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ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician's choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or 'all' patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician's choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2-ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53-altered patients. In summary, ARPIs outperform taxanes and physician's choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 .
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Previous studies have reported inconsistent results about exogenous melatonin's sleep-promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta-analysis of double-blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep-related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose-response and meta-regression models were estimated to explore how time of administration, dose, and other treatment-related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose-response meta-analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta-regression models showed that insomnia status (ß = 0.50, p < 0.001) and time between treatment administration and the sleep episode (ß = -0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day (ß = -0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep.
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Melatonina , Ensayos Clínicos Controlados Aleatorios como Asunto , Trastornos del Inicio y del Mantenimiento del Sueño , Melatonina/administración & dosificación , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Sueño/efectos de los fármacosRESUMEN
OBJECTIVE: Evidence on the optimal "dose" of cognitive behavioral therapy (CBT) for treating major depressive disorder is sparse. This analysis aimed to evaluate the dose-response curve in CBT using a nonlinear approach, whereby "dose" was defined as number of treatment sessions. The dose-response curve of CBT was compared to other psychotherapies and pharmacological treatments for depression. METHOD: A systematic review and metaregression analysis of randomized controlled trials (RCTs) examining the efficacy of CBT in adults with acute depression was conducted. Treatment arms examining other psychosocial or pharmacological interventions were also analyzed. Cubic spline metaregression techniques were used to model nonlinear dose-response curves. RESULTS: Seventy-two studies and 7,377 participants were included. Modeling the dose-response curve between change of depression symptom severity and the number of CBT sessions resulted in a nonlinear curve characterized by a strong improvement in symptom severity from baseline within the first eight sessions. Symptom reduction continues in the further course of the treatment, but at a slower pace. A similar pattern of symptom development was found for other therapies as well, although the prominence of early improvement and overall effect sizes vary across treatment arms. CONCLUSION: Results imply a general tendency for the strongest alleviation of depressive symptom severity in early stages of CBT treatment, thus, if aiming at symptom alleviation, speak for short CBT interventions. However, these findings have to be discussed in the light of the limited data regarding the sustainability of treatment effects in short-term therapies and effects beyond symptomatic changes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Terapia Cognitivo-Conductual , Trastorno Depresivo Mayor , Humanos , Terapia Cognitivo-Conductual/métodos , Trastorno Depresivo Mayor/terapia , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Importance: Noninvasive brain stimulation (NIBS) interventions have been shown to be efficacious in several mental disorders, but the optimal dose stimulation parameters for each disorder are unknown. Objective: To define NIBS dose stimulation parameters associated with the greatest efficacy in symptom improvement across mental disorders. Data Sources: Studies were drawn from an updated (to April 30, 2023) previous systematic review based on a search of PubMed, OVID, and Web of Knowledge. Study Selection: Randomized clinical trials were selected that tested transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) for any mental disorder in adults aged 18 years or older. Data Extraction and Synthesis: Two authors independently extracted the data. A 1-stage dose-response meta-analysis using a random-effects model was performed. Sensitivity analyses were conducted to test robustness of the findings. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The main outcome was the near-maximal effective doses of total pulses received for TMS and total current dose in coulombs for tDCS. Results: A total of 110 studies with 4820 participants (2659 men [61.4%]; mean [SD] age, 42.3 [8.8] years) were included. The following significant dose-response associations emerged with bell-shaped curves: (1) in schizophrenia, high-frequency (HF) TMS on the left dorsolateral prefrontal cortex (LDLPFC) for negative symptoms (χ2 = 9.35; df = 2; P = .009) and TMS on the left temporoparietal junction for resistant hallucinations (χ2 = 36.52; df = 2; P < .001); (2) in depression, HF-DLPFC TMS (χ2 = 14.49; df = 2; P < .001); (3) in treatment-resistant depression, LDLPFC tDCS (χ2 = 14.56; df = 2; P < .001); and (4) in substance use disorder, LDLPFC tDCS (χ2 = 33.63; df = 2; P < .001). The following significant dose-response associations emerged with plateaued or ascending curves: (1) in depression, low-frequency (LF) TMS on the right DLPFC (RDLPFC) with ascending curve (χ2 = 25.67; df = 2; P = .001); (2) for treatment-resistant depression, LF TMS on the bilateral DLPFC with ascending curve (χ2 = 5.86; df = 2; P = .004); (3) in obsessive-compulsive disorder, LF-RDLPFC TMS with ascending curve (χ2 = 20.65; df = 2; P < .001) and LF TMS on the orbitofrontal cortex with a plateaued curve (χ2 = 15.19; df = 2; P < .001); and (4) in posttraumatic stress disorder, LF-RDLPFC TMS with ascending curve (χ2 = 54.15; df = 2; P < .001). Sensitivity analyses confirmed the main findings. Conclusions and Relevance: The study findings suggest that NIBS yields specific outcomes based on dose parameters across various mental disorders and brain regions. Clinicians should consider these dose parameters when prescribing NIBS. Additional research is needed to prospectively validate the findings in randomized, sham-controlled trials and explore how other parameters contribute to the observed dose-response association.
