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Several classes of concomitant medications have been shown to affect oncological outcomes in patients with prostate cancer (PCa). We assessed the association between the use of commonly prescribed concomitant medications and biochemical relapse-free survival (bRFS) in patients with localised PCa treated with radiotherapy and androgen deprivation therapy (ADT). A secondary pooled analysis of two phase III randomised trials was carried out. In the first trial, patients with localised PCa with clinical stage T1b-T3, prostate-specific antigen <30 ng/ml and Gleason score ≤7 were treated with radical radiotherapy and 6 months of ADT starting 4 months before or concomitantly with radiotherapy. In the second trial, patients with high-risk PCa were treated with radical radiotherapy and 36 months of ADT with randomisation to three-dimensional conformal or intensity-modulated radiotherapy. Information on concomitant medications was collected from the medical record. Univariable and multivariable Cox regression was used to identify factors associated with bRFS. Overall, 486 patients were evaluable. The median follow-up was 125 months; 10-year bRFS was 83.7%. On univariable analysis, receipt of metformin was significantly associated with worse bRFS. Ten-year bRFS was 73% and 85% for patients with and without concomitant metformin (adjusted hazard ratio 2.11, 95% confidence interval 1.03–4.33). Similar evidence of an association was observed with sulfonamide-based α1-receptor blockers (adjusted hazard ratio 2.72, 95% confidence interval 1.31–5.66). However, no such association was seen with receipt of quinazoline-based α1-receptor blockers (adjusted hazard ratio 1.09, 95% confidence interval 0.42–2.82). There was no significant association between bRFS and receipt of all other medication classes considered. In this population of patients with localised PCa treated with radiotherapy and ADT, receipt of concomitant metformin and sulfonamide-based α1-receptor blockers was associated with inferior biochemical outcome. Randomised trials are required to assess the true effect of these medications on oncological outcomes in localised PCa. • Concomitant metformin was associated with poorer biochemical control following radiotherapy and androgen deprivation. • This is directionally opposite to prior studies showing superior prostate cancer outcomes in patients receiving metformin. • Receipt of sulfonamide-based α1-receptor blockers was also associated with inferior biochemical outcome in this cohort. [ABSTRACT FROM AUTHOR]

Metastatic castrate sensitive prostate cancer (mCSPC) is a heterogeneous disease state with patients having variable prognosis. Although several life-prolonging systemic agents are available, there is no robust multivariable model to predict prognosis and improve risk stratification in mCSPC. The purpose of our study was to investigate if baseline disease attributes, patient level characteristics, and blood-based markers are associated with overall survival in patients with de novo metastatic castrate sensitive prostate cancer. We used data from LATITUDE, a phase III randomized controlled trial in which men with de novo mCSPC were randomly allocated to either ADT plus abiraterone or ADT with placebo. Patients with non-missing data (n=1,058) were randomly split in a 70:30 ratio to training (n=743) and testing (n=315) sets. Elastic net regression was used for variable selection. A multivariable Cox regression model for overall survival (OS) was then fitted using the selected variables. The predictive accuracy of the model was assessed on the testing set using the time-dependent area under curve (tAUC) with bootstrapped confidence intervals for OS and radiographic progression-free survival (rPFS). The 11 prognostic variables in the final model were performance status, number of skeletal metastases, Gleason score, presence of liver metastasis, baseline pain score, albumin, LDH, PSA, hemoglobin, and treatment arm (abiraterone vs placebo). The tAUC of the model for predicting OS at 2- and 3-years was 0.74 (95% confidence intervals [CI], 0.67-0.80) and 0.72 (95% CI, 0.65-0.77), respectively. The tAUC for progression-free survival at 2- and 