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Background: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma.Methods: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999.Findings: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths.Interpretation: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies.Funding: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program. [ABSTRACT FROM AUTHOR]

Objectives: To determine the role of previous psychiatric disorders including substance use disorders on emergency department (ED) patients on involuntary holds and compare presentations, treatment, and outcomes based on cause. Methods: We conducted a retrospective study of patients ≥ 18 years old on involuntary holds in the ED of a tertiary care center from January 1, 2013, to November 30, 2015. Demographic and clinical information were collected. Those with and without prior psychiatric disorder including substance use disorder were compared. Results: We identified 251 patients of which 129 (51.4%) had a psychiatric disorder, 23 (9.2%) had a substance use disorder, and 86 (34.3%) had both. Thirteen patients (5.2%) had no psychiatric disorder or substance use disorder and the majority 10 (76.9%) were on involuntary holds due to suicidal threats related to pain or another medical problem. Patients without a psychiatric or substance use disorder were older (55 years [17.8] vs 42 [19]; P = 0.01), more likely to be married (10 [76.9%] vs 64 [26.9%]; P < 0.001), and had more medical comorbidities (10 [76.9%] vs 114 [47.9%]; P = 0.049) compared with those without a psychiatric or substance use disorder. Conclusion: Patients on involuntary holds most commonly have pre-existing psychiatric disorder including substance use disorder. Patients on involuntary holds without history of psychiatric disorder often have severe pain or other active medical conditions which may contribute to suicidal thoughts. Addressing these underlying medical issues may be crucial in preventing further psychiatric decompensation. [ABSTRACT FROM AUTHOR]

Objectives: This study describes the specific threats of harm to others that led to the use of the Baker Act, the Florida involuntary hold act for emergency department (ED) evaluations. The study also summarizes patient demographics, concomitant psychiatric diagnoses, and emergent medical problems.Methods: This is a retrospective review of 251 patients evaluated while on involuntary hold from January 1, 2014 through November 30, 2015 at a suburban acute care hospital ED. The data that were collected included demographic information, length of stay, reason for the involuntary hold, psychiatric disorder, substance use, medical illness, and violence in the ED. The context of the homicidal threat also was collected.Results: We found that 13 patients (5.2%) were homicidal. Three patients had homicidal ideations alone, whereas 10 made homicidal threats toward others. Of the 10 making homicidal threats, 7 named a specific person to harm. Ten of the 13 homicidal patients (76.9%) also were suicidal. Eleven patients (84.6%) had a psychiatric disorder: 9 patients (69.2%) had a depressive disorder and 8 patients (61.5%) had a substance use disorder. Eight patients had active medical problems that required intervention in the ED.Conclusions: We found that three-fourths of patients expressing homicidal threats also were suicidal. The majority of patients making threats of harm had a specific plan of action to carry out the threat. It is important to screen any patient making homicidal threats for suicidal ideation. If present, there is a need to implement immediate management appropriate to the level of the suicidal threat, for the safety of the patient. Eighty-five percent of patients making a homicidal threat had a previously documented psychiatric disorder, the most common being a depressive disorder. This finding differs from previous studies in which psychosis predominated. More than 60% of homicidal patients had an unrelated medical disorder requiring intervention. It is important not to overlook these medical disorders while focusing on the psychiatric needs of the patient; most of our homicidal patients proved to be cooperative in the ED setting. [ABSTRACT FROM AUTHOR]