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Trastornos Mentales , Estimulación Transcraneal de Corriente Directa , Estimulación Magnética Transcraneal , Humanos , Estimulación Magnética Transcraneal/métodos , Estimulación Transcraneal de Corriente Directa/métodos , Trastornos Mentales/terapia , Adulto , Masculino , Femenino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Artificial intelligence (AI) as an independent reader of screening mammograms has shown promise, but there are few prospective studies. Our aim was to conduct a prospective clinical trial to examine how AI affects cancer detection and false positive findings in a real-world setting. METHODS: ScreenTrustCAD was a prospective, population-based, paired-reader, non-inferiority study done at the Capio Sankt Göran Hospital in Stockholm, Sweden. Consecutive women without breast implants aged 40-74 years participating in population-based screening in the geographical uptake area of the study hospital were included. The primary outcome was screen-detected breast cancer within 3 months of mammography, and the primary analysis was to assess non-inferiority (non-inferiority margin of 0·15 relative reduction in breast cancer diagnoses) of double reading by one radiologist plus AI compared with standard-of-care double reading by two radiologists. We also assessed single reading by AI alone and triple reading by two radiologists plus AI compared with standard-of-care double reading by two radiologists. This study is registered with ClinicalTrials.gov, NCT04778670. FINDINGS: From April 1, 2021, to June 9, 2022, 58 344 women aged 40-74 years underwent regular mammography screening, of whom 55 581 were included in the study. 269 (0·5%) women were diagnosed with screen-detected breast cancer based on an initial positive read: double reading by one radiologist plus AI was non-inferior for cancer detection compared with double reading by two radiologists (261 [0·5%] vs 250 [0·4%] detected cases; relative proportion 1·04 [95% CI 1·00-1·09]). Single reading by AI (246 [0·4%] vs 250 [0·4%] detected cases; relative proportion 0·98 [0·93-1·04]) and triple reading by two radiologists plus AI (269 [0·5%] vs 250 [0·4%] detected cases; relative proportion 1·08 [1·04-1·11]) were also non-inferior to double reading by two radiologists. INTERPRETATION: Replacing one radiologist with AI for independent reading of screening mammograms resulted in a 4% higher non-inferior cancer detection rate compared with radiologist double reading. Our study suggests that AI in the study setting has potential for controlled implementation, which would include risk management and real-world follow-up of performance. FUNDING: Swedish Research Council, Swedish Cancer Society, Region Stockholm, and Lunit.