3-years was 0.71 (95% CI, 0.64-0.76) and 0.76 (95% CI, 0.70-0.82), respectively. We stratified patients as high, intermediate, or low risk based on 33% and 67% quantiles of the risk score. The 3-year OS in the three risk groups were 34.2% (95%CI, 25.9-45.1), 56.6% (95%CI, 47.8-67.0), and 78.4% (95%CI, 70.2-87.5), respectively. We developed a prognostic model for predicting OS in men with newly diagnosed mCSPC. We validated our 11-variable model and demonstrated a high level of prognostic accuracy, significantly exceeding that described in previous models in mCSPC patients The model consists of standard laboratory markers, patient characteristics, and disease attributes that are essential for guiding treatment decisions in this patient population and provides a way to tailor treatment and stratify patients for participation in future clinical trials. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Both oncologic outcomes and patient-reported outcomes are important in localized prostate cancer patients. However, it remains unknown if there is any association between patient-reported outcomes and oncologic outcomes. In this secondary analysis of a randomized controlled study, we sought to explore the association of patient-reported outcome with long-term oncologic outcomes including event-free survival (EFS) and metastasis-free survival (MFS) in localized prostate cancer (PCa) patients.Materials/methods: Patients with newly diagnosed PCa with T-stage cT1b-T3a, Gleason score £7 and PSA < 30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. Patient-reported symptom burden was evaluated using EORTC QoL questionnaire PR.25. Clinically meaningful deterioration was defined by a threshold of 10 points. Landmark analyses were performed to determine the association of deterioration of urinary bother, bowel bother, and sexual activity separately with EFS (time to biochemical or clinical relapse or death), and MFS (time to distant metastasis or death) in patients who were alive and event-free at 9 months after randomization. We interpreted P-values conservatively considering multiple analyses.Results: A total of 393 patients were eligible for this study with 194 in the neoadjuvant group and 199 in the concurrent group. In a landmark population of 391 patients, after adjusting for age, Gleason score, baseline PSA, ECOG performance score, and treatment group, deterioration of urinary bother was associated with worse EFS (hazard ratio [HR] 1.78, 95% confidence intervals [CI]: 1.21-2.62, P < 0.003) and MFS (HR: 1.67, 95% CI: 1.10-2.53, P = 0.01). However, no such association was found with deterioration of bowel bother or sexual activity with EFS or MFS. Inverse proportionality weight (IPW) based adjusted 15-year EFS was 40% and 51% in patients with and without short-term worsening of urinary bother (P = 0.007, IPW-based log rank). 15-year IPW-based adjusted MFS was 60.4% and 45.4% for the two groups (P = 0.026, IPW-based log rank).Conclusion: In a cohort of localized prostate cancer patients, worsening of urinary bother was associated with 78% increase in the relative risk of relapse or death and 67% increase in the relative risk of distant metastases or death. Further investigations are needed to explore the underlying mechanism of this association in the context of ADT and radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose. – To identify SF2 as a prognostic factor of late complications from radiosurgery in patients treated for AVM.Patients and Methods. – Five patients with AVM treated in three canadian institutions and who suffered clinically significant neurological sequelaes secondary to radiosurgery were identified. Their fibroblasts were cultured and their radiation sensitivity tested to determine the SF2 for each patient.Results. – Patients who developed a neurological complication from radionecrosis, secondary to radiosurgery had an SF2 different than the two control patients with AVM and no complications and also from a group of five cancer patients without late radiation complications (P = 0.005).Conclusion. – Radiosurgery is an elective procedure. The identification of a subgroup of patients who are radiosensitive and at a higher risk of radiation induced complications can allow the treatment team to reduce the risk of such complications. SF2 as a new predictive factor should be incorporated in predictive models of risk from treatment of AVM by radiosurgery. This work needs to be confirmed in a larger cohort of patients. [Copyright &y& Elsevier]

