The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Retinal Vascular Measurements and Mortality Risk: Evidence From the UK Biobank Study.

Purpose: This study aimed to investigate the association between quantitative retinal vascular measurements and the risk of all-cause and premature mortality. Methods: In this population-based cohort study using the UK Biobank data, we employed the Retina-based Microvascular Health Assessment System to assess fundus images for image quality and extracted 392 retinal vascular measurements per fundus image. These measurements encompass six categories of vascular features: caliber, density, length, tortuosity, branching angle, and complexity. Univariate Cox regression models were used to identify potential indicators of mortality risk using data on all-cause and premature mortality from death registries. Multivariate Cox regression models were then used to test these associations while controlling for confounding factors. Results: The final analysis included 66,415 participants. After adjusting for demographic, health, and lifestyle factors and genetic risk score, 18 and 10 retinal vascular measurements were significantly associated with all-cause mortality and premature mortality, respectively. In the fully adjusted model, the following measurements of different vascular features were significantly associated with all-cause mortality and premature mortality: arterial bifurcation density (branching angle), number of arterial segments (complexity), interquartile range and median absolute deviation of arterial curve angle (tortuosity), mean and median values of mean pixel widths of all arterial segments in each image (caliber), skeleton density of arteries in macular area (density), and minimum venular arc length (length). Conclusions: The study revealed 18 retinal vascular measurements significantly associated with all-cause mortality and 10 associated with premature mortality. Those identified parameters should be further studied for biological mechanisms connecting them to increased mortality risk. Translational Relevance: This study identifies retinal biomarkers for increased mortality risk and provides novel targets for investigating the underlying biological mechanisms.

Global evolving patterns and cross-country inequalities of inflammatory bowel disease burden from 1990 to 2019: a worldwide report.

AIMS: Inflammatory bowel disease (IBD) is a global disease. We aim to summarize the latest epidemiological patterns of IBD at the national, regional and global levels to give well-deserved attention and outline facilitating measures to reduce the disease burden. METHODS: We collected the incidence, prevalence, mortality and disability-adjusted life years (DALYs) of IBD in 204 countries and territories from 1990 to 2019 using data from the Global Burden of Disease Study 2019. We further calculated the estimated annual percentage change (EAPC) to qualify the temporal trends of IBD burden by sex, age and region over the past 30 years. RESULTS: Globally, a total of 404.55 thousand incident cases, 4898.56 thousand prevalent cases, 41.00 thousand deaths and 1622.50 thousand DALYs of IBD were estimated in 2019. The age-standardized DALYs decreased from 27.2 in 1990 to 20.15 per 100,000 people in 2019, with an EAPC of -1.04. The high socio-demographic index regions presented pronounced age-standardized rates (ASRs) consistently over the last 30 years. The high-income North America had the highest ASRs in 2019, followed by Western Europe and Australasia. No gender difference was observed after being stratified by sex. CONCLUSIONS: The accumulated IBD patients are expected to increase in the future due to the increased rate of IBD in developing countries, and social aging in developed countries. Understanding the changes in epidemiological patterns helps to provide evidence to mitigate the rising burden of IBD.

A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAFV600 mutant advanced melanoma (INTERIM).

BACKGROUND: BRAF+MEK inhibitors extend life expectancy of patients with BRAFV600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen. METHODS: Patients with BRAFV600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold. RESULTS: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAFV600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS. CONCLUSION: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.

Comparison of three-weekly and six-weekly pembrolizumab United Kingdom prescribing practice for advanced and resected melanoma.