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Neoplasias de la Mama , Mamografía , Femenino , Humanos , Masculino , Inteligencia Artificial , Neoplasias de la Mama/diagnóstico por imagen , Detección Precoz del Cáncer/métodos , Mamografía/métodos , Estudios Prospectivos , SueciaRESUMEN
OBJECTIVE: To evaluate the performance of risk calculators (RCs) predicting lymph node invasion (LNI) and extraprostatic extension (EPE) in men undergoing transperineal magnetic resonance imaging/transrectal ultrasound (TRUS)-fusion template saturation biopsy (TTSB) and conventional systematic TRUS-guided biopsy (SB). PATIENTS AND METHODS: The RCs were tested in a consecutive cohort of 645 men undergoing radical prostatectomy with extended pelvic LN dissection between 2005 and 2019. TTSB was performed in 230 (35.7%) and SB in 415 (64.3%) men. Risk of LNI and EPE was calculated using the available RCs. Discrimination, calibration, and clinical usefulness stratified by different biopsy techniques were assessed. RESULTS: Lymph node invasion was observed in 23 (10%) and EPE in 73 (31.8%) of cases with TTSB and 53 (12.8%) and 158 (38%) with SB, respectively. RCs showed an excellent discrimination and acceptable calibration for prediction of LNI based on TTSB (area under the curve [AUC]/risk estimation: Memorial Sloan Kettering Cancer Center [MSKCC]-RC 0.79/-4%, Briganti (2012)-RC 0.82/-4%, Gandaglia-RC 0.81/+6%). These were comparable in SB (MSKCC-RC 0.78/+2%; Briganti (2012)-RC 0.77/-3%). Decision curve analysis (DCA) revealed a net benefit at threshold probabilities between 3% and 6% when TTSB was used. For prediction of EPE based on TTSB an inferior discrimination and variable calibration were observed (AUC/risk estimation: MSKCC-RC 0.71/+8% and Martini (2018)-RC 0.69/+2%) achieving a net benefit on DCA only at risk thresholds of >17%. Performance of RCs for prediction of LNI and EPE based on SB showed comparable results with a better performance in the DCA for LNI (risk thresholds 1-2%) and poorer performance for EPE (risk threshold >20%). This study is limited by its retrospective single-institution design. CONCLUSIONS: The potentially more accurate grading ability of TTSB did not result in improved performance of preoperative RCs. Prediction tools for LNI proved clinical usefulness while RCs for EPE did not.
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Nomogramas , Neoplasias de la Próstata , Masculino , Humanos , Estudios Retrospectivos , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Ganglios Linfáticos/patología , Biopsia , Prostatectomía , Biopsia Guiada por Imagen/métodosRESUMEN
BACKGROUND: Adherence to adjuvant tamoxifen therapy is suboptimal, and acceptance of tamoxifen for primary prevention is poor. Published results indicate effect of low-dose tamoxifen therapy. Using questionnaire data from a randomised controlled trial, we describe side effects of standard and low-dose tamoxifen in healthy women. METHODS: In the KARISMA trial, 1440 healthy women were randomised to 6 months of daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. Participants completed a 48-item, five-graded Likert score symptom questionnaire at baseline and follow-up. Linear regression models were used to identify significant changes in severity levels across doses and by menopausal status. RESULTS: Out of 48 predefined symptoms, five were associated with tamoxifen exposure (hot flashes, night sweats, cold sweats, vaginal discharge and muscle cramps). When comparing these side effects in premenopausal women randomised to low doses (2.5, 5 mg) versus high doses (10, 20 mg), the mean change was 34% lower in the low-dose group. No dose-dependent difference was seen in postmenopausal women. CONCLUSIONS: Symptoms related to tamoxifen therapy are influenced by menopausal status. Low-dose tamoxifen, in contrast to high-dose, was associated with less pronounced side effects, a finding restricted to premenopausal women. Our findings give new insights which may influence future dosing strategies of tamoxifen in both the adjuvant and preventive settings. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03346200.
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Neoplasias de la Mama , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Tamoxifeno/uso terapéutico , Sofocos/inducido químicamente , Sofocos/tratamiento farmacológico , Sofocos/prevención & control , Premenopausia , Encuestas y Cuestionarios , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inducido químicamente , Antineoplásicos Hormonales/efectos adversosRESUMEN
Objective: To investigate the association of metabolic side effects with antipsychotic dose, we conducted a dose-response meta-analysis of randomized controlled trials (RCTs) in which antipsychotics were administered to people with schizophrenia. The primary outcome was mean change in weight. The secondary outcomes were the mean changes in metabolic parameters.Data Sources: MEDLINE, Embase, PubMed, PsyARTICLES, PsycINFO, Cochrane Database of Systematic Reviews, and different trial registries were searched for articles published in English until February 2021.Study Selection: We identified fixed-dose RCTs with first- or second-generation antipsychotics. The quality of RCTs was measured with Cochrane's Risk of Bias tool.Data Extraction: We performed a dose-response meta-analysis.Results: We retained 52 RCTs including 22,588 participants. With the exception of aripiprazole long-acting injectable (LAI), all investigated antipsychotics presented significant dose-response associations with weight, from lurasidone with a quasi-parabolic shaped curve (9 studies, estimation of 95% effective dose [ED95; 59.93 mg/d] = 0.53 kg/6 wk) to olanzapine LAI with a curve that continued to increase with the dose (1 study, ED95 [15.05 mg/d] = 4.29 kg/8 wk). All curves could be ordered in 3 different classes of shapes-quasi-parabolic, plateau, and ascending.Conclusions: We found significant dose-response associations for weight and metabolic variables, with a unique signature for each antipsychotic. Weight gain can occur at a relatively low median effective dose, and increasing doses can be associated with greater weight gain for some drugs. Despite several limitations, including the limited number of available studies, our results may provide useful information for preventing weight gain and metabolic disturbance by adapting antipsychotic doses.Registration: PROSPERO ID number CRD42021176569.