Stereotactic radiosurgery (SRS) is a noninvasive alternative to microsurgery in the management of acoustic neuromas. Single fraction Gamma Knife SRS of acoustic neuromas results in high rates of local control (85-97 %). CyberKnife (CK) Robotic SRS is an alternative technique delivering the same quality SRS but with the benefits of a frameless treatment system allowing for fractionated treatment. The body of evidence in its use for acoustic neuromas is less robust. We present mature outcomes of a large cohort of patients treated with CK at a single institution. This study consisted of 120 acoustic neuroma patients treated with CK from Sept 2010 until March 2016. Patients with complete hearing loss were treated with a single 12 Gy fraction (6 Pts). Those with hearing preservation or moderate to large tumors were treated with 18 Gy in 3 fractions (114pts). Follow-up T2 axial MRIs (0.50 mm slice) were analyzed to evaluate rates of tumor control and incidence of pseudo-progression. To obtain volumetric response data, MRI images were contoured on PACs imaging station using Aquarius Net version 4.4.13 by a single radiation oncologist. Patients range in age from 15 to 91 (mean 58). The median follow up time was 60 months. Mean tumor size was 2.8 cm3 (Range 0.1-30). Progression occurred in 4 patients (local control rate of 97%). Pseudo-progression was seen in 17 cases. For patients with pseudo-progression mean time to the maximum imaged tumor volume post treatment was 5 months (Range of 3 to 12 months) with an average volume increase of 11% (Max 31%). Mean time to subsequent regression to pre-treatment size was 15 months (Range of 10-23) No pseudo-progression led to subsequent local recurrence. There were low rates of late toxicity. One patient who progressed suffered CN VII palsy prior to salvage surgery. All other patients had preserved CNV and CNVII function and there was no case of brain stem necrosis. Cyberknife offered high rates of durable local control (97 %) for acoustic neuromas with low rates of toxicity. Pseudo-progression was seen in 14% of patients and was not a predictor for treatment failure. The authors. Has not received any funding. S. Malone: Honoraria (self): Janssen; Honoraria (self): Astellas; Travel / Accommodation / Expenses: TerSera; Honoraria (self): AstraZeneca; Honoraria (self): AMGEN; Travel / Accommodation / Expenses: Sanofi; Honoraria (self): Abbvie; Honoraria (self): Bayer. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Conventionally, patients who do not experience a biochemical recurrence (BCR) within 5 years of radiotherapy (RT) for non-metastatic prostate cancer (PCa) are considered cured. However, the natural history of disease after this landmark time remains poorly understood. Similarly, the natural history following BCR within five years of RT remains unexplored. We performed a pooled analysis of men enrolled in 21 randomized controlled trials with long-term follow-up to determine incidence of subsequent cancer-specific events including distant metastasis (DM) and prostate cancer-specific mortality (PCSM) in both groups. Individual patient data were obtained from the MARCAP consortium. Cumulative incidence of DM was estimated using competing risk methods considering any deaths as competing events. Competing risk regression (for DM and PCa-specific mortality [PCSM]) were applied to determine the association between treatment strategy (e.g., escalating RT dose with or without androgen deprivation therapy) with DM and PCSM after adjustment for time to BCR, tumor stage, Gleason score, age at treatment, and baseline PSA. Time of randomization was used to define the intervals to events of interest. Overall, of the 13,468 eligible patients across 21 trials, 3,902 experienced a BCR event within 5 years (median follow-up = 137 months, interquartile range [IQR] = 135 – 139). Among patients who did not experience any BCR by 5 years (n = 9,566), median follow-up was 129 (IQR = 128 – 130) months. The