Hazard Ratio Estimates Research Articles

Discovery of pathway-independent protein signatures associated with clinical outcome in human cancer cohorts

Proteomic data provide a direct readout of protein function, thus constituting an information-rich resource for prognostic and predictive modeling. However, protein array data may not fully capture pathway activity due to the limited number of molecules and incomplete pathway coverage compared to other high-throughput technologies. For the present study, our aim was to improve clinical outcome prediction compared to published pathway-dependent prognostic signatures for The Cancer Genome Atlas (TCGA) cohorts using the least absolute shrinkage and selection operator (LASSO). RPPA data is particularly well-suited to the LASSO due to the relatively low number of predictors compared to larger genomic data matrices. Our approach selected predictors regardless of their pathway membership and optimally combined their RPPA measurements into a weighted risk score. Performance was assessed and compared to that of the published signatures using two unbiased approaches: 1) 10 iterations of threefold cross-validation for unbiased estimation of hazard ratio and difference in 5-year survival (by Kaplan–Meier method) between predictor-defined high and low risk groups; and 2) a permutation test to evaluate the statistical significance of the cross-validated log-rank statistic. Here, we demonstrate strong stratification of 445 renal clear cell carcinoma tumors from The Cancer Genome Atlas (TCGA) into high and low risk groups using LASSO regression on RPPA data. Median cross-validated difference in 5-year overall survival was 32.8%, compared to 25.2% using a published receptor tyrosine kinase (RTK) prognostic signature (median hazard ratios of 3.3 and 2.4, respectively). Applicability and performance of our approach was demonstrated in three additional TCGA cohorts: ovarian serous cystadenocarcinoma (OVCA), sarcoma (SARC), and cutaneous melanoma (SKCM). The data-driven LASSO-based approach is versatile and well-suited for discovery of new protein/disease associations.

The effect of duration of therapy for treatment of Staphylococcus aureus blood stream infection: an application of cloning to deal with immortal-time bias in an analysis of data from a cohort study (BSI-FOO).

To estimate the effect of treatment duration on in-hospital mortality in patients with Staphylococcus aureus blood stream infection and demonstrate the biases that can arise when immortal-time bias is ignored. We compared three treatment strategies: short therapy (<10 days), intermediate (10-18 days) and long (>18 days). Twenty-eight-day all-cause in-hospital mortality. Using data from the BSI-FOO study, we implemented an approach proposed by Hernán to overcome confounding and immortal-time biases. The first stage is to clone all participants, so that each participant is assigned to each treatment strategy. Second, observations are censored when their data becomes inconsistent with their assigned strategy. Finally, inverse-probability weights are applied to adjust for potential selection. We compared our results to a naïve approach where immortal-time bias is ignored. Of the 1903 participants in BSI-FOO, 587 were eligible and included in the analysis. After cloning, the weighted estimates of hazard ratio of mortality for short versus long therapy was 1.74 (95% CI 1.36, 2.24) and for intermediate versus long therapy was 1.09 (0.98, 1.22). In the naïve approach, the hazard ratios with reference to the long therapy group are 37.4 (95% CI 18.9 to 74.4) in the short therapy group and 4.1 (95% CI 1.9 to 8.9) in the intermediate therapy group. Our findings suggest that duration of therapy >18 days is beneficial with respect to 28-day in-hospital mortality, however, there remains uncertainty around the efficacy of reducing duration of treatment to 10-18 days.

Novel antihyperglycaemic drugs and prevention of chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes: population based cohort study

ObjectiveTo determine whether the use of glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, separately, is associated with a decreased risk of...

Risk Factors for the Development of Post-Infectious Bronchiolitis Obliterans in Children: A Systematic Review and Meta-Analysis.

Post-infectious bronchiolitis obliterans (PIBO), one of the major complications of respiratory tract infection, is commonly underdiagnosed. To identify the risk groups that may develop PIBO and avoid misdiagnoses, we investigated the risk factors associated with the development of PIBO. We searched PubMed, Embase, and MEDLINE databases for studies that included risk factors for the development of PIBO published from inception to 13 June 2022. We limited our search to studies that reported the estimates of odds ratio (OR), hazard ratio (HR), or relative risks for developing PIBO. A fixed-effect and a random-effect model were used. We included seven studies reporting data on the risk factors for PIBO in 344 children with PIBO and 1310 control children. Twenty-two variables, including sex, age, respiratory pathogens, symptoms, laboratory and radiologic findings, and mechanical ventilation, were mentioned in at least one study. The significant risk factors mentioned in two or more studies included elevated lactate dehydrogenase levels, pleural effusion, hypoxemia, sex, and mechanical ventilation. The significance of the duration of hospitalization and fever as risk factors for PIBO differed when the studies were classified according to the statistical method. In addition, the risk factors differed according to respiratory infection pathogens. This meta-analysis identified potential risk factors associated with the development of PIBO. The results of this study highlight the importance of avoiding misdiagnosis and help establish management strategies for patients at a high risk of developing PIBO.

