Yasumasa Niwa

Interleukin-8 Promoter Polymorphism Increases the Risk of Atrophic Gastritis and Gastric Cancer in Japan

Host genetic susceptibility may influence gastric carcinogenesis caused by Helicobacter pylori infection. We aimed to clarify the relationship of interleukin (IL)-8 polymorphism with the risk of atrophic gastritis and gastric cancer. We examined IL-8 −251 T > A, IL-1B −511 C > T, and IL-1RN intron 2 polymorphisms in 252 healthy controls, 215 individuals with atrophic gastritis, and 396 patients with gastric cancer. We also investigated the effect of the IL-8 polymorphism on IL-8 production and histologic degree of gastritis in noncancerous gastric mucosa. Although no correlation was found in the analysis of the IL-1B and IL-1RN polymorphisms, IL-8 −251 A/A genotype held a higher risk of atrophic gastritis [odds ratio (OR), 2.35; 95% confidence interval (CI), 1.12-4.94] and gastric cancer (OR, 2.22; 95% CI, 1.08-4.56) compared with the T/T genotype. We also found that the A/A genotype increased the risk of upper-third location (OR, 3.66; 95% CI, 1.46-9.17), diffuse (OR, 2.79; 95% CI, 1.21-6.39), poorly differentiated (OR, 2.70; 95% CI, 1.14-6.38), lymph node (OR, 2.50; 95% CI, 1.01-6.20), and liver metastasis (OR, 5.63; 95% CI, 1.06-30.04), and p53-mutated (OR, 1.91; 95% CI, 1.13-3.26) subtypes of gastric cancer. The A/A and A/T genotypes were significantly associated with higher levels of IL-8 protein compared with the T/T genotype. Neutrophil infiltration score was significantly higher in the A/A genotype than in the T/T genotype. In conclusion, we showed that the IL-8 −251 T > A polymorphism is associated with higher expression of IL-8 protein, more severe neutrophil infiltration, and increased risk of atrophic gastritis and gastric cancer.

Preoperative staging of superficial esophageal carcinoma: comparison of an ultrasound probe and standard endoscopic ultrasonography ☆ ☆☆ ★

BACKGROUND In diagnosing superficial esophageal carcinoma, it is necessary to differentiate mucosal carcinoma from submucosal carcinoma because mucosal carcinoma has a good prognosis and local treatment is likely to be successful. We evaluated an ultrasound probe and endoscopic ultrasonography (EUS) in the staging of superficial esophageal carcinoma. METHODS From October 1992 to September 1994, 22 patients with 25 lesions (7 mucosal carcinomas, 18 submucosal carcinomas) were examined preoperatively with both the probe and EUS. The ultrasound findings were compared with histologic findings in all cases. RESULTS The accuracy rates of the depth of invasion by the ultrasound probe were 86% (6 to 7) for mucosal carcinoma and 94% (17 to 18) for submucosal carcinoma, total 92% (23 to 25); by EUS 71% (5 to 7) for mucosal carcinoma and 78% (14 to 18) for submucosal carcinoma, total 76% (19 to 25). In the evaluation of lymph node metastasis, the overall accuracy was 56% by the ultrasound probe (sensitivity 25% and specificity 80%) and 67% by EUS (sensitivity 50% and specificity 80%). CONCLUSIONS The ultrasound probe was more convenient to use and more accurate than EUS in the evaluation of the depth of invasion of superficial esophageal carcinoma.

Endoscopic resection of Peutz-Jeghers polyps throughout the small intestine at double-balloon enteroscopy without laparotomy

BACKGROUND Small-bowel enteroscopy with the double-balloon method was developed to improve access to the small intestine. This study evaluated the usefulness of this method for the resection of small-intestinal Peutz-Jeghers polyps. METHODS Two patients with Peutz-Jeghers syndrome underwent nonsurgical double-balloon enteroscopic resection of polyps throughout the small intestine. OBSERVATIONS Multiple polyps in the jejunum were successfully resected via the oral route, as were the polyps in the ileum via the anal route. All 18 polyps (10-60 mm in size) were resected without subsequent bleeding or perforation. Histopathologically, 3 large polyps (>30 mm diameter) were hamartomas with adenomatous components. CONCLUSIONS Double-balloon enteroscopy was safe and useful for the diagnosis and the treatment of Peutz-Jeghers polyps throughout the small intestine. Double-balloon enteroscopic polypectomy might preclude complications of Peutz-Jeghers syndrome, including intussusception, bleeding, and tumorogenesis, thereby obviating the need for multiple laparotomies.

Intraductal papillary mucinous neoplasms of the pancreas: differentiation of malignant and benign tumors by endoscopic ultrasound findings of mural nodules.

