Hiroki Kawai

Prospective clinical study of EUS-guided choledochoduodenostomy for malignant lower biliary tract obstruction.

OBJECTIVES:Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) has recently been reported as an alternative to percutaneous transhepatic biliary drainage (PTBD) in cases of biliary obstruction, when endoscopic biliary drainage (EBD) is unsuccessful. However, prospective studies of EUS-CDS have not yet been performed. We conducted a prospective study to evaluate the safety, feasibility, and efficacy of EUS-CDS in patients with malignant lower biliary tract obstruction.METHODS:A prospective study to confirm the safety of EUS-CDS was carried out in 6 patients, followed by a trial to evaluate the feasibility and efficacy of EUS-CDS in 12 additional patients. We placed a plastic stent from the duodenal bulb into the extrahepatic bile duct under EUS guidance using an oblique viewing echoendoscope, needle knife, guidewire, and biliary dilators.RESULTS:The site of extrahepatic bile duct puncture was the common hepatic duct in 15 patients and the common bile duct in 3 patients. Mean diameter of the punctured extrahepatic bile ducts was 10u2009mm (range: 6–20u2009mm). Technical and functional success rates were 94% (17/18) and 100% (17/17), respectively. Median procedure time was 30u2009min (range: 10–52u2009min). Median duration to first oral intake after the procedure was 1 day (range: 1–3 days). Early complications were encountered in three (17%) patients, including focal peritonitis in two patients and hemobilia in one patient. During the follow-up period (median: 163 days; range: 46–484 days), 12 stent occlusion events were observed in nine patients. Re-intervention with exchange of the occluded stent was successful in 8 of 12 (66%) times. Severe early and late complications were not encountered in any patients in this study. Median duration of stent patency by Kaplan–Meier analysis was 272 days.CONCLUSIONS:EUS-CDS is safe, feasible, and effective as an alternative to PTBD and EBD in cases of malignant distal biliary tract obstruction. Prospective randomized studies are needed to compare the safety and efficacy of various kinds of endoscopic devices used in EUS-CDS and to compare EUS-CDS with PTBD or EBD.

Endoscopic ultrasound-guided fine-needle aspiration biopsy for the diagnosis of gastrointestinal stromal tumors in the stomach.

BackgroundFor the diagnosis of gastric submucosal tumors (SMTs), endoscopic ultrasound (EUS) alone does not reveal the complete pathology, such as the degree of malignancy, and EUS-guided fine-needle aspiration biopsy (EUS-FNAB) has been reported to be more useful. Recently, most cases initially diagnosed as leiomyosarcomas have received further study with immunohistochemical staining and have been given the new diagnosis of gastrointestinal stromal tumors (GISTs). The degree of malignancy of GISTs differs widely in clinical aspects. In this study, we examined whether EUS-FNAB was useful in diagnosing GISTs and differentiating their degrees of malignancy.MethodsFrom January 1997 to March 2002, 21 cases of gastric GISTs were diagnosed from the immunohistochemical staining of specimens resected at Aichi Cancer Center Hospital. Of these 21 patients, 14 (5 with high-grade malignancy and 9 with low-grade malignancy) underwent EUS-FNAB preoperatively, and were examined further: their EUS-FNAB specimens were submitted for additional immunohistochemical testing.ResultsThe EUS-FNAB specimens from all patients were positive for c-kit and CD34 immunohistochemical testing, coinciding with the staining results of the resected specimens. The MIB-1 labeling indices in specimens of high-grade malignancy were significantly higher than those of low-grade malignancy. If we assumed that a tumor with an MIB-1 labeling index of more than 5% was a high-grade malignancy, the diagnostic accuracy was 85.7%.ConclusionsThe EUS-FNAB procedure is a useful tool for diagnosing GISTs of the stomach with immunohistochemical staining. When used with MIB-1 staining, the procedure may indicate GIST prognosis and influence decisions regarding therapeutic strategies.