Racial Disparities in Patients with Stage IIIC Endometrial Cancer

<h3>Purpose/Objective(s)</h3> To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma (EC). <h3>Materials/Methods</h3> A retrospective multi-institutional cohort study was conducted across 13 Northern American academic centers and included patients with stage IIIC endometrial carcinoma (EC) who received both chemotherapy and radiation in an adjuvant setting. Overall survival (OS) and recurrence-free survival (RFS) were calculated by Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. Propensity score matching was used to estimate the effect of race on survival outcomes. Statistical analyses were conducted using statistical software. <h3>Results</h3> A total of 90 Black and 568 non-Black patients (83%) were identified with a median age at diagnosis of 62 (Interquartile Range (IQR) 55-70). Median follow-up was 45.3 months (IQR 24-71 months). Black patients were significantly older (p<0.0001), had significantly more non-endometrioid histology (p<0.0001), grade 3 tumors (p<0.0001) and were more likely to have >1 positive paraaortic lymph nodes (PALN) compared to non-black patients. The presence of lymphovascular space invasion (LVSI), depth of myometrial involvement, number of total nodes involved, adnexal and cervical involvement and stage were not correlated with race (all p>0.1). As for treatment type, chemoradiotherapy sequencing approach was not correlated with race and no difference in number of chemotherapy cycles between Black and non-Black patients (p=0.32) was observed. Black patients were more often treated with external beam radiation therapy (EBRT) (43.3% and 24%, respectively) while a higher proportion of non-black patients received both EBRT and vaginal cuff brachytherapy (VBT) (65% vs. 38 %) (P<0.0001) despite similar cervical involvement. The 5-year estimated OS and RFS rates were 45% and 47% compared to 77% and 68% for Black patients vs. non-black patients, respectively (p<0.001). After propensity score matching, the 2 groups were well balanced for most of the covariates (age, histology, stage, grade, number of positive PALN, adnexal and cervical involvement) except for depth of myometrial invasion and radiation type. The estimated hazard ratios (HRs) of Black vs. non-Black patients were 1.613 (95% CI = (1.01, 2.575), p-value = 0.045) for OS and 1.487 (95% CI = (0.906, 2.440), p-value = 0.116) for RFS, indicating that Black patients have significantly worse OS. RFS differences did not reach statistical significance. <h3>Conclusion</h3> Compared to non-Black patients, Black patients have higher rates of non-endometrioid histology, grade 3 tumors and number of PALNs. After propensity score matching, Black patients had worse OS but no statistically significant difference in RFS. Racial disparities could be mitigated by better access to care, equitable inclusion on randomized trials, and identification of genomic/molecular differences to better tailor adjuvant treatment.

The Prognostic Value of Circulating Tumor DNA during Post-Radiotherapy Surveillance in Esophageal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Esophageal squamous cell carcinoma (ESCC) is a common form of esophageal carcinoma in East Asian countries, while there is an unmet need for reliable biomarkers aiding in early detection of relapse/metastasis and prognosis stratification. Here, we investigated whether circulating tumor DNA (ctDNA) tests could detect relapse/metastasis prior to radiological imaging, and explored the prognostic value of ctDNA monitoring after radiotherapy/chemoradiotherapy (RT/CRT) in ESCC. <h3>Materials/Methods</h3> Treatment-naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose (37.8–50.4Gy to subclinical areas at risk and 44.94–59.92 Gy to the gross tumor and involved lymph nodes). Serial plasma samples were collected at baseline (T₀) and four landmark time-points: week 4 of RT/CRT (T₁), 1–3 months post RT/CRT (T₂), 3–6 months post RT/CRT (T₃), and at least 12 months post RT/CRT (T₄). ctDNA was analyzed using next-generation sequencing of 474 cancer-relevant genes. Kaplan-Meier curves were generated for progression-free survival (PFS), overall survival (OS), locoregional recurrence-free survival (LRFS), as well as distant metastasis-free survival (DMFS), and Cox proportional hazards models were fitted to estimate hazard ratios (HR) with 95% confidence intervals (CI). <h3>Results</h3> A total of 139 plasma samples from 40 eligible patients were analyzed (median age: 64 [range: 40–78], 88% males, 95% stage III/IV, 70% baseline ctDNA shedding), and the median follow-up time was 20.6 months (range: 12.2–33.3). Radiological progression was observed in 17 patients, of whom 13 (77%) had detectable post-RT/CRT ctDNA with a mean lead time of 5.5 months compared to radiological imaging. ctDNA positivity at T₁ or T₂ was associated with inferior PFS (T₁, HR: 3.60, 95% CI: 1.30–10.01; T₂, HR: 5.45, 95% CI: 1.72–17.26) and OS (T₁, HR: 2.70, 95% CI: 0.99–7.36; T₂, HR: 4.02, 95% CI: 1.27–12.75). Patients achieving ctDNA clearance between T₀ and T₁/T₂ had superior PFS compared to those with failure to clear ctDNA (T₁, HR: 0.31, 95% CI: 0.08–1.13; T₂, HR: 0.11; 95% CI: 0.02–0.61). Furthermore, ctDNA positivity at T₁ was identified as a potential indicator of worse LRFS (HR: 4.43, 95% CI: 1.31–15.04), while it was less profoundly associated with DMFS. <h3>Conclusion</h3> ctDNA was identified as a robust biomarker for early detection of disease progression and post-RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility in guiding post-RT/CRT treatments for locoregional control.