Objectives: Patients requiring involuntary holds are frequently seen in the emergency department (ED). Much of what is known comes from studies of patients at urban academic centers. Our aim was to describe the demographic and clinical characteristics of patients who were evaluated while on involuntary status at a suburban ED.Methods: The medical records of patients seen in the ED requiring involuntary hold status between January 1, 2014 and November 30, 2015 were reviewed. Demographic and clinical variables including medical and psychiatric comorbidity were collected. A subanalysis was performed comparing patients who attempted suicide with all other involuntary patients.Results: Two hundred fifty-one patient records were reviewed; 215 patients (85.3%) had psychiatric disorders-depression was the most common (57%)-and 108 patients (43%) had substance use disorders. Only 13 patients (5.2%) had neither a psychiatric disorder nor a history of substance use. Twenty-two patients (8.8%) were violent in the ED. Thirteen patients (5.2%) were readmitted, and 1 patient died within 30 days of discharge from the ED. One hundred twenty-four patients (49.4%) had medical disorders. Suicidal ideation was the most common reason for involuntary hold (n = 185, 73.7%); 63 patients (25.1%) attempted suicide. Compared with other involuntary patients, the patients who attempted suicide were less likely to use opiates (odds ratio 0.27, 95% confidence interval 0.08-0.94, P = 0.04) and to have medical disorders (odds ratio 0.52, 95% confidence interval 0.28-0.98, P = 0.04).Conclusions: Patients in this study differed from those in urban centers with respect to sex and psychiatric disorder; however, substance misuse was common in both settings. Suicidal ideation including suicide attempt was the most common reason for involuntary status. Patients who attempted suicide were similar to other patients on involuntary hold with respect to demographic and clinical variables. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to review the association between timeliness to completion of a discharge summary to 30-day readmission to the hospital.Methods: This was a retrospective chart review of 109 patients discharged from Mayo Clinic Hospital.Results: Twenty-four of these patients were readmitted within 30 days. The time to completion of discharge summary was categorized for these readmissions to <72 hours: 15 (20%), between 72 hours and 7 days: 2 (11.1%), and >7 days: 7 (43.7%). There was no statistical significance for readmission for discharge summaries completed between 72 hours and 7 days compared with <72 hours (P = 0.44). There was statistical significance correlating readmission within 30 days to the discharge summary completed >7 days compared with <72 hours (P = 0.04).Conclusions: This study found that discharge summaries completed >7 days have an increased association with 30-day readmission rate. [ABSTRACT FROM AUTHOR]

Objectives: Anemia is common in patients presenting with acute congestive heart failure (CHF); when hemoglobin (HGB) declines to low levels, it can result in worse outcomes. The aim of this study was to determine a level of HGB on admission or discharge that affects outcomes in patients with CHF and then to evaluate the effect of the low HGB levels on these outcomes.Methods: We conducted a retrospective cohort study of 756 patients admitted with acute CHF during the period January 1, 2011-December 31, 2014. We used multivariable regression analysis to evaluate the relation among HGB levels and three major outcomes: 3-year mortality, 30-day readmission rate, and length of stay (LOS).Results: Compared with patients with HGB ≥10 g/dL, patients with HGB <10 g/dL on discharge from the hospital had higher mortality (3-year survival 46% vs 33%, P = 0.023) and 30-day readmission rates (23% vs 14%; P = 0.008) and increased LOS (4.8 vs 3.2 days, P < 0.001). Patients with admission HGB <10 g/dL had higher mortality rates (3-year survival 45% vs 32%, P = 0.019) and increased LOS (4.5 vs 3.4 days, P = 0.014). A lower admission HGB value was associated with higher 30-day readmission rates, but it was not statistically significant (P = 0.06).Conclusions: An HGB level <10 g/dL on admission or discharge in patients hospitalized with acute CHF is associated with a significantly worse outcome. [ABSTRACT FROM AUTHOR]

Background: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.Methods: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.Findings: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.Interpretation: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.Funding: F Hoffmann-La Roche, Genentech. [ABSTRACT FROM AUTHOR]

The article discusses a study on the potential for improving disease control and quality of life in prostate cancer patients with intermittent androgen deprivation. It mentions the hypothesis that replacing androgens prior to disease progression will prolong androgen dependence. A luteinizing hormone-releasing hormone analogue and an antiandrogen were given to the study's participants. Intermittent therapy was found to be associated with better erectile function and mental health at month 3.

