Background
Adjuvant therapy for gastric cancer is a standard among the world with no regimen selection criteria. Also, prognostic factors except for tumor staging have not been established. We aimed ...to identify prognostic and predictive markers for gastric cancer adjuvant therapy from large randomized controlled trials with standard lymph node dissection.
Methods
Three studies: ACTS-GC, CLASSIC, and SAMIT were found and selected for a pooled analysis, following PRISMA guideline. The integrity of individual participant data (IPD) was verified in the eligible 3527 patients registered, and fixed-effect model was used. The primary endpoint was relapse-free survival (RFS) and the secondary endpoint was overall survival (OS).
Results
Age was a significant prognostic factor in addition to tumor stages both in “surgery alone” and “adjuvant” groups. Adjuvant therapy was effective for every TN stage; however, it tended to be more effective in T1–2 than in T3–4. Also, it was more effective in low- or middle-BMI than in high-BMI group with Hazard ratio HRs: 0.58, 0.58, and 1.05, respectively. Capecitabine plus oxaliplatin (CAPOX) was more effective than S-1 for T1–2, N2–3, and differentiated type with HRs between 0.59 and 0.70, but with no difference among TNM stages. Combining histology to TN; the HRs in differentiated T1–2 N1–3 groups were between 0.29 and 0.45. For T3–4 N0–1 group, S-1 was likely to be effective, not significant.
Conclusions
Age is a significant prognostic factor both in surgery alone and adjuvant group. CAPOX is more effective for differentiated T1–2 tumors with lymph node metastasis.
Elucidation of the genetic susceptibility factors for diabetic retinopathy (DR) is important to gain insight into the pathogenesis of DR, and may help to define genetic risk factors for this ...condition. In the present study, we conducted a three-stage genome-wide association study (GWAS) to identify DR susceptibility loci in Japanese patients, which comprised a total of 837 type 2 diabetes patients with DR (cases) and 1,149 without DR (controls). From the stage 1 genome-wide scan of 446 subjects (205 cases and 241 controls) on 614,216 SNPs, 249 SNPs were selected for the stage 2 replication in 623 subjects (335 cases and 288 controls). Eight SNPs were further followed up in a stage 3 study of 297 cases and 620 controls. The top signal from the present association analysis was rs9362054 in an intron of RP1-90L14.1 showing borderline genome-wide significance (Pmet = 1.4×10(-7), meta-analysis of stage 1 and stage 2, allele model). RP1-90L14.1 is a long intergenic non-coding RNA (lincRNA) adjacent to KIAA1009/QN1/CEP162 gene; CEP162 plays a critical role in ciliary transition zone formation before ciliogenesis. The present study raises the possibility that the dysregulation of ciliary-associated genes plays a role in susceptibility to DR.
Summary Background The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to ...assess the superiority of sequential treatment (paclitaxel then tegafur and uracil UFT or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. Methods We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20–80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0–1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m2 per day), S-1 only (80 mg/m2 per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m2 ) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. Findings We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2–57·6) and that of sequential treatment was 57·2% (53·4–60·8; hazard ratio HR 0·92, 95% CI 0·80–1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2–56·6) and that of the S-1 group was 58·2% (54·4–61·8; HR 0·81, 95% CI 0·70–0·93, p=0·0048; pnon-inferiority =0·151). The most common grade 3–4 haematological adverse event was neutropenia (41 11% of 359 patients in the UFT group, 48 13% of 363 in the S-1 group, 46 13% of 355 in the paclitaxel then UFT group, and 83 23% of 356 in the paclitaxel then S-1 group). The most common grade 3–4 non-haematological adverse event was anorexia (21 6%, 24 7%, seven 2%, and 18 5%, respectively). Interpretation Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. Funding Epidemiological and Clinical Research Information Network.
Background/Aims
A risk-based approach to clinical research may include a central statistical assessment of data quality. We investigated the operating characteristics of unsupervised statistical ...monitoring aimed at detecting atypical data in multicenter experiments. The approach is premised on the assumption that, save for random fluctuations and natural variations, data coming from all centers should be comparable and statistically consistent. Unsupervised statistical monitoring consists of performing as many statistical tests as possible on all trial data, in order to detect centers whose data are inconsistent with data from other centers.