Mortality risk increased in colonic diverticular disease: a nationwide cohort study

There are limited population cohort data on overall and cause-specific mortality in colonic diverticular disease. To measure overall and cause-specific mortality in colonic diverticular disease, compared to matched reference individuals and siblings. Population-based cohort study ("the ESPRESSO study") in Sweden. There were 97,850 cases with a medical diagnosis of diverticular disease (defined by international classification of disease codes) and colorectal histology identified in 1987-2017 from histopathology reports. The mortality risk between individuals with colonic diverticular disease and matched reference individuals (n=453/634) from the general population was determined. Cox regression models adjusted for comorbidity estimated hazard ratios (HRs) for all-cause mortality. During follow-up, there were 32,959 deaths in individuals with colonic diverticular disease (44/1000 person-years) compared with 127,153 in matched reference individuals (34/1000 person-years), resulting in an HR of 1.27 (95%CI 1.25-1.29). Also compared to siblings, colonic diverticular disease patients were at increased risk of death, HR 1.39 (95%CI 1.33-1.45). Mortality risks were further increased in colonic diverticular disease patients with a colorectal biopsy showing any mucosal inflammation HR 1.36; (95%CI 1.33-1.38), with the most significant increase during the first year after diagnosis HR 2.18; (95%CI 2.05-2.32). Mortality in colonic diverticular disease is increased over reference individuals in the general population. The presence of mucosal inflammation on colorectal biopsies is a predictor of increased risk of mortality.

Age, sex, race, BMI, and duration of diabetes differences in cardiovascular outcomes with glucose lowering drugs in type 2 diabetes: A systematic review and meta-analysis.