BACKGROUND: Pembrolizumab is approved for the treatment of advanced and resected melanoma and was originally licensed as a three-weekly infusion (Q3W). In April 2019, a six-weekly infusion schedule (Q6W) was also approved. We retrospectively reviewed pembrolizumab prescribing for patients with melanoma across multiple United Kingdom (UK) centres to compare the safety and efficacy of Q6W with Q3W in real-world clinical practice. METHODS: Case notes for melanoma patients treated with pembrolizumab between April 2019 and August 2020 at eight UK centres were reviewed. Prespecified baseline characteristics of the Q3W and Q6W cohorts were compared, as well as toxicity and efficacy outcomes. Prescribers were surveyed about their prescribing practice. RESULTS: Two hundred seventy-seven patients were included: 116 commenced Q3W and 161 commenced Q6W pembrolizumab. The proportion of Q6W prescriptions varied by the centre (range 32-88%). Patient factors associated with an increased likelihood of receiving Q3W over Q6W were preexisting autoimmune comorbidity (odds ratio [OR] 0.33; 95% confidence interval [CI] 0.12-0.82) and treatment for advanced (versus resected) disease (OR 0.54; 95%CI 0.33-0.90). Toxicity outcomes were broadly similar for Q6W and Q3W: 14.9% versus 15.5% ≥ grade 3 Common Terminology Criteria for Adverse Events. Estimated 12-month recurrence-free survival for adjuvantly treated patients was 78.9% for Q6W and 74.2% for Q3W (hazard ratio [HR] 0.93; 95%CI 0.50-1.73). Estimated 12-month progression-free survival for advanced patients was 41.8% for Q6W and 55.9% for Q3W (HR 1.21, 95%CI 0.67-2.18). CONCLUSIONS: Q6W is an appropriate option for administering pembrolizumab, given the opportunity to reduce the health service resource burden.

Refining the Intraoperative Identification of Suspected High-Grade Glioma Using a Surgical Fluorescence Biomarker: GALA BIDD Study Report.

BACKGROUND: Improving intraoperative accuracy with a validated surgical biomarker is important because identifying high-grade areas within a glioma will aid neurosurgical decision-making and sampling. METHODS: We designed a multicentre, prospective surgical cohort study (GALA-BIDD) to validate the presence of visible fluorescence as a pragmatic intraoperative surgical biomarker of suspected high-grade disease within a tumour mass in patients undergoing 5-aminolevulinic acid (5-ALA) fluorescence-guided cytoreductive surgery. RESULTS: A total of 106 patients with a suspected high-grade glioma or malignant transformation of a low-grade glioma were enrolled. Among the 99 patients who received 5-ALA, 89 patients were eligible to assess the correlation of fluorescence with diagnosis as per protocol. Of these 89, 81 patients had visible fluorescence at surgery, and 8 patients had no fluorescence. A total of 80 out of 81 fluorescent patients were diagnosed as high-grade gliomas on postoperative central review with 1 low-grade glioma case. Among the eight patients given 5-ALA who did not show any visible fluorescence, none were high-grade gliomas, and all were low-grade gliomas. Of the seven patients suspected radiologically of malignant transformation of low-grade gliomas and with visible fluorescence at surgery, six were diagnosed with high-grade gliomas, and one had no tissue collected. CONCLUSION: In patients where there is clinical suspicion, visible 5-ALA fluorescence has clinical utility as an intraoperative surgical biomarker of high-grade gliomas and can aid surgical decision-making and sampling. Further studies assessing the use of 5-ALA to assess malignant transformation in all diffuse gliomas may be valuable.

Clinical and biological markers predictive of treatment response associated with metastatic pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) offers limited benefits, but survival outcomes vary. Reliable predictive response biomarkers to guide patient management are lacking. METHODS: Patient performance status, tumour burden (determined by the presence or absence of liver metastases), plasma protein biomarkers (CA19-9, albumin, C-reactive protein and neutrophils) and circulating tumour DNA (ctDNA) were assessed in 146 patients with metastatic PDAC prior to starting either concomitant or sequential nab-paclitaxel + gemcitabine chemotherapy in the SIEGE randomised prospective clinical trial, as well as during the first 8 weeks of treatment. Correlations were made with objective response, death within 1 year and overall survival (OS). RESULTS: Initial poor patient performance status, presence of liver metastases and detectable mutKRAS ctDNA all correlated with worse OS after adjusting for the different biomarkers of interest. Objective response at 8 weeks also correlated with OS (P = 0.026). Plasma biomarkers measured during treatment and prior to the first response assessment identified ≥10% decrease in albumin at 4 weeks predicted for worse OS (HR 4.75, 95% CI 1.43-16.94, P = 0.012), while any association of longitudinal evaluation of mutKRAS ctDNA with OS was unclear (ß = 0.024, P = 0.057). CONCLUSIONS: Readily measurable patient variables can aid the prediction of outcomes from combination chemotherapy used to treat metastatic PDAC. The role of mutKRAS ctDNA as a tool to guide treatment warrants further exploration. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Association of SCN1A, SCN2A, and UGT2B7 Polymorphisms with Responsiveness to Valproic Acid in the Treatment of Epilepsy.