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: A multicenter, retrospective analysis in Japan

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II1 GI–FL. Of the 125 patients, the small intestine was examined in 70 patients, with double‐balloon endoscopy and/or capsule endoscopy. The most frequently involved GI–FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP‐positive group. During a median follow up of 40u2003months, six patients showed disease progression. Patients with involvement of the DSP had better progression‐free survival (PFS) than those without such involvement (Pu2003=u20030.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI–FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532–1536)

Clinical Features and Prognosis of Gastric MALT Lymphoma With Special Reference to Responsiveness to H. pylori Eradication and API2-MALT1 Status

BACKGROUND AND AIM:Clinicopathologic characteristics and prognosis of Helicobacter pylori eradication-resistant gastric MALT lymphoma have not been well clarified. We analyzed a consecutive series of gastric MALT lymphomas at our institution regarding treatment, clinical course, and prognosis, with special reference to responsiveness to H. pylori eradication and presence of API2-MALT1.METHODS:Subjects were 92 consecutive patients with gastric MALT lymphoma. Seventy were H. pylori positive, and 87 received H. pylori eradication therapy. The remaining five cases were API2-MALT1 positive and did not receive eradication treatment. Second-line treatments were radiation therapy, total gastrectomy, and chemotherapy (rituximab, rituximab plus CHOP, or rituximab plus 2-chlorodeoxyadenosine).RESULTS:Gastric MALT lymphoma was classified into three groups, except one case with API2-MALT1 who responded to H. pylori eradication therapy: responders without API2-MALT1 (group A, N = 56, 65%), nonresponders without API2-MALT1 (group B, N = 16, 19%), and nonresponders with API2-MALT1 (group C, N = 14, 16%). Most cases in group A attained complete remission (CR) in 2 or 3 months and CR persisted for an average of 51.1 months (3–134 months). Recurrence was only seen in one case. In groups B and C, radiation therapy, chemotherapy, and total gastrectomy resulted in CR in 13, 5, and 2 cases, respectively. In 5 group B patients and 6 group C patients who did not undergo second-line therapy, disease did not progress for an average of 10.4 and 40.1 months, respectively. In 1 group C case who did not receive second-line treatment, lymphoma metastasized to the lung 12 yr after eradication. All group B patients and all but 2 group C patients remain alive; one of these deaths was from gastric carcinoma developing 7 yr after eradication.CONCLUSION:Gastric MALT lymphoma responding to H. pylori eradication demonstrated good prognosis, and for nonresponsive cases, second-line treatments resulted in CR. However, careful observation for development of gastric carcinoma and disease progression is essential during follow-up of API2-MALT1-positive MALT lymphoma when patients decline second-line treatment.

EUS-Guided Biliary Drainage.

Endoscopic ultrasonography (EUS) combines endoscopy and intraluminal ultrasonography, and allows imaging with a high-frequency transducer over a short distance to generate high-resolution ultrasonographic images. EUS is now a widely accepted modality for diagnosing pancreatobiliary diseases. EUS-guided fine-needle aspiration (EUS-FNA) using a curved linear-array echoendoscope was initially described more than 20 years ago, and since then many researchers have expanded its indications to sample diverse lesions and have also used it for various therapeutic purposes. EUS-guided biliary drainage (EUS-BD) is one of the therapeutic procedures that has been developed using a curved linear-array echoendoscope. Technically, EUS-BD includes rendezvous techniques via transesophageal, transgastric, and transduodenal routes, EUS-guided choledochoduodenostomy (EUS-CDS), and EUS-guided hepaticogastrostomy (EUS-HGS). Published data have demonstrated a high success rate, albeit with a comparatively high rate of nonfatal complications for EUS-CDS and EUS-HGS, and a comparatively low success rate with a low complication rate for the rendezvous technique. At present, these procedures represent an alternative to surgery or percutaneous transhepatic biliary drainage (PTBD) for patients with obstructive jaundice when endoscopic biliary drainage (EBD) has failed. However, these procedures should be performed in centers with extensive experience in linear EUS and therapeutic biliary ERCP. Large prospective studies are needed in the near future to establish standardized EUS-BD procedures as well as to perform controlled comparative trials between EUS-BD and PTBD, between rendezvous techniques and direct-access techniques (EUS-CDS and EUS-HGS), and between EBD and EUS-BD.

