Summary Background Current staging methods do not accurately predict the risk of disease recurrence and benefit of adjuvant chemotherapy for patients who have had surgery for stage II colon cancer. ...We postulated that expression patterns of multiple microRNAs (miRNAs) could, if combined into a single model, improve postoperative risk stratification and prediction of chemotherapy benefit for these patients. Method Using miRNA microarrays, we analysed 40 paired stage II colon cancer tumours and adjacent normal mucosa tissues, and identified 35 miRNAs that were differentially expressed between tumours and normal tissue. Using paraffin-embedded specimens from a further 138 patients with stage II colon cancer, we confirmed differential expression of these miRNAs using qRT-PCR. We then built a six-miRNA-based classifier using the LASSO Cox regression model, based on the association between the expression of every miRNA and the duration of individual patients' disease-free survival. We validated the prognostic and predictive accuracy of this classifier in both the internal testing group of 138 patients, and an external independent group of 460 patients. Findings Using the LASSO model, we built a classifier based on the six miRNAs: miR-21-5p, miR-20a-5p, miR-103a-3p, miR-106b-5p, miR-143-5p, and miR-215. Using this tool, we were able to classify patients between those at high risk of disease progression (high-risk group), and those at low risk of disease progression (low-risk group). Disease-free survival was significantly different between these groups in every set of patients. In the initial training group of patients, 5-year disease-free survival was 89% (95% CI 77·3–94·4) for the low-risk group, and 60% (46·3–71·0) for the high-risk group (hazard ratio HR 4·24, 95% CI 2·13–8·47; p<0·0001). In the internal testing set of patients, 5-year disease-free survival was 85% (95% CI 74·3–91·8) for the low-risk group, and 57% (42·8–68·5) for the high-risk group (HR 3·63, 1·86–7·01; p<0·0001), and in the independent validation set of patients, was 85% (79·6–89·0) for the low-risk group and 54% (46·4–61·1) for the high-risk group (HR 3·70, 2·56–5·35; p<0·0001). The six-miRNA-based classifier was an independent prognostic factor for, and had better prognostic value than, clinicopathological risk factors and mismatch repair status. In an ad-hoc analysis, the patients in the high-risk group were found to have a favourable response to adjuvant chemotherapy (HR 1·69, 1·17–2·45; p=0·0054). We developed two nomograms for clinical use that integrated the six-miRNA-based classifier and four clinicopathological risk factors to predict which patients might benefit from adjuvant chemotherapy after surgery for stage II colon cancer. Conclusion Our six-miRNA-based classifier is a reliable prognostic and predictive tool for disease recurrence in patients with stage II colon cancer, and might be able to predict which patients benefit from adjuvant chemotherapy. It might facilitate patient counselling and individualise management of patients with this disease. Funding Natural Science Foundation of China.
The aim of the present study was to investigate the long-term effects of alcohol septal ablation (ASA) on left ventricular (LV) and right ventricular (RV) remodeling in patients with obstructive ...hypertrophic cardiomyopathy (HC) using cardiovascular magnetic resonance (CMR). CMR was performed at baseline and 16 months after ASA in 38 patients with obstructive HC (mean age 48 ± 9 years) despite optimal medical treatment. ASA resulted in significant reductions of LV outflow tract gradient (mean 89 ± 22 vs 24 ± 12 mm Hg, p <0.001) and improvements in New York Heart Association functional class (p <0.001) during the follow-up period. LV remote mass and septal mass decreased from 98.34 ± 37.02 to 84.23 ± 34.71 g and from 77.56 ± 16.40 to 68.43 ± 14.02 g, respectively (p <0.001 for both) at 16-month follow-up. There were significant reductions of RV mass (mean 53.69 ± 7.12 vs 47.49 ± 6.17 g, p <0.001) and improvements in RV end-diastolic volume (mean 110.58 ± 22.47 vs 124.22 ± 24.17 ml, p <0.001) and the RV ejection fraction (p <0.001) during 16-month follow-up. Linear regression analysis showed that LV outflow tract gradient reduction was correlated significantly with LV remote mass reduction (r = 0.475, p = 0.003) and RV mass reduction (r = 0.535, p = 0.001) at 16-month follow-up. In conclusion, successful ASA can lead to positive biventricular reverse remodeling, showing significant reductions of RV and LV mass as well as increased RV and LV end-diastolic volumes during follow-up.
Background Disability and mortality represent the most relevant clinical outcomes after acute ischemic stroke. Recently, a number of prognostic models of acute ischemic stroke have been developed, ...but they have not been extensively validated. In this study, we evaluated the ability of 3 prognostic models including the iScore, the PLAN score, and the ASTRAL score in predicting clinical poor outcomes or mortality at 6 months in patients with acute ischemic stroke. Methods A total of 323 patients were divided into a good-prognosis group and a poor-prognosis group based on the modified Rankin Scale. Model discrimination was quantified by calculating the area under the receiver operating characteristic (ROC) curve, and calibration was assessed by Hosmer–Lemeshow goodness of fit test and Pearson correlation coefficient. Results We identified 96 (29.7%) patients with poor prognosis, including 21 who were dead. All 3 models showed good ability in predicting poor prognosis and mortality in patients with acute ischemic stroke (all ROC > .70). There was no difference between these 3 models in terms of sensitivity and accuracy (all P > .05). Conclusions The results of this study suggest that the iScore, the PLAN score, and the ASTRAL score were equal in predicting 6-month poor prognosis and mortality in patients with acute ischemic stroke. Overall, there was a very high correlation between observed and expected outcomes at the risk score level.
