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1.
Background

Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.

Methods

Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.

Results

Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.

Conclusion

Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

  相似文献   
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Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially‐methylated genes between responders and non–responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression‐free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC.  相似文献   
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Background

On April 1, 2016, the Ministerial ordinance was enforced, and musculoskeletal examination of the extremities was made mandatory. From 2008, the University of us started musculoskeletal direct examination. To expand the examination, from 2016, we started to use the marksheet-type questionnaire. This study aimed to report the results of a musculoskeletal examination and investigate the association between musculoskeletal examination and age/gender and reports the reliability of the collected questionnaire data.

Methods

Direct musculoskeletal examination was performed in K school by 7 orthopedic surgeons. A marksheet-type screening questionnaire was distributed to all the elementary and junior high school students in Tsukuba and Hitachiomiya cities. The rates of abnormal findings for scoliosis, standing flexion, full squatting with the heels on the floor, general joint laxity, and standing on one leg, torticollis, and flat feet were calculated. We compared the results of the questionnaire and direct examination and calculated sensitivity, specificity, and odds ratio.

Results

A total of 1844 students in K school had direct examination, and 22,494 questionnaires were able to correct in Tsukuba and Hitachiomiya cities. The rates of abnormal findings in direct examination/questionnaire in scoliosis, standing flexion, full squat, general joint laxity, standing on one leg, torticollis and flat foot were 18.7% (344/1842)/5.1% (1094/21441), 20.2% (372/1841)/26.6% (5817/22078), 6.2% (114/1832)/6.9% (1516/22101), 7.5% (1648/22252), 4.9% (1100/22077), 2.2% (31/1844)/1.2% (272/21687), and 12.5% (231/1842)/8.7% (1785/20871), respectively. Sensitivities of the questionnaire for scoliosis, stand flexion, full squatting, torticollis, and flat feet were 16.8% (53/316), 67.9% (250/368), 48.2% (55/114), 18.9% (7/37), and 32.2% (65/202), respectively.

Conclusion

We reported the result of musculoskeletal examination. Accuracy and reliability of this questionnaire were not satisfactory. To perform high quality musculoskeletal examinations, we will aim to increase the quality of screening methods.  相似文献   
6.
The effect of alcohol intake on varicose veins (VV) has not been determined by its consumption level. The aim of this study was to investigate the association between alcohol intake and VV in an elderly general population. Using a cross‐sectional approach, the Shimane CoHRE Study data, comprising a total of 1060 participants, were analyzed. By multivariate regression analysis adjusted with basic characteristics, past work history, lifestyle‐related factors and medical history, compared with non‐drinkers, mild drinkers (<20.0 g/day) showed a significantly lower adjusted odds ratio (aOR) of VV (aOR = 0.64, P = 0.036). In a similar way, regular drinkers (1–5 days/week) showed a significantly lower aOR of VV when compared with occasional drinkers (aOR = 0.57, P = 0.032). VV and alcohol intake showed J‐curve relationships. In a stratified analysis by alcohol consumption levels, the association of smoking and VV were also observed in moderate to heavy drinkers and habitual drinkers. These findings can provide better understanding of pathophysiological mechanism and be used for evidence‐based patient education.  相似文献   
7.
This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.  相似文献   
8.
We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.  相似文献   
9.
We report a case of a manicurist who developed an allergic skin reaction to acrylates, manifested by itchy erythema, papules, vesicles and fissures on her hands, fingertips, forearm and eyelids. Patch tests showed positive reactions to three nail products used: ethylene glycol dimethacrylate, 2‐hydroxyethyl methacrylate, ethyl acrylate and 2‐hydroxyethyl acrylate in (meth)acrylate series. By using gel nail products, our patient became sensitized to 2‐hydroxyethyl methacrylate. We assume that this had been the trigger, leading to the occurrence of cross‐reactions between numerous acrylates including ethylene glycol dimethacrylate, ethyl acrylate and 2‐hydroxyethyl acrylate. When handling nail products, it is necessary to prevent airway sensitization, contact sensitization and cross‐reaction between various acrylates.  相似文献   
10.
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