Many trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC).
To systematically review trials of prostate radiotherapy.
Using a prospective framework ...(framework for adaptive meta-analysis FAME), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators.
We included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only.
Hazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis.
We identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval CI 0.81–1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84–1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67–0.82, p=0.94×10−8) and FFS (HR=0.76, 95% CI 0.69–0.84, p=0.64×10−7), equivalent to ∼10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden—a pattern consistent across trials and outcome measures, including survival (<5, ≥5; interaction HR=1.47, 95% CI 1.11–1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases.
Prostate radiotherapy should be considered for men with mHSPC with a low metastatic burden.
Prostate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered.
This prospectively designed systematic review showed that prostate radiotherapy did not improve survival in unselected men. A difference in effect by metastatic burden was evident across included trials and outcomes; 3-yr survival increased by 7% in men with fewer than five bone metastases.
Summary Background Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to ...investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis. Methods For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel). Findings We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 93% of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68–0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5–14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58–0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12–19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 53% of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 95% CI 0·69–1·09; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 59% of 3978 men) showed that docetaxel improved failure-free survival (0·70 0·61–0·81; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5–10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 88% of 3109 men) showed that addition of bisphosphonates improved survival (0·88 0·79–0·98; p=0·025), which translates to 5% (1–8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 0·83–1·07; p=0·323), which translates to an absolute improvement in survival of 2% (−3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 66% of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 0·89–1·18; p=0·724) or zoledronic acid (0·98 0·82–1·16; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials. Interpretation The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small. Funding Medical Research Council UK.
It is unclear whether adjuvant or early salvage radiotherapy following radical prostatectomy is more appropriate for men who present with localised or locally advanced prostate cancer. We aimed to ...prospectively plan a systematic review of randomised controlled trials (RCTs) comparing these radiotherapy approaches.
We used a prospective framework for adaptive meta-analysis (FAME), starting the review process while eligible trials were ongoing. RCTs were eligible if they aimed to compare immediate adjuvant radiotherapy versus early salvage radiotherapy, following radical prostatectomy in men (age ≥18 years) with intermediate-risk or high-risk, localised or locally advanced prostate cancer. We searched trial registers and conference proceedings until July 8, 2020, to identify eligible RCTs. By establishing the ARTISTIC collaboration with relevant trialists, we were able to anticipate when eligible trial results would emerge, and we developed and registered a protocol with PROSPERO before knowledge of the trial results (CRD42019132669). We used a harmonised definition of event-free survival, as the time from randomisation until the first evidence of either biochemical progression (prostate-specific antigen PSA ≥0·4 ng/mL and rising after completion of any postoperative radiotherapy), clinical or radiological progression, initiation of a non-trial treatment, death from prostate cancer, or a PSA level of at least 2·0 ng/mL at any time after randomisation. We predicted when we would have sufficient power to assess whether adjuvant radiotherapy was superior to early salvage radiotherapy. Investigators supplied results for event-free survival, both overall and within predefined patient subgroups. Hazard ratios (HRs) for the effects of radiotherapy timing on event-free survival and subgroup interactions were combined using fixed-effect meta-analysis.
We identified three eligible trials and were able to obtain updated results for event-free survival for 2153 patients recruited between November, 2007, and December, 2016. Median follow-up ranged from 60 months to 78 months, with a maximum follow-up of 132 months. 1075 patients were randomly assigned to receive adjuvant radiotherapy and 1078 to a policy of early salvage radiotherapy, of whom 421 (39·1%) had commenced treatment at the time of analysis. Patient characteristics were balanced within trials and overall. Median age was similar between trials at 64 or 65 years (with IQRs ranging from 59 to 68 years) across the three trials and most patients (1671 77·6%) had a Gleason score of 7. All trials were assessed as having low risk of bias. Based on 270 events, the meta-analysis showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy (HR 0·95, 95% CI 0·75–1·21; p=0·70), with only a 1 percentage point (95% CI −2 to 3) change in 5-year event-free survival (89% vs 88%). Results were consistent across trials (heterogeneity p=0·18; I2=42%).
This collaborative and prospectively designed systematic review and meta-analysis suggests that adjuvant radiotherapy does not improve event-free survival in men with localised or locally advanced prostate cancer. Until data on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy as it offers the opportunity to spare many men radiotherapy and its associated side-effects.
UK Medical Research Council.
Biological and genetic factors, as well as contextual influences, contribute to the etiology of externalizing behaviors in children and adolescents. The current project used a longitudinal design to ...examine how individual vulnerability for externalizing behavior is influenced by the interplay among biological/genetic and environmental factors, and how this occurs across development. We investigated the influence of dopamine receptor D4 genotype (DRD4), child temperament, and household chaos on children's externalizing behaviors using a sample of twins/triplets tested at the ages of 4 and 5 years (n = 229), including a subset of these who were tested again in middle childhood (ages 7–13 years; n = 174). Multilevel linear regression modeling demonstrated that the DRD4‐7repeat genotype, 4‐year‐old negative affectivity, and household chaos at the age of 4 years were related to 5‐year‐old externalizing behaviors. Stability in externalizing behaviors from the age of 5 years to middle childhood was demonstrated. A significant interaction between DRD4 and household chaos showed that children with no 7‐repeat DRD4 alleles had significantly higher levels of externalizing in homes with extremely low levels of parent‐reported chaos, suggesting a “goodness‐of‐fit” pattern of gene–environment interaction. These findings suggest that risk for childhood externalizing behaviors is likely multifaceted and differs across developmental periods.
