Incidence and imaging characteristics of difficult to detect retrospectively identified brain metastases in patients receiving repeat courses of stereotactic radiosurgery.

PURPOSE: During stereotactic radiosurgery (SRS) planning for brain metastases (BM), brain MRIs are reviewed to select appropriate targets based on radiographic characteristics. Some BM are difficult to detect and/or definitively identify and may go untreated initially, only to become apparent on future imaging. We hypothesized that in patients receiving multiple courses of SRS, reviewing the initial planning MRI would reveal early evidence of lesions that developed into metastases requiring SRS. METHODS: Patients undergoing two or more courses of SRS to BM within 6 months between 2016 and 2018 were included in this single-institution, retrospective study. Brain MRIs from the initial course were reviewed for lesions at the same location as subsequently treated metastases; if present, this lesion was classified as a "retrospectively identified metastasis" or RIM. RIMs were subcategorized as meeting or not meeting diagnostic imaging criteria for BM (+ DC or -DC, respectively). RESULTS: Among 683 patients undergoing 923 SRS courses, 98 patients met inclusion criteria. There were 115 repeat courses of SRS, with 345 treated metastases in the subsequent course, 128 of which were associated with RIMs found in a prior MRI. 58% of RIMs were + DC. 17 (15%) of subsequent courses consisted solely of metastases associated with + DC RIMs. CONCLUSION: Radiographic evidence of brain metastases requiring future treatment was occasionally present on brain MRIs from prior SRS treatments. Most RIMs were + DC, and some subsequent SRS courses treated only + DC RIMs. These findings suggest enhanced BM detection might enable earlier treatment and reduce the need for additional SRS.

A individually randomized controlled trial comparing Healer-led vs. clinician- led training to improve personal protective equipment use among traditional healers in South Africa.

Like allopathic healthcare workers, healers are also exposed to patients' blood and body fluids. A widespread practice is the traditional "injection," in which the healer performs subcutaneous incisions to rub herbs directly into the bloodied skin, resulting in 1,500 blood exposures over their lifetime. We tested the impact of healer-led PPE training, staffed by trained traditional healers who reported using PPE during each risky clinical encounter vs. healthcare worker (HCW)-led PPE training sessions. We randomized 136 healers into one of the two study arms (67 in the healer-led group, 69 in the HCW-led group) and assessed the impact of trainer on PPE skills and use over a six-month period. All healers received one in-person day of didactic and practical training followed by three sessions at the healers' home. Participants were largely female (80%), averaged 51 years old, and practiced as a healer for an average of 17 years. Almost 44% either disclosed themselves as HIV+ or received a positive HIV test result at study initiation. Healers in the HCW arm showed equivalent PPE scores as those trained by traditional healers at baseline and at seven months. Healers in both arms self-reported high levels of glove use during"injections," with no statistical difference of use by study arm. When we assessed actual gloves and razor blades disposed of each month, a similar trend emerged. No one seroconverted during the study period. The need for PPE support among traditional healers cannot be ignored. Traditional healers can be trained to effectively disseminate PPE knowledge and skills to other traditional healers. With an estimated 200,000 traditional healers in South Africa, it is imperative that all of them have access to PPE training and supplies to prevent HIV, HCV, or HBV infections. Trial registration: ClinicalTrials.gov, NCT04440813. Registered 17 June 2020, https://clinicaltrials.gov/ct2/show/NCT04440813.

Are higher follicle-stimulating hormone levels before androgen deprivation therapy for prostate cancer associated with oncological and cardiac outcomes and overall survival?-a population-level analysis.