Purpose: Weekly paclitaxel, concurrent radiation, and androgen deprivation (ADT) were evaluated in patients with high-risk prostate cancer (PC) with or without prior prostatectomy (RP). Methods and Materials: Eligible post-RP patients included: pathological T3 disease, or rising prostate-specific antigen (PSA) ≥0.5 ng/mL post-RP. Eligible locally advanced PC (LAPC) patients included: 1) cT2b-4N0N+, M0; 2) Gleason score (GS) 8–10; 3) GS 7 + PSA 10–20 ng/mL; or 4) PSA 20–150 ng/mL. Treatment included ADT (4 or 24 months), weekly paclitaxel (40, 50, or 60 mg/m2/wk), and pelvic radiation therapy (total dose: RP = 64.8 Gy; LAPC = 70.2 Gy). Results: Fifty-nine patients were enrolled (LAPC, n = 29; RP, n = 30; ADT 4 months, n = 29; 24 months, n = 30; whites n = 29, African Americans [AA], n = 28). Baseline characteristics (median [range]) were: age 67 (45–86 years), PSA 5.9 (0.1–92.1 ng/mL), GS 8 (6–9). At escalating doses of paclitaxel, 99%, 98%, and 95% of doses were given with radiation and ADT, respectively, with dose modifications required primarily in RP patients. No acute Grade 4 toxicities occurred. Grade 3 toxicities were diarrhea 15%, urinary urgency/incontinence 10%, tenesmus 5%, and leukopenia 3%. Median follow-up was 75.3 months (95% CI: 66.8–82.3). Biochemical progression occurred in 24 (41%) patients and clinical progression in 11 (19%) patients. The 5- and 7-year OS rates were 83% and 67%. There were no differences in OS between RP and LAPC, 4- and 24-month ADT, white and AA patient categories. Conclusions: In addition to LAPC, to our knowledge, this is the first study to evaluate concurrent chemoradiation with ADT in high-risk RP patients. With a median follow-up of 75.3 months, this trial also represents the longest follow-up of patients treated with taxane-based chemotherapy with EBRT in high-risk prostate cancer. Concurrent ADT, radiation, and weekly paclitaxel at 40 mg/m2/week in RP patients and 60 mg/m2/week in LAPC patients is feasible and well-tolerated. [ABSTRACT FROM AUTHOR]

Abstract: Background: The endothelin-A receptor (ETAR) has been implicated in the progression of prostate cancer. Objectives: To investigate the safety and efficacy of the specific ETAR antagonist ZD4054 in patients with metastatic hormone-resistant prostate cancer (HRPC). Design, setting, and participants: Double-blind, placebo-controlled, randomised, parallel-group, multicentre, phase 2 trial in patients attending cancer centres with HRPC and bone metastases who were pain free or mildly symptomatic for pain. Intervention: Patients were randomised to receive once-daily oral tablets of ZD4054 10mg, or ZD4054 15mg, or placebo. Measurements: The primary end point was time to progression, defined as clinical progression, requirement for opiate analgesia, objective progression of soft-tissue metastases, or death in the absence of progression. Secondary end points included overall survival, time to prostate-specific antigen (PSA) progression, and safety. Statistical significance was preset at 20%. Results and limitations: A total of 312 patients were randomised (ZD4054 10mg, n =107; ZD4054 15mg, n =98; placebo, n =107). At the primary analysis, median time to progression was 3.6 mo, 4.0 mo, and 3.8 mo in the placebo, ZD4054 10mg, and ZD4054 15mg groups, respectively, with no statistically significant difference between ZD4054 groups and placebo (hazard ratio [HR] vs placebo for the ZD4054 10mg group: 0.88 [80% CI: 0.71–1.09]; HR vs placebo for the ZD4054 15mg group: 0.83 [80% CI: 0.66–1.03]). However, a signal for prolonged overall survival was observed in the ZD4054 treatment groups versus placebo, based on 40 deaths. At a subsequent analysis after 118 deaths, this survival benefit was confirmed (HR vs placebo for the ZD4054 10mg group, 0.55 [80% CI: 0.41–0.73], p =0.008; HR vs placebo for the ZD4054 15mg group, 0.65 [80% CI: 0.49–0.86], p =0.052) but the differences in time to progression remained nonsignificant. Median overall survival was 17.3 mo, 24.5 mo, and 23.5 mo in the placebo group, the ZD4054 10mg group, and the ZD4054 15mg group, respectively. Discordance between results for time to progression and overall survival may be due to the sensitivity of the definition of progression. Adverse events were in line with the expected pharmacologic effects of an ETAR antagonist. Conclusions: The primary end point of time to progression was not achieved in this study, but an improvement was seen in overall survival in both active treatment arms. ZD4054 was well tolerated. Trial registration: Clinicaltrials.gov NCT00090363. [Copyright &y& Elsevier]