PURPOSE: The efficacy of valproic acid (VPA) varies widely in clinical treatment of epileptic patients. Our study is aimed at exploring a potential association between polymorphisms of SCN1A, SCN2A, and UGT2B7 genetic factors and VPA responses. METHODS: In this observational study, a total of 114 epileptic patients only treated with VPA for at least 1 year were included to explore the genetic polymorphisms of drug responses (mean follow-up time: 3.68 ± 1.78 years). Thirty-one single-nucleotide polymorphisms (SNPs) in three candidate genes that related with drug-metabolizing enzymes and receptors were genotyped. RESULTS: Of the 31 SNPs, eight were significantly associated with VPA responses, including rs1381105, rs2162600, rs10197716, rs2119068, rs2119067, rs353116, rs353112 and rs6740895. The interaction between rs10197716 and rs2119068 was the most significantly correlated with VPA responses compared with other combinations (the highest VPA-responsive rate 0.92 versus the lowest VPA-responsive rate 0.33, p = 0.007). CONCLUSION: The study indicated that eight SNPs and SNP-SNP interaction may be associated with VPA responses in Chinese Han epileptic patients. The SNPs were rs1381105 (SCN1A), rs2162600 (SCN1A), rs10197716 (SCN2A), rs2119068 (SCN2A), rs2119067 (SCN2A), rs353116 (SCN2A), rs353112 (SCN2A) and rs6740895 (SCN2A), respectively. The interaction between the three pairs of rs10197716-rs2119068, rs10197716-rs11889342 and rs7598931-rs12233719 was the most significant for VPA. This implied that these SNPs may play an important role in the pharmacogenomics mechanism of valproic acid.

Trajectories of Haemoglobin and incident stroke risk: a longitudinal cohort study.

BACKGROUND: Studies have demonstrated that high or low haemoglobin increases the risk of stroke. Previous studies, however, performed only a limited number of haemoglobin measurements, while there are dynamic haemoglobin changes over the course of a lifetime. This longitudinal cohort study aimed to classify the long-term trajectory of haemoglobin and examine its association with stroke incidence. METHODS: The cohort consisted of 11,431 participants (6549 men) aged 20 to 50 years whose haemoglobin was repeatedly measured 3-9 times during 2004-2015. A latent class growth mixture model (LCGMM) was used to classify the long-term trajectory of haemoglobin concentrations, and hazard ratios (HRs) and 95% confidence intervals (95% CI) according to the Cox proportional hazard model were used to investigate the association of haemoglobin trajectory types with the risk of stroke. RESULTS: Three distinct trajectory types, high-stable (n = 5395), normal-stable (n = 5310), and decreasing (n = 726), were identified, with stroke incidence rates of 2.7, 1.9 and 3.2 per 1000 person-years, respectively. Compared to the normal-stable group, after adjusting for the baseline covariates, the decreasing group had a 2.94-fold (95% CI 1.22 to 7.06) increased risk of developing stroke. Strong evidence was observed in men, with an HR (95% CI) of 4.12 (1.50, 11.28), but not in women (HR = 1.66, 95% CI 0.34, 8.19). Individuals in the high-stable group had increased values of baseline covariates, but the adjusted HR (95% CI), at 1.23 (0.77, 1.97), was not significant for the study cohort or for men and women separately. CONCLUSIONS: This study revealed that a decreasing haemoglobin trajectory was associated with an increased risk of stroke in men. These findings suggest that long-term decreasing haemoglobin levels might increase the risk of stroke.

Trajectories of Lipids Profile and Incident Cardiovascular Disease Risk: A Longitudinal Cohort Study.