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Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Revisiones Sistemáticas como Asunto , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inducido químicamente , Aumento de PesoRESUMEN
OBJECTIVE: To estimate the dose-response associations between non-occupational physical activity and several chronic disease and mortality outcomes in the general adult population. DESIGN: Systematic review and cohort-level dose-response meta-analysis. DATA SOURCES: PubMed, Scopus, Web of Science and reference lists of published studies. ELIGIBILITY CRITERIA: Prospective cohort studies with (1) general population samples >10 000 adults, (2) ≥3 physical activity categories, and (3) risk measures and CIs for all-cause mortality or incident total cardiovascular disease, coronary heart disease, stroke, heart failure, total cancer and site-specific cancers (head and neck, myeloid leukaemia, myeloma, gastric cardia, lung, liver, endometrium, colon, breast, bladder, rectum, oesophagus, prostate, kidney). RESULTS: 196 articles were included, covering 94 cohorts with >30 million participants. The evidence base was largest for all-cause mortality (50 separate results; 163 415 543 person-years, 811 616 events), and incidence of cardiovascular disease (37 results; 28 884 209 person-years, 74 757 events) and cancer (31 results; 35 500 867 person-years, 185 870 events). In general, higher activity levels were associated with lower risk of all outcomes. Differences in risk were greater between 0 and 8.75 marginal metabolic equivalent of task-hours per week (mMET-hours/week) (equivalent to the recommended 150 min/week of moderate-to-vigorous aerobic physical activity), with smaller marginal differences in risk above this level to 17.5 mMET-hours/week, beyond which additional differences were small and uncertain. Associations were stronger for all-cause (relative risk (RR) at 8.75 mMET-hours/week: 0.69, 95% CI 0.65 to 0.73) and cardiovascular disease (RR at 8.75 mMET-hours/week: 0.71, 95% CI 0.66 to 0.77) mortality than for cancer mortality (RR at 8.75 mMET-hours/week: 0.85, 95% CI 0.81 to 0.89). If all insufficiently active individuals had achieved 8.75 mMET-hours/week, 15.7% (95% CI 13.1 to 18.2) of all premature deaths would have been averted. CONCLUSIONS: Inverse non-linear dose-response associations suggest substantial protection against a range of chronic disease outcomes from small increases in non-occupational physical activity in inactive adults. PROSPERO registration number CRD42018095481.
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Enfermedades Cardiovasculares , Neoplasias , Masculino , Adulto , Femenino , Humanos , Estudios Prospectivos , Enfermedades Cardiovasculares/prevención & control , Ejercicio Físico/fisiología , Enfermedad CrónicaRESUMEN
Trial-level surrogates are useful tools for improving the speed and cost effectiveness of trials but surrogates that have not been properly evaluated can cause misleading results. The evaluation procedure is often contextual and depends on the type of trial setting. There have been many proposed methods for trial-level surrogate evaluation, but none, to our knowledge, for the specific setting of platform studies. As platform studies are becoming more popular, methods for surrogate evaluation using them are needed. These studies also offer a rich data resource for surrogate evaluation that would not normally be possible. However, they also offer a set of statistical issues including heterogeneity of the study population, treatments, implementation, and even potentially the quality of the surrogate. We propose the use of a hierarchical Bayesian semiparametric model for the evaluation of potential surrogates using nonparametric priors for the distribution of true effects based on Dirichlet process mixtures. The motivation for this approach is to flexibly model relationships between the treatment effect on the surrogate and the treatment effect on the outcome and also to identify potential clusters with differential surrogate value in a data-driven manner so that treatment effects on the surrogate can be used to reliably predict treatment effects on the clinical outcome. In simulations, we find that our proposed method is superior to a simple, but fairly standard, hierarchical Bayesian method. We demonstrate how our method can be used in a simulated illustrative example (based on the ProBio trial), in which we are able to identify clusters where the surrogate is, and is not useful. We plan to apply our method to the ProBio trial, once it is completed.