Background and Aim:Intraductal papillary mucinous neoplasms (IPMNs) have a wide pathologic spectrum and it is difficult to differentiate malignant from benign tumors. The aim of this study was to identify predictors of malignancy using contrast-enhanced endoscopic ultrasound (CE-EUS). Subjects and Methods:In our institute, main duct type and mixed type IPMNs, branch duct type IPMNs with mural nodules, and IPMNs with coexistent invasive ductal cancer were indications for surgery. Eighty-seven IPMNs (14 main duct, 25 mixed, and 48 branch duct type) were resected and CE-EUS findings were compared with pathologic findings. Twelve clinicopathological variables and CE-EUS morphologic findings were assessed. Mural nodules defined as blood flow supplied protrusions were classified into 4 types: type I: low papillary nodule, type II: polypoid nodule, type III: papillary nodule, and type IV: invasive nodule. Results:Forty-two, 26, 16, and 3 were pathologically diagnosed as adenoma, noninvasive carcinoma, invasive IPMNs, and coexistent invasive ductal cancer, respectively. Multivariable logistic regression analysis showed that types III/IV mural nodule (odds ratio = 10.8; 95% confidential intervals = 2.75–56.1) and symptomatic IPMNs (odds ratio = 4.31; 95% confidential intervals = 1.37–14.7) were significant for malignancy. For mural nodule diameter, invasive IPMNs were significantly larger, but types III and IV mural nodules were more frequently associated with malignancy, particularly invasive cancer, at 88.9% and 91.7%, respectively. The diagnosis of IPMNs with types III or IV mural nodule as malignant resulted in a sensitivity of 60%, specificity of 92.9%, and accuracy of 75.9%. Conclusions:In conclusion, new morphologic criteria were useful to identify the malignant potentials of IPMNs.

Outcome after enteroscopy for patients with obscure GI bleeding : diagnostic comparison between double-balloon endoscopy and videocapsule endoscopy

BACKGROUND Double-balloon endoscopy (DBE) and videocapsule endoscopy (VCE) have been useful in managing obscure GI bleeding (OGIB). OBJECTIVE This study compared diagnostic yields of OGIB between DBE and VCE, and evaluated the outcome after DBE. DESIGN A single-center retrospective study. SETTING A tertiary-referral hospital. PATIENTS Between June 2003 and February 2007, 162 consecutive patients with OGIB were enrolled and treated. The diagnostic yield between VCE and DBE was compared in 74 patients. MAIN OUTCOME MEASUREMENTS Comparison of diagnostic yields between DBE and VCE, and the prognosis after DBE. RESULTS Of 162 patients, 95 (59%) were diagnosed with small-bowel diseases. They were treated by medical, enteroscopic, and surgical therapies (n = 35, 30, and 30, respectively). A comparison of the overall diagnostic yield between DBE (64%) and VCE (54%) was not significantly different. The 4 VCE-positive DBE-negative cases were because of inaccessibility of DBE. The 11 VCE-negative DBE-positive cases were because of a failure to detect lesions in the proximal small bowel and the Roux-en-Y loop, and because of diverticula. At a median follow-up of 555 days after DBE, 11 patients with small-bowel diseases developed rebleeding; all were treated by enteroscopic or medical therapies. Vascular diseases, comorbidities, especially portal hypertensive disease and chronic renal failure that required hemodialysis, and severe anemia (Hb </=7.0 g/dL) were associated with rebleeding. LIMITATIONS A retrospective comparative study, and participation bias. CONCLUSIONS A complementary combination between DBE and VCE was useful for the management of OGIB. In particular, patients with vascular disease, comorbidities, and severe anemia should be intensively treated.

MDM2 Promoter Polymorphism Is Associated With Both an Increased Susceptibility to Gastric Carcinoma and Poor Prognosis

PURPOSE Recently, a single-nucleotide polymorphism in the MDM2 promoter (SNP309) has been found to lower the age of onset of tumors and increase the occurrence of multiple primary tumors in Li-Fraumeni syndrome, and accelerate the development of sporadic adult soft tissue sarcoma. The aim of this study was to determine whether SNP309 is associated with susceptibility to gastric carcinoma and its prognosis. PATIENTS AND METHODS In a case-control study including 438 controls and 410 patients with sporadic gastric carcinoma, MDM2 SNP309 was genotyped. Serum pepsinogens (PGs) I and II were measured in 438 control subjects and 253 cases selected from 410 patients. Tumor tissue was immunostained with p53 and examined for mutations in exons 5 to 8 of p53 using polymerase chain reaction-based single strand conformational polymorphism analysis and direct sequencing. RESULTS The risk of overall gastric carcinoma for SNP309 (G/G) was significantly increased when compared with T carriers (P = .039), especially carcinomas with extragastric tumors (P = .005), carcinoma with severe atrophic gastritis positive for PG assay (PG I level < 70 ng/mL and PG I/II < 3.0; P = .005), antral carcinoma (P = .020), intestinal-type carcinoma (P = .023), p53-immunopositive carcinoma (P = .007), and carcinoma with p53 mutations (P = .007). No significant difference in age at diagnosis was observed among genotypes. SNP309 (G/G) was an independent marker of poor overall survival in advanced carcinoma (hazard ratio, 3.16; 95% CI, 1.22 to 8.20; P = .018). CONCLUSION This study provides evidence supporting the association of SNP309 with gastric carcinogenesis via p53 tumor suppressor pathway, extragastric tumorigenesis, and poor prognosis.