SummaryBackgroundSummarized data of cardiovascular outcomes trials (CVOTs) of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have shown a reduction in major adverse cardiovascular event (MACE), whether these benefits are extended in certain risk groups (elderly or obese patients or those with a longer duration of diabetes) or certain minorities (Black participants) are not clearly established. We aimed to provide overall hazard ratios (HRs) estimates for MACE of SGLT2i and GLP-1 RAs stratified by age (< 65 years vs. ≥ 65 years and < 75 years vs. ≥ 75 years), sex (male vs. female), race (Black vs. White, Black vs. Asian, and White vs. Asian), body mass index (BMI: < 30 kg/m2 vs. ≥ 30 kg/m2), and duration of diabetes (< 10 years vs. ≥ 10 years).MethodsWe performed a MEDLINE database search from inception up to July 31, 2022 to identify all placebo-controlled phase 3 CVOTs that evaluated the efficacy of SGLT2i and GLP-1 RAs on vascular events at least 1-year after randomisation in participants with type 2 diabetes, and we selected those reporting hazard ratios (HRs) for the specific risk groups for MACE. Differences on MACE in risk groups were examined using a random-effect meta-analysis. The study protocol was registered on PROSPERO (CRD42022347901).FindingsA total of 11 studies fulfilled the prespecified criteria, comprising 96,580 patients with T2D were included. Of these patients, 61,975 (64.2%) were male, 34,605 (35.8%) were female, and race groups included 74,982 (77.6%) White, 7760 (8.0%) Asian, and 4023 (4.2%) Black. In two SGLT2i trials, the HR (95% CI) for long-term diabetes duration more than10 years versus short duration was 0.84 (0.77–0.93) vs. 1.02 (0.89–1.16), respectively (Pinteraction = 0.03). In four SGLT2i trials, the MACE benefit was similar by sex (Pinteraction = 0.13), age (Pinteraction = 0.36), BMI (Pinteraction = 0.69), and race groups (Pinteraction = 0.86 between Black and White, Pinteraction = 0.98 between Black and Asian, and Pinteraction = 0.69 between White and Asian). For GLP-1 RAs, the MACE benefit from the seven trials tended to be greater for Asian (0.71, [0.58–0.87]) than for White (0.87, [0.81–0.94]), (Pinteraction = 0.07). In two GLP-1 RAs trials, the MACE outcome was reduced by 22% (0.78, 0.63–0.95) in elderly patients (≥ 75 years) while no difference was observed in those < 75 years (0.87; 0.75–1.01), (Pinteraction = 0.37). In the remaining risk groups, the MACE benefit was similar by sex (Pinteraction = 0.37), age < 65 years (Pinteraction = 0.80), duration of diabetes (Pinteraction = 0.70), and race (Pinteraction = 0.57 between Black and White, and Pinteraction = 0.15 between Black and Asian), BMI (Pinteraction = 0.78). Risk of bias was lower, and overall heterogeneity was high for sex with SGLT2i, and moderate to low for the remaining comparisons, with a I2 values ranging from 0% to 54%.InterpretationIn patients with type 2 diabetes at highest risk of cardiovascular disease or established cardiovascular disease, a greater benefit on MACE was found for elderly patients and for Asian individuals compared with White individuals with GLP-1 RAs, and those with a long duration of diabetes with SGLT2i. These findings could help in providing guidance for treatment prescription and facilitate selection and stratification of patients for future CVOTs. Furthermore, pooled individual patient-level data are urgently needed to support our conclusions, and to derive definitive evidence.FundingNone.

Long-Term Association between Intensive Medical Treatment and the Incidence of Cardiovascular Outcomes in Patients with Dyslipidemia: an Observational Study.

IntroductionThe management of patients with dyslipidemia (DLP) requires intensive medical follow-up as an essential part of treatment and to reduce the risk of cardiovascular (CV) outcomes. The aim of this study was to evaluate whether adherence to medical treatment changed the prevalence of CV disease events in a retrospective 7-year follow-up analysis.MethodsThis retrospective study involved 92 patients divided into two groups according to their adherence: the REG group with 64 patients who had medical appointments from 2012 to 2018, and the DROP group, with 28 patients who had medical appointments in 2012 but did not complete regular appointments until 2018. Cox proportional hazard models were fitted to estimate hazard ratios associated with CV outcomes as primary endpoints.ResultsWe observed a total of 32 cases of acute myocardial infarction (AMI) in the study population, 17 (338.41 pY) in the REG group and 15 (62.97 pY) in the DROP group. An increased hazard of AMIs was observed in the DROP group compared with the REG group by follow-up time (p < 0.001). We found that previous events of AMI and congestive heart failure (CHF) were associated with progression to treatment dropout (p < 0.05) and that two drugs were considered a risk factor for treatment dropout, diuretics and fibrates (p < 0.05).ConclusionsA reduced hazard of AMI was observed in patients who complete a greater number of medical appointments and receive multidisciplinary treatment on a regular basis.

A meta-analytic framework to adjust for bias in external control studies.

While randomized controlled trials (RCTs) are the gold standard for estimating treatment effects in medical research, there is increasing use of and interest in using real-world data for drug development. One such use case is the construction of external control arms for evaluation of efficacy in single-arm trials, particularly in cases where randomization is either infeasible or unethical. However, it is well known that treated patients in non-randomized studies may not be comparable to control patients-on either measured or unmeasured variables-and that the underlying population differences between the two groups may result in biased treatment effect estimates as well as increased variability in estimation. To address these challenges for analyses of time-to-event outcomes, we developed a meta-analytic framework that uses historical reference studies to adjust a log hazard ratio estimate in a new external control study for its additional bias and variability. The set of historical studies is formed by constructing external control arms for historical RCTs, and a meta-analysis compares the trial controls to the external control arms. Importantly, a prospective external control study can be performed independently of the meta-analysis using standard causal inference techniques for observational data. We illustrate our approach with a simulation study and an empirical example based on reference studies for advanced non-small cell lung cancer. In our empirical analysis, external control patients had lower survival than trial controls (hazard ratio: 0.907), but our methodology is able to correct for this bias. An implementation of our approach is available in the R package ecmeta.