Methods
We conducted simulations using data from a large multicenter trial conducted in Japan for patients with advanced gastric cancer. The actual trial data were contaminated in computer simulations for varying percentages of centers, percentages of patients modified within each center and numbers and types of modified variables. The unsupervised statistical monitoring software was run by a blinded team on the contaminated data sets, with the purpose of detecting the centers with contaminated data. The operating characteristics (sensitivity, specificity and Youden’s J-index) were calculated for three detection methods: one using the p-values of individual statistical tests after adjustment for multiplicity, one using a summary of all p-values for a given center, called the Data Inconsistency Score, and one using both of these methods.
Results
The operating characteristics of the three methods were satisfactory in situations of data contamination likely to occur in practice, specifically when a single or a few centers were contaminated. As expected, the sensitivity increased for increasing proportions of patients and increasing numbers of variables contaminated. The three methods showed a specificity better than 93% in all scenarios of contamination. The method based on the Data Inconsistency Score and individual p-values adjusted for multiplicity generally had slightly higher sensitivity at the expense of a slightly lower specificity.
Conclusions
The use of brute force (a computer-intensive approach that generates large numbers of statistical tests) is an effective way to check data quality in multicenter clinical trials. It can provide a cost-effective complement to other data-management and monitoring techniques.
Background
The prognosis for stage 3 gastric cancer is not satisfactory, even with S-1 adjuvant chemotherapy. A randomized phase II trial was conducted to compare two and four courses of neoadjuvant ...S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. The primary endpoint was overall survival. We clarified the impact of these regimens on the secondary endpoints, including the clinical and pathological responses, chemotherapy-related toxicities, and surgical results.
Methods
Patients received S-1 (80 mg/m
2
for 21 days with 1 week’s rest)/cisplatin (60 mg/m
2
at day 8) or paclitaxel/cisplatin (80 and 25 mg/m
2
, respectively, on days 1, 8, and 15 with 1 week’s rest) as neoadjuvant chemotherapy.
Results
Eighty-three patients were assigned to arm A (two courses of SC,
n
= 21), arm B (four courses of SC,
n
= 20), arm C (two courses of PC,
n
= 21), and arm D (four courses of PC,
n
= 21). Pathological response rate was 43 % in arm A, 40 % in arm B, 29 % in arm C, and 38 % in arm D. Pathological complete response was only observed in arms B (10 %) and D (10 %). Most bone marrow toxicities, nausea, vomiting, alopecia, and fatigue were slightly higher but acceptable in arms B and D. Grade 3/4 surgical morbidities were not commonly observed in all four arms.
Conclusions
Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen.
Background
Peritoneal carcinomatosis is common after curative resection of gastric cancer. Intraperitoneal administration of paclitaxel (PTX) is known to control ovarian peritoneal metastases.
...Patients and methods
Patients with either linitis plastica or T4 cancer with high risk of peritoneal metastasis or recurrence but whose cancer was considered resectable were preregistered. After their cancer had been confirmed intraoperatively as resectable, the patients were randomized into either group A (PTX at 60 mg/m
2
intraperitoneally on the day of surgery and on days 14, 21, 28, 42, 49, and 56) or group B (PTX at 80 mg/m
2
administered intravenously by the identical schedule) before being treated by evidence-based chemotherapy. The primary end point was the 2-year survival rate. Safety, the secondary end point, was also analyzed. The study has been registered as UMIN000002957.
Results
Of 177 preregistered patients, 83 underwent treatment (39 by intraperitoneal administration and 44 by intravenous administration). There was no difference in patient demographics between the two groups. The incidences of surgical complications were similar between the groups, except for transient bowel obstruction observed exclusively in group A. The relative dose intensity of PTX was 81.4 % for group A and 76.3 % for group B. There was one death due to pulmonary thrombosis and a case of anaphylaxis that led to termination of the protocol treatment (group B). Other adverse events were mild and manageable.
Conclusions
Intraperitoneal administration of PTX from the day of gastrectomy did not result in a higher incidence of surgical complications and adverse reactions when compared with intravenous administration of PTX.
Background
Accuracy of the radiologic diagnosis of gastric cancer staging after neoadjuvant chemotherapy remains unclear.
Methods
Patients enrolled in the COMPASS trial, a randomized phase II study ...comparing two and four courses of S-1 plus cisplatin and paclitaxel and cisplatin followed by gastrectomy, were examined. The radiologic stage was determined by using thin-slice computed tomography (CT) or multidetector low CT by following Habermann’s method.
