achieved safely.

Efficacy of endoscopic diagnosis and treatment for postoperative biliary leak.

BACKGROUND/AIMS: The purpose of this study was to evaluate the efficacy of endoscopic approaches for the diagnosis and treatment of postoperative biliary leak. METHODOLOGY: Endoscopic retrograde cholangiopancreatography (ERCP) was performed in eight patients with postoperative biliary leak. Of 8 cases, 6 had biliary leak alone (4 cases with a cystic duct leak and 2 cases with a bile duct leak) and 2 cases with a bile duct leak were associated with a bile duct stricture. Endoscopic sphincterotomy (ES) and endoscopic biliary stenting (EBS) were employed in 5 patients and nasobiliary tube drainage (NBD) without ES was performed in 3 patients. RESULTS: In all the patients, ERCP was successfully performed and could demonstrate exact nature and site of postoperative bile duct injuries. In 2 patients with a concomitant bile duct stricture, repetitive endoprosthesis placements were required. The remaining six patients with biliary leak alone were successfully treated by temporary stenting, i.e., ES and EBS (n = 3), and NBD (n = 3). CONCLUSIONS: The patients with postoperative biliary leaks can be successfully diagnosed by ERCP and treated by temporary endoscopic methods. Among various endoscopic treatments, NBD alone appears to be preferable in treating patients with small bile leaks. However, cases with a concomitant bile duct stricture were intractable and required longer period of stenting.

Association between anomalous pancreaticobiliary ductal union and adenomyomatosis of the gall-bladder.

A frequent association of biliary tract carcinoma and anomalous pancreaticobiliary ductal union (APBD) is well recognized, especially gall-bladder carcinoma in undilated type APBD. However, little is known about the presence and incidence of adenomyomatosis (AMT) of the gall-bladder, a presumed premalignant lesion, in patients with APBD. This retrospective study was conducted to elucidate the clinical features and incidence of AMT in APBD patients with relation to undilated type and dilated type APBD. We reviewed the clinicopathological records of 30 patients with APBD (28 women and two men) encountered during the past 10 years. Among them, 22 patients underwent cholecystectomy and the resected specimens were subjected to histopathological examinations. Eleven cases of APBD patients were undilated type and 11 cases were dilated type. Adenomyomatosis was found in six (55%) of 11 undilated type and one (9%) of 11 dilated type, and fundal type was predominantly observed in six (86%) of seven AMT. An overall incidence of AMT in APBD patients was 32%. An undilated type of APBD is frequently associated with AMT and we believe, therefore, that clinicians should be aware of a possible coexistence of APBD and AMT.

Splenic hamartoma associated with thrombocytopenia.

A case of splenic hamartoma associated with thrombocytopenia is reported. A 70-year-old man was referred to our hospital because of carcinoma of the body of the pancreas. Hematological examination disclosed thrombocytopenia and elevated serum CA19-9 and Span-1 levels. In addition to typical findings of pancreatic carcinoma, a solid mass was observed in the spleen by imaging procedures. On ultrasonography, the splenic mass was well demarcated and slightly hypoechoic. Computed tomography demonstrated a homogeneous low-density mass 5 cm in diameter. On T1- and T2-weighted magnetic resonance images, the splenic mass was demonstrated as low intensity and high intensity, respectively. On selective angiography, the tumor was hypervascular. Distal pancreatectomy plus splenectomy was performed. Microscopically, the splenic tumor consisted of red pulp tissue and was diagnosed as splenic hamartoma.

Thickened inner hypoechoic layer of the gallbladder wall in the diagnosis of anomalous pancreaticobiliary ductal union with endosonography.

BACKGROUND: An anomalous pancreaticobiliary ductal union (APBD) is a high-risk factor for biliary tract carcinoma, which often is not diagnosed before overt malignancy. The early detection of APBD is therefore clinically important. We evaluated the gallbladder wall in APBD patients with endoscopic ultrasonography. METHODS: Clinicopathologic features and ultrasonographic findings of the gallbladder in 33 consecutive patients with APBD between 1986 and 1995 were studied in relation to two subtypes of APBD, that is, undilated (n = 17) and dilated (n = 16). The gallbladder wall was evaluated with conventional ultrasonography and/or endoscopic ultrasonography. Histologic examinations of 25 resected gallbladders were made. RESULTS: Fourteen of the seventeen patients with undilated type APBD (82%) had diffuse thickened gallbladder wall of 4 mm or more, whereas 5 of the 16 with dilated type (31%) had this finding (p < 0.01). The thickened gallbladder wall consisted sonographically of two layers: diffuse thickened inner hypoechoic layer and outer hyperechoic layer. Mucosal hyperplasia was histologically found in 8 of 9 cases (89%) with thickened inner hypoechoic layer on endoscopic ultrasonography. Mucosal hyperplasia was observed in 10 of 11 undilated type APBD cases (91%) in which cholecystectomy was performed. In addition, the presence of anomalous union was shown by endoscopic ultrasonography in 9 of 11 patients with undilated type APBD (82%) and all 7 of those with dilated type. The characteristic ultrasonographic pattern of diffuse thickened inner hypoechoic layer was observed exclusively in patients with mucosal hyperplasia of the gallbladder associated with APBD among 2085 endoscopic ultrasonography examinations performed during the study period. CONCLUSIONS: Diffuse thickened inner hypoechoic layer of the gallbladder wall was frequently observed in APBD patients, especially those with the undilated type, on ultrasonography and/or endoscopic ultrasonography. This finding corresponded histologically to mucosal hyperplasia of the gallbladder mucosa. Thickened inner hypoechoic layer is a useful ultrasonographic sign that indicates mucosal hyperplasia of the gallbladder and, particularly, the possible coexistence of undilated type APBD before the appearance of overt malignancy.