The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has ...been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population.
A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia.
A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7.
Stroke patients with cognitive impairment no dementia (CIND) moderate are at higher risk of developing dementia, while CIND mild patients are not at increased risk of developing dementia.
Novel immune checkpoint blockade strategies are being evaluated in clinical trials and include targeting the lymphocyte activation gene 3 (LAG-3) checkpoint, alone or in combination with PD-1/PD-L1 ...blockade. We investigated LAG-3 expression and its prognostic value in a large series of breast cancer patients, and correlated LAG-3 expression with key biomarkers including PD-1 and PD-L1.
LAG-3 expression was evaluated by immunohistochemistry on two tissue microarray series incorporating 4322 breast cancer primary excision specimens (N = 330 in the training and N = 3992 in the validation set) linked to detailed clinicopathologic, biomarker and long-term clinical outcome data. PD-1 and PD-L1 expressions were also evaluated by immunohistochemistry. Stromal or intra-epithelial tumor infiltrating lymphocytes (sTILs or iTILs) expressing LAG-3 or PD-1 were assessed by absolute count. PD-L1 expression was evaluated as the percentage of positive carcinoma cells per core. Kaplan–Meier curves and Cox proportional hazard models were used for survival analyses.
After locking down interpretation cut-offs on the training set, LAG-3+ iTILs were found in 11% of cases in the validation set. In both sets, LAG-3+ iTILs were significantly associated with negative prognostic factors: young age, large tumor size, high proliferation, HER2E and basal-like breast cancer subtypes. In multivariate analyses, breast cancer patients with LAG-3+ iTILs had a significantly improved breast cancer-specific survival hazard ratio (HR): 0.71, 95% CI 0.56–0.90, particularly among estrogen receptor-negative patients (HR: 0.50, 95% CI 0.36–0.69). Furthermore, we found that 53% of PD-L1+ and 61% of PD-1+ cases were also positive for LAG-3+ iTILs. Concurrent infiltration of LAG-3+ and CD8+ iTILs was significantly associated with increased breast cancer-specific survival (HR: 0.49, 95% CI 0.32–0.74).
LAG-3+ iTILs are enriched in estrogen receptor-negative breast cancers and represent an independent favorable prognostic factor. In addition, a high proportion of PD-1/PD-L1+ tumors are co-infiltrated with LAG-3+ TILs, supporting potential immune checkpoint blockade combination strategies as a treatment option for breast cancer patients.
Exposure to ambient air pollution is associated with a significant number of deaths. Much of the evidence associating air pollution with adverse effects is from North American and Europe, partially ...due to incomplete data in other regions limiting location specific examinations. The aim of the current paper is to leverage satellite derived air quality data to examine the relationship between ambient particulate matter and all-cause and cause-specific mortality in Asia.
Six cohorts from the Asia Cohort Consortium provided residential information for participants, recruited between 1991 and 2008, across six countries (Bangladesh, India, Iran, Japan, South Korea, and Taiwan). Ambient particulate material (PM2·5) levels for the year of enrolment (or 1998 if enrolled earlier) were assigned utilizing satellite and sensor-based maps. Cox proportional models were used to examine the association between ambient air pollution and all-cause and cause-specific mortality (all cancer, lung cancer, cardiovascular and lung disease). Models were additionally adjusted for urbanicity (representing urban and built characteristics) and stratified by smoking status in secondary analyses. Country-specific findings were pooled via random-effects meta-analysis.
More than 300,000 participants across six cohorts were included, representing more than 4-million-person years. A positive relationship was observed between a 5 µg/m (Dockery et al., 1993) increase in PM2·5 and cardiovascular mortality (HR: 1·06, 95 % CI: 0.99, 1·13). The additional adjustment for urbanicity resulted in increased associations between PM2.5 and mortality outcomes, including all-cause mortality (1·04, 95 % CI: 0·97, 1·11). Results were generally similar regardless of whether one was a current, never, or ex-smoker.
Using satellite and remote sensing technology we showed that associations between PM2.5 and all-cause and cause-specific Hazard Ratios estimated are similar to those reported for U.S. and European cohorts.
This project was supported by the Health Effects Institute. Grant number #4963-RFA/18–5. Specific funding support for individual cohorts is described in the Acknowledgements.
Aim
The frail elderly surgical patient is at increased risk of morbidity after major surgery. A transdisciplinary Geriatric Surgery Service (GSS) has been shown to produce consistently positive ...results in our institution. A trans‐institutional transdisciplinary Start to Finish (STF) programme was initiated incorporating seamless prehabilitation and rehabilitation to enhance the outcome further.
Method
Patients who underwent major colorectal resection in Khoo Teck Puat Hospital and were managed under the GSS from January 2007 to December 2014 were included in this prospective study. The STF programme was initiated from January 2012. The surgical outcome of patients managed under the GSS before the initiation of STF was compared with that after its implementation.
Results
There were 57 patients after the initiation of the STF programme compared with 60 patients managed before STF. There were 26.4% and 25% of frail patients in the STF group compared with the non‐STF group (P = 0.874). The mean length of hospital stay was significantly shorter in the STF group (8.4 days vs 11.0 days, P = 0.029). Functional recovery in patients available for follow‐up at 6 weeks showed 100% (46/46) recovery in the elective STF group who received prehabilitation and 95.7% (45/47) in the elective non‐STF group who did not (P = 0.157). There were no significant differences in a Clavien–Dindo complication score of Grade 3 or more and 30‐day mortality between the two groups.
Conclusion
Through a trans‐institutional transdisciplinary approach, we managed to achieve a significantly shorter hospital stay in frail patients having colorectal surgery. All elective patients who received prehabilitation achieved full functional recovery.
Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with ...patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy.
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•N-linked glycosylation of PD-L1 hinders its recognition by PD-L1 antibodies•Removal of glycosylation enhances anti-PD-L1 signal in a variety of bioassays•Patient sample deglycosylation prevents false-negative detection of PD-L1•Deglycosylated PD-L1 is a more reliable biomarker to guide immunotherapy
Histological detection of PD-L1 may guide therapy with anti-PD-1/PD-L1 antibodies but some PD-L1-negative tumors respond to these treatments. Lee et al. show that enzymatic deglycosylation of tissue sections improves PD-L1 detection and its predictive value, and could potentially impact patient stratification.
ER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically ...relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only.
Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan–Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance.
All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%–100%).
Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.
► Production of methanol and ethanol from agricultural, forestry and animal waste. ► Sugarcane bagasse shows the highest potential for methanol production. ► Production of methanol is lowest with ...animal wastes. ► Tree stems show a promising potential for ethanol production. ► No ethanol production from animal wastes.
The production of methanol from agricultural, forestry, livestock, poultry, and fishery waste via pyrolysis was investigated. Pyrolysis was conducted in a tube furnace at 450–500°C. Sugarcane bagasse showed the methanol production (5.93wt.%), followed by roots and sawdust with 4.36 and 4.22wt.%, respectively. Animal waste offered the lowest content of methanol, as only 0.46, 0.80, and 0.61wt.% were obtained from fishery, goat, and cow waste, respectively. It was also observed that the percentage of methanol increased with an increase in volatile compounds while the percentage of ethanol increased with the percentage of ash and fix carbon. The data indicate that, pyrolysis is a means for production of methanol and ethanol after further optimization of the process and sample treatment.
Most of the human genome is transcribed into protein-noncoding RNAs (ncRNAs), including small ncRNAs and long ncRNAs (lncRNAs). Over the past decade, rapidly emerging evidence has increasingly ...supported the view that lncRNAs serve key regulatory and functional roles in mammal cells. HIV-1 replication relies on various cell functions. To date, while the involvement of host protein factors and microRNAs (miRNAs) in the HIV-1 life cycle has been extensively studied, the relationship between lncRNAs and HIV-1 remains uncharacterized. Here, we have profiled 83 disease-related lncRNAs in HIV-1-infected T cells. We found NEAT1 to be one of several lncRNAs whose expression is changed by HIV-1 infection, and we have characterized its role in HIV-1 replication. We In the abstract, added definition of INS OK, or should "cis-acting" be added?report here that the knockdown of NEAT1 enhances virus production through increased nucleus-to-cytoplasm export of Rev-dependent instability element (INS)-containing HIV-1 mRNAs. IMPORTANCE Long protein-noncoding RNAs (lncRNAs) play roles in regulating gene expression and modulating protein activities. There is emerging evidence that lncRNAs are involved in the replication of viruses. To our knowledge, this report is the first to characterize a role contributed by an lncRNA, NEAT1, to HIV-1 replication. NEAT1 is essential for the integrity of the nuclear paraspeckle substructure. Based on our findings from NEAT1 knockdown, we have identified the nuclear paraspeckle body as another important subcellular organelle for HIV-1 replication.
Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data ...provided by whole genome and transcriptome sequencing and analysis (WGTA) presents an opportunity to align a much larger proportion of patients to therapies.
Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number, and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected.
Clinically actionable targets were identified for 83% of patients, 37% of whom received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, PARP inhibitors, and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%), and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies.
Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.
NCT02155621
•A prospective study of 570 patients used whole genome and transcriptome analysis (WGTA) for real-time treatment options•Of 248 WGTA-informed treatments, 46% resulted in clinical benefit to the patient•RNA expression information was as valuable as DNA-based information for selecting treatments with clinical benefit•Integrated data informs selection of standard-of-care therapies, clinical trial enrollment and off-label use•This study supports the use of whole genome and transcriptome analysis in clinical cancer care
Abstract Purpose The primary purpose of this study was to measure the impact of the 21-gene Recurrence Score® result on systemic treatment recommendations and to perform a prospective health economic ...analysis in stage I–II, node-negative, oestrogen receptor positive (ER+) breast cancer. Methods Consenting patients with ER+ node negative invasive breast cancer and their treating medial oncologists were asked to complete questionnaires about treatment preferences, level of confidence in those preferences and a decisional conflict scale (patients only) after a discussion of their diagnosis and risk without knowledge of the Recurrence Score. At a subsequent visit, the assay result and final treatment recommendations were discussed prior to both parties completing a second set of questionnaires. A Markov health state transition model was constructed, simulating the costs and outcomes experienced by a hypothetical ‘assay naïve’ population and an ‘assay informed’ population. Results One hundred and fifty-six patients across two cancer centres were enrolled. Of the 150 for whom successful assay results were obtained, physicians changed their chemotherapy recommendations in 45 cases (30%; 95% confidence interval (CI) 22.8–38.0%); either to add (10%; 95% CI 5.7–16.0%) or omit (20%; 95% CI 13.9–27.3%) adjuvant chemotherapy. There was an overall significant improvement in physician confidence post-assay ( p < 0.001). Patient decisional conflict also significantly decreased following the assay ( p < 0.001). The simulation model found an incremental cost-effectiveness ratio of Canadian Dollars (CAD) $6630/quality-adjusted life years (QALY). Conclusion Within the context of a publicly funded health care system, the Recurrence Score assay significantly affects adjuvant treatment recommendations and is cost effective in ER+ node negative breast cancer.
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