Randomised phase II trial of irinotecan plus S-1 in patients with gemcitabine-refractory pancreatic cancer.

BACKGROUND: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m-2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group. CONCLUSIONS: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

Intraprostatic ethanol diffusion: comparison of two injection methods using ex vivo human prostates.

BACKGROUND: Intraprostatic injection of ethanol has been previously tested in clinical trials as a potential treatment of BPH, with variable outcomes. As evident from animal studies, the inconsistency was owing to various degrees of ethanol backflow along the needle tract. In acute canine experiments, we previously documented that using convection enhanced delivery (CED) eliminates backflow and improves ethanol distribution. The goal of this study was to compare the diffusion pattern between a microporous hollow fiber catheter (MiHFC) and a standard needle in human prostates from organ donors. METHODS: Prostates were harvested from cadaveric organ donors immediately after removal of organs for transplant. After trimming off excess fat and weighing, prostates were injected with absolute ethanol. The total injected volume was 25% of the calculated prostate volume. One lateral lobe was injected using a single lumen 21-gauge control needle. The contralateral lobe was injected with the same volume but using a MiHFC. Immediately after injection, prostates were fixed en bloc in 10% neutral-buffered formalin, and then sectioned. Three-dimensional reconstruction was performed to determine lesion volume based on hematoxylin- and eosin-stained cross-sections. RESULTS: Three fresh human prostates were harvested and injected. The time from harvest to intraprostatic injection was 15-35 min. The lesion created by the MiHFC was 1.14±0.52 cm(3), whereas that from the control needle was 0.28±0.10 cm(3) (P=0.038). No backflow was observed along the needle tract of the MiHFC. CONCLUSIONS: This study shows that freshly harvested human prostates can be used to evaluate new treatments using intraprostatic injection. Similar to in vivo canine experiments, the ethanol lesion sizes were significantly bigger with the use of a MiHFC when compared with a standard single lumen needle.

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.

Japanese multicenter experience of endoscopic necrosectomy for infected walled-off pancreatic necrosis: The JENIPaN study.

BACKGROUND AND STUDY AIMS: Only a few large cohort studies have evaluated the efficacy and safety of endoscopic necrosectomy for infected walled-off pancreatic necrosis (WOPN). Therefore, a multicenter, large cohort study was conducted to evaluate the efficacy and safety of endoscopic necrosectomy and to examine the procedural details and follow-up after successful endoscopic necrosectomy. PATIENTS AND METHODS: A retrospective review was conducted in 16 leading Japanese institutions for patients who underwent endoscopic necrosectomy for infected WOPN between August 2005 and July 2011. The follow-up data were also reviewed to determine the long-term outcomes of the procedures. RESULTS: Of 57 patients, 43 (75 %) experienced successful resolution after a median of 5 sessions of endoscopic necrosectomy and 21 days of treatment. Complications occurred in 19 patients (33 %) during the treatment period. Six patients died (11 %): two due to multiple organ failure and one patient each from air embolism, splenic aneurysm, hemorrhage from a Mallory - Weiss tear, and an unknown cause. Of 43 patients with successful endoscopic necrosectomy, recurrent cavity formation was observed in three patients during a median follow-up period of 27 months. CONCLUSIONS: Endoscopic necrosectomy can be an effective technique for infected WOPN and requires a relatively short treatment period. However, serious complications can arise, including death. Therefore, patients should be carefully selected, and knowledgeable, skilled, and experienced operators should perform the procedure. Further research into safer technologies is required in order to reduce the associated morbidity and mortality.

Endoscopic management of malignant biliary obstruction by means of covered metallic stents: primary stent placement vs. re-intervention.

BACKGROUND AND STUDY AIMS: Recent progress in chemotherapy has prolonged the survival of patients with malignant biliary strictures, leading to increased rates of stent occlusion. Occlusion of covered metallic stents now occurs in about half of all patients with malignant biliary strictures. The removal of metallic stents followed by placement of a second stent has been attempted, but outcomes remain controversial. The aim of the current study was to evaluate the effectiveness and safety of the primary placement and secondary placement (re-intervention) of covered metallic stents and to assess the feasibility and safety of stent removal. PATIENTS AND METHODS: The study included 186 patients with unresectable malignant biliary strictures who underwent primary stent placement between October 2001 and March 2010.  Covered biliary self-expandable metal stents (SEMSs) were removed in 39 of these patients, and 36 underwent re-intervention. The patency times, occlusion rates of the first stent and re-intervention, success rates of stent removal, and complications were investigated. RESULTS: Covered SEMSs were placed in 186 patients. The median patency time of the first stent was 352 days. Stent occlusion occurred in 48.9 % of the patients and was mainly caused by debris or food residue (37 %), dislocation (19 %), and migration with hyperplasia (19 %). Stent removal was attempted in 50 patients and was successful without complication in 39 (78 %). Most of the patients in whom stent removal was unsuccessful had migration with hyperplasia. The median patency time of the second stent was 263 days. The stent patency time did not significantly differ between the first and the second stent. CONCLUSIONS: Covered SEMSs could be safely removed at the time of stent occlusion. Patency rates were similar for initial stent placement and re-intervention.

