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Purpose: We aimed to examine whether cardiorespiratory fitness and leg strength can be estimated based on their relationship with physical performance tests in Japanese breast cancer survivors. Methods: Participants were 50 sedentary women aged 20 to 59 years who have received breast surgery in the past 2 to 13 months after diagnosis of invasive breast cancer (stage I-IIa). Cardiorespiratory fitness and leg strength were measured by peak oxygen consumption (VO2peak), and one-repetition maximum for leg press (leg press 1RM). Physical performance tests were performed 6-min walk test, chair stand test, and grip strength. Using multiple regression analysis, we developed prediction equations for VO2peak and leg strength based on their associations with the physical performance tests. The validity of the estimation equations was assessed using Bland–Altman plots. Results: Mean age, VO2peak, and leg press 1RM were 48 ± 6 years, 25.0 ± 3.6 mL/kg/min, and 95 ± 32 kg, respectively. Multiple regression analysis yielded 6-min walk test distance, age, height, and body weight as predictors of VO2peak. Measured VO2peak and predicted VO2peak showed a moderate positive correlation (r = 0.463, p < 0.001). Chair stand test, grip strength, age, height, and body weight were selected as predictors of leg press 1RM. There was a strong positive correlation between predicted and measured leg press 1RM (r = 0.754, p < 0.001). Conclusion: The results suggest that leg strength can be predicted using physical performance tests. However, further examination may be needed to determine whether cardiorespiratory fitness can be predicted based on 6-min walk test. [ABSTRACT FROM AUTHOR]

A binary classification problem is common in medical field, and we often use sensitivity, specificity, accuracy, negative and positive predictive values as measures of performance of a binary predictor. In computer science, a classifier is usually evaluated with precision (positive predictive value) and recall (sensitivity). As a single summary measure of a classifier's performance, F1 score, defined as the harmonic mean of precision and recall, is widely used in the context of information retrieval and information extraction evaluation since it possesses favorable characteristics, especially when the prevalence is low. Some statistical methods for inference have been developed for the F1 score in binary classification problems; however, they have not been extended to the problem of multi-class classification. There are three types of F1 scores, and statistical properties of these F1 scores have hardly ever been discussed. We propose methods based on the large sample multivariate central limit theorem for estimating F1 scores with confidence intervals. [ABSTRACT FROM AUTHOR]

The effect of duration of cigarette smoking cessation on colorectal cancer risk by molecular subtypes remains unclear. Using duplication-method Cox proportional-hazards regression analyses, we examined associations between duration of smoking cessation and colorectal cancer risk according to status of CpG island methylator phenotype (CIMP), microsatellite instability, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, or DNA methyltransferase-3B (DNMT3B) expression. Follow-up of 134,204 individuals in 2 US nationwide prospective cohorts (Nurses' Health Study (1980–2008) and Health Professionals Follow-up Study (1986–2008)) resulted in 1,260 incident rectal and colon cancers with available molecular data. Compared with current smoking, 10–19, 20–39, and ≥40 years of smoking cessation were associated with a lower risk of CIMP-high colorectal cancer, with multivariate hazard ratios (95% confidence intervals) of 0.53 (0.29, 0.95), 0.52 (0.32, 0.85), and 0.50 (0.27, 0.94), respectively (Ptrend = 0.001), but not with the risk of CIMP-low/CIMP-negative cancer (Ptrend = 0.25) (Pheterogeneity = 0.02, between CIMP-high and CIMP-low/CIMP-negative cancer risks). Differential associations between smoking cessation and cancer risks by microsatellite instability (Pheterogeneity = 0.02), DNMT3B expression (Pheterogeneity = 0.03), and BRAF (Pheterogeneity = 0.10) status appeared to be driven by the associations of CIMP-high cancer with microsatellite instability–high, DNMT3B-positive, and BRAF-mutated cancers. These molecular pathological epidemiology data suggest a protective effect of smoking cessation on a DNA methylation–related carcinogenesis pathway leading to CIMP-high colorectal cancer. [ABSTRACT FROM PUBLISHER]