Results
A total of 75 patients registered in the COMPASS study who underwent surgical resection were examined in this study. The radiologic T and pathologic T stages were not significantly correlated (
p
= 0.221). The radiologic accuracy and rates of underdiagnosis and overdiagnosis were 42.7, 10.7, and 46.7%, respectively. When patients were stratified according to the pathologic response of the primary tumor, the correlation was not significant in either the responders (
n
= 32,
p
= 0.410) or the nonresponders (
n
= 43,
p
= 0.742). The radiologic accuracy was 37.5% in the responders and 42.7% in the nonresponders. The radiologic N and pathologic N stages were significantly correlated (
p
= 0.000). The radiologic accuracy and rates of underdiagnosis and overdiagnosis were 44, 29.3, and 26.7%, respectively. When stratifying the patients with measurable lymph nodes according only to the radiologic response, the correlation was significant in the nonresponders (
n
= 23,
p
= 0.035) but not in the responders (
n
= 28,
p
= 0.634). The radiologic accuracy was 39.3% in the responders and 52.1% in the nonresponders.
Conclusions
Restaging using CT after neoadjuvant chemotherapy for gastric cancer is considered to be inaccurate and unreliable. In particular, the radiologic T-staging determined after neoadjuvant chemotherapy should not be considered in clinical decision-making.
Introduction
We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the β-cell function for long-term periods in patients with slowly progressive type 1 ...diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA).
Methods
In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used.
Results
On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (
n
= 6,
n
= 5 at 48 months) compared to the P group (
n
= 5,
n
= 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (
p
= 0.014 and
p
= 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (
p
= 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased.
Conclusion
The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the β-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors.
Clinical trial registration
Japanese Clinical Trials Registry UMIN000003693.
To describe phenotype and genotype characteristics of age-related macular degeneration (AMD) in Japanese patients.
A case-control study.
A total of 550 case-control samples composed of 408 ...consecutive AMD cases and 142 controls.
Clinical information assessing age, gender, affected eyes, fundus features, and fluorescein/indocyanine green angiograms were systematically evaluated. Four single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the complement factor H (CFH) gene, 1 SNP (rs11200638) in the high-temperature requirement factor A1 (HTRA1) gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were assessed using TaqMan technology.
The clinical phenotype information and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms.
Of Japanese patients with neovascular AMD (nAMD), 219 (58.7%) had typical nAMD and 154 (41.3%) had polypoidal choroidal vasculopathy (PCV). The frequency of bilateral exudative involvement was similar between typical nAMD (15.5%) and PCV (13.6%) (P = 0.613). Significant soft drusen were observed in the fellow eyes of 88 (47.6%) of 185 patients with unilateral typical nAMD and in 25 (18.8%) of 133 patients with unilateral PCV (P = 1.24x10(-7)). A serous pigment epithelium detachment was seen in 55 (25.1%) of 219 patients with typical nAMD and in 64 (41.6%) of 154 patients with PCV. A significant association was noted in CFH-rs800292, CFH-rs1410996, CFH-rs2274700, and HTRA1-rs11200638 with AMD development (P = 2.36x10(-5), 7.18x10(-5), 7.18x10(-5), 2.70x10(-7), respectively; population attributable risk = 57.3%, 57.8%, 57.8%, and 58.9%, respectively). We estimated the highest-risk group to have an approximately 70-fold greater risk of nAMD compared with the lowest-risk group when analyzing a combination of 4 SNPs in the CFH and HTRA1 genes.
The Japanese AMD phenotype is characterized by a higher frequency of PCV, male predominance, and lower frequency of bilateral presentation compared with Caucasian AMD. Genotype analyses demonstrate a significant population attributable risk for SNPs in the CFH and HTRA1 genes and demonstrate joint effects for both genes. Gene variants in both CFH and HTRA1 contribute significantly to the AMD phenotype in a Japanese population.
Backgrounds
In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is ...platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294).
Methods
HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m
2
bid for 14 days plus cisplatin 80 mg/m
2
on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety.
Results
Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6–5.1), which was longer than the 2-month protocol-specified threshold (
p
< 0.001). Median OS was 13.7 months (95% CI 9.0–17.7) and ORR was 8/30 (26.7%) (95% CI 14.2–44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%).
Conclusions
XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1.
Trial registration
NCT01412294.
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