Background The association between low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides with cardiovascular disease (CVD) has been well studied. No previous studies considered trajectory of these lipids jointly. This study aims to characterize longitudinal trajectories of lipid profile jointly and examine its impact on incident CVD. Methods and Results A total of 9726 participants (6102 men), aged from 20 to 58 years who had lipids repeatedly measured 3 to 9 times, were included in the study. Three distinct trajectories were identified using the multivariate latent class growth mixture model: inverse U-shape (18.72%; n=1821), progressing (66.03%; n=6422), and U-shape (15.25%; n=1483). Compared with the U-shape class, the adjusted hazard ratio and 95% CI were 1.33 (1.05-1.68) and 1.49 (1.14-1.95) for the progressing and inverse U-shape class, respectively. The area under the curve was calculated using the integral of the model parameters. In the adjusted model, total and incremental area under the curve of lipid profile were significantly associated with CVD risk. Furthermore, the model-estimated levels and linear slopes of lipids were calculated at each age point according to the latent class growth mixture model model parameters and their first derivatives, respectively. After adjusting for covariates, standardized odds ratio of slope increases gradually from 1.11 (1.02, 1.21) to 1.21 (1.12, 1.31) at 20 to 40 years and then decreased to 1.02 (0.94, 1.11) until 60 years. Conclusions These results indicate that the lipids profile trajectory has a significant impact on CVD risk. Age between 20 and 42 years is a crucial period for incident CVD, which has implications for early lipids intervention.

Small-area spatial statistical analysis of malaria clusters and hotspots in Cameroon;2000-2015.

BACKGROUND: Malaria prevalence in Cameroon is a major public health problem both at the regional and urban-rural geographic scale. In 2016, an estimated 1.6 million confirmed cases, and 18,738 cases were reported in health facilities and communities respectively, with about 8000 estimated deaths. Several studies have estimated malaria prevalence in Cameroon using the analytical techniques at the regional scale. We aimed at identifying malaria clusters and hotspots at the urban-rural geographic scale from the Demographic and Health Survey (DHS) data for households between 2000 and 2015 using ArcGIS for intervention programs. METHODS: To identify malaria hotspots and analyze the pattern of distribution, we used the optimized hotspots toolset and spatial autocorrelation respectively in ArcGIS 10.3 for desktop. We also used Pearson's Correlation analysis to identify associative environmental factors using the R-software 3.4.1. RESULTS: The spatial distribution of malaria showed statistically significant clustered pattern for the year 2000 and 2015 with Moran's indexes 0.126 (P < 0.001) and 0.187 (P < 0.001) respectively. Meanwhile, the years 2005 and 2010 with Moran's indexes 0.001 (P = 0.488) and 0.002 (P = 0.318) respectively, had a random malaria distribution pattern. There exist varying degrees of malaria clusters and statistically significant hotspots in the urban-rural areas of the 12 administrative regions. Malaria cases were associated with population density and some environmental covariates; rainfall, enhanced vegetation index and composite lights (P < 0.001). CONCLUSION: This study identified urban-rural areas with high and low malaria clusters and hotspots. Our maps can be used as supportive tools for effective malaria control and elimination, and investments in malaria programs and research, malaria prevention, diagnosis and treatment, surveillance, should pay more attention to urban-rural geographic scale.

[Association between hematocrit and risk of incident hypertension: a cohort study].

Objective: To explore the association between hematocrit level and risk of incident hypertension. Method: Subjects who participated at least two times routine health check-up in Health Management Center of Shandong Province Hospital between January 2005 and January 2010 were eligible for inclusion. After excluding participants with known hypertension and other related diseases, a prospective cohort with 20 606 subjects (female: 8 218, male: 12 388) was established. Cox-proportional hazard model was used to assess the association between hematocrit and the development of hypertension for female and male respectively. Results: During the 51 352 person-years of follow-up, newly developed hypertension was confirmed in 3 695 cases. For female, the age-adjusted hazard ratios (95%CI) for incident hypertension were 1.00 (reference), 1.06(0.86-1.29), 1.37(1.14-1.65), 1.60(1.34-1.92), respectively (P for trend<0.000 1) through the 3 quartiles of hematocrit levels.After adjusting multiple factors (age, smoking, drinking habit, physical activity, body mass index(BMI), systolic blood pressure, fasting blood glucose, serum creatinine, high-density lipoprotein, gamma-glutamyl transferase, white blood count), the hazard ratios (95%CI) were 1.00(reference), 1.05(0.85-1.29), 1.25(1.03-1.51), and 1.22(1.00-1.48), respectively (P for trend=0.016 9). For male, the hazard ratio (the highest vs. the lowest hematocrit level) after adjusting age or age and life style factors (smoking, drinking habit, physical activity) was 1.23 (1.11-1.37), 1.21(1.09-1.35), respectively. Other analyses of relationship hematocrit with incident hypertension were not statistically significant in male. Conclusions: Higher hematocrit level is associated with higher risk of incident hypertension, especially in female.