The minor allele (G) of rs4939827, a SMAD7 (18q21) intronic variant, is associated with a lower risk of developing colorectal cancer (CRC) and poorer survival after diagnosis. Our objective was to evaluate the associations of this variant with different tumor phenotype and intratumoral molecular characteristics. We evaluated 1509 CRC cases and 2307 age-matched controls nested within the Nurses’ Health Study and the Health Professionals Follow-up Study. We used the TaqMan assay to genotype rs4939827 and logistic regression to assess the association of rs4939827 with risk of CRC according to different phenotypic and molecular characteristics. We found that the minor allele (G) in rs4939827 (SMAD7, 18q21) was associated with a lower risk of developing tumor stage pT1 or pT2 CRC [multivariate odds ratio (OR), 0.73; 95% confidence interval (CI) 0.62–0.87] but not tumor stage pT3 or pT4 (multivariate OR, 1.07; 95% CI 0.93–1.23, P for heterogeneity = 1.2 × 10−4). The association between rs4939827 and CRC also significantly differed by methylation of RUNX3 (P for heterogeneity = 0.005). Among those with CRC, the minor allele (G) in rs4939827 was significantly associated with poorer overall survival (hazards ratio, 1.20; 95% CI, 1.02–1.42). We can conclude that the minor allele (G) of the germline intronic SMAD7 variant rs4939827 is associated with a lower risk of CRC with earlier tumor stage and CRC without methylation of the tumor suppressor RUNX3. These findings suggest that individuals with this SMAD7 variant that develop CRC are more probably to have tumors with greater invasiveness and methylation of RUNX3, which potentially contributes to their poorer observed survival. [ABSTRACT FROM PUBLISHER]

Background: Mononucleotide tracts in the coding regions of the TGFBR2 and BAX genes are commonly mutated in microsatellite instability-high (MSI-high) colon cancers. The receptor TGFBR2 plays an important role in the TGFB1 (transforming growth factor-b, TGF-b) signaling pathway, and BAX plays a key role in apoptosis. However, a role of TGFBR2 or BAX mononucleotide mutation in colorectal cancer as a prognostic biomarker remains uncertain. Methodology/Principal Findings: We utilized a database of 1072 rectal and colon cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study). Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusted for clinical, pathological and molecular features including the CpG island methylator phenotype (CIMP), LINE-1 methylation, and KRAS, BRAF and PIK3CA mutations. MSI-high was observed in 15% (162/1072) of all colorectal cancers. TGFBR2 and BAX mononucleotide mutations were detected in 74% (117/159) and 30% (48/158) of MSI-high tumors, respectively. In Kaplan-Meier analysis as well as univariate and multivariate Cox regression analyses, compared to microsatellite stable (MSS)/MSI-low cases, MSI-high cases were associated with superior colorectal cancer-specific survival [adjusted HR, 0.34; 95% confidence interval (CI), 0.20-0.57] regardless of TGFBR2 or BAX mutation status. Among MSI-high tumors, TGFBR2 mononucleotide mutation was associated with CIMP-high independent of other variables [multivariate odds ratio, 3.57; 95% CI, 1.66-7.66; p = 0.0011]. Conclusions: TGFBR2 or BAX mononucleotide mutations are not associated with the patient survival outcome in MSI-high colorectal cancer. Our data do not support those mutations as prognostic biomarkers (beyond MSI) in colorectal carcinoma. [ABSTRACT FROM AUTHOR]

Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5×10-7) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30×10-7, 3.30×10-7, and 4.41×10-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Gaps in colonoscopy skills among endoscopists, primarily due to experience, have been identified, and solutions are critically needed. Hence, the development of a real-time robust detection system for colorectal neoplasms is considered to significantly reduce the risk of missed lesions during colonoscopy. Here, we develop an artificial intelligence (AI) system that automatically detects early signs of colorectal cancer during colonoscopy; the AI system shows the sensitivity and specificity are 97.3% (95% confidence interval [CI] = 95.9%–98.4%) and 99.0% (95% CI = 98.6%–99.2%), respectively, and the area under the curve is 0.975 (95% CI = 0.964–0.986) in the validation set. Moreover, the sensitivities are 98.0% (95% CI = 96.6%–98.8%) in the polypoid subgroup and 93.7% (95% CI = 87.6%–96.9%) in the non-polypoid subgroup; To accelerate the detection, tensor metrics in the trained model was decomposed, and the system can predict cancerous regions 21.9 ms/image on average. These findings suggest that the system is sufficient to support endoscopists in the high detection against non-polypoid lesions, which are frequently missed by optical colonoscopy. This AI system can alert endoscopists in real-time to avoid missing abnormalities such as non-polypoid polyps during colonoscopy, improving the early detection of this disease. [ABSTRACT FROM AUTHOR]

