Analysis of somatic mutations provides insight into the mutational processes that have shaped the cancer genome, but such analysis currently requires large cohorts. We develop deconstructSigs, which ...allows the identification of mutational signatures within a single tumor sample.
Application of deconstructSigs identifies samples with DNA repair deficiencies and reveals distinct and dynamic mutational processes molding the cancer genome in esophageal adenocarcinoma compared to squamous cell carcinomas.
deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine.
The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear.
To ...determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication.
Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013.
Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys.
After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% 95% CI, 22.3%-27.6%). Only 96 of 253 discontinuations (37.9% 95% CI, 32.0%-44.3%) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% 95% CI, 8.2%-12.0%). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio OR, 0.25 95% CI, 0.15-0.43; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 95% CI, 0.92-1.00; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 95% CI, 2.29-4.43; P < .001).
In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.
We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune ...response and immune evasion in patients with NSCLC.
We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti-PD-1/anti-PD-L1 drugs.
As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell-excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti-PD-1/PD-L1 drugs.
We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
Cancer is a disease reliant on the generation of mutations and the subsequent selection of those subpopulations endowed with the greatest fitness advantage. Beginning with a heterogeneous landscape ...of somatic alterations, various selective pressures acting on a tumor can shape the way it evolves. In this review, we first discuss the current bioinformatics tools available to tease apart the heterogeneous nature of a tumor and second consider the impact that evolutionary forces have on sculpting a tumor. Neighboring subclones may alter the microenvironment cultivating either cooperation or competition between clonal populations. Additionally, the harsh environment brought about by therapy and the immune system may force adaptation. Finally, we examine recent analyses focused on precancerous samples, which help to reveal clonal selection occurring during the earliest stages of tumor development, as well as work that has identified patterns of somatic evolution observed in normal tissues.
Intraoperative adverse events (iAEs) are associated with adverse postoperative outcomes and cause a significant healthcare burden. However, a critical appraisal of iAEs is lacking. Considering the ...details of iAEs could benefit postoperative care. We comprehensively analyzed iAEs in a large series including all types of operations and their relation to postoperative complications.
All patients enrolled in the multicenter ClassIntra
validation study (NCT03009929) were included in this analysis. The surgical and anesthesia team prospectively recorded all iAEs. Two researchers, blinded to each other's ratings, appraised all recorded iAEs according to their origin into four categories: surgery, anesthesia, organization, or other, including subcategories such as organ injury, arrhythmia, or instrument failure. They further descriptively analyzed subcategories of all iAEs. Postoperative complications were assessed using the Comprehensive Complication Index (CCI
), a weighted sum of all postoperative complications according to the Clavien-Dindo classification. The association of iAE origins in addition to the severity grade of ClassIntra
on CCI
was assessed with a multivariable mixed-effects generalized linear regression analysis.
Of 2520 included patients, 778 iAEs were recorded in 610 patients. The origin was surgical in 420 (54%), anesthesia in 283 (36%), organizational in 34 (4%), and other in 41 (5%) events. Bleeding (
= 217, 28%), hypotension (
= 118, 15%), and organ injury (
= 98, 13%) were the three most frequent subcategories in surgery and anesthesia, respectively. In the multivariable mixed-effect analysis, no significant association between the origin and CCI
was observed.
Analyzing the type and origin of an iAE offers individualized and contextualized information. This detailed descriptive information can be used for targeted surveillance of intra- and postoperative care, even though the overall predictive value for postoperative events was not improved by adding the origin in addition to the severity grade.
The relevance of femoral neck fractures (FNFs) increases with the ageing of numerous societies, injury-related decline is observed in many patients. Treatment strategies have evolved towards primary ...joint replacement, but the impact of different approaches remains a matter of debate. The aim of this trial was to evaluate the benefit of an anterior minimally-invasive (AMIS) compared to a lateral Hardinge (LAT) approach for hemiarthroplasty in these oftentimes frail patients.
Four hundred thirty-nine patients were screened during the 44-months trial, aiming at the evaluation of 150 patients > 60 yrs. of age. Eligible patients were randomised using an online-tool with completely random assignment. As primary endpoint, early mobility, a predictor for long-term outcomes, was evaluated at 3 weeks via the "Timed up and go" test (TUG). Secondary endpoints included the Functional Independence Measure (FIM), pain, complications, one-year mobility and mortality.
A total of 190 patients were randomised; both groups were comparable at baseline, with a predominance for frailty-associated factors in the AMIS-group. At 3 weeks, 146 patients were assessed for the primary outcome. There was a reduction in the median duration of TUG performance of 21.5% (CI - 41.2,4.7, p = 0.104) in the AMIS-arm (i.e., improved mobility). This reduction was more pronounced in patients with signs of frailty or cognitive impairment. FIM scores increased on average by 6.7 points (CI 0.5-12.8, p = 0.037), pain measured on a 10-point visual analogue scale decreased on average by 0.7 points (CI: - 1.4,0.0, p = 0.064). The requirement for blood transfusion was lower in the AMIS- group, the rate of complications comparable, with a higher rate of soft tissue complications in the LAT-group. The mortality was higher in the AMIS-group.