Small-bowel obstruction: diagnostic comparison between double-balloon endoscopy and fluoroscopic enteroclysis, and the outcome of enteroscopic treatment.

BACKGROUND Small-bowel obstruction (SBO) sometimes remains undiagnosed and untreatable without surgery. OBJECTIVE To evaluate the diagnostic yields of SBO between double-balloon endoscopy (DBE) and fluoroscopic enteroclysis (FE), and the outcome of enteroscopic treatment. DESIGN Single-center, retrospective, and prospective study. SETTING Tertiary-referral hospital. PATIENTS Between June 2003 and July 2007, 66 consecutive patients with SBO were enrolled, investigated, and treated. MAIN OUTCOME MEASUREMENTS A comparison of diagnostic yields between DBE and FE, and the prognosis after enteroscopic balloon dilation. RESULTS The diagnostic yield of DBE for SBO (95%) was higher than that of FE (71%) in 59 patients who underwent both examinations (P= .004). The first treatment included 27 surgical, 25 enteroscopic, and 14 conservative therapies. Of 47 enteroscopic balloon dilation procedures in 22 patients, 45 (96%) were successful. Of 16 patients with Crohns disease, 11 (69%) remained asymptomatic over the postdilation follow-up period but 5 relapsed: 2 recovered by repeated dilations, but 3 required surgery. Of 6 patients who had diseases other than Crohns disease, 4 (67%) remained asymptomatic but 2 relapsed: one with remission of metastasis recovered by repeated dilations, and one with ischemic enteritis required surgery. Anastomotic stricture was an independent marker of the symptom-free outcome (hazard ratio 0.037-0.084, P= .037). Two acute pancreatitis, one perforation, and one exacerbation of SBO complications occurred. LIMITATIONS Small sample size and participation bias. CONCLUSIONS DBE was useful for the diagnosis of SBO. Balloon dilation is considered an alternative to surgery in patients with fibrotic strictures both related and unrelated to Crohns disease.

Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer

BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120mg/day S-1 for 2 weeks with 100mg/m2 oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60mg/m2 cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.

Carcinoid tumors of the gastrointestinal tract: evaluation with endoscopic ultrasonography

To evaluate the usefulness of endoscopic ultrasonography for carcinoid tumors, we examined 29 patients with gastrointestinal carcinoid tumors (5 gastric, 7 duodenal, and 17 rectal). The smallest size detectable by endoscopic ultrasonography was 2 mm in diameter histologically. The cross-sectional image of the tumors was primarily oval to round. The internal echo was generally hypoechoic and homogeneous. The margins were clearly visualized, and the contour was somewhat smooth. The tumors were mainly located in the third layer. The second layer covered the tumor with the third layer at its base, and it abutted the tumor and became indistinct near its upper interface. These findings were especially recognized in lesions with submucosal invasion and were similar at all sites. The overall accuracy of determining the depth of invasion using endoscopic ultrasonography was 75% (27 of 36 lesions). Limited to the lesions detectable by endoscopic ultrasonography, the accuracy was 90%. Endoscopic ultrasonography was useful in determining the presence of local metastases. Moreover, endoscopic ultrasonography allowed direct detection of perigastrointestinal lymph node metastases (75%, three of four patients). In conclusion, endoscopic ultrasonography was found to be useful for the staging of gastrointestinal carcinoid tumors by determining depth of involvement and presence of perigastrointestinal lymph node metastases.

The utility of endoscopic ultrasonography and endoscopy in the endoscopic mucosal resection of early gastric cancer

OBJECTIVE To clarify the usefulness of endoscopic ultrasonography (EUS) and endoscopy in the endoscopic mucosal resection (EMR) of early gastric cancer.Patients/Methods—EMR was performed in 61 patients with early gastric cancer over the past five years. The accuracy of the assessment of the depth of cancerous invasion was studied in 49 patients who had EUS before EMR. Forty eight patients were treated with endoscopy alone; in these patients, EUS and endoscopic findings correlated with the clinical course. RESULTS Forty six patients showed no changes in the submucosal layer or deeper structures on EUS. Pathologically these included 37 patients with mucosal cancer and nine with submucosal cancer showing very slight submucosal infiltration. Three patients showed diffuse low echo changes in the submucosal layer on EUS; pathologically, these included two with submucosal cancer and one with mucosal cancer with a peptic ulcer scar within the tumour focus. Of 48 patients receiving endoscopic treatment alone, 45 showed no tumour recurrence or evidence of metastases on EUS and endoscopy. Three cases of recurrence were observed. Two of these patients had a surgical gastrectomy, and one was re-treated endoscopically. In the former cases, the surgical results correlated well with assessment by EUS and endoscopy. In addition, the latter patient who was re-treated endoscopically after evaluation with EUS and endoscopy has so far had no recurrence. CONCLUSION The combined use of EUS and endoscopy is effective in diagnosing the depth of cancerous invasion in patients undergoing EMR as well as in clarifying changes both within and between anatomic levels during follow up.