Objective

To conduct a meta-analysis of randomized trials to comprehensively compare the effect of endovascular thrombectomy (EVT) versus intravenous thrombolysis (IVT) plus EVT on functional independence (modified Rankin Scale (mRS) 0-2) after acute ischemic stroke due to large vessel occlusions (AIS-LVO).

Methods

We searched Pubmed, EMBASE, CENTRAL, and clinicaltrials.gov from January 2000 to February 2021 and abstracts presented at the International Stroke Conference in March 2021 to identify trials comparing EVT alone versus IVT plus EVT in AIS-LVO. Five non-inferiority margins established in the literature were assessed: -15%, -10%, -6.5%, -5%, and -1.3% for the risk difference for functional independence at 90 days.

Results

Four trials met the selection criteria, enrolling 1633 individuals, with 817 participants randomly assigned to EVT alone and 816 to IVT plus EVT. Crude cumulative rates of 90-day functional independence were 46.0% with EVT alone versus 45.5% with IVT plus EVT. Pooled results showed the risk difference of functional independence was 1% (95% CI -4% to 5%) between EVT alone versus IVT plus EVT. The lower 95% CI bound of -4% fell within the non-inferiority margins of -15%, -10%, -6.5%, and -5%, but not -1.3%. Pooled results also showed the risk difference between EVT alone versus IVT plus EVT was 1% (95% CI -3% to 5%) for mRS 0-1, and 1% (95% CI -1% to 3%) for symptomatic intracranial hemorrhage.

Conclusions

This meta-analysis suggests that EVT alone is non-inferior to IVT plus EVT for several, but not the most stringent, non-inferiority margins.

Aims

Relative bleeding risks of different antithrombotic agents in heart failure (HF) patients is an important consideration in treatment decision making, making detailed comparative analysis desirable. The aim of this study was to conduct a network meta-analysis to investigate the major bleeding risk for individual novel oral anticoagulants (NOACs) vs. aspirin among patients with HF.

Methods and results

We searched Pubmed, EMBASE, Cochrane Collaboration Central Register of Controlled Clinical Trials, and Clinicaltrials.gov from 1966 to November 2019 to identify relevant randomized clinical trials. Studies comparing individual NOACs vs. aspirin were analysed using direct study-level meta-analysis. Studies comparing aspirin to warfarin and NOACs to warfarin were then additionally added using network (direct and indirect) study-level meta-analysis. Primary endpoint was major bleeding. Final analysis included nine trials with 34 367 participants, including one direct comparison trial (apixaban vs. aspirin) and eight indirect comparison trials against the shared warfarin comparator (four aspirin trials and one trial each of apixaban, dabigatran, rivaroxaban, and edoxaban). For apixaban, network meta-analysis combing direct and indirect comparison showed that major bleeding risk might not be different between apixaban and aspirin (odds ratio, 1.18 [95% confidence interval, 0.38 to 3.65]) in HF patients. In contrast, indirect-comparison meta-analysis showed dabigatran, rivaroxaban, and edoxaban compared with aspirin might be associated with a higher risk of major bleeding in HF patients.

Conclusions

In network meta-analysis, apixaban might be associated with a comparable risk of major bleeding compared with aspirin in patients with HF, while other NOACs might be associated with a higher risk. However, such results were not strongly convincing because of lack of direct comparison in an original trial and small sample size of trials and participants. A clinical trial directly comparing apixaban vs. aspirin in patients with HF and sinus rhythm may be worth undertaking.

Objective

To examine whether a history of sexually transmitted infections (STIs) or positive STI serology is associated with prevalent and incident benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS)-related outcomes in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Methods

Self-reported history of STIs (gonorrhoea, syphilis) was ascertained at baseline, and serological evidence of STIs (Chlamydia trachomatis, Trichomonas vaginalis, human papillomavirus (HPV)-16, HPV-18, herpes simplex virus type 2, human herpesvirus type 8 and cytomegalovirus) was detected in baseline serum specimens. We used data collected on the baseline questionnaire, as well as results from the baseline prostate-specific antigen (PSA) test and digital rectal examination (DRE), to define prevalent BPH/LUTS-related outcomes as evidence of LUTS (self-reported diagnosis of an enlarged prostate/BPH, BPH surgery or nocturia [waking ≥2 times/night to urinate]) and evidence of prostate enlargement (PSA > 1.4 ng/mL or prostate volume ≥30 mL) in men without prostate cancer. We created a similar definition of incident BPH using data from the follow-up questionnaire completed 5-13 years after enrolment (self-reported diagnosis of an enlarged prostate/BPH or nocturia), data on finasteride use during follow-up, and results from the follow-up PSA tests and DREs. We used Poisson regression with robust variance estimation to calculate prevalence ratios (PRs) in our cross-sectional analysis of self-reported (n = 32 900) and serologically detected STIs (n = 1 143) with prevalent BPH/LUTS, and risk ratios in our prospective analysis of self-reported STIs with incident BPH/LUTS (n = 5 226).

Results

Generally null results were observed for associations of a self-reported history of STIs and positive STI serologies with prevalent and incident BPH/LUTS-related outcomes, with the possible exception of T. vaginalis infection. This STI was positively associated with prevalent nocturia (PR 1.36, 95% confidence interval (CI) 1.18-1.65), prevalent large prostate volume (PR 1.21 95% CI 1.02-1.43), and any prevalent BPH/LUTS (PR 1.32 95% CI 1.09-1.61); too few men had information on both STI serologies and incident BPH/LUTS to investigate the associations between T. vaginalis infection and incident BPH/LUTS-related outcomes.

Conclusions

Our findings do not support associations of several known STIs with BPH/LUTS-related outcomes, although T. vaginalis infection may warrant further study.

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10^-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS_PSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10^-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10^-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10^-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions. METHODS: Germline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes (APC, ELP1, GPR161, PTCH1, SUFU, TP53) were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls. RESULTS: Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10-3), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10-8). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were ELP1 (p=3.0x10-4) and SUFU (p=1.4x10-3). CONCLUSION: Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)₂D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)₂D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (P _{heterogeneity} = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)₂D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.