A brief review of low-dose rate (LDR) and high-dose rate (HDR) brachytherapy boost for high-risk prostate

For patients with unfavorable or high-risk prostate cancer, dose escalated radiation therapy leads to improved progression free survival but attempts to deliver increased dose by external beam radiation therapy (EBRT) alone can be limited by late toxicities to nearby genitourinary and gastrointestinal organs at risk. Brachytherapy is a method to deliver dose escalation in conjunction with EBRT with a potentially improved late toxicity profile and improved prostate cancer related outcomes. At least three randomized controlled trials have demonstrated improved biochemical control with the addition of either low-dose rate (LDR) or high-dose rate (HDR) brachytherapy to EBRT, although only ASCENDE-RT compared brachytherapy to dose-escalated EBRT but did report an over 50% improvement in biochemical failure with a LDR boost. Multiple single institution and comparative research series also support the use of a brachytherapy boost in the DE-EBRT era and demonstrate excellent prostate cancer specific outcomes. Despite improved oncologic outcomes with a brachytherapy boost in the high-risk setting, the utilization of both LDR, and HDR brachytherapy use is declining. The acute genitourinary toxicities when brachytherapy boost is combined with EBRT, particularly a LDR boost, are of concern in comparison to EBRT alone. HDR brachytherapy boost has many physical properties inherent to its rapid delivery of a large dose which may reduce acute toxicities and also appeal to the radiobiology of prostate cancer. We herein review the evidence for use of either LDR or HDR brachytherapy boost for high-risk prostate cancer and summarize comparisons between the two treatment modalities

Treatment patterns and overall survival outcomes among patients aged 80 yr or older with high-risk prostate cancer

BACKGROUND: Elderly patients diagnosed with high-risk prostate cancer (PCa) present a therapeutic dilemma of balancing treatment of a potentially lethal malignancy with overtreatment of a cancer that may not threaten life expectancy. OBJECTIVE: To investigate treatment patterns and overall survival outcomes in this group of patients. DESIGN SETTING AND PARTICIPANTS: A retrospective cohort study was conducted. We queried the National Cancer Database for high-risk PCa in patients aged 80 yr or older diagnosed during 2004-2016. INTERVENTION: Eligible patients underwent no treatment following biopsy (ie, observation), androgen deprivation therapy (ADT) alone, radiation therapy (RT) alone, RT + ADT, or surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier, log rank, and multivariate Cox proportional hazard regression was performed to compare overall survival (OS). RESULTS AND LIMITATIONS: A total of 19 920 men were eligible for analysis, and the most common treatment approach was RT + ADT (7401 patients; 37.2%). Observation and ADT alone declined over time (59.3% in 2004 vs 47.5% in 2016). There was no observed difference in OS between observation and ADT alone (adjusted hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.99-1.09; CONCLUSIONS: This analysis demonstrates that the use of definitive local therapy, including surgery or RT ± ADT, is increasing and is associated with a 50% reduction in overall mortality compared with observation or ADT alone. While prospective validation is warranted, elderly men with high-risk disease eligible for definitive management should be counseled on the risks, including a possible compromise in OS, with deferring definitive management. PATIENT SUMMARY: Elderly men are more often diagnosed with higher-risk prostate cancer but are less likely to receive curative treatment options than younger men. Our analysis demonstrates that for men ≥80 yr of age with high-risk prostate cancer, definitive local therapy, including surgery or radiation therapy and/or androgen deprivation therapy, is associated with a 50% reduction in overall mortality compared with observation or androgen deprivation therapy alone. We therefore recommend that life expectancy (ie, physiologic age) be taken into account, over chronologic age, and that elderly men with good life expectancy (eg, \u3e5 yr; minimal comorbidity) should be offered definitive, life-prolonging therapy

The implementation research institute: Training mental health implementation researchers in the United States

Abstract Background The Implementation Research Institute (IRI) provides two years of training in mental health implementation science for 10 new fellows each year. The IRI is supported by a National Institute of Mental Health (NIMH) R25 grant and the Department of Veterans Affairs (VA). Fellows attend two annual week-long trainings at Washington University in St. Louis. Training is provided through a rigorous curriculum, local and national mentoring, a ‘learning site visit’ to a federally funded implementation research project, pilot research, and grant writing. Methods This paper describes the rationale, components, outcomes to date, and participant experiences with IRI. Results IRI outcomes include 31 newly trained implementation researchers, their new grant proposals, contributions to other national dissemination and implementation research training, and publications in implementation science authored by the Core Faculty and fellows. Former fellows have obtained independent research funding in implementation science and are beginning to serve as mentors for more junior investigators. Conclusions Based on the number of implementation research grant proposals and papers produced by fellows to date, the IRI is proving successful in preparing new researchers who can inform the process of making evidence-based mental healthcare more available through real-world settings of care and who are advancing the field of implementation science

Effectiveness of postoperative radiotherapy after radical cystectomy for locally advanced bladder cancer