Causes of death in an unselected population with first time venous thromboembolism

Abstract Background and aim Causes of death in an unselected population with first-time community acquired venous thromboembolism (VTE) is largely unknown in the contemporary era of direct oral anticoagulation (DOAC). Material and methods All patients &amp;gt;18 years of age who had a visit for any medical reason to any of 5 different emergency departments (EDs) in our city from 1st January 2016 to 31st December 2017 were included. We identified all patients with any incident VTE (deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) at the time of the ED visit. Cox regression models were used to estimate hazards ratios (HR) with 95% confidence intervals (CIs) for all-cause mortality and cause-specific death in patients with any VTE, using all other ED patients as the reference group. Results In total, 409,971 patients had an ED visit during the study period, of whom 2% were diagnosed with VTE (DVT= 4,817, PE= 3,147). During a median follow up of 2.6 years, 1265 (16%) and 25,191 (6.3%) patients died within the VTE and reference group respectively. The adjusted risk of cancer related death was nearly 3-fold in patient with DVT (HR 2.7; 95% CI, 2.4–3.1), and 5-fold in PE patients (HR 4.6; 95% CI, 4.1–5.1 respectively), compared to the referent. A diagnosis of PE at the ED visit was associated with a 50% increased risk of cardiovascular death (HR 1.5; 95% CI, 1.2–1.9). Conclusion Patients with VTE have a high risk of all-cause mortality, including non-cancer related death and cardiovascular death despite improvements of diagnosis and treatment with DOAC. The study findings indicate that further improvement is needed in VTE management. Funding Acknowledgement Type of funding sources: None.

The prognostic significance of bundle branch block in acute heart failure: a systematic review and meta-analysis.

The aim of this study was to conduct a meta-analysis of prospective studies assessing the relationship between bundle branch block (BBB) or wide QRS and risk of all-cause mortality in patients with acute heart failure (AHF). We searched the PubMed, Scopus and Web of Science database from inception to February 2022 to identify single centre or multicentre studies including a minimum of 400 patients and assessing the association between BBB or wide QRS and mortality in patients with AHF. Study-specific hazard ratio (HR) estimates were combined using a random-effects meta-analysis. Two meta-analyses were performed: (1) grouping by conduction disturbance and follow-up length and, (2) using the results from the longest follow-up for each study and grouping by the type of BBB. The meta-analysis included 21 publications with a total of 116,928 patients. Wide QRS (considering right (RBBB) and left (LBBB) altogether) was associated with a significant increment in the risk of all-cause mortality (pooled adjusted HR 1.112, 95% CI 1.065-1.160). The increased risk of death was also present when LBBB (HR 1.121, 95% CI 1.042-1.207) and RBBB (HR 1.187, 95% CI 1.045-1.348) were considered individually. There was no difference in risk between LBBB and RBBB (P for interaction = 0.533). Other outcomes including sudden death, rehospitalization and a combination of cardiovascular death or rehospitalization were also increased in patients with BBB or wide QRS. This meta-analysis suggests a modest increase in the risk of all-cause mortality among patients with AHF and BBB or wide QRS, irrespective of the type of BBB.

Association between Long-Term Ambient PM2.5 Exposure and Cardiovascular Outcomes among U.S. Hemodialysis Patients

Background and Aim: Ambient PM2.5 is a ubiquitous air pollutant with established adverse cardiovascular (CV) effects. However, quantitative estimates of PM2.5 exposure associations on CV outcomes in susceptible populations are limited. This study assessed the impact of long-term PM2.5 on CV events and cardiovascular disease (CVD)-specific mortality among patients receiving maintenance in-center hemodialysis (HD). Methods: We conducted a retrospective cohort study with 314,079 adult kidney failure patients initiating HD between 2011 and 2016 identified from the United State Renal Data System. Estimated daily ZIP code-level PM2.5 concentrations were used to calculate each participant’s annual-average PM2.5 exposure based on the dialysis clinics visited during the 365 days prior to the outcome. CV event and CVD-specific mortality were ascertained based on ICD-9/ICD-10 diagnostic codes and recorded cause of death from form 2746. Discrete time hazards models were used to estimate hazards ratios (HRs) per 1 µg/m3 in annual-average PM2.5 adjusting for temperature, humidity, day of the week, season, age at baseline, race, employment status, and geographic region. Effect measure modification was assessed for age, sex, race, and baseline comorbidities. Results: Annual-average PM2.5 of 1 µg/m3 was associated with increased hazard rates in CV events (HR: 1.02, 95% CI: 1.01, 1.02) and CVD-specific mortality (1.02, 95% CI: 1.02, 1.03). The association was more pronounced for people who initiated dialysis at an older age, had COPD at baseline, or were Asian. Evidence of effect modification was also observed across strata of race, and other baseline comorbidities. Conclusions: Long-term ambient PM2.5 exposure was positively associated with CV outcomes among patients receiving maintenance in-center HD. Patients who had advanced age, COPD, or reported to be Asian, appeared to be more susceptible to long-term PM2.5 adverse effects. Keywords: Air pollution, long-term, vulnerable population, dialysis patients

Comparative Effectiveness of BNT162b2 and mRNA-1273 Booster Dose After BNT162b2 Primary Vaccination Against the Omicron Variants: A Retrospective Cohort Study Using Large-Scale Population-Based Registries in Japan.