estimated 10-year cumulative incidence rates (95% CI) of DM and PCSM were 3.3% (2.9–3.7) and 1.2% (1.0–1.4), respectively. On competing risk regression, we did not find sufficient evidence to reject the null hypothesis of no association of upfront treatment with relative incidence of post-BCR DM and PCSM. Among patients who experienced a BCR within five years of RT, 10-year rates of DM and PCSM were 39.3% (37.7–40.8) and 29.0% (27.5–30.5), respectively. Among PCa patients treated with RT those who do not experience a BCR event by 5 years, the overall 10-year rates of DM and PCSM are approximately 3% and 1%, consistent with a curative state. However, for patients with BCR within 5 years, 10-year DM and PCSM rates approach 40% and 30%, consistent with aggressive disease. Further work will help refine the definition of "cure" following RT. [ABSTRACT FROM AUTHOR]

Thymol, a monoterpene phenol derivative of cymene, is found in abundance in the essential oils of Thymus , Origanum , and Lippia species. The present study investigated the gastroprotective actions of thymol (10, 30, and 100 mg/kg, p.o.) in the acute (ethanol- and nonsteroidal anti-inflammatory drug-induced ulcers) and chronic (acetic acid-induced ulcers) ulcer models in rats. Some of the mechanisms underlying to the gastroprotective effect of thymol were investigated in the ethanol-induced ulcer model. Gastric secretion parameters (volume, pH, and total acidity) were also evaluated by the pylorus ligature model, and the mucus in the gastric content was determined. The anti- Helicobacter pylori activity of thymol was performed using the agar-well diffusion method. Thymol (10, 30, and 100 mg/kg) produced dose dependent reduction ( P < 0.01) on the total lesion area in the ethanol-induced ulcer model. The gastroprotective response caused by thymol (30 mg/kg) was significantly attenuated ( P < 0.001) by intraperitoneal treatment of rats with indomethacin (a non-selective inhibitor of cyclo-oxygenase, 10 mg/kg) and glibenclamide (ATP-sensitive K + channel blocker, 10 mg/kg), but not by dl -Propargylglycine (PAG, a cystathionine-γ-lyase inhibitor, 25 mg/kg) and N w -nitro- l -arginine methyl ester hydrochloride ( l -NAME, a non-selective inhibitor of nitric oxide synthase, 70 mg/kg). Thymol (30 and 100 mg/kg) also reduced the ulcer index ( P < 0.05) and the total lesion area ( P < 0.001) in the indomethacin- and acetic-acid-induced ulcer models, respectively. In the model pylorus ligature, the treatment with thymol failed to significantly change the gastric secretion parameters. However, after treatment with thymol (30 and 100 mg/kg), there was a significant increase ( P < 0.01) in mucus production. Thymol no showed anti- H . pylori activity in vitro . Collectively, the present results provide convincing evidence that thymol displays gastroprotective actions on the acute and chronic ulcer models through mechanisms that involve increased in the amount of mucus, prostaglandins, and ATP-sensitive K + channels. [ABSTRACT FROM AUTHOR]

Pre-clinical studies suggest that prior LT could portend neuroendocrine differentiation and could result in compromised response to subsequent lines of systemic therapy including androgen deprivation therapy (ADT) or androgen receptor pathway inhibitors (ARPI). In contrary, clinical studies show conflicting findings in this domain. Our analysis further explores whether prior local therapy plays a modifying role on the first line treatment effect on OS. Additionally, we investigate whether prior local therapy have an independent association with OS and radiographic progression free survival in this cohort. We performed an individual patient data based meta-analysis of COU-AA-302 and ACIS trials that included men with chemotherapy naïve mCRPC. In the first trial, patients were randomly assigned to ADT versus ADT plus abiraterone (ADT+AA-P) while in the second one, patients were randomly assigned to ADT+AA-P versus ADT plus apalutamide plus AA-P (APA + AA-P). We applied a hierarchical multivariable Bayesian Cox proportional hazard regression model to determine if there was any difference in treatment effect on overall survival (OS) among patients stratified by prior LT. Further, we determined the