Background:
Aromatase inhibitors (AIs) are recommended as the preferred therapy for postmenopausal women with hormone receptor-positive (HR+) breast cancer. As a result, aromatase ...inhibitor-associated musculoskeletal symptom (AIMSS) have become a major problem leading to therapy discontinuation and decreased quality of life in patients receiving adjuvant AIs treatment. Multiple therapies have been attempted, but have yielded limited clinical results. This study will be performed to determine whether acupoint thread embedding (ATE) combined with Wenshen Bugu Decoction can effectively treat AIMSS, so as to improve the AIs medication compliance of postmenopausal breast cancer patients.
Methods:
This study will utilize a randomized, 2 parallel groups controlled trial design. A total of 128 eligible postmenopausal breast cancer women with AIMSS will be randomized to receive a 12-week treatment with Wenshen Bugu Decoction alone (control group) or in combination with ATE (treatment group) in a 1:1 ratio. The primary outcome will be the 12 week Brief Pain Inventory Worst Pain (BPI-WP) score. The secondary outcome measures will include response rate, Brief Pain Inventory-Short Form (BFI-SF), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Functional Assessment of Cancer Therapy-Endocrine Symptom (FACT-ES), Functional Assessment of Cancer Therapy-Breast (FACT-B), bone marrow density (BMD), blood markers of bone metabolite, Morisky medication adherence scale-8 (MMAS-8), credibility and expectancy, and survival outcomes.
Discussion:
This trial may provide clinical evidence that ATE combined with Wenshen Bugu Decoction can be beneficial for treating AIMSS among postmenopausal breast cancer survivors. Our findings will be helpful to enhance the quality of life and reduce the occurrence of AIs withdrawal.
Polyamines (PAs) play diverse roles in plant growth and development, as well as responses to environmental stimuli. In this study, the effects of PAs on rice salt tolerance were investigated. Salt ...stress resulted in the alteration of endogenous PAs levels in rice roots and leaves, where spermidine (Spd) and spermine (Spm) contents were increased, and putrescine (Put) content was decreased. RT-qPCR analysis revealed that PAs biosynthesis-related genes ADC1, ODC, and Arginase were significantly downregulated by salt treatment; however, SAMDC transcription was significantly upregulated. Exogenous Spm enhanced rice salt tolerance remarkably; however, exogenous Put and Spd undermined rice salt tolerance. Transgenic rice plants overexpressing SAMDC display a higher ratio of Spm/(Put+Spd) and enhanced salt tolerance. Salt stress also increased polyamine oxidase activities in rice, resulting in elevated reactive oxygen species (ROS) production. Our findings revealed that accumulation of Put and Spd substantially reduced salt tolerance in rice, likely by facilitating ROS production; whereas, conversion of Put and Spd to Spm contributes to rice salt tolerance.
Improved markers for predicting recurrence are needed to stratify patients with localised (stage I–III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel ...assay integrating three modalities—clinical, genomic, and histopathological—to improve the predictive accuracy for localised renal cell carcinoma recurrence.
In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI).
The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825–0·876 vs 0·608–0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio HR 4·57, 95% CI 2·49–8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19–6·59; p<0·0001).
Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy.
National Natural Science Foundation of China, and National Key Research and Development Program of China.
Summary Background China has a quarter of all patients with multidrug-resistant tuberculosis (MDRTB) worldwide, but less than 5% are in quality treatment programmes. In a before-and-after study we ...aimed to assess the effect of a comprehensive programme to provide universal access to diagnosis, treatment, and follow-up for MDRTB in four Chinese cities (population 18 million). Methods We designated city-level hospitals in each city to diagnose and treat MDRTB. All patients with smear-positive pulmonary tuberculosis diagnosed in Center for Disease Control (CDC) clinics and hospitals were tested for MDRTB with molecular and conventional drug susceptibility tests. Patients were treated with a 24 month treatment package for MDRTB based on WHO guidelines. Outpatients were referred to the CDC for directly observed therapy. We capped total treatment package cost at US$4644. Insurance reimbursement and project subsidies limited patients' expenses to 10% of charges for services within the package. We compared data from a 12 month programme period (2011) to those from a retrospective survey of all patients with MDRTB diagnosed in the same cities during a baseline period (2006–09). Findings 243 patients were diagnosed with MDRTB or rifampicin-resistant tuberculosis during the 12 month programme period compared with 92 patients (equivalent to 24 per year) during the baseline period. 172 (71%) of 243 individuals were enrolled in the programme. Time from specimen collection for resistance testing to treatment initiation decreased by 90% (from median 139 days IQR 69–207 to 14 days 10–21), the proportion of patients who started on appropriate drug regimen increased 2·7 times (from nine 35% of 26 patients treated to 166 97% of 172), and follow-up by the CDC after initial hospitalisation increased 24 times (from one 4% of 23 patients to 163 99% of 164 patients). 6 months after starting treatment, the proportion of patients remaining on treatment increased ten times (from two 8% of 26 patients to 137 80% of 172), and 116 (67%) of 172 patients in the programme period had negative cultures or clinical–radiographic improvement. Patients' expenses for hospital admission after MDRTB diagnosis decreased by 78% (from $796 to $174), reducing the ratio of patients' expenses to annual household income from 17·6% to 3·5% (p<0·0001 for all comparisons between baseline and programme periods). However, 36 (15%) patients did not start or had to discontinue treatment in the programme period because of financial difficulties. Interpretation This comprehensive programme substantially increased access to diagnosis, quality treatment, and affordable treatment for MDRTB. The programme could help China to achieve universal access to MDRTB care but greater financial risk protection for patients is needed. Funding Bill & Melinda Gates Foundation.
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