Purpose: Men with castration-resistant prostate cancer (CRPC) experience disease progression at different rates. The purpose of this study was to quantify the strength of patient preferences for delaying prostate cancer progression utilizing a discrete choice experiment (DCE) and valuing 3 health states in the continuum of CRPC.Patients and Methods: Men with CRPC, recruited from US patient panels, completed a cross-sectional web-based survey. The survey consisted of vignette-based time trade-off and a DCE designed to quantify patients' willingness to pay to delay metastatic CRPC. Three health states were presented: (1) living with non-metastatic castration-resistant prostate cancer (nmCRPC) (2) living with metastatic CRPC (mCRPC) before chemotherapy, and (3) living with mCRPC either on or after chemotherapy. The DCE consisted of 15 hypothetical choices with attributes characterizing CRPC (pain, fatigue, out of pocket cost, dosing, and time until cancer metastasizes). Patients' willingness to pay for changes in each attribute were derived.Results: A total of 176 patients with CRPC were surveyed (mean age: 64.2 years; 74% nmCRPC). Patients valued the nmCRPC health state (0.865) significantly higher than mCRPC before chemotherapy (0.743) or mCRPC on or after chemotherapy (0.476), both P < 0.001. In the DCE, patient treatment valuation was most affected by increasing the number of months until cancer metastasized; patients were willing to pay an additional $682 per month to delay time to metastases from 6 to 24 months (95% Confidence Interval: $387-$977) and additional $1,041 per month to delay time to metastasis to 48 months (95% Confidence Interval: $591-$1,490).Conclusions: The results of this study demonstrated men with CRPC place significant value on delaying metastases. This study represents the first time 2 stated preference methods, time trade-off and DCE, were used together to understand patients' preferences and valuation of health states in CRPC. [ABSTRACT FROM AUTHOR]

Introduction: Androgen deprivation therapy has been shown to improve cancer control when combined with radiotherapy. Relugolix is an oral GnRH receptor antagonist that achieves rapid profound testosterone suppression, which may increase the perception and/or impact of fatigue. This study sought to evaluate neoadjuvant relugolix-induced fatigue in prostate cancer patients prior to the start of stereotactic body radiation therapy (SBRT)., Methods: Relugolix was initiated at least two months before SBRT. The 13-item Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire was collected at baseline and one hour prior to SBRT initiation. A five-point scale was used to score individual items. Overall scores range from 0-52 and individual item scores were converted to 0-100, with higher scores reflecting less fatigue. Five "experience" items explored self-perceptions of fatigue, and eight "impact" items sought to evaluate the effect of fatigue on daily activities. Items were evaluated for statistical significance (paired t-test, p < 0.05) and clinical significance (minimally important difference (MID); 0.5 standard deviation from baseline)., Results: Between March 2021 to December 2023, 89 men were treated at Georgetown with neoadjuvant relugolix and SBRT. Mean age was 71 years (range: 49-87). Median initiation of relugolix was 4.5 months prior to SBRT (range: 2-14.2 months). 93% patients achieved castration (testosterone levels ≤ 50 ng/dL) and 85% patients achieved profound castration (testosterone levels ≤ 20 ng/dL). 87 patients completed the FACIT-F questionnaire, with an average overall score of 45.6 at baseline and 41.0 at SBRT initiation. This difference was statistically and clinically significant (p < 0.01, MID = 3.55). Patients experienced an increase in fatigue for 12 of 13 items, with statistically significant changes for 11 items. Three of five experience items showed a clinically significant increase in fatigue. Only two of eight impact items were clinically significant., Discussion: Our study shows that relugolix significantly increases fatigue, affecting multiple areas of life. While the fatigue does not appear to generally impact a patient's ability to carry out normal activities, patients demonstrate frustration with being too tired for these activities. It is essential for clinicians to counsel prostate cancer patients on the impact of neoadjuvant relugolix on quality-of-life issues like fatigue., Competing Interests: SC serves as a clinical consultant to Sumitomo Pharma/Pfizer Inc. ND is on the Speaker Bureau for Sumitovant Biopharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hsueh, Gallagher, Koh, Shah, Danner, Zwart, Ayoob, Kumar, Leger, Dawson, Suy and Collins.)