BACKGROUND: Local-regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database. METHODS: We identified ≥ pT3pN0-3M0 LABC patients in the National Cancer Database diagnosed 2004-2014 who underwent RC ± PORT. OS was calculated using Kaplan-Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not. RESULTS: 15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2-21.8) for PORT vs 20.8 months (95% CI, 20.3-21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78-0.97); P = 0.008. A one-to-three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity-matched cohort, median OS was 19.8 months (95% CI, 18.0-21.6) for PORT vs 16.9 months (95% CI, 15.6-18.1) for no PORT (P = 0.030). In the propensity-matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P \u3c 0.01 all). CONCLUSION: In this observational cohort, PORT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of PORT in selected patients with LABC, regardless of histology. Prospective trials of PORT are warranted

Logistical, technical, and radiation safety aspects of establishing a radiopharmaceutical therapy program: A case in Lutetium-177 prostate-specific membrane antigen (PSMA) therapy

Prostate-specific membrane antigen (PSMA) is a cell surface protein highly expressed in nearly all prostate cancers, with restricted expression in some normal tissues. The differential expression of PSMA from tumor to non-tumor tissue has resulted in the investigation of numerous targeting strategies for therapy of patients with metastatic prostate cancer. In March of 2022, the FDA granted approval for the use of lutetium-177 PSMA-617 (Lu-177-PSMA-617) for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Therefore, the use of Lu-177-PSMA-617 is expected to increase and become more widespread. Herein, we describe logistical, technical, and radiation safety considerations for implementing a radiopharmaceutical therapy program, with particular focus on the development of operating procedures for therapeutic administrations. Major steps for a center in the U.S. to implement a new radiopharmaceutical therapy (RPT) program are listed below, and then demonstrated in greater detail via examples for Lu-177-PSMA-617 therapy

CT-based online adaptive radiotherapy improves target coverage and organ at risk (OAR) avoidance in stereotactic body radiation therapy (SBRT) for prostate cancer

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is an emerging treatment modality for clinically localized prostate cancer (PCa). Online daily adaptive radiotherapy (ART) could potentially improve the therapeutic ratio of prostate SBRT by accounting for inter-fraction variation in target and OAR volumes. To our knowledge, no group has evaluated the clinical utility of a novel AI-augmented CT-based ART system for prostate SBRT. In this study we hypothesized that adaptive prostate SBRT plans would result in improved target coverage and lower dose to OARs in comparison to unadapted treatment plans. METHODS: Seven patients with favorable intermediate to oligometastatic PCa treated with 5-fx prostate adaptive SBRT were retrospectively reviewed. Patients were treated with 3625 cGy to the prostate and seminal vesicles. 6 patients additionally received 2500 cGy to the pelvic nodes, 5 patients underwent a boost to 4000 cGy to the prostate. For each fraction, a CBCT was acquired and OARs (rectum, bladder, bowel, sigmoid, femurs) were segmented/deformed using AI. CTVs were rigidly registered. Volumes were adjusted manually and PTV expansions added. Adaptive treatment plans were developed based on the contoured targets and OARs and dose to these volumes for the adapted vs. initial plans were compared for each fraction. V100 and the D0.03 cc between scheduled and adapted treatment plans were compared using a Student\u27s RESULTS: Seven patients completed 35 Fx\u27s of adaptive RT. Daily adaptation resulted in a statistically significant mean improvement in PTV V100 for all targets: [21.4 % ± 4.3 % for PTV 4000 (p \u3c 0.0001); 8.7 % ± 1.1 % for PTV 3625 (p \u3c 0.0001); and 11.5 % ± 3.1 % for PTV 2500 (p = 0.0013)]. Mean rectal D0.03 was significantly reduced by 38.8 cGy ± 5.95 cGy (p \u3c 0.0001) per fraction (194 cGy/5 fractions) compared to the initial plans. There was a modest increase in bladder dose of 10.9 cGy ± 4.93 cGy per fraction (p = 0.0424) for the adaptive plans. The adaptive plans met bladder constraints for every fraction. There were no statistically significant differences between sigmoid or bowel dose for adapted vs. initial plans. No patients experienced acute CTCAE grade ≥ 3 GI/GU adverse events (median F/U 9.5 months). All statistically significant differences were maintained in the presence and absence of rectal hydrogel spacer (p \u3c 0.05). CONCLUSIONS: CT-based online adaptive SBRT resulted in statistically significant and clinically meaningful improvements in PTV coverage and D0.03 cc dose to the rectum. A trial evaluating CT adaptive whole-pelvis prostate SBRT is underway

The Conformal Sector of F-theory GUTs

D3-brane probes of exceptional Yukawa points in F-theory GUTs are natural hidden sectors for particle phenomenology. We find that coupling the probe to the MSSM yields a new class of N = 1 conformal fixed points with computable infrared R-charges. Quite surprisingly, we find that the MSSM only weakly mixes with the strongly coupled sector in the sense that the MSSM fields pick up small exactly computable anomalous dimensions. Additionally, we find that although the states of the probe sector transform as complete GUT multiplets, their coupling to Standard Model fields leads to a calculable threshold correction to the running of the visible sector gauge couplings which improves precision unification. We also briefly consider scenarios in which SUSY is broken in the hidden sector. This leads to a gauge mediated spectrum for the gauginos and first two superpartner generations, with additional contributions to the third generation superpartners and Higgs sector.Comment: v2: 51 pages, 2 figures, remark added, typos correcte