independent association of exposure to prior LT with radiographic progression-free survival (rPFS) and OS in the entire study cohort. Overall, 2032 patients (n=527 in ADT group; n=1020 in ADT+AA-P group; n=485 to APA+AA-P) were included in this study; of whom, 339 in the ADT group, 559 in the AA-P group, and 234 in the APA+AA-P group had prior LT. Among patients with prior LT, 253 had radical prostatectomy (RP) alone, 345 had RP plus radiotherapy (RT), and 534 had RT alone, respectively. Relative to ADT+AA-P, we found no difference in treatment effect on OS from ADT alone (hazard ratio [HR] for the interaction term: 0.90; 95% credible interval [CrI]: 0.69-1.17) or APA+AA-P (HR for the interaction term: 1.29 [0.99-1.69]), among patients with and without prior LT. We did not find any significant association of LT modality with rPFS (HR for RP: 0.98 [0.81-1.18]; HR for RT: 0.99 [0.86-1.16]; and HR for RP+RT: 1.03 [0.86-1.23]) and OS (HR for RP: 0.84 [0.69-1.02]; HR for RT: 1.03 [0.89-1.19]; and HR for RP+RT: 0.88 [0.73-1.05]) in the overall study cohort. In this meta-analysis, we did not find any significantly compromised treatment effects from first line ARPI in patients who received prior LT. Further, there was no significant association of prior LT modality with risk of radiographic progression or deaths, respectively. [ABSTRACT FROM AUTHOR]

Both acute and late toxicity after prostate radiotherapy arise from normal tissue irradiation at the time of treatment. The association between acute toxicity and late toxicity remains poorly understood. We sought to characterize the relationship between acute and late genitourinary (GU) and gastrointestinal (GI) toxicity, both as scored by physicians and as reported by patients, among patients receiving radiotherapy for prostate cancer. Individual patient data for trials that had acute and late GU and GI toxicity data were extracted from the MARCAP consortium. Physician-reported acute (≤3 months from treatment) and late (>3 months from treatment) GU and GI toxicity were graded using Radiation Therapy Oncology Group criteria or Common Terminology Criteria. Urinary and bowel patient-reported quality of life (QOL) data from Expanded Prostate Cancer Index Composite (EPIC) questionnaires were used to identify late QOL decrements greater than twice the minimal clinically important difference (>2x MCID) at any time beyond 3 months post-treatment. MCID was defined as half of the standard deviation at baseline. Generalized linear mixed models were used to examine the relationship between acute grade ≥2 GU and GI toxicity and both late grade ≥2 GU and GI toxicity and late decrement >2x MCID in urinary and bowel QOL. These were adjusted for age, performance status, receipt of androgen deprivation therapy (ADT), use of intensity modulated radiotherapy (IMRT), and use of moderate hypofractionation. 6,349 patients from seven trials were included (conventional fractionation: n = 4,128; moderate hypofractionation: n = 2,221). Median follow-up was 76 months (interquartile range [IQR], 59-101 months). 71.3% received IMRT. Median equivalent dose (EQD2) was 74 Gy (IQR, 72-76 Gy). 51.8% received ADT. Rates of acute grade ≥2 GU and GI toxicity were 29.6% and 14.9%, respectively. Rates of late grade ≥2 GU and GI toxicity were 15.7% and 15.2%, respectively, while rates of urinary and bowel QOL decrement >2x MCID were 19% and 33%, respectively. Acute grade ≥2 GU toxicity was associated with late grade ≥2 GU toxicity (odds ratio [OR] 2.09, P <0.001), and acute grade ≥2 GI toxicity was associated with late grade ≥2 GI toxicity (OR 2.94, P <0.001). Similarly, acute grade ≥2 GU toxicity was associated with late urinary QOL decrement >2x MCID (OR 1.46, P = 0.02), and acute grade ≥2 GI toxicity was associated with late bowel QOL decrement >2x MCID (OR 2.00, P <0.001). Acute toxicity following conventionally fractionated or moderately hypofractionated prostate radiotherapy was significantly associated with late GU and GI toxicity as defined both by physician scoring and patient-reported QOL metrics. These data suggest that efforts to prevent acute toxicity may translate into reduced risks of late toxicity. [ABSTRACT FROM AUTHOR]