BackgroundDirect comparative effectiveness of booster doses of BNT162b2 and mRNA-1273 after BNT162b2 primary vaccination is unknown.MethodsWe investigated comparative effectiveness of BNT162b2 and mRNA-1273 booster dose using data from registry systems for vaccination and COVID-19 infection in a local city in Japan. We followed participants aged ≥16 years who completed the BNT162b2 primary vaccination between November 22, 2021, and April 15, 2022. We collected information on age, sex, vaccination status, vaccine type, and infection status. Age was categorized as 16–44, 45–64, 65–84, and ≥85 years. Vaccine effectiveness for mRNA-1273 and no booster vaccination against BNT162b2 was estimated using age-stratified Cox regression adjusted for age, sex, and days since the second vaccination. The estimated hazard ratios for mRNA-1273 and no booster vaccinations were integrated separately using random effects meta-analyses.ResultsDuring the study period, we identified 62,586 (40.4%), 51,490 (33.2%), and 40,849 (26.4%) participants who received BNT162b2, mRNA-1273, and no booster dose, respectively. The median age was 69, 71, and 47 years for BNT162b2, mRNA-1273, and no booster dose, respectively. The integrated hazard ratio with reference to BNT162b2 was 1.72 for no booster vaccination and 0.62 for mRNA-1273. The comparative effectiveness of mRNA-1273 was similar across age categories.ConclusionsBoth homologous and heterologous vaccinations are effective against Omicron variants. In the head-to-head comparison, the effect was stronger in people who received heterologous vaccination than in those who received homologous vaccination. These findings may help improve logistics and decision making in future vaccination programs.

Survival disparities for childhood cancers exist when defined by race/ethnicity and sex

BackgroundThere are documented racial/ethnic and sex differences in pediatric cancer survival; however, it is unknown whether pediatric cancer survival disparities exist when race/ethnicity and sex are considered jointly. MethodsUsing SEER data (2000–2017), we estimated survival differences by race/ethnicity within sexes and by sex within race/ethnicity (White, Black, Hispanic, and Asian/Pacific Islander [API]) for 17 cancers in children aged (0–19 years). Kaplan-Meier curves (Log-Rank p-values) were assessed. Cox regression was used to estimate hazards ratios (HRs) and 95 % confidence intervals (95 % CIs) between race/ethnicity/sex and cancer. ResultsWe included 51,759 cases (53.6 % male, 51.9 % White). There were statistically significant differences in 18-year survival by race/ethnicity-sex for 12/17 cancers. Within sexes, minorities had an increased risk of death compared to Whites for various cancers including acute lymphoblastic leukemia (ALL) (females: HispanicHR: 1.78, 95 % CI: 1.52, 2.10; BlackHR: 1.70, 95 % CI: 1.29, 2.24; APIHR: 1.42, 95 % CI: 1.07–1.89; males ALL: HispanicHR: 1.58, 95 % CI: 1.39,1.79; BlackHR: 1.57, 95 % CI: 1.26,1,95; API-HR: 1.39, 95 % CI: 1.11, 1.75) and astrocytoma (females: HispanicHR: 1.49, 95 % CI: 1.19, 1.85; BlackHR: 1.67, 95 % CI: 1.29, 2.17; API-HR: 1.51, 95 % CI: 1.05, 2.15; males: HispanicHR:1.27, 95 % CI: 1.04, 1.56; BlackHR: 1.69, 95 % CI: 1.32, 2.17; API-HR: 1.92, 95 % CI: 1.43, 2.58). Sex differences in survival within racial/ethnic groups were observed for White (ALL, osteosarcoma), Hispanic (medulloblastoma), and API (Primitive Neuro-Ectodermal Tumor [PNET]) children. ConclusionsThere are disparities in survival by both race/ethnicity and sex highlighting the societal and biologic influences these features have on survival in children with cancer.

