Genetic Predisposition to Ischemic Stroke

Background and Purpose—The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk.Methods—We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets).Results—In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33–2.31) and 1.99 (95% confidence interval, 1.19–3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001).Conclusions—The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors

Randomized phase II trial of first-line treatment with tailored irinotecan and S-1 therapy versus S-1 monotherapy for advanced or recurrent gastric carcinoma (JFMC31-0301)

Objective: The pharmacokinetics of irinotecan vary markedly between individuals. This study sought to compare tailored irinotecan and S-1 therapy with S-1 monotherapy for the treatment of patients with advanced/recurrent gastric cancer. Methods: Patients with advanced/recurrent gastric cancer were randomized to receive tailored irinotecan and S-1 (arm A) or S-1 alone (arm B). Arm A received S-1 (80-120 mg/m2/day) for 14 days, with irinotecan on days 1 and 15. The initial irinotecan dose of 75 mg/m2 (level 0) was adjusted for toxicity during the previous course. In arm B, S-1 (80-120 mg/day) was administered alone for 28 days, followed by 14 days without therapy. Results: Ninety-five patients were randomized (48 to arm A and 47 to arm B). The response rate of the primary tumor (Japanese criteria) was 25.0% in arm A (12/48) and 14.9% in arm B (7/47), whereas the response rates according to Response Evaluation Criteria In Solid Tumors (RECIST) were 27.8% (10/36) versus 21.9% (7/32). Hematological toxicity, anorexia, and diarrhea were significantly more common in arm A, but both arms had similar grade 3-4 toxicities. Conclusion: These findings suggest the usefulness of tailored irinotecan plus S-1 therapy for gastric cancer

Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer

Background. In Japan, a study comparing the effectiveness and safety of irinotecan plus S-1 (IRIS) with those of a combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in patients with advanced or recurrent colorectal cancer demonstrated that IRIS was non-inferior to FOLFIRI. We previously reported that IRIS is also effective as first-line treatment. Patients and Methods. Eligibility criteria included inoperable recurrent colorectal cancer with a confirmed diagnosis of adenocarcinoma, age ≥ 20 years, and no history of prior chemotherapy. S-1 (40-60 mg twice daily) was given orally on days 1 to 14, and irinotecan (100 mg/m2) and bevacizumab (5 mg/kg) were given intravenously on days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results. A total of 52 eligible patients were enrolled from October 2007 through March 2009. In safety analysis, the incidences of grade 3 or 4 adverse reactions were as follows: neutropenia, 27%; hypertension, 21%; and diarrhea, 17%. The overall response rate was 57.7%. Median progression-free survival was 16.7 months. Conclusion. IRIS plus bevacizumab is a well-tolerated, highly effective chemotherapeutic regimen that is easy to administer