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Ensayos Clínicos como Asunto , Humanos , Teorema de Bayes , Resultado del TratamientoRESUMEN
INTRODUCTION: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021. METHODS AND ANALYSIS: The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing. ETHICS AND DISSEMINATION: ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04488081.
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COVID-19 , Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Teorema de Bayes , Humanos , Pandemias , SARS-CoV-2 , Resultado del TratamientoRESUMEN
Importance: Mortality rates resulting from bladder cancer have remained unchanged for more than 30 years. The surgical community has put hope in robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in an effort to improve surgical outcomes and bladder cancer survival without strong supporting evidence. Objective: To evaluate perioperative, safety, and survival outcome differences between RARC with ICUD and open radical cystectomy (ORC). Design, Setting, and Participants: This nationwide population-based cohort study used data from the Swedish National Register of Urinary Bladder Cancer and population-based Cause of Death Register, which includes clinical information on tumor characteristics, treatment, and survival and covers approximately 97% of patients with urinary bladder cancer in Sweden. All patients who underwent radical cystectomy for bladder cancer in any hospital between January 2011 and December 2018 were included. Follow-up data were collected until December 2019. Data analysis was conducted from June to December 2020. Exposures: RARC or ORC. Main Outcomes and Measures: The main outcomes were all-cause and cancer-specific mortality between RARC and ORC, compared using propensity score matching. Secondary outcomes were differences in perioperative outcomes after the different surgical approaches. Results: Throughout the observation period, 889 patients underwent RARC and 2280 patients underwent ORC at 24 Swedish hospitals. The median (IQR) age was 71 (66-76) years and 2386 patients (75.3%) were men. After a median (IQR) follow-up of 47 (28-71) months, the 5-year cancer-specific mortality rates were 30.2% (variance, 1.59) for ORC and 27.6% (variance, 3.12) for RARC, and the overall survival rates were 57.7% (variance, 2.46) for ORC and 61.4% (variance, 5.11) for RARC. In the propensity score-matched analysis, RARC was associated with a lower all-cause mortality (hazard ratio, 0.71; 95% CI, 0.56-0.89; P = .004). Compared with ORC, RARC was associated with a lower estimated blood loss (median [IQR] 150 [100-300] mL vs 700 [400-1300] mL; P < .001), intraoperative transfusion rate (odds ratio [OR], 0.05; 95% CI, 0.03-0.08; P < .001), and shorter length of stay (median [IQR], 9 [6-13] days vs 13 [10-17] days; P < .001), and with a higher lymph node yield (median [IQR], 20 [15-27] lymph nodes vs 14 [8-24] lymph nodes; P < .001) and 90-day rehospitalization rate (OR, 1.28; 95% CI, 1.02-1.60; P = .03). The RARC group, compared with the ORC group had lower risk of Clavien-Dindo grade III or higher complications (OR, 0.62; 95% CI, 0.43-0.87; P = .009). Conclusions and Relevance: These findings suggest that compared with ORC, RARC with ICUD was associated with a lower overall mortality rate, fewer high-grade complications, and more favorable perioperative outcomes.
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Procedimientos Quirúrgicos Robotizados , Robótica , Neoplasias de la Vejiga Urinaria , Anciano , Estudios de Cohortes , Cistectomía/efectos adversos , Cistectomía/métodos , Femenino , Humanos , Masculino , Procedimientos Quirúrgicos Robotizados/métodos , Suecia/epidemiología , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
ProBio is an outcome-adaptive, multiarm, multiple-assignment randomised, biomarker-driven platform trial in men with metastatic castration-resistant prostate cancer. Here we describe the amended clinical protocol, focusing on expansion of the trial to include patients with de novo metastatic hormone-sensitive prostate cancer.