Background: Androgen deprivation therapy (ADT), commonly delivered via a luteinizing hormone-releasing hormone (LHRH) agonist, is the standard treatment for advanced prostate cancer (PC). While quite effective, it has been associated with an increased risk of major adverse cardiovascular events (MACE). The exact mechanisms are not clear. However, it has been theorized that follicle-stimulating hormone (FSH), a pituitary hormone that is involved in controlling normal testosterone levels, which is decreased with LHRH-agonist therapy, may be the culprit. We performed a retrospective population-level study to test the link of FSH levels on the development of MACE, castrate-resistant PC (CRPC), and death among men starting ADT. Methods: All men (n=1,539) who had an FSH level between 1999 and 2018 within 2 years prior to starting ADT and complete data were identified within the Veterans Affairs (VA) Health System. FSH was dichotomized as low/normal (≤8 IU/mL) and high (>8 IU/mL), using established cut-points. The associations between FSH and time to MACE, death, and CRPC were tested using log-rank tests and multivariable Cox proportional hazards models. Results: Patients with high FSH were older (median 76 vs. 73 years, P<0.001), started ADT earlier (median 2007 vs. 2009, P=0.027), and had lower body mass index (BMI) (median 29.1 vs. 30.1 kg/m2, P=0.004) compared to those with low/normal FSH. On multivariable analysis, there was no association between FSH and time from ADT to MACE, CRPC, or death. Conclusions: In this population-level study of men receiving an FSH test prior to starting ADT, there was no association between FSH levels and time from ADT to MACE, CRPC, or death. Although further studies are needed, these results do not support a link between pre-ADT FSH and long-term oncological or cardiovascular outcomes.

Clinical Factors Associated With 30-Day Mortality Among Patients Undergoing Radiation Therapy for Brain Metastases.

Purpose: Existing brain metastasis prognostic models do not identify patients at risk of very poor survival after radiation therapy (RT). Identifying patient and disease risk factors for 30-day mortality (30-DM) after RT may help identify patients who would not benefit from RT. Methods and Materials: All patients who received stereotactic radiosurgery (SRS) or whole-brain RT (WBRT) for brain metastases from January 1, 2017, to September 30, 2020, at a single tertiary care center were included. Variables regarding demographics, systemic and intracranial disease characteristics, symptoms, RT, palliative care, and death were recorded. Thirty-day mortality was defined as death within 30 days of RT completion. The Kaplan-Meier method was used to estimate median overall survival. Univariate and multivariable logistic regression models were used to assess associations between demographic, tumor, and treatment factors and 30-DM. Results: A total of 636 patients with brain metastases were treated with either WBRT (n = 117) or SRS (n = 519). The most common primary disease types were non-small cell lung (46.7%) and breast (19.8%) cancer. Median survival time was 6 months (95% CI, 5-7 months). Of the 636 patients, 75 (11.7%) died within 30 days of RT. On multivariable analysis, progressive intrathoracic disease (hazard ratio [HR], 4.67; 95% CI, 2.06-10.60; P = .002), progressive liver and/or adrenal metastases (HR, 2.20; 95% CI, 1.16-3.68; P = .02), and inpatient status (HR, 4.51; 95% CI, 1.78-11.42; P = .002) were associated with dying within 30 days of RT. A higher Karnofsky Performance Status (KPS) score (HR, 0.95; 95% CI, 0.93-0.97; P < .001), synchronous brain metastases at time of initial diagnosis (HR, 0.45; 95% CI, 0.21-0.96; P = .04), and outpatient palliative care utilization (HR, 0.45; 95% CI, 0.20-1.00; P = .05) were associated with surviving more than 30 days after RT. Conclusions: Multiple factors including a lower KPS, progressive intrathoracic disease, progressive liver and/or adrenal metastases, and inpatient status were associated with 30-DM after RT. A higher KPS, brain metastases at initial diagnosis, and outpatient palliative care utilization were associated with survival beyond 30 days. These data may aid in identifying which patients may benefit from brain metastasis-directed RT.

Time from biopsy to radical prostatectomy by race in an equal-access healthcare system: Results from the SEARCH cohort.

BACKGROUND: We previously showed that within an equal-access health system, race was not associated with the time between prostate cancer (PC) diagnosis and radical prostatectomy (RP). However, in the more recent time-period of the study (2003-2007), Black men had significantly longer times to RP. We sought to revisit the question in a larger study population with more contemporary patients. We hypothesized that time from diagnosis to treatment would not differ by race, even after accounting for active surveillance (AS) and the exclusion of men at very low to low risk of PC progression. METHODS: We analyzed data from 5885 men undergoing RP from 1988 to 2017 at eight Veterans Affairs Hospitals from SEARCH. Multiple linear regression was used to compare time from biopsy to RP and to examine the risk of delays (>90 and >180 days) between races. In sensitivity analyses we excluded men deemed to have initially chosen AS based on having >365 days from biopsy to RP and men at very low to low PC risk for progression according to National Comprehensive Cancer Network Clinical Practice Guidelines. RESULTS: At biopsy, Black men (n = 1959) were younger, had lower body mass index, and higher prostate specific antigen levels, (all p < 0.02), compared to White men (n = 3926). Time from biopsy to RP was longer in Black men (mean days: 98 vs. 92; adjusted ratio of mean number of days, 1.07 [95% confidence interval: 1.03-1.11], p < 0.001); however, there were no differences in delays >90 or >180 days after adjusting for confounders (all p ≥ 0.286). Results were similar following the exclusion of men potentially under on AS and at very low and low risk. CONCLUSIONS: In an equal-access healthcare system, we did not find evidence of clinically relevant differences in time from biopsy to RP in Black versus White men.