Introduction: Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT)., Methods: Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage., Results: The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother., Discussion: In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction., Competing Interests: SC serves as a clinical consultant to Sumitomo Pharma/Pfizer Inc. ND is on the Speaker Bureau for Sumitovant Biopharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hsueh, Gallagher, Koh, Eden, Shah, Wells, Danner, Zwart, Ayoob, Kumar, Leger, Dawson, Suy, Rubin and Collins.)

Background: Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery., Methods: Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up., Results: From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery., Conclusion: Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Shah et al.)

Introduction: Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy. Prostate SBRT offers an abbreviated treatment course with comparable efficacy to conventionally fractionated radiotherapy. Relugolix is a new oral GnRH receptor antagonist which achieves rapid, sustained testosterone suppression. This prospective study sought to evaluate early testosterone suppression and PSA response following relugolix and SBRT for intermediate to high prostate cancer., Methods: Relugolix was initiated at least 2 months prior to SBRT. Interventions to improve adherence were not utilized. PSA and total testosterone levels were obtained prior to and 1-4 months post SBRT. Profound castration was defined as serum testosterone ≤ 20 ng/dL. Early PSA nadir was defined as the lowest PSA value within 4 months of completion of SBRT. Per prior trials, we examined the percentage of patients who achieved PSA level of ≤ 0.5 ng/mL and ≤ 0.2 ng/mL during the first 4 months post SBRT., Results: Between July 2021 and January 2023, 52 men were treated at Georgetown with relugolix (4-6 months) and SBRT (36.25-40 Gy in 5 fractions) per an institutional protocol (IRB 12-1775). Median age was 71 years. 26.9% of patients were African American and 28.8% were obese (BMI ≥30 kg/m2). The median pretreatment PSA was 9.1 ng/ml. 67% of patients were ≥ Grade Group 3. 44 patients were intermediate- and 8 were high-risk. Patients initiated relugolix at a median of 3.6 months prior to SBRT with a median duration of 6.2 total months. 92.3% of patients achieved profound castration during relugolix treatment. Poor drug adherence was observed in 2 patients. A third patient chose to discontinue relugolix due to side effects. By post-SBRT month 4, 87.2% and 74.4% of patients achieved PSA levels ≤ 0.5 ng/ml and ≤ 0.2 ng/ml, respectively., Discussion: Relugolix combined with SBRT allows for high rates of profound castration with low early PSA nadirs. We observed a 96% testosterone suppresion rate without the utilization of scheduled cues/reminders. This finding supports the notion that patients with localized prostate cancer can consistently and successfully follow an oral ADT protocol without daily reminders. Given relugolix's potential benefits over injectable GnRH receptor agonists, its usage may be preferred in specific patient populations (fear of needles, prior cardiovascular events). Future studies should focus on boundaries to adherence in specific underserved populations., Competing Interests: Author MF was employed at the company Myovant Sciences, Inc., United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Gallagher, Xiao, Hsueh, Shah, Danner, Zwart, Ayoob, Yung, Simpson, Fallick, Kumar, Leger, Dawson, Suy and Collins.)

Background: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer., Patients and Methods: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy., Results: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity., (© 2022. The Author(s).)

Purpose: In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance., Patients and Methods: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate., Results: Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2-71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%., Conclusions: Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed., (©2021 American Association for Cancer Research.)

Lymph node recurrent prostate cancer is a common clinical scenario that is likely to increase significantly with the widespread adoption of novel positron emission tomography (PET) agents. Despite increasing evidence that localized therapy is disease modifying, most men with lymph node recurrent prostate cancer receive only systemic therapy with androgen deprivation therapy (ADT). For men who receive localized therapy the intent is often to delay receipt of systemic therapy. Little evidence exists on the optimal combination of local and systemic therapy in this patient population. In this hypothesis generating review, we will outline the rationale and propose a framework for combining involved field SBRT with risk adapted intermittent ADT for hormone sensitive nodal recurrent prostate cancer. In patients with a limited number of nodal metastases, involved field stereotactic body radiation therapy (SBRT) may have a role in eliminating castrate-resistant clones and possibly prolonging the response to intermittent ADT. We hypothesize that in a small percentage of patients, such a treatment approach may lead to long term remission or cure., Competing Interests: SP Collins and BT Collins serve as clinical consultants to Accuray Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carrasquilla, Creswell, Pepin, Wang, Forsthoefel, McGunigal, Bullock, Lei, Collins, Lischalk, Esposito, Aghdam, Kumar, Suy, Leger, Hankins, Dawson and Collins.)