Heavy smoking history interacts with chemoradiotherapy for esophageal cancer prognosis: A retrospective study

Smoking is a well‐known risk factor for esophageal cancer. However, there are few reports that directly evaluate smoking as a prognostic factor for esophageal cancer. Moreover, scarce evidence is available on whether smoking interacts with major treatment modalities of esophageal cancer. In this study we retrospectively analyzed 364 patients with esophageal squamous cell cancer who were treated between 2001 and 2005 at our institution. Background characteristics, including smoking history, were analyzed as potential prognostic factors. Of the 363 patients, 76 patients (20.9%) were non‐smokers or light smokers (non‐heavy), whereas 287 patients (79.1%) were heavy smokers. The 5‐year survival rate for non‐heavy smokers and heavy smokers was 61.8% (95%u2003confidence interval [CI]: 49.1–72.2) vs 44.6% (95% CI: 38.2–50.9), respectively. In a multivariate Cox model (adjusted for age, gender, performance status, alcohol consumption, histology, tumor length, International Union Against Cancer [UICC] stage, and treatment), the hazard ratio for heavy smokers in comparison with non‐heavy smokers was 1.73 (95% CI: 1.12–2.68; Pu2003=u20030.013). When we stratified by treatment method, heavy smoking was significantly associated with poor survival only in patients treated by chemoradiotherapy (hazard ratio, 2.43; 95% CI: 1.38–4.27; Pu2003=u20030.002). More importantly, a statistically significant interaction between heavy smoking history and treatment modality was observed (Pu2003=u20030.041). Our results indicated that smoking history is strongly associated with poor prognosis in patients with esophageal cancer, especially those treated by chemoradiotherapy. Further investigation is warranted to explain this different prognosis.

Neutropenia as a prognostic factor in advanced gastric cancer patients undergoing second-line chemotherapy with weekly paclitaxel

BACKGROUNDnNeutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several types of cancers, although there are no reports in pretreated patients.nnnMETHODSnWe retrospectively analyzed 242 patients with advanced gastric cancer (AGC) who received weekly paclitaxel (Taxol) as second-line chemotherapy. Background characteristics and neutropenia as time-varying covariates (TVCs) were analyzed as prognostic factors.nnnRESULTSnOf the 242 patients, mild neutropenia (grades 1-2) occurred in 101 patients (41.7%) and severe neutropenia (grades 3-4) occurred in 63 patients (26.0%). The other 78 patients (32.2%) did not experience neutropenia. According to a multivariate Cox model with neutropenia as a TVC, hazard ratios of death were 0.61 [95% confidence interval (CI) 0.43-0.85; P = 0.004] for patients with mild neutropenia and 0.61 (95% CI 0.41-0.88; P = 0.009) for those with severe neutropenia. Among the patients in landmark analysis (landmark of 2.5 months; median time to treatment failure of paclitaxel), mild and severe neutropenia remained significant prognostic factors.nnnCONCLUSIONSnOur results indicate that neutropenia during chemotherapy is associated with improved survival in patients with AGC who received weekly paclitaxel as second-line chemotherapy. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy.