A modeling study to estimate prostate cancer-specific mortality on active surveillance for men with favorable intermediate-risk prostate cancer: Results from the SEARCH cohort.

PURPOSE: Limited data exist to help surgeons decide between active surveillance (AS) versus treatment for men with favorable intermediate risk (FIR) prostate cancer. To estimate the theoretical excess risk of prostate cancer-specific mortality (PCSM) with AS versus radical prostatectomy (RP), we determined the risk of PCSM in FIR men undergoing RP and modeled the PCSM risk for AS using a range of increased PSCM scenarios ranging from 1.25x to 2x higher relative to RP. MATERIALS AND METHODS: We retrospectively reviewed data from men undergoing RP from 1988 to 2017 at 8 Veterans Affairs hospitals within the SEARCH cohort. Men with FIR PC were identified using the NCCN risk criteria. Risk of PCSM at 5, 10, and 15 years after RP was estimated. Using these estimates, PCSM was then modeled for AS using a range of increased risk of PCSM relative to RP ranging from 1.25x to 2x higher. RESULTS: For the 920 FIR men identified, 5-, 10-, and 15-year survival estimates for PCSM after RP were 99.9%, 99.0%, and 97.8%, respectively. If the risk of PCSM on AS were 1.25-2x greater than RP, there would be 0.54%-2.17% excess risk of PCSM at 15 years. CONCLUSIONS: The risk of death for FIR after RP is very low. Assuming even modestly increased PCSM with AS versus RP, the excess risk of death for AS in FIR is low even up to 15 years. These data support the consideration of AS as a relatively safe alternative to RP in FIR men, though prospective randomized trials are needed to validate these findings.

Low contralateral neck recurrence risk with ipsilateral neck radiotherapy in N2b tonsillar squamous cell carcinoma.

OBJECTIVES: To characterize factors including nodal burden, pre-treatment imaging, and other patient factors which may influence the role of ipsilateral neck radiotherapy (IRT) in tonsillar squamous cell carcinoma (SCC) with multiple involved ipsilateral nodes. METHODS: Patients with cT1-2N0-2bM0 (AJCC 7th edition) tonsillar SCC treated with definitive radiation therapy (RT) at Duke University Medical Center from 1/1/1990-10/1/2019 were identified. Patient, tumor, and treatment characteristics were compared between those that received bilateral neck RT (BRT) versus IRT. Recurrence-free survival (RFS) was estimated with Kaplan-Meier method. A subset analysis of patients with N2b disease was performed. Patterns of recurrence were analyzed. RESULTS: 120 patients with cT1-2N0-2b tonsillar SCC were identified, including 71 with N2b disease (BRT: n = 30; IRT: n = 41). Median follow-up was 80 months (range: 7-209). No N2b patients who received IRT had > 1 cm of soft palate/base of tongue extension. N2b patients treated with IRT had a median of 3 (range 2-9) involved lymph nodes, with median largest nodal dimension of 2.8 cm (range 1.3-4.8 cm). 93 % of N2b patients who received IRT had staging by PET/CT, and 100 % received IMRT. For N2b patients treated with IRT, there were no contralateral neck recurrences, and 10 year RFS was 95 % (95 % CI 82 %-98 %). CONCLUSIONS: For patients treated with IRT for well-lateralized N2b tonsillar SCC, we observed high rates of local control with no observed contralateral neck recurrence. These data suggest that BRT is not universally necessary for patients with multiple involved ipsilateral nodes, particularly in the setting of baseline staging with PET/CT.

Modifiable patient-reported factors associated with cancer-screening knowledge and participation in a community-based health assessment.

BACKGROUND: We sought to identify modifiable factors associated with cancer screening in a community-based health assessment. METHODS: 24 organizations at 47 community events in central North Carolina distributed a 91-item survey from April-December 2017. Responses about (1) interest in disease prevention, (2) lifestyle choices (e.g., diet, tobacco), and (3) perceptions of primary care access/quality were abstracted to examine their association with self-reported screening participation and knowledge about breast, prostate, and colorectal cancer. RESULTS: 2135/2315 participants (92%; 38.5% White, 38% Black, 9.9% Asian) completed screening questions. >70% of screen-eligible respondents reported guideline-concordant screening. Healthy dietary habits were associated with greater knowledge about breast and colorectal cancer screening; reporting negative attitudes about and barriers to healthcare were associated with less breast, prostate, and colorectal cancer screening. Having a place to seek medical care (a proxy for primary care access) was independently associated with being ∼5 times as likely to undergo colorectal screening (OR 4.66, 95% CI 1.58-13.79, all p < 0.05). CONCLUSIONS: In this diverse, community-based sample, modifiable factors were associated with screening engagement, highlighting opportunities for behavioral intervention.

Impact of Race on Outcomes of High-Risk Patients With Prostate Cancer Treated With Moderately Hypofractionated Radiotherapy in an Equal Access Setting.

Background: Moderately hypofractionated radiotherapy (MHRT) is an accepted treatment for localized prostate cancer; however, limited MHRT data address high-risk prostate cancer (HRPC) and/or African American patients. We report clinical outcomes and toxicity profiles for individuals with HRPC treated in an equal access system. Methods: We identified patients with HRPC treated with MHRT at a US Department of Veterans Affairs referral center. Exclusion criteria included < 12 months follow-up and elective nodal irradiation. MHRT included 70 Gy over 28 fractions or 60 Gy over 20 fractions. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicities were graded using Common Terminology Criteria for Adverse Events, version 5.0. Clinical endpoints, including biochemical recurrence-free survival (BRFS), distant metastases-free survival (DMFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using Kaplan-Meier methods. Clinical outcomes, acute toxicity, and late toxicity-free survival were compared between African American and White patients with logistic regression and log-rank testing. Results: Between November 2008 and August 2018, 143 patients with HRPC were treated with MHRT and followed for a median of 38.5 months; 82 (57%) were African American and 61 were White patients. Concurrent androgen deprivation therapy (ADT) was provided for 138 (97%) patients for a median duration of 24 months. No significant differences between African American and White patients were observed for 5-year OS (73% [95% CI, 58%-83%] vs 77% [95% CI, 60%-97%]; P = .55), PCSS (90% [95% CI, 79%-95%] vs 87% [95 % CI, 70%-95%]; P = .57), DMFS (91% [95% CI, 80%-96%] vs 81% [95% CI, 62%-91%]; P = .55), or BRFS (83% [95% CI, 70%-91%] vs 71% [95% CI, 53%-82%]; P = .57), respectively. Rates of acute grade 3+ GU and GI were low overall (4% and 1%, respectively). Late toxicities were similarly favorable with no significant differences by race. Conclusions: Individuals with HRPC treated with MHRT in an equal access setting demonstrated favorable clinical outcomes that did not differ by race, alongside acceptable rates of acute and late toxicities.

Are higher pre-diagnosis follicle stimulating hormone levels associated with long-term prostate cancer risk?

BACKGROUND: Follicle stimulating hormone (FSH) is a pituitary hormone that helps regulate testosterone homeostasis. Although it is generally accepted that FSH levels increase with LHRH-agonist therapy for prostate cancer (PC), the specific impact of FSH levels on risk of PC diagnosis is largely unknown. The objective of this study was to perform a population-level analysis to assess the association between FSH levels and PC diagnosis. METHODS: All men (n = 386,018) who had a pre-PC diagnosis FSH level and complete data were identified within the Veterans Affairs Health System between 1999 and 2018. The association between FSH level and time from FSH test to PC diagnosis was tested using stratified Cox proportional hazards models. Multivariable models were adjusted for age, year, race, body mass index, and Charlson comorbidity index. Due to nonproportional hazards over time, time to PC was modeled separately: ≤4 years after an FSH test and >4 years following an FSH test. RESULTS: Median age at first FSH level was 64 years (interquartile range [IQR]: 54-72), median year of FSH was 2010 (IQR: 2005-2014), and 70% of the cohort was white. Median follow-up was 76 months (IQR: 38-126) during which 17,519 men (4.5%) were diagnosed with PC. On multivariable analysis, in the first 4 years after FSH test, there was no association between FSH and time to PC diagnosis. Starting from 4 years after FSH test, on multivariable analysis, a higher FSH level was associated with lower risk of PC with continuous modeling, but found no association with log continuous and categorical modeling. CONCLUSIONS: In this population-level study among male veterans receiving an FSH test for an unknown clinical indication, associations between FSH levels and PC risk were inconsistent and likely driven by selection bias and confounding variables. Future studies should consider different study designs.