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm., (©2020 American Association for Cancer Research.)

Background: In this trial we assessed the efficacy and tolerability of TRC105, a chimeric monoclonal antibody that targets CD105 (endoglin) in patients with advanced, previously treated urothelial carcinoma (UC)., Patients and Methods: Patients received TRC105 15 mg/kg every 2 weeks on days 1 and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) at 6 months. Secondary end points included safety, toxicity, and overall survival (OS). CD105 expression was evaluated using immunohistochemistry (IHC) in a separate cohort of 50 UC patients. Biomarker studies included immune subsets, circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and osteopontin., Results: Of 13 patients enrolled, 12 were evaluable for OS and PFS. The 3-month PFS probability was 18.2% (median PFS, 1.9 months [95% confidence interval (CI), 1.8-2.1 months). This met the criterion for ending accrual on the basis of the 2-stage design. Median OS was 8.3 months (95% CI, 3.3-17.0 months). IHC for CD105 scores was not associated with T stage (P = .26) or presence of lymph nodes (P = .64). Baseline levels of regulatory T and B cells, CEPs, and changes in CEC level after TRC105 exhibited trends toward an association with PFS or OS. CTCs pre- and post-TRC105 were detected in 4 of 4 patients., Conclusion: Although TRC105 was well tolerated, it did not improve 6-month PFS in heavily pretreated patients with advanced UC. CD105 staining was present in 50% of UC tumors at different intensities. Our observations on the pharmacodynamic significance of immune subsets, CECs, and CTCs warrant further study., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The standard localized therapies for prostate cancer include external-beam radiation therapy, brachytherapy and radical prostatectomy. There are several novel approaches in development aimed at improving local disease control and survival, and reducing post-treatment complications. In low-to-intermediate-risk patients, new radiation approaches are being explored to include hypofractionated robotic radiation therapy. For high-risk patients, the focus is on multimodality approaches, especially the addition of chemotherapy. Recent developments in radiation therapy and adjuvant chemotherapy are the focus of this review.

A multidisciplinary approach to prostate cancer has become the rule and not the exception. Involving the entire team, which includes a medical oncologist, from the time of initial diagnosis is optimal. This facilitates maximal patient education regarding treatment options and enhances informed decision making. A coordinated approach also promotes enrollment on clinical trials, which are often, multimodality, especially in high-risk early stage prostate cancer. Integrated therapeutic strategies throughout the patient's disease course can improve both patient care and satisfaction

Objectives: In the search for an early measure of response in hormone refractory prostate cancer (HRPC), most have targeted changes in serum prostate-specific antigen (PSA). Up to this point, no one has targeted changes in serum hemoglobin during treatment. If dynamic changes in hemoglobin after treatment provide additive prognostic information to dynamic changes in PSA, then we should consider and test ways to incorporate serum hemoglobin into measures of response in HRPC., Methods: Our patients consisted of 321 men who were studied on Cancer and Leukemia Group B protocols 9181 and 9182. We fit serial values of PSA and hemoglobin with an exponential model: y = exp(alpha + beta*t + gamma*t(2)) with y symbolizing either PSA or hemoglobin and t denoting time. We then used the Cox proportional hazard model to relate the parameters of the model (alpha, beta, and gamma) to subsequent survival., Results: We found that the exponential model fit serial measurements of both PSA and serum hemoglobin well, and all three of the parameters for both markers related closely to subsequent survival (P < or = 0.003). The Cox model suggested a composite hazard score (HS) as a way to consolidate the information from serial measurements of both serum markers, and we observed that those with HS < 0 enjoyed a longer survival., Conclusion: Because serial measurements of serum hemoglobin during treatment of HRPC add prognostic information to serial measurements of PSA, we hypothesize that combining the dynamic changes in serum hemoglobin with those of PSA could lead to an improved measure of response in HRPC.