Although health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localised prostate cancer. We report the association of baseline HR-QoL metrics with overall survival and toxicity in localised prostate cancer. This was a secondary analysis of a phase III randomised controlled study conducted in a single-payer health system. Patients with Gleason score ≤7, clinical stage T1b–T3a and prostate-specific antigen <30 ng/ml were randomised to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate radiotherapy. HR-QoL scores were estimated using the European Organisation for Research and Treatment of Cancer QoL questionnaire. A multistate Markov model was used to determine the association of baseline HR-QoL metrics with overall survival and a multilevel multivariable Cox regression was used to determine the association with the incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P < 0.025 was considered as statistically significant. Overall, 393 patients with baseline HR-QoL data were included in this analysis: 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio 1.020, 95% confidence interval 1.010–1.030, P = 0.02) and dyspnoea (hazard ratio 1.020, 95% confidence interval 1.003–1.030, P = 0.01) were associated with inferior overall survival. Baseline dyspnoea was associated with a higher incidence of grade ≥3 toxicity (hazard ratio 1.020, 95% confidence interval 1.010–1.030, P = 0.023). In a cohort of localised prostate cancer patients treated with radiotherapy and short-term ADT, a 10-point higher baseline financial difficulty or dyspnoea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnoea, we noted a 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity. • A 10-point higher baseline financial difficulty portended a 20% increased risk of death. • A 10-point higher baseline dyspnoea portended a 20% increased risk of death. • A 10-point increase in dyspnoea, was associated with 20% increase in the risk of grade ≥3 late toxicity. [ABSTRACT FROM AUTHOR]

The purpose of this study was to test the hypothesis that sucralfate, a gastric ulcer medication, would alter plasma concentrations of total carbon dioxide (tCO2), lactate (LA), sodium (Na+), potassium (K+), chloride (Cl-) and total protein (TP), as well as calculated plasma strong ion difference (SID) and packed cell volume (PCV) in horses subjected to a simulated race test (SRT). Six unfit Standardbred mares (∼520 kg, 9-18 years) were used in a randomized crossover design with the investigators blinded to the treatment given. The horses were assigned to either a control (40-50 mL apple sauce administered orally (PO)) or a sucralfate (20 mg/kg bodyweight dissolved in 40-50 mL apple sauce administered PO) group. Each horse completed a series of SRTs during which blood samples were taken via jugular venipuncture at five sampling intervals (prior to receiving treatment, prior to SRT, immediately following exercise, and at 60 and 90 min post-SRT). During the SRTs, each horse ran on a treadmill fixed on a 6% grade for 2 min at a warm-up speed (4 m/s) and then for 2 min at a velocity predetermined to produce VO2max Each horse then walked at 4 m[s for 2 min to complete the SRT. Plasma tCO2, electrolytes, LA, and blood PCV and TP were analysed at all intervals. No differences (P > 0.05) were detected between control and sucralfate for any of the measured variables. There were differences (P < 0.05) in tCO2, SID, PCV, TP, LA and electrolyte concentrations relative to sampling time. However, these differences were attributable to the physiological pressures associated with acute exercise and were not an effect of the medication. It was concluded that sucralfate did not alter plasma tCO2 concentration in this study. [ABSTRACT FROM AUTHOR]