Storytelling can stimulate learning by delivering scientific content within a narrative that increases comprehension and engagement. In this article I describe the coevolutionary arms race between ...toxic newts and predatory garter snakes. This engaging story centers on the use of a deadly neurotoxin called tetrodotoxin (TTX) as an antipredator defense. Some species of newts contain TTX in their tissues, but resistance to TTX has developed through convergent evolution in garter snakes and other species. TTX resistance results from mutated voltage-gated sodium channels. These channels, whether TTX resistant or not, are found in all animals and are vital to the function of nervous and muscle tissues. Through reciprocal selection, coevolution has created phenotypic matching between toxic newts and TTX-resistant garter snakes across their range in the western United States. In other words, as newts became more poisonous, garter snakes became more resistant. These results and the scientific process behind them are discussed in detail. This story can be used by educators to provide a unifying and engaging backdrop as students learn multiple aspects of biology, such as protein structure, genetics, phylogenetics, electrical signaling, evolution, and the process of science.
The blood brain barrier (BBB) plays a critically important role in the regulation of central nervous system (CNS) homeostasis, but also represents a major limitation to treatments of brain ...pathologies. In recent years, focused ultrasound (FUS) in conjunction with gas-filled microbubble contrast agents has emerged as a powerful tool for transiently and non-invasively disrupting the BBB in a targeted and image-guided manner, allowing for localized delivery of drugs, genes, or other therapeutic agents. Beyond the delivery of known therapeutics, FUS-mediated BBB opening also demonstrates the potential for use in neuromodulation and the stimulation of a range of cell- and tissue-level physiological responses that may prove beneficial in disease contexts. Clinical trials investigating the safety and efficacy of FUS-mediated BBB opening are well underway, and offer promising non-surgical approaches to treatment of devastating pathologies. This article reviews a range of pre-clinical and clinical studies demonstrating the tremendous potential of FUS to fundamentally change the paradigm of treatment for CNS diseases.
Objective: This study aimed (a) to determine whether older drivers looked less often for potential threats while turning than younger drivers and (b) to compare the effectiveness of active and ...passive training on older drivers’ performance and evaluation of their driving skills in intersections. Background: Age-related declines in vision, physical abilities, psychomotor coordination, and cognition combine to make it less likely that older drivers will look for potential threats during a turn. Research suggests that active training should be an effective means of improving older drivers’ performance and self-awareness. Method: In Experiment 1, younger and older participants drove a series of virtual intersection scenarios, were shown video replays, and were provided feedback. In Experiment 2, older drivers were assigned to one of three cohorts: active simulator training, passive classroom training, or no training. Pre- and posttraining simulator and field drives assessed training effectiveness. Results: In Experiment 1, older drivers looked less often during turns than younger drivers. Customized feedback was successful in altering drivers’ perception of their abilities. In Experiment 2, active training increased a driver’s probability of looking for a threat during a turn by nearly 100% in both posttraining simulator and field drives. Those receiving passive training or no training showed no improvement. Conclusion: Compared with passive training, active training is a more effective strategy for increasing older drivers’ likelihood of looking for threats during a turn. Application: The results of this research can guide the development of programs that could reduce intersection crashes among older drivers.
Summary
Symbiodiniaceae are a diverse family of marine dinoflagellates, well known as coral endosymbionts. Isolation and in vitro culture of Symbiodiniaceae strains for physiological studies is a ...widely adopted tool, especially in the context of understanding how environmental stress perturbs Symbiodiniaceae cell functioning. While the bacterial microbiomes of corals often correlate with coral health, the bacterial communities co‐cultured with Symbiodiniaceae isolates have been largely overlooked, despite the potential of bacteria to significantly influence the emergent physiological properties of Symbiodiniaceae cultures. We examined the physiological response to heat stress by Symbiodiniaceae isolates (spanning three genera) with well‐described thermal tolerances, and combined these observations with matched changes in bacterial composition and abundance through 16S rRNA metabarcoding. Under thermal stress, there were Symbiodiniaceae strain‐specific changes in maximum quantum yield of photosystem II (proxy for health) and growth rates that were accompanied by changes in the relative abundance of multiple Symbiodiniaceae‐specific bacteria. However, there were no Symbiodiniaceae‐independent signatures of bacterial community reorganisation under heat stress. Notably, the thermally tolerant Durusdinium trenchii (ITS2 major profile D1a) had the most stable bacterial community under heat stress. Ultimately, this study highlights the complexity of Symbiodiniaceae‐bacteria interactions and provides a first step towards uncoupling their relative contributions towards Symbiodiniaceae physiological functioning.
Bacterial biofilm formation is a complex developmental process involving cellular differentiation and the formation of intricate 3D structures. Here we demonstrate that exposure to ferric chloride ...triggers rugose biofilm formation by the uropathogenic Escherichia coli strain UTI89 and by enteric bacteria Citrobacter koseri and Salmonella enterica serovar typhimurium . Two unique and separable cellular populations emerge in iron-triggered, rugose biofilms. Bacteria at the air–biofilm interface express high levels of the biofilm regulator csgD , the cellulose activator adrA , and the curli subunit operon csgBAC . Bacteria in the interior of rugose biofilms express low levels of csgD and undetectable levels of matrix components curli and cellulose. Iron activation of rugose biofilms is linked to oxidative stress. Superoxide generation, either through addition of phenazine methosulfate or by deletion of sodA and sodB , stimulates rugose biofilm formation in the absence of high iron. Additionally, overexpression of Mn-superoxide dismutase, which can mitigate iron-derived reactive oxygen stress, decreases biofilm formation in a WT strain upon iron exposure. Not only does reactive oxygen stress promote rugose biofilm formation, but bacteria in the rugose biofilms display increased resistance to H ₂O ₂ toxicity. Altogether, we demonstrate that iron and superoxide stress trigger rugose biofilm formation in UTI89. Rugose biofilm development involves the elaboration of two distinct bacterial populations and increased resistance to oxidative stress.
PDF