Fine needle aspiration using forward-viewing endoscopic ultrasonography.

BACKGROUND AND STUDY AIM: A prototype forward-viewing instrument has been developed for therapeutic endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA). We had the opportunity to use this forward-viewing echo endoscope and to study its clinical usefulness, mainly for diagnostic EUS-FNA. PATIENTS AND METHODS: The prototype forward-viewing echo endoscope was used for 15 months between November 2006 and March 2010, in a study group comprising 47 consecutive patients. Diagnostic EUS-FNA was done in 38 patients and the diagnostic accuracy of the forward-viewing device was compared with that from an oblique-viewing echo endoscope in reference patients who were matched by disease and puncture route. Therapeutic EUS was done in nine patients (pseudocyst drainage in six; celiac ganglia neurolysis, biliary drainage, and pancreatic duct drainage in one each). RESULTS: Diagnostic EUS-FNA provided a correct diagnosis in 97.4 % (37/38 patients), which was not significantly different from the 94.7 % (36/38) in the reference patients. Lesions considered difficult to access with an oblique-viewing scope, such as those located at the fornix, or the head of the pancreas, or associated with strictures, were easily punctured, as were those located at the body or tail of the pancreas or at the porta hepatis. Treatment was successful in all nine patients who underwent therapeutic EUS procedures. None of the 47 patients had any complications. CONCLUSIONS: A forward-viewing echo endoscope that allows target sites to be punctured more perpendicularly with minimal effort, can be used for diagnostic EUS-FNA and this may be advantageous, depending on the site of target lesions.

Identification of the DSPP mutation in a new kindred and phenotype-genotype correlation.

OBJECTIVE: Hereditary dentin defects can be grouped into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia. Tooth enamel is considered normal in patients with hereditary dentin defects, but is easily worn down and fractured due to DSPP mutation-induced altered dentin properties. The purposes of this study were to identify genetic cause of a family with type II DGI and enamel defects. MATERIALS AND METHODS: We identified a family with type II DGI and a unique form of hypoplastic enamel defect affecting occlusal third of the crown. Family members were recruited for the genetic analysis and DNA was obtained from peripheral whole blood. RESULTS: Mutational analysis revealed a T to A transversion in exon 3 of the DSPP (c.53T>A, p.V18D). Haplotype analysis showed that the same mutation arose separately in two different families having DGI with similar enamel defects, indicating that this phenotype is associated with this specific DSPP mutation. Clinical features suggest that enamel formation was affected in the affected individuals during early amelogenesis, in addition to the dentin defect. CONCLUSIONS: We observed that a DSPP gene mutation not only influences dentinogenesis but also affects early stage amelogenesis.

GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis.

Associations between bladder cancer risk and NAT2 and GSTM1 polymorphisms have emerged as some of the most consistent findings in the genetic epidemiology of common metabolic polymorphisms and cancer, but their interaction with tobacco use, intensity and duration remain unclear. In a New England population-based case-control study of urothelial carcinoma, we collected mouthwash samples from 1088 of 1171 cases (92.9%) and 1282 of 1418 controls (91.2%) for genotype analysis of GSTM1, GSTT1 and NAT2 polymorphisms. Odds ratios and 95% confidence intervals of bladder cancer among New England Bladder Cancer Study subjects with one or two inactive GSTM1 alleles (i.e. the 'null' genotype) were 1.26 (0.85-1.88) and 1.54 (1.05-2.25), respectively (P-trend = 0.008), compared with those with two active copies. GSTT1 inactive alleles were not associated with risk. NAT2 slow acetylation status was not associated with risk among never (1.04; 0.71-1.51), former (0.95; 0.75-1.20) or current smokers (1.33; 0.91-1.95); however, a relationship emerged when smoking intensity was evaluated. Among slow acetylators who ever smoked at least 40 cigarettes/day, risk was elevated among ever (1.82; 1.14-2.91, P-interaction = 0.07) and current heavy smokers (3.16; 1.22-8.19, P-interaction = 0.03) compared with rapid acetylators in each category; but was not observed at lower intensities. In contrast, the effect of GSTM1-null genotype was not greater among smokers, regardless of intensity. Meta-analysis of the NAT2 associations with bladder cancer showed a highly significant relationship. Findings from this large USA population-based study provided evidence that the NAT2 slow acetylation genotype interacts with tobacco smoking as a function of exposure intensity.

Interaction of Rhei Rhizoma extract with cytochrome P450 3A and efflux transporters in rats.

Traditional Chinese herbal medicines are frequently prescribed in pharmacotherapy in Japan. In the present study, we evaluated the possible interaction of several herbal extracts including Rhei Rhizoma extract with cytochrome P450 (CYP) 3A and efflux transporters such as P-glycoprotein and multidrug resistance-associated protein (MRP) 2. Rhei Rhizoma extract (100 microg/ml) significantly suppressed the CYP3A-mediated 6beta-hydroxylation of testosterone in hepatic microsomes, and increased the extent of bioavailability of midazolam, a typical CYP3A substrate, in rats. Also, Rhei Rhizoma extract (300 microg/ml) significantly suppressed P-glycoprotein-mediated efflux transport of rhodamine 123 (Rho123) in rat everted intestine. In an in-vivo study, Rhei Rhizoma extract added to intestinal perfusate at a concentration of 300 microg/ml significantly suppressed the intestinal exsorption of Rho123, though it exerted no effect on the biliary excretion of Rho123. Furthermore, the in-vitro and in-vivo MRP2-mediated intestinal efflux of 2,4-dinitrophenyl-S-glutathione was significantly suppressed by Rhei Rhizoma extract (1000 microg/ml). In conclusion, Rhei Rhizoma extract, which is taken orally at doses of 0.5-1 g each or 1-3 g daily in clinical practice, may cause pharmacokinetic herb-drug interactions in the process of the intestinal and/or hepatic CYP3A-mediated drug metabolism and P-glycoprotein- and/or MRP2-mediated efflux transport in the intestine.

Sarcomatous transformation in a cellular angiofibroma: a case report.

Cellular angiofibroma is a rare benign mesenchymal tumour of middle-aged adults. This tumour is usually located in the vulvovaginal or inguinoscrotal region. This report describes the case of a patient with a 3.5 cm subcutaneous mass, 2 cm below the left anterior superior iliac spine. Grossly, the mass had tan-white cut surface with a 1.5 cm tan-yellow, whorled, well-delineated nodule. Histologically, the tumour was composed primarily of cytologically bland spindle cells set in a collagenous stroma, with multiple dilated vessels. Other areas showed an abrupt transition to hypercellular sarcomatous elements, including pleomorphic cells with high mitotic activity. The tumour cells were diffusely positive for vimentin and factor XIIIa, and weakly positive for CD34. The patient did not develop any recurrences or metastases, and expired 3 years later of metastatic poorly differentiated carcinoma of unknown origin. This is believed to be the first reported case of sarcomatous transformation in a cellular angiofibroma.

Measuring tumor volume with three-dimensional endoscopic ultrasonography: an experimental and clinical study (including video).

BACKGROUND AND STUDY AIMS: The Olympus EU-IP2 three-dimensional endoscopic ultrasound (3D-EUS) imaging system makes it possible to display tumors in three dimensions and estimate their volume. MATERIALS AND METHODS: Experimental and clinical studies of the volume estimation function of the Olympus EU-IP2 system was carried out to evaluate its accuracy and assess the extent of tumor shrinkage caused by fixation, dehydration, and staining. Results. In the experimental studies, compared with the actual volume of a 1000-mm (3) gelatin column, the estimated volume was found to be equivalent to 114 +/- 1.8 % with the 3R probe and 143 +/- 0.8 % with the 2R probe (mean plus or minus standard deviation). The mean estimated volume of tumor models was 127 +/- 8.5 % with the 3R probe and 131 +/- 6.8 % with the 2R probe. Greater distance from the probe was associated with a greater degree of error than the target object's size, angle, or the number of traces of its outline made. In the clinical studies, compared with the histologically determined tumor volume (100 %), the mean estimated tumor volume was 178 +/- 48.2 % in situ, 168 +/- 31.3 % in resected specimens, and 137 +/- 31.5 % after fixation. Fixation, dehydration, and staining were thus associated with tumor shrinkage. CONCLUSIONS: The volume of gastrointestinal lesions can be estimated by 3D-EUS, although it is overestimated in comparison with actual values. 3D-EUS also allows direct comparisons to be made between the tumor volume before surgery and the volume of fixed pathological specimens, so that the rate of tumor shrinkage can be estimated.

Influence of endoscopic papillary balloon dilation and endoscopic sphincterotomy on sphincter of oddi function: a randomized controlled trial.