Prior evidence from randomized controlled trials (RCTs) suggests that sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) impacts clinical outcomes, with a potential interplay with pelvic nodal RT (PNRT). Herein, we aim to further investigate this finding across 12 RCTs, and assess the interplay of ADT sequencing with PNRT in localized prostate cancer (LPCa). The Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) consortium was accessed to obtain individual patient data (IPD) from 12 RCTs that included patients with LPCa who received neoadjuvant/concurrent (neo/conc) or concurrent/adjuvant (conc/adj) short-course ADT (4-6 months) with either prostate-only RT (PORT) or PNRT. Inverse probability of treatment weighting (IPTW) analyses were performed to balance treatment groups, with weights derived from propensity scores as a function of age, initial PSA, Gleason Score, T stage and mid-trial enrollment year. The primary endpoint was metastasis-free survival (MFS), as assessed by IPTW-adjusted Cox regression. IPTW-adjusted Fine and Gray competing risk models were developed to evaluate biochemical recurrence (BCR), distant metastasis (DM) and prostate cancer-specific mortality (PCSM). The regression models include ADT sequencing, PNRT and their interaction to account for effect modification. Overall, 7409 patients were included (6325 neo/conc, 1084 conc/adj) with a median follow-up of 10.2 years (10.3 neo/conc, 9.9 conc/adj). Conc/adj ADT was associated with improved MFS (10-year estimates: 66.3% vs. 60.6%, HR 0.70 [95% CI 0.59-0.83], p<0.0001), BCR (26.2% vs. 35.2%, sHR 0.43 [95% CI 0.34-0.56], p<0.0001), DM (11.5% vs. 9.0%, sHR 0.55 [95% CI 0.36-0.85], p=0.0073), and PCSM (4.6% vs. 6.2%, sHR 0.33 [95% CI 0.19-0.57], p<0.0001). A significant interaction between ADT sequencing and PNRT for all the above endpoints was observed (P-interaction <0.0001 for all). In patients receiving PORT, conc/adj ADT was associated with significantly improved BCR, DM, MFS and PCSM. In contrast, patients receiving PNRT neoadj/conc ADT was associated with significantly improved DM, MFS and PCSM. Comparing the 4 groups based on ADT sequencing and use of PNRT, after IPTW, conc/adj ADT with PORT (reference) had superior MFS compared to neo/conc + PORT (HR 1.59 [95% CI 1.33-1.91], p<0.0001), neo/conc + PNRT (HR 1.96 [95% CI 1.60-2.39], p<0.0001), or conc/adj +PNRT (HR 1.94 [95% CI 1.51-2.50], p<0.0001). The sequencing of ADT with RT was significantly associated with clinical outcomes, with evidence of a significant interaction based on use of PNRT. PORT with conc/adj vs. neo/conc ADT had improved MFS, while PNRT with neo/conc vs. conc/adj ADT had improved MFS. Overall PORT with conc/adj ADT had superior outcomes. Given the non-randomized nature of the current pooled analysis, we await the results of NRG/RTOG 0924 to understand the role of PNRT in LPCa with neo/conc ADT sequencing. [ABSTRACT FROM AUTHOR]

Patient reported quality of life (QOL) outcomes are pivotal endpoints to determine treatment efficacy and safety. However, it remains unknown if treatment induced change in patient reported QOL outcomes correlate with survival in localized prostate cancer (LPCa). We performed an exploratory analysis of a phase III randomized controlled study to determine the association of treatment induced dynamic change in patient reported global QOL with long-term overall survival (OS) and disease-free survival (DFS) in LPCa treated with radiotherapy (RT) and androgen deprivation therapy (ADT). LPCa patients with Gleason score ≤7, clinical stage T1b-T3a, and PSA <30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 mos starting 4 mos before prostate RT or concomitant and adjuvant ADT for 6 mos starting concurrently with RT. Patient reported QOL outcomes were collected using EORTC QOL questionnaires. We used the global QOL (G-QOL) score from C30 questionnaire. Increase in G-QOL score indicated improvement in global QOL. To capture the association between the dynamic change in the G-QOL of each patient and the hazard of outcome, we utilized the framework of multivariate joint modeling for longitudinal and survival outcomes. For the time-to-event submodel, a Cox proportional hazard regression model was built with covariables including treatment arm, baseline PSA, tumor stage, Gleason score, and age. For the longitudinal submodel, a linear mixed effect model was built with an interaction term for treatment arm and time of evaluation in addition to fixed covariables - treatment arm, time of evaluation, baseline G-QOL score and age. Time of assessment was included as a random slope while patients were included as random intercepts in the mixed models. The two submodels were linked through a random effect. Baseline hazard was modeled using penalized splines. A two-sided