P11.19.B Bevacizumab in recurrent WHO grade 2-3 gliomas

Abstract Background Medical management of recurrent WHO grade 2-3 (rGII/III) gliomas is not well established. Bevacizumab (BEV) is an option at malignant recurrence. Yet, very few data are available in this indication. The aim of this study is to describe clinical outcomes in patients treated with BEV. Material and Methods A retrospective study was conducted including patients treated by BEV for a rGII/III glioma at our institution (2011 - 2019). Data were collected from medical records. Tumor samples were reviewed according to the WHO 2016 classification. Efficacy was assessed according RANO criteria. Progression Free Survival (PFS) and Overall Survival (OS) from BEV initiation were estimated using the Kaplan-Meier method. A Cox proportional hazards model was performed to estimate Hazard Ratios with 95% Confident Intervals (CI). Results A total of 81 patients was included (sex ratio: 1.6 M/W, median age at diagnosis: 38). Among them, 46 patients (56.8%) had a grade 2 and 35 (43.2%) a grade 3 glioma. The histological forms were astrocytoma (grade 2 -3) IDH mutated in 27 patients (33.3%), IDHwt in 15 patients (18.5%) and oligodendroglioma (grade 2 - 3) in 13 patients (16%). Twenty-six patients were not reclassified. Previous treatment included tumor resection for all patients (second intervention in 22.2%). First-line medical treatment consisted of chemotherapy in 60.5% patients before any radiotherapy. Chemotherapy was rechallenged in 52 patients (64.2%). All patients but one received radiation therapy and 19 patients (23.5%) received a reirradiation. BEV was administered at 10 or 15mg/kilogram every 2 or 3 weeks. All patients had a contrast enhancement on MRI at baseline. Median number of BEV cycles was 7 [1-79], in association with chemotherapy in 45.7%. Partial response, stable disease and progressive disease was observed in 27.2%, 22.2% and 50.6% respectively. Median OS from BEV introduction was 7.6 months (95% CI [5.5;9.9]). Median PFS was 4.9 months (95% CI [3.7;6.1]). In univariate analysis, grade 2 (Odd Ratio (OR)=0.41, 95% CI [0.17;1.02], p=0.054), Ki67&amp;lt;7% (OR=0.41, 95% CI [0.15;1.21], p=0.079) and initial total surgical resection (OR=2.75, 95% CI [0.68;11.11], p=0.097) showed a trend for delayed progression. BEV was stopped for progression in 70.4%, for toxicity in 8.6% and for others reasons in 21% patients. Twenty-four patients (29.6%) discontinued BEV without progression (medical decision, BEV toxicity or patient decision). Presence of 1p19q codeletion (OR=0.24, 95% CI [0.07;0.84], p=0.023) and age ≥ 38 (OR=0.36, 95% CI [0.13;0.99], p=0.042) at diagnosis were more frequent in this sub-population. Out these of 24 patients, 8 showed survival from 3 months to 5 years without any other treatment. Conclusion BEV can be a good option for patients with rGII/III glioma. One third of them stopped treatment without progression, reaching a survival of several years for some of them.

Methodological Considerations on COVID-19 Mortality in Cancer Patients: A Systematic Review and Meta-Analysis.

Patients with cancer are at risk for severe COVID-19. Previous studies examining mortality in cancer patients with COVID-19 have produced inconclusive results. Several published meta-analyses have aimed to estimate this association; however, because of methodological limitations in study selection and data aggregation, these studies do not reliably estimate the independent association between cancer and COVID-19 mortality. We conducted this systematic review and meta-analysis to determine whether cancer is an independent risk factor for COVID-19 mortality. A literature search was performed in PubMed to identify studies that compared COVID-19 mortality in adult patients with and without cancer. Selection criteria included polymerase chain reaction-confirmed COVID-19, multivariate adjustment and/or matching for mortality risk estimates, and inclusion of hospitalized noncancer controls. Adjusted odds ratios and/or hazard ratios for mortality based on cancer status were extracted. Odds ratio and hazard ratio estimates were pooled using a random effects model. The analysis included 42 studies comprising 129 840 patients: 8612 cancer patients and 121 228 noncancer patients. Of these studies, 18 showed a null difference in survival between cancer and noncancer patients with COVID-19, and 24 studies showed statistically significantly worse survival in cancer patients with COVID-19. Meta-analysis revealed an increased risk of mortality in patients with cancer compared with noncancer patients with COVID-19 (odds ratio = 1.93, 95% confidence interval = 1.55 to 2.41; hazard ratio = 1.54, 95% confidence interval = 1.29 to 1.84). We conclude that cancer is an independent risk factor for mortality in unvaccinated patients admitted for or diagnosed with COVID-19 during hospitalization.

Positive association between dietary exposure to polybrominated diphenyl ethers and breast cancer risk in the French E3N cohort: The role of vegetable oil consumption.