Association of lipid profile biomarkers with breast cancer by molecular subtype: analysis of the MEND study.

There is conflicting evidence on the role of lipid biomarkers in breast cancer (BC), and no study to our knowledge has examined this association among African women. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of lipid biomarkers-total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides-with odds of BC overall and by subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC) for 296 newly diagnosed BC cases and 116 healthy controls in Nigeria. Each unit standard deviation (SD) increase in triglycerides was associated with 39% increased odds of BC in fully adjusted models (aOR: 1.39; 95% CI: 1.03, 1.86). Among post-menopausal women, higher total cholesterol (aOR: 1.65; 95% CI: 1.06, 2.57), LDL cholesterol (aOR: 1.59; 95% CI: 1.04, 2.41), and triglycerides (aOR: 1.91; 95% CI: 1.21, 3.01) were associated with increased odds of BC. Additionally, each unit SD increase in LDL was associated with 64% increased odds of Luminal B BC (aOR 1.64; 95% CI: 1.06, 2.55). Clinically low HDL was associated with 2.7 times increased odds of TNBC (aOR 2.67; 95% CI: 1.10, 6.49). Among post-menopausal women, higher LDL cholesterol and triglycerides were significantly associated with increased odds of Luminal B BC and HER2 BC, respectively. In conclusion, low HDL and high LDL are associated with increased odds of TN and Luminal B BC, respectively, among African women. Future prospective studies can definitively characterize this association and inform clinical approaches targeting HDL as a BC prevention strategy.

Comparing Outcomes of Oligometastases Treated with Hypofractionated Image-Guided Radiotherapy (HIGRT) with a Simultaneous Integrated Boost (SIB) Technique versus Metastasis Alone: A Multi-Institutional Analysis.

PURPOSE: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. METHODS: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan-Meier method and compared between the two techniques using the log-rank test. RESULTS: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4-71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55-74%; p = 0.24)), disease-free survival (60% (95% CI: 40-75%; p = 0.40)), or overall survival (88% (95% CI: 73-95%; p = 0.26)), between the MA and SIB cohorts. CONCLUSION: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.

Lifestyle and sociodemographic factors associated with treatment choice of clinically localized prostate cancer in an equal access healthcare system.

Sociodemographic and lifestyle factors may play a role in determining whether patients with clinically localized prostate cancer (PC) are managed with active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT); however, these relationships have not been well examined. In a cross-sectional study conducted within an equal access healthcare system, multivariable adjusted regression analysis revealed that living with a spouse or partner was associated with a 65% lower chance of being managed by RT (P = 0.001) and 57% lower risk of being managed by AS (P = 0.042) compared with RP. No other sociodemographic or lifestyle factors were independently associated with treatment modality.

Effect of Large Prostate Volume on Efficacy and Toxicity of Moderately Hypofractionated Radiation Therapy in Patients With Prostate Cancer.

Purpose: To evaluate the effect of prostate volume on outcomes after moderately hypofractionated radiation therapy (mHFRT) for prostate cancer. Methods and Materials: Prostate cancer patients treated with mHFRT at a Veteran's Affairs Medical Center from August 20, 2008, to January 31, 2018, were identified. Patients were placed into a large prostate planning target volume (LPTV) cohort if their prostate PTV was in the highest quartile. Acute/late genitourinary (GU) and gastrointestinal toxicity events among patients with and without LPTV were compared. Multivariable analyses estimated the effect of factors on toxicity. Overall survival, biochemical recurrence-free survival, and freedom from late GU/gastrointestinal toxicity of patients with and without LPTV were estimated via Kaplan-Meier. Results: Four hundred and seventy-two patients were included. Ninety-three percent received 70 Gy in 2.5 Gy fractions; 75% received androgen deprivation therapy. Median follow-up was 69 months. Patients with LPTV (PTV >138.4 cm3) had a higher late 2 + GU toxicity compared with those without (59% vs 48%, P = .03). Earlier time to late 2 + GU toxicity was associated with LPTV (hazard ratio 1.36; 95% confidence interval [CI], 1.00-1.86; P = .047), androgen deprivation therapy use (hazard ratio 1.60; 95% CI, 1.13-2.27; P = .01), and higher baseline American Urologic Association symptom score (odds ratio 1.03; 95% CI, 1.02-1.05; P < .001). At 2 years, freedom from late 2 + GU toxicity was 46% (95% CI, 47%-54%) for those with LPTV versus 61% (95% CI, 55%-65%) for those without (P = .04). Late grade 3 GU toxicity was 7% for those with LPTV and 4% for those without. No differences in overall survival or biochemical recurrence-free survival were observed between patients with or without LPTV. Conclusions: LPTV did not affect efficacy of mHFRT for prostate cancer; however, it was associated with increased risk and earlier onset of late grade 2 + GU toxicity.

A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND).

BACKGROUND: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide. METHODS: We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO2peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values. RESULTS: The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (-0.31 L/min, -10.9%; p < 0.01) and relative CRF (-3.2 mL/kg/min, -8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17. CONCLUSIONS: This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity. GOV IDENTIFIER: NCT02256111.

A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer.

BACKGROUND: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients. METHODS: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19. RESULTS: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51-85 years), and men had received a median of two prior therapies (range 1-3). Median PSA was 54 ng/dl (range 0-393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6-3.6 months), and median overall survival was 7.4 months (85% CI 2.8-12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder. CONCLUSIONS: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population.

Metabolic Syndrome and Risk of Breast Cancer by Molecular Subtype: Analysis of the MEND Study.

BACKGROUND: Metabolic syndrome (MetS) is characterized by a cluster of biological irregularities. The purpose of this analysis was to examine the association of MetS with BC among Nigerian women, and for the first time evaluate this association by molecular subtype. MATERIALS AND METHODS: MetS was defined as having at least 3 out of 5 of: high blood pressure (≥ 130/85 mm Hg), reduced HDL (< 50 mg/dL), elevated triglyceride (> 150 mg/dL), high waist circumference (≥ 80 cm), and prior diagnosis of diabetes or elevated fasting glucose level (≥ 100 mg/dL). Among 296 newly diagnosed BC cases and 259 healthy controls, multivariable logistic regression models were utilized to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) for the association between MetS and BC overall. Multinomial logistic regression models were used to evaluate each molecular subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC). RESULTS: After adjusting for age, socio-demographic and reproductive risk factors, there was a positive association between MetS and BC (aOR: 1.84, 95% CI: 1.07, 3.16). In stratified analyses, MetS was associated with BC regardless of BMI status; however, the estimate was significant only among normal weight women (aOR: 3.85; 95% CI: 1.25, 11.90). MetS was significantly associated with TNBC subtype (aOR: 4.37, 95% CI: 1.67, 11.44); associations for other molecular subtypes were not statistically significant. CONCLUSION: MetS appears to be a robust risk factor for BC, particularly for TNBC. Public health and clinical interventions can provide substantial benefits in reducing the burden of MetS and preventing BC among Nigerian women.

Prostate weight and prostate cancer outcomes after radical prostatectomy: Results from the SEARCH cohort study.

BACKGROUND: Smaller prostates have been linked to unfavorable clinical characteristics and poor short-term outcomes following radical prostatectomy (RP). We examined the relation between prostate weight at RP and prostate cancer (PC) outcomes post-RP. METHODS: Men in the SEARCH cohort undergoing RP between 1988 and 2017 (N = 6242) were studied for PC-specific mortality (PCSM) as the primary outcome, and for biochemical recurrence (BCR), castration-resistant PC (CRPC) and metastasis as secondary outcomes. Hazard ratios (HR) and 95% confidence intervals (CI) were determined for associations between prostate weight and outcomes using Fine-Gray competing risk regression multivariable analyses. Sensitivity analyses were also carried out following exclusion of: (i) men with extreme prostate weights (<20 g and ≥100 g); and (ii) men with elevated prostate specific antigen (PSA) levels. RESULTS: Median values for age, pre-RP PSA and prostate weight were 63 years, 6.6 ng/ml, and 42.0 g, respectively. During a median follow-up of 7.9 years, 153 (3%) died from PC, 2103 (34%) had BCR, 203 (3%) developed CRPC, and 289 (5%) developed metastases. Prostate weight was not associated with PCSM in the main analyses (multivariable HR = 1.43; 95% CI: 0.87-2.34) or in sensitivity analyses. Prostate weight was inversely associated with BCR in the main analyses (multivariable HR = 0.70; 95%CI: 0.61-0.79) which was unchanged in sensitivity analyses. HRs for prostate weight and CRPC and metastasis were elevated but statistical significance was not attained. Similar results were observed in sensitivity analyses. CONCLUSIONS: Inconsistent results for prostate weight and short-term vs longer-term outcomes highlight the need to better understand the complex biology leading to prostate size and the relevance of prostate size as a predictor of PC outcomes.

Establishing ADC-Based Histogram and Texture Features for Early Treatment-Induced Changes in Head and Neck Squamous Cell Carcinoma.

The purpose of this study was to assess baseline variability in histogram and texture features derived from apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI (DW-MRI) examinations and to identify early treatment-induced changes to these features in patients with head and neck squamous cell carcinoma (HNSCC) undergoing definitive chemoradiation. Patients with American Joint Committee on Cancer Stage III-IV (7th edition) HNSCC were prospectively enrolled on an IRB-approved study to undergo two pre-treatment baseline DW-MRI examinations, performed 1 week apart, and a third early intra-treatment DW-MRI examination during the second week of chemoradiation. Forty texture and six histogram features were derived from ADC maps. Repeatability of the features from the baseline ADC maps was assessed with the intra-class correlation coefficient (ICC). A Wilcoxon signed-rank test compared average baseline and early treatment feature changes. Data from nine patients were used for this study. Comparison of the two baseline ADC maps yielded 11 features with an ICC ≥ 0.80, indicating that these features had excellent repeatability: Run Gray-Level Non-Uniformity, Coarseness, Long Zone High Gray-Level, Variance (Histogram Feature), Cluster Shade, Long Zone, Variance (Texture Feature), Run Length Non-Uniformity, Correlation, Cluster Tendency, and ADC Median. The Wilcoxon signed-rank test resulted in four features with significantly different early treatment-induced changes compared to the baseline values: Run Gray-Level Non-Uniformity (p = 0.005), Run Length Non-Uniformity (p = 0.005), Coarseness (p = 0.006), and Variance (Histogram) (p = 0.006). The feasibility of histogram and texture analysis as a potential biomarker is dependent on the baseline variability of each metric, which disqualifies many features.

Association of body composition with odds of breast cancer by molecular subtype: analysis of the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Nigerian Women (MEND) study.

BACKGROUND: The association between obesity and breast cancer (BC) has been extensively studied among US, European and Asian study populations, with often conflicting evidence. However, despite the increasing prevalence of obesity and associated conditions in Africa, the continent with the highest age-standardized BC mortality rate globally, few studies have evaluated this association, and none has examined in relation to molecular subtypes among African women. The current analysis examines the association between body composition, defined by body mass index (BMI), height, and weight, and BC by molecular subtype among African women. METHODS: We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between measures of body composition and BC and molecular subtypes among 419 histologically confirmed cases of BC and 286 healthy controls from the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Women of Nigerian Descent (MEND) case-control study. RESULTS: Higher BMI (aOR: 0.79; 95% CI: 0.67, 0.95) and weight (aOR: 0.83; 95% CI: 0.69, 0.98) were associated with reduced odds of BC in adjusted models, while height was associated with non-statistically significant increased odds of BC (aOR: 1.07, 95% CI: 0.90, 1.28). In pre/peri-menopausal, but not post-menopausal women, both higher BMI and weight were significantly associated with reduced odds of BC. Further, higher BMI was associated with reduced odds of Luminal A, Luminal B, and HER2-enriched BC among pre/peri-menopausal women, and reduced odds of triple-negative BC among post-menopausal women. CONCLUSIONS: Higher BMI and weight were associated with reduced odds of BC overall and by molecular subtype among West African women. Larger studies of women of African descent are needed to definitively characterize these associations and inform cancer prevention strategies.