p-value <0.025 was chosen to be the threshold for statistical significance. A total of 388 patients were eligible for this study – 191 belonged to the neoadjuvant arm while 197 to the adjuvant arm. At a median follow-up of 148 mos, a total of 133 deaths were recorded. On joint modelling, an increase in G-QOL score by 10 units (the threshold for clinically meaningful change) was associated with a 11.2% decrease in the hazard of death (hazard ratio [HR] per 1 unit increase G-QOL: 0.988, 95% CI: 0.980-0.996; p=0.007). An increase in G-QOL score by 10 units was associated with 10% decrease in the hazard of progression or death (HR per 1 unit increase in G-QOL: 0.990; 95% CI: 0.984-0.999; p=0.023). Treatment induced improvement in global QOL is a predictor for improved DFS and OS in LPCa. This suggests a significant interplay of patient-reported quality of life and quantity of life in LPCa which could mainly be driven by the non-cancer specific mortality in this patient population. Judicious use of these QOL metrics could guide risk stratification and potentially inform treatment decision in these patients [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Radiotherapy (RT) dose escalation for localized prostate cancer has not demonstrated improvement in overall survival (OS) from individual trials. It is unclear if the use of androgen deprivation therapy (ADT) effects the potential benefit of dose escalation. Therefore, to achieve sufficient power to answer this question, we performed a meta-analysis of randomized trials evaluating the benefit of RT dose escalation in localized prostate cancer.Materials/methods: The Meta-Analysis of Randomized clinical trials in Cancer of the Prostate (MARCAP) Consortium was formed to obtain IPD from multiple randomized controlled trials. Patients were categorized based on RT dose and use and duration of ADT. Short-term ADT (STADT) was defined as ≤6 months, long-term ADT (LTADT) as 18-36 months, and low and high dose RT as < or ≥74 Gy EQD2. IPD from 15 trials (n = 13,864 patients) were used. The primary endpoint of all analyses was OS, with metastasis-free survival (MFS) and the incidence of biochemical recurrence (BCR) as secondary endpoints. Sensitivity analyses using only trials with direct and relevant randomization (10 trials; n = 9,775 patients) were used to perform a network meta-analysis (NMA).Results: The median follow-up was 8.5 years (IQR 5.6-11.2). Escalating dose in the absence of ADT did not improve OS (HR 0.92, 95% CI 0.79-1.08) or MFS (HR 0.91, 95% CI 0.78-1.07). In the presence of STADT, high dose RT significantly improved OS (HR 0.79, 95% CI 0.67-0.94) and MFS (HR 0.80, 95% CI 0.68-0.94), as well as in the presence of LTADT for OS (HR 0.64, 95% CI 0.50-0.82) and MFS (HR 0.71, 95% CI 0.57-0.89). On sensitivity analysis using the NMA, dose escalation did not significantly improve outcomes in the absence of ADT (OS: HR 1.00, 95% CI 0.75-1.34; MFS: HR 0.97, 95% CI 0.67-1.41) or in the presence of STADT (OS: HR 0.95, 95% CI 0.54-1.67; MFS: HR 0.89, 95% CI 0.46-1.70) or LTADT (OS: HR 0.75, 95% CI 0.38-1.47; MFS: HR 0.78, 95% CI 0.36-1.67). In both the pooled comparison and the NMA, dose escalation improved BCR without ADT (NMA HR 0.53, 95% CI 0.32-0.88) in the presence of STADT (NMA HR 0.37, 95% CI 0.16-0.84), but not in the presence of LTADT (NMA HR 0.46, 95% CI 0.18-1.21).Conclusion: Dose-escalation alone does not improve MFS or OS. In the presence of STADT or LTADT, the impact of dose-escalation differed when pooling non-randomized comparisons (which is prone to selection bias) versus performing an NMA restricted to only direct randomized comparisons (which is affected by limited network connectivity). BCR was more consistently improved. Given the uncertain impact on survival and the potential for increased toxicity, future studies using biomarker selection are needed to better personalize which patients benefit most from dose escalation. [ABSTRACT FROM AUTHOR]

Background Circulating PCSK9 levels are higher in women than men, in postmenopausal than premenopausal women, and in pregnant than non-pregnant women, suggesting that sex hormones may be related to PCSK9 levels. We have examined the relationship between serum estradiol (E2) and testosