Comparative toxicity outcomes of proton-beam therapy versus intensity-modulated radiotherapy for prostate cancer in the postoperative setting

Background Despite increasing utilization of proton-beam therapy (PBT) in the postprostatectomy setting, no data exist regarding toxicity outcomes relative to intensity-modulated radiotherapy (IMRT). The authors compared acute and late genitourinary (GU) and gastrointestinal (GI) toxicity outcomes in patients with prostate cancer (PC) who received treatment with postprostatectomy IMRT versus PBT. Methods With institutional review board approval, patients with PC who received adjuvant or salvage IMRT or PBT (70.2 gray with an endorectal balloon) after prostatectomy from 2009 through 2017 were reviewed. Factors including combined IMRT and PBT and/or concurrent malignancies prompted exclusion. A case-matched cohort analysis was performed using nearest-neighbor 3-to-1 matching by age and GU/GI disorder history. Logistic and Cox regressions were used to identify univariate and multivariate associations between toxicities and cohort/dosimetric characteristics. Toxicity-free survival (TFS) was assessed using the Kaplan-Meier method. Results Three hundred seven men (mean +/- SD age, 59.7 +/- 6.3 years; IMRT, n = 237; PBT, n = 70) were identified, generating 70 matched pairs. The median follow-up was 48.6 and 46.1 months for the IMRT and PBT groups, respectively. Although PBT was superior at reducing low-range (volumes receiving 10% to 40% of the dose, respectively) bladder and rectal doses (all P = .05). Five-year grade >= 2 GU and grade >= 1 GI TFS was 61.1% and 73.7% for IMRT, respectively, and 70.7% and 75.3% for PBT, respectively; and 5-year grade >= 3 GU and GI TFS was >95% for both groups (all P >= .05). Conclusions Postprostatectomy PBT minimized low-range bladder and rectal doses relative to IMRT; however, treatment modality was not associated with clinician-reported GU/GI toxicities. Future prospective investigation and ongoing follow-up will determine whether dosimetric differences between IMRT and PBT confer clinically meaningful differences in long-term outcomes

Cancer disparities in Southeast Asia: intersectionality and a call to action.

Southeast Asia has a population of over 680 million people—approximately half the population of India and twice the population of the United States—and is a region marked by rich and complex histories and cultures, dynamic growth, and unique and evolving health challenges.1 Despite the momentum of economic development, health inequalities persist. These inequities have been aggravated since the COVID-19 pandemic, which pushed millions further into poverty, possibly exacerbating health disparities, especially among populations who suffer vulnerabilities.2 Particularly salient are the challenges associated with providing adequate care for people with cancer, a leading cause of morbidity and mortality in the region.1,2 Cancer incidence and mortality in the region are projected to rise in the coming decades, given population growth and rapidly changing socioeconomic and geopolitical factors, as well as a host of interrelated and dynamic environmental, behavioral, and occupational risk factors.1, 2, 3 Large epidemiologic studies have demonstrated differences among Southeast Asian countries in terms of cancer incidence and mortality.3 Epidemiologic patterns can be attributed to variations in complex risk factors, access to screening and cancer care, and likely genetic predisposition.1, 2, 3 However, these differences also underscore that within each country exist richly diverse populations that experience disparities in cancer risk, screening, care access, outcomes, and survivorship in ways that require further examination. We draw attention to disparities in cancer in Southeast Asian countries. We highlight the need to study cancer disparities affecting minoritised groups in Southeast Asia—not only along lines of race/ethnicity, but also people minoritised along lines of sex/gender, socioeconomic status, religion, geography, and others. We highlight the intersectionality of elements of an individual's identity. Intersectionality, developed by critical race theorist Professor Kimberlé Crenshaw in 1989, is an analytic framework borne out of Black American feminist scholarship, that examines how a person's sociopolitical identities lead to disparate balances of privilege and discrimination.4 An intersectional approach would demonstrate that an individual or a community does not only experience economic poverty as the sole barrier to improved health; such an approach would examine how other identities such as religion or immigration status affect access to care. These different social determinants of health are not mutually exclusive; their interrelationships are complex, with consequences for health.5 We leverage the intersectional approach, which parallels the inherently syncretic cultures and histories of Southeast Asian nations, and explore how these identities impact access to cancer care. Meaningful cancer research focusing on peoples of Southeast Asia could present many opportunities for intervention and improvement

A2ML1 and otitis media : novel variants, differential expression, and relevant pathways

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.Peer reviewe

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Local Consolidative Therapy for Oligometastatic Non-Small Cell Lung Cancer

In the last 20 years, significant strides have been made in our understanding of the biological mechanisms driving disease pathogenesis in metastatic non-small cell lung cancer (NSCLC). Notably, the development and application of predictive biomarkers as well as refined treatment regimens in the form of chemoimmunotherapy and novel targeted agents have led to substantial improvements in survival. Parallel to these remarkable advancements in modern systemic therapy has been a growing recognition of &ldquo;oligometastatic disease&rdquo; as a distinct clinical entity&mdash;defined by the presence of a controlled primary tumor and &le;5 sites of metastatic disease amenable to local consolidative therapy (LAT), with surgery or stereotactic ablative body radiotherapy (SABR). To date, three randomized studies have provided clinical evidence supporting the use of LAT/SABR in the treatment of oligometastatic NSCLC. In this review, we summarize clinical evidence from these landmark studies and highlight ongoing trials evaluating the use of LAT/SABR in a variety of clinical contexts along the oligometastatic disease spectrum. We discuss important implications and caveats of the available data, including considerations surrounding patient selection and application in routine clinical practice. We conclude by offering potential avenues for further investigation in the oligometastatic disease space

Factors influencing noncompletion of radiotherapy among men with localized prostate cancer

199 Background: Treatment non-completion may occur with radiotherapy (RT), especially with protracted treatment courses such as RT for prostate cancer, and may affect the efficacy of RT. For men with localized prostate cancer managed with primary RT, we evaluated associations between rates of treatment non-completion and RT fractionation schedules. Methods: The National Cancer Database identified men diagnosed from 2004-2014 treated with primary RT. Patients receiving 180cGy/fraction (conventional), 200cGy/fraction (conventional), 250cGy/fraction (moderate hypofractionation), and 300cGy/fraction (moderate hypofractionation) were defined as having completed radiotherapy if they received ≥40 fractions, ≥37 fractions, ≥28 fractions, and ≥19 fractions, respectively. Stereotactic body radiotherapy (SBRT) was defined as 5-8 fractions of 600-800cGy/fraction. Odds ratios compared rates of treatment noncompletion, adjusting for various sociodemographic covariates. Propensity-adjusted multivariable Cox regression assessed the association between treatment completion and overall survival. Results: Of 93,079 patients, 90.5% (N = 84,260) received conventional fractionation, 2.3% (N = 2,181) received moderate hypofractionation, and 7.1% (N = 6,638) received SBRT. Rates of non-completion were 10.0% (N = 8,406) among patients who received conventional fractionation, 7.5% (N = 163) among patients who received moderate hypofractionation, and 1.7% (N = 115) among patients who received SBRT (OR versus conventional: 0.214, 95%CI 0.177-0.258, P < 0.001). The rate of non-completion among 15,417 African American patients was 11.8%, compared to 8.8% among 74,189 white patients (OR 1.39, 95%CI 1.31-1.47, P < 0.001). On subgroup analysis, the disparity in non-completion persisted for conventional fractionation (12.4% vs. 9.4%, OR 1.36, 95%CI 1.29-1.44, P < 0.001) and moderate hypofractionation (13.6% vs. 6.6%, OR 2.24, 95%CI 1.52-3.29, P < 0.001), but not for SBRT (2.0% vs. 1.6%, OR 1.25, 95%CI 0.76-2.06, P = 0.384). Non-completion was associated with worse survival on propensity-adjusted multivariate analysis (HR 1.37, 95%CI 1.31-1.43, P < 0.001). Conclusions: SBRT was associated with lower rates of RT non-completion among men with localized prostate cancer. African American race was associated with greater rates of treatment non-completion, although the disparity may be decreased among men receiving SBRT