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Biomarcadores , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/terapiaRESUMEN
BACKGROUND: Several studies evaluated prostate cancer (PCa) outcomes in Black men on active surveillance (AS); most studies contained few Black men and results were conflicting. We performed a systematic review and meta-analyze of race and outcomes on AS. METHODS: A systematic search was performed for articles of men with Grade Group 1 or 2 (GG1 or GG2) PCa on AS. All studies required race-specific comparative progression data. Progression to treatment, PSA, or biopsy progression were considered and relative risk (RR) estimates of Black men progressing were extracted and pooled using random-effects models. Differences by study-level characteristics were evaluated using subgroup and a cumulative meta-analysis by time. RESULTS: In total, 12 studies were included (3137 Black and 12,206 non-Black men); eight prospective (27%, n = 4210) and four retrospectives (73%, n = 11,133) cohorts. The overall RR of progression for Black men was 1.62 (95%CI, 1.21-2.17), I2 = 64% (95% CI, 32-80%), (χ2 = 30.23; P = 0.001; τ2 = 0.16). Black men with GG1 PCa alone had a higher pooled progression: RR = 1.81 (95% CI, 1.23-2.68). Including only studies with clinical progression (excluding progression to treatment), potentiated results: RR = 1.82 (95%CI, 1.27-2.60). However, a cumulative meta-analysis demonstrated decreasing pooled effect over time, with contemporary studies after 2019 showing a tempered effect (RR: 1.29, 95% CI: 1.20-1.39). CONCLUSIONS: Many studies attribute racial disparity in PCa to delayed presentation of disease, however, AS is unique since all AS eligible men have a low grade and stage PCa. Our findings suggest Black men may have an increased risk of progression during AS, but the association is not so strong that Black men should be discouraged from undergoing AS. Indeed, contemporary evidence suggests stricter inclusion, better confirmatory testing or better access to care may temper these findings. Importantly, these results utilize self-reported race, a social construct that has many limitations.
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Neoplasias de la Próstata , Biopsia , Humanos , Masculino , Clasificación del Tumor , Estudios Prospectivos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/terapia , Espera VigilanteRESUMEN
Determining the optimal antipsychotic target dose in acute phase treatment is of high clinical relevance. The effect of antipsychotics on negative symptoms should be taken into account because patients will often continue on the treatment received in the acute phase. Therefore, we conducted a formal dose-response meta-analysis of negative symptoms and positive symptoms based on a systematic review of fixed-dose randomized controlled trials (RCTs) that examined the effectiveness of antipsychotics for the acute exacerbation of schizophrenia. Forty RCTs included a total of 15,689 patients. The 95% effective doses per day for the 13 antipsychotics included and 3 long acting were mostly different for negative and positive symptoms: amisulpride (481 mg, 690.6 mg); aripiprazole (11.9 mg, 11 mg); asenapine (7.61 mg, 5.66 mg); brexpiprazole (2.1 mg, 4 mg); cariprazine (4 mg, 6.51 mg); haloperidol (6.34 mg, 7.36 mg); lurasidone (58.2 mg, 86.3 mg); olanzapine (15.5 mg, 9.52 mg); olanzapine long-acting injection (15.7 mg, 13.5 mg); paliperidone (7.2 mg, 7 mg); paliperidone long-acting injection (7.5 mg, 5.9 mg); quetiapine instant-release (264.2 mg, 316.5 mg); quetiapine extended-release (774 mg, 707.2 mg); risperidone (7.5 mg, 7.7 mg); risperidone long-acting injection (5.13 mg, 6.7 mg); sertindole (13.5 mg, 16.3 mg); and ziprasidone (71.6 mg, 152.6 mg). The shape of the dose-response curves varied across different drugs with most drugs showing a plateau at higher doses. Most dose-response curves suggested that the near-maximum effective doses could be in the lower-to-medium range of the licensed dose. Additional RCTs are necessary to establish the optimal dose.
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BACKGROUND: Negative symptoms are a core aspect of psychopathology in schizophrenia. Currently available pharmacological agents have proven minimally efficacious for remediating negative symptoms. A promising treatment avenue is the intranasal administration of the neuropeptide oxytocin. However, there have been inconsistencies in effects of oxytocin on negative symptoms throughout the literature, and factors leading to inconsistent effects are unclear. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials to compare the effectiveness of oxytocin with placebo for the treatment of negative symptoms and determine moderators of treatment effect. Random effects meta-analyses and dose-response meta-analysis were performed on mean changes in negative symptoms. RESULTS: In an initial analysis of all 9 identified randomized clinical trials, intranasal oxytocin showed no significant effect on negative symptoms. For higher doses (>40-80 IU), a beneficial effect on negative symptoms was found with a moderate effect size, but this effect disappeared after exclusion of 1 outlier study. The dose-response meta-analysis predicted that higher doses of oxytocin may be more efficacious for negative symptoms. For positive symptoms, no beneficial effect of oxytocin was found in the main meta-analysis, but the dose-response meta-analysis suggested a potential advantage of higher doses. CONCLUSIONS: The present results show no consistent beneficial effect of intranasal oxytocin for the treatment of negative and positive symptoms. The dose-response meta-analysis does not allow drawing any firm conclusions but suggests that high doses of intranasal oxytocin may be more efficacious. If future studies are conducted, an effort to reach adequate CNS concentrations for a sufficient duration is required.