Exposure to endocrine-disrupting chemicals, like Polybrominated diphenyl ethers (PBDEs), is suspected of playing a role in the occurrence of breast cancer. Moreover, there is growing evidence that food chemical contaminants, especially lipophilic ones such as PBDEs, could interact with different components of the diet. The objective of the present study was to assess the association between dietary intake of PBDEs and breast cancer risk in the French E3N cohort study, and to investigate the potential modification of this association by vegetable oil consumption. The study included 67879 women. Intakes of eight PBDEs were estimated using food consumption data from a validated semi-quantitative food frequency questionnaire, and food contamination levels measured by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES). Cox proportional hazards models were used to estimate Hazard Ratios (HR) and 95% Confidence Intervals (CI) for the association between total PBDEs dietary intake and breast cancer risk. Interaction measures for vegetable oil consumption were estimated on both additive and multiplicative scales. The women were followed for a maximum of 21.4years, and 5 686 developed an incident breast cancer. A positive linear trend was highlighted between dietary intake of PBDEs in quintile groups and breast cancer risk, borderline with statistical significance (p-trend=0.06, HRQ5vsQ1 and 95% CI: 1.09 [0.99;1.20]). Interaction measures for vegetable oil consumption were significant in both additive and multiplicative scales. Higher effect sizes of the association were highlighted in high consumers of vegetable oil, i.e. ≥4.6g/day (HRQ5vsQ1 and 95% CI: 1.23 [1.08; 1.40]), and almost no effect were found in low consumers (HRQ5vsQ1 and 95% CI: 0.97 [0.86; 1.10]). Highlighting such interactions between nutrients and chemicals is crucial to develop efficient dietary recommendations to limit the negative health effects associated with exposure to food chemical contaminants.

Analysis of A Disintegrin and Metalloprotease 17 (ADAM17) Expression as a Prognostic Marker in Ovarian Cancer Patients Undergoing First-Line Treatment Plus Bevacizumab.

To find prognostic factors for advanced ovarian cancer patients undergoing first-line therapy with carboplatin, paclitaxel and bevacizumab, we investigated the expression of a disintegrin and metalloprotease 17 (ADAM17) in cancer tissues. ADAM17 has been involved in ovarian cancer development, progression and cell resistance to cisplatin. Tissue microarrays from 309 ovarian cancer patients enrolled in the MITO16A/MANGO-OV2 clinical trial were analyzed by immunohistochemistry for ADAM17 protein expression. Intensity and extent of staining were combined into a semi-quantitative visual grading system (H score) which was related to clinicopathological characteristics of cases and the clinical outcome of patients by univariate and multivariate Cox regression models. ADAM17 immunostaining was detected in most samples, mainly localized in the tumor cells, with variable intensity across the cohort. Kaplan–Meier survival curves, generated according to the best cut-off value for the ADAM17 H score, showed that high ADAM17 expression was associated with worse prognosis for PFS and OS. However, after the application of a shrinkage procedure to adjust for overfitting hazard ratio estimates, the ADAM17 value as prognostic factor was lost. As subgroup analysis suggested that ADAM17 expression could be prognostically relevant in cases with no residual disease at baseline, further studies in this patient category may be worth planning.

COVID-19 Booster Vaccination in the U.S. Military, August 2021–January 2022

IntroductionA booster dose of messenger RNA vaccine protects against severe COVID-19 outcomes. This study examined the incidence of COVID-19 booster vaccination among active-duty U.S. military servicemembers between August 2021 and January 2022, factors associated with vaccination uptake, and trends over time.MethodsThis was a retrospective cohort study of active-duty military personnel using data from the Defense Medical Surveillance System. Participants were included if they served in the active component from August 2021 through January 2022 and were eligible to receive a COVID-19 booster dose by January 2022. Adjusted hazard ratio estimates of time to booster vaccination were calculated using Cox proportional hazards regression.ResultsLower booster vaccine uptake was seen in the U.S. military (25%) than among the general U.S. population at the same time (45%). Booster vaccination increased with older age, with greater education, with higher income, among women, and among those stationed overseas; it decreased with previous COVID-19 infection and use of the Janssen vaccine. There were no significant racial or ethnic disparities in booster vaccination.ConclusionsIn the absence of a compulsory vaccination policy, lower booster vaccine uptake was seen among servicemembers than among the general U.S. population, particularly among members who were younger, were male, Marines, and had a previous history of infection. Low vaccination rates not only increase the risk of acute and long-term health effects from COVID-19 among servicemembers, but they also degrade the overall readiness of the U.S. military.