Serum tumor antigen REG4 as a diagnostic biomarker in pancreatic ductal adenocarcinoma

Background and AimsSerum biomarkers for the early detection of pancreatic cancer are not currently available. We evaluated the usefulness of a novel serum marker, REG4, in the diagnosis of pancreatic cancer, as compared to carbohydrate antigen (CA) 19-9.MethodsWe collected pretherapeutic sera from 92 patients with pancreatic cancer, as well as sera from 28 patients with other pancreatic tumors, 11 patients with pancreatitis, and 69 healthy controls. Serum levels of REG4 were measured using a standard sandwich enzyme-linked immunosorbent assay (ELISA).ResultsCompared with healthy controls, serum levels of REG4 were higher in pancreatic cancer patients (Pxa0<xa00.001), and in patients with pancreatitis (Pxa0<xa00.001). Receiver operating characteristic (ROC) analysis indicated that serum REG4 performed better than serum CA19-9 for distinguishing patients with pancreatic cancer from healthy controls [areas under the curve (AUC) for REG4 and CA19-9 were 0.922 and 0.884, respectively]. When we validated the study, the sensitivity of REG4 for pancreatic cancer was 94.9%, specificity was 64.0%, and accuracy was 77.5% for the REG4 cutoff value of 3.49xa0ng/ml. No correlation was seen between serum REG4 and CA19-9 levels, with the sensitivity, specificity, and accuracy of the combined markers reaching 100.0, 60.0, and 77.5%, respectively. No significant differences were seen among any stages of pancreatic cancer. In surgical specimens, immunohistochemical analysis found a correlation between serum REG4 levels and REG4 expression in pancreatic cancers.ConclusionsREG4 is expressed in pancreatic cancer, and serum levels of REG4 offer a useful indicator for distinguishing between patients with pancreatic cancer and healthy subjects. Serum REG4 has potential for use as a screening serum marker for pancreatic cancers, including early-stage cancers.

Folate intake along with genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase in patients with advanced gastric cancer.

Background: A relationship between dietary folate intake and efficacy of fluorouracil (FU) is supported by preclinical data. Furthermore, there are several reports that evaluated genetic polymorphisms of MTHFR (methylenetetrahydrofolate reductase) or TYMS (thymidylate synthase) and efficacy of FU. However, to our knowledge, there are no reports that evaluate simultaneously the effects of folate intake and genetic polymorphisms on clinical outcome of gastric cancer patients. Methods: We retrospectively analyzed the survival impact of estimated folate intake by a food frequency questionnaire and MTHFR and TYMS polymorphisms in 132 patients with advanced gastric cancer who were treated with first-line FU-based chemotherapy. Results: Median overall survival was 11.3 months (95% confidence interval, 9.4-13.4 mo) and median progression-free survival was 5.2 months (95% confidence interval, 4.1-6.3 mo). Patients with folate intake of >260 μg/day (n = 88) showed longer overall survival compared with low folate intake (n = 44; overall survival, 12.2 versus 8.4 mo). In a multivariate Cox model, patients who had folate intake of >260 μg/day, MTHFR 677 TT polymorphism, and TYMS-3′ untranslated region 6-bp insertion were associated with better survival. Similar tendency was observed in progression-free survival. No interaction was observed between folate intake and favorable genotypes. Conclusion: Folate intake and genetic polymorphisms of MTHFR and TYMS were associated with better clinical outcome by FU-based chemotherapy in advanced gastric cancer. Impact: Our results suggested folate intake and folate-related genetic polymorphisms may play an important role in efficacy of FU-based chemotherapy in advanced gastric cancer. Cancer Epidemiol Biomarkers Prev; 19(5); 1311–9. ©2010 AACR.

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912

BACKGROUNDnSince the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer.nnnPATIENTS AND METHODSnEndoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point.nnnRESULTSnMultivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08-1.75; P = 0.010], performance status ≥ 1 (HR 1.45; 95% CI 1.13-1.86; P = 0.004), and number of metastatic sites ≥ 2 (HR 1.66; 95% CI 1.28-1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56-1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1.nnnCONCLUSIONnThese correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer.nnnCLINICAL TRIAL NUMBERnC000000062, www.umin.ac.jp.