BACKGROUND AND STUDY AIM: Endoscopic papillary balloon dilation (EPBD) is assumed to have a theoretical advantage over endoscopic sphincterotomy (EST) in preserving sphincter of Oddi function because it does not involve cutting the biliary sphincter. Although attempts have been made to study the influence of EPBD and EST on sphincter of Oddi function, there is little agreement on this issue. In this study we used a method different from those described in previous reports to clarify whether EPBD or EST preserves sphincter of Oddi function better. PATIENTS AND METHODS: 200 patients with bile duct stones who met the eligibility criteria were randomly assigned to EPBD (n = 104) or an EST (n = 96) group. Sphincter of Oddi function was estimated by measurement of the activity of pancreatic enzymes in the common bile duct (CBD). Pure bile was collected immediately before EPBD or EST, at 1 week and at 1 year after the procedure. We also statistically investigated 14 factors other than EPBD or EST that might have the potential to affect sphincter of Oddi function. RESULTS: There was no significant difference between the baseline characteristics of the EPBD and EST groups. A total of 91 patients (46 in the EPBD group and 45 in the EST group) remained in the trial. Pure bile was collected from the CBD of 86 patients (43 EPBD and 43 EST) 1 week after the procedure. CBD stones were extracted successfully in all cases. Before the procedure, there were no significant differences in the levels of the five pancreatic enzymes between the EPBD and EST groups. At 1 week after the procedure, in both groups, there were significant increases in the levels of the five pancreatic enzymes. At 1 year after the procedure a complete series of pancreatic enzyme analyses was done in 33 patients (12 EPBD and 21 EST). There was no significant difference between the levels of the five pancreatic enzymes immediately before and 1 year after EPBD and EST. When the pancreatic enzyme levels of the two groups were directly compared, there was no significant difference at 1 year after the procedure, but the EPBD group had significantly higher levels at 1 week following the procedure. CONCLUSION: In this study it was found that in patients with CBD stones both EPBD and EST preserve sphincter of Oddi function.

Intraprostatic ethanol chemoablation via transurethral and transperineal injection.

OBJECTIVES: To further assess the safety and feasibility of prostatic chemoablation with ethanol and to address previous concerns associated with transperineal injection using a canine model. MATERIALS AND METHODS: The study included 25 dogs; normal saline or 98% dehydrated ethanol were injected into the prostate using both routes, at volumes of 25-50% of the total prostate volume. The prostate and adjacent structures were examined grossly and histopathologically after the dogs were killed humanely at 4 h, 7 days and 12 weeks after injection. RESULTS: Transperineal injection resulted in tissue necrosis in all prostates and significant extraprostatic necrosis in two of three animals treated. With transurethral injection, the control groups showed minimal change, whereas the group injected with ethanol resulted in lesions with variable necrosis and location. CONCLUSIONS: Intraprostatic chemoablation is possible with ethanol injection both transperineally and transurethrally. Transperineal ethanol injections were associated with more extraprostatic necrosis. Transurethral injections resulted in larger amounts of necrosis in the prostatic parenchyma with minimal extraprostatic effects. However, the extent of prostatic necrosis/ablation was inconsistent and further research is warranted.

Endoscopic mucosal resection in the management of gastric carcinoid tumors.

BACKGROUND AND STUDY AIMS: Gastric carcinoid tumors are a rare disease. Previously, total gastrectomy was regarded as the treatment of choice. However, differences in biological malignancy have recently led to the increased use of endoscopic mucosal resection (EMR) for treatment. We studied the outcome of EMR in patients with gastric carcinoids who were treated at our hospital and discuss the indications for endoscopic treatment. PATIENTS AND METHODS: Between 1986 and 1999 we carried out gastric mucosal resection in five patients with gastric carcinoid tumors. The procedure used for EMR was either strip biopsy or endoscopic aspiration mucosectomy. RESULTS: The carcinoid tumors measured 10 mm or less in four of the five patients. Two patients had type A gastritis, and all had hypergastrinemia. There was no evidence of recurrence during follow-up (range 6 - 66 months; mean 32.6 months). CONCLUSION: EMR is useful in the management of type 1 gastric carcinoids as classified by Rindi (hypergastrinemia; tumor diameter of 10 mm or less).

Giant hamartoma of the ascending colon in an adult with ulcerative colitis.

We report an unusual case of giant colonic hamartoma in a 50-yr-old man with ulcerative colitis. The clinical, endoscopic, and histological aspects of this case are discussed. In addition, the possible pathogenesis of colonic hamartoma is reviewed and related to our patient with ulcerative colitis.