Thymic carcinoma (TC) is a rare cancer with a poor prognosis and limited treatment options, especially after relapse. In this open-label, two-stage, multicentre, single-arm and phase II trial, the main eligibility criteria were unresectable or recurrent TC, an Eastern Cooperative Oncology Group–performance status of 0 or 1, progression after at least one chemo(radio)therapy and no history of autoimmune disease. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. The primary end-point was response rate (RR) as evaluated by central review using Response Evaluation Criteria In Solid Tumours (RECIST), version 1.1. The planned sample size was 15 for each stage, with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5% and power of 80%. Between July 1 and August 16 2016, 15 patients were accrued in the first stage. Response was assessable in all patients, and 13 had squamous histology. Median follow-up time was 14.1 months (range: 2.4–17.5). The median number of nivolumab received was eight (range: 3–33). RR was 0% (95% confidential interval [CI]: 0–21.8). Eleven patients had stable disease (SD) including five patients with SD for 24 or more weeks. Median progression-free survival was 3.8 months (95% CI: 1.9–7.0). Two patients experienced immune-related serious adverse events (grade III aspartate aminotransferase (AST) increase and grade II adrenal insufficiency). Because the early termination criteria (less than one responder) were fulfilled during the first stage, the patient accrual was terminated. Despite the small number of patients, nivolumab was unable to produce tumour shrinkage by RECIST in previously treated unresectable or recurrent TC. • Thymic carcinoma (TC) is a rare cancer with a poor prognosis and limited treatment options. • This is the first phase II trial of nivolumab for pretreated unresectable or recurrent TC. • Nivolumab produced no responders among the 15 patients accrued during the first stage. • Only two patients developed serious immune-related adverse events, both of which were resolved. • However, the disease control rate of 73% suggested some clinical benefit of nivolumab in TC. [ABSTRACT FROM AUTHOR]

Abstract: Background: Evidence suggests that insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3, also known as IMP3) represents a promising cancer biomarker. However, the clinical, pathological, molecular and prognostic features of IGF2BP3-positive colorectal cancers remain uncertain. Materials and methods: We evaluated IGF2BP3 expression by immunohistochemistry in 671 rectal and colon cancer cases that form part of a molecular pathological epidemiology database. Cox proportional hazards regression models were used to compute mortality hazard ratio (HR), adjusting for clinical, pathological and molecular features, including microsatellite instability, the CpG island methylator phenotype, LINE-1 methylation and KRAS, BRAF and PIK3CA mutations. Results: Among 671 colorectal cancers, 234 (35%) tumours were positive for IGF2BP3. In contrast, normal colorectal epithelium was negative for IGF2BP3 in all 403 specimens of normal mucosa adjacent to carcinoma. IGF2BP3 positivity was associated with poor differentiation (p =0.0003), stage III-IV disease (p =0.0081), BRAF mutation (p =0.031), and LINE-1 hypomethylation (p =0.020). IGF2BP3 positivity was significantly associated with shorter colorectal cancer-specific [log-rank p <0.0001; multivariate HR, 1.37; 95% confidence interval (CI), 1.02–1.84] and overall survival (log-rank p =0.0004; multivariate HR, 1.32; 95% CI, 1.05–1.66). Conclusions: IGF2BP3 expression in colorectal cancer is associated with adverse clinical outcome. Our findings support a role for IGF2BP3 as a diagnostic and/or prognostic biomarker in colorectal cancer. [Copyright &y& Elsevier]

Purpose: Approximately 30% to 50% of contact lens (CL) wearers report dry eye symptoms. Meibomian gland dysfunction has been recognized as a possible cause of CL-related dry eye. This study investigated the influence of CL wear on the meibomian glands using a newly developed meibographic technique. Design: Cross-sectional observational case series. Participants: Contact lens wearers (n = 121; 47 men, 74 women; mean age±standard deviation, 31.8±8.0 years) and healthy volunteers (n = 137; 71 men, 66 women; mean age±standard deviation, 31.4±15.1 years). Methods: The following tests were performed: slit-lamp examinations of the eyelids, corneal and conjunctival staining using fluorescein, measurement of the tear film breakup time, evaluation of the meibomian glands using noncontact meibography, and measurement of tear production using the Schirmer I test. Partial or complete loss of the meibomian glands was scored for each eyelid using 4 grades (meiboscores): grade 0 (no loss of meibomian glands) through grade 3 (the area characterized by gland dropout was more than 66% of the total area containing the meibomian glands). The meiboscores for the upper and lower eyelids were summed for each subject. Main Outcome Measures: Score of meibomian gland changes (meiboscore), tear film breakup time, and Schirmer test value. Results: The meiboscore was significantly higher (P<0.0001) in CL wearers (mean, 1.72; 95% confidence interval, 1.47–1.96) than in the control group (mean, 0.96; 95% confidence interval, 0.73–1.19). The average meiboscore of CL wearers was similar to that of a 60- to 69-year-old age group from the normal population. A significant positive correlation was observed between the duration of CL wear and the meiboscore. Conclusions: Contact lens wear is associated with a decrease in the number of functional meibomian glands. This decrease is proportional to the duration of CL wear. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]