These results, similar to previous reports, support the concept that in elderly patients at risk of frailty, the AMIS approach for hemiarthroplasty can be beneficial, since early mobilisation and pain reduction potentially reduce deconditioning, morbidity and loss of independence. The results are, however, influenced by a plethora of factors. Only improvements in every aspect of the therapeutic chain can lead to optimisation of treatment and improve outcomes in this growing patient population.
www.clinicaltrials.gov : NCT01408693 (registered August 3rd 2011).
Despite efforts to increase diversity in neuroscience trials, racial and ethnic minority groups remain underrepresented. Disparities in clinical trial participation could reflect unequal ...opportunities to participate and may contribute to decreased generalizability of findings and failure to identify important differences in efficacy and safety outcomes.
We retrospectively reviewed the F. Hoffmann-La Roche database for global, multicenter, neuroscience clinical trials from February 2016 to February 2021 and summarized and stratified race and ethnicity distributions by clinical trial therapeutic area and by country. These data were then compared to national population data for each study's targeted age group (available for studies conducted in the US, Canada, and the UK). The underrepresentation or overrepresentation of each racial and ethnic group was summarized.
The analysis population included 8015 participants from 47 countries. Globally, 85.6 % of participants were White, 7.1 % were Asian, 1.6 % were Black, 1.3 % were American Indian or Alaska Native, less than 0.1 % were Native Hawaiian or other Pacific Islander, 0.7 % were of multiple races, and 3.6 % were of other/unknown race. White individuals predominated in all but one trial. Black individuals were underrepresented in all trials but one. Asian individuals were overrepresented in approximately 20 % of trials. In the US, 7.3 % of participants were of Hispanic or Latino ethnicity vs 16.4 % of the US population.
The findings and learnings from this summary and analysis demonstrate the need for continued awareness and new approaches in designing studies that reflect population diversity.
Objectives To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for ...recruitment failure in pediatric and adult RCTs. Study design A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. Results We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). Conclusion Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.
To compare long-term results of Lichtenstein's operation versus mesh plug repair for open inguinal hernia repair.
The technique of best choice in open prosthetic inguinal hernia repair remains a ...subject of ongoing debate.
In this prospective, randomized controlled multicenter trial, patients with primary or recurrent inguinal hernias were randomized to undergo either Lichtenstein's operation or mesh plug repair. The primary endpoint was the long-term recurrence rate. Secondary endpoints included chronic pain, sensibility disorders, and reoperation rate.
In total, 697 hernias in 594 patients were randomized (297 patients per group). At a median follow-up of 6.5 years, 528 (76%) operated hernias in 444 (75%) patients were clinically evaluated. The recurrence rate was similar in both groups mesh plug: 21/268 hernias = 7.8%; Lichtenstein: 21/260 hernias = 8.1%; adjusted odds ratio (OR): 0.92; 95% confidence interval (CI): 0.51, 1.68; P = 0.795. We did not find a significant difference for chronic pain (Visual Analog Scale score >3) (OR: 0.58; 95% CI: 0.31, 1.09; P = 0.088) and sensory testing (17% vs 20% of patients; OR: 0.53; 95% CI: 0.21, 1.37; P = 0.190) between the 2 groups. There were less reoperations in the mesh plug than in the Lichtenstein's operation group (OR: 0.43; 95% CI: 0.22, 0.85; P = 0.016).
The long-term results of this trial indicate not enough evidence for differences in recurrence, chronic pain, and sensibility disorders between mesh plug repair and Lichtenstein's operation but a lower likelihood for reoperation for mesh plug repair. Estimates for all endpoints were statistically not significant or based on large CIs.
ClinicalTrials.gov Identifier: NCT01637818.
Background Chronic pain is a common complication after inguinal hernia repair. The objective of this randomized trial was to assess the effect of intraoperative infiltration with local anesthetic ...versus placebo on the development of chronic pain after inguinal hernia repair. Methods Patients with single- or double-sided inguinal hernia were enrolled in a randomized, controlled, triple-blinded trial with a sequential adaptive design. Hernias were randomized to 1 of 2 treatment groups. The intervention group received a local infiltration of 20 mL bupivacaine 0.25% and the placebo group 20 mL saline 0.9% at the end of the operation. Two interim analyses were performed according to predefined stopping criteria allowing for design and sample size adaption. The primary endpoint was chronic pain defined on a visual analog scale (VAS) as ≥30 in any quality (at rest, lying, walking, climbing stairs, and bending over) 3 months postoperatively. A logistic regression model was built to compare the incidence of chronic pain using generalized estimating equations to adjust for clustering in bilateral hernias. Results Among 357 patients, there were 406 hernias randomized. A total of 5.8% (10/173) experienced VAS ≥ 30 in any quality in the intervention group and 2.3% (4/174) in the placebo group ( P = .114) at 3 months postoperatively. Multivariable analysis revealed no evidence of between-group differences for the development of any pain (odds ratio OR, 1.03; 95% CI, 0.67–1.57; P = .905), whereas preoperative pain was an independent risk factor (OR, 2.52; 95% CI, 1.12–5.68; P = .025). Conclusion We did not find any evidence that intraoperative infiltration of local anesthetic had an impact on the development of chronic postoperative pain.
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