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Oxitocina/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Intranasal , Relación Dosis-Respuesta a Droga , Humanos , Evaluación de Resultado en la Atención de Salud , Oxitocina/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Esquizofrenia/fisiopatologíaRESUMEN
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated with poor prognosis in patients initiating androgen receptor signalling inhibitors (ARSi). We performed a post hoc analysis of an amalgamated baseline circulating tumour DNA (ctDNA) mutational landscape dataset of ARSi-treated men with mCRPC (n = 342). We associated the detected hotspot, pathogenic, and/or high impact protein function-affecting perturbations in 39 genes into 13 pathways. Progression-free (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and multivariate Cox regression models. Driver gene alterations were detected in 192/342 (56.1%) evaluable patients. An increased number of affected pathways, coined pathway complexity index (PCI), resulted in a decremental PFS and OS, and was independently associated with prognosis once ≥3 pathway or gene classes were affected (PFS HR (95%CI): 1.7 (1.02-2.84), p = 0.04, and OS HR (95%CI): 2.5 (1.06-5.71), p = 0.04). Additionally, visceral disease and baseline PSA and plasma ctDNA levels were independently associated with poor prognosis. Elevated PCI is associated with poor ARSi outcome and supports comprehensive genomic profiling to better infer mCRPC prognosis.
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PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms. PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis. RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group. CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.
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Densidad de la Mama/efectos de los fármacos , Neoplasias de la Mama/prevención & control , Tamoxifeno/administración & dosificación , Adulto , Anciano , Antineoplásicos Hormonales/administración & dosificación , Método Doble Ciego , Detección Precoz del Cáncer , Femenino , Humanos , Mamografía , Persona de Mediana EdadRESUMEN
OBJECTIVES: To evaluate the postoperative complication and mortality rate following laparoscopic radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in octogenarians. PATIENTS AND METHODS: We conducted a retrospective analysis comparing postoperative complication and mortality rates depending on age in a consecutive series of 1890 patients who underwent RARC with ICUD for bladder cancer between 2004 and 2018 in 10 European centres. Outcomes of patients aged <80 years and those aged ≥80 years were compared with regard to postoperative complications (Clavien-Dindo grading) and mortality rate. Cancer-specific mortality (CSM) and other-cause mortality (OCM) after surgery were calculated using the non-parametric Aalen-Johansen estimator. RESULTS: A total of 1726 patients aged <80 years and 164 aged ≥80 years were included in the analysis. The 30- and 90-day rate for high-grade (Clavien-Dindo grades III-V) complications were 15% and 21% for patients aged <80 years compared to 11% and 13% for patients aged ≥80 years (P = 0.2 and P = 0.03), respectively. In a multivariable logistic regression analysis adjusting for pre- and postoperative variables, age ≥80 years was not an independent predictor of high-grade complications (odds ratio 0.6, 95% confidence interval 0.3-1.1; P = 0.12). The non-cancer-related 90-day mortality was 2.3% for patients aged ≥80 years and 1.8% for those aged <80 years, respectively (P = 0.7). The estimated 12-month CSM and OCM rates for those aged <80 years were 8% and 3%, and for those aged ≥80 years, 15% and 8%, respectively (P = 0.009 and P < 0.001). CONCLUSIONS: The minimally invasive approach to RARC with ICUD for bladder cancer in well-selected elderly patients (aged ≥80 years) achieved a tolerable high-grade complication rate; the 90-day postoperative mortality rate was driven by cancer progression and the non-cancer-related rate was equivalent to that of patients aged <80 years. However, an increased OCM rate in this elderly group after the first year should be taken into account. These results will support clinicians and patients when balancing cancer-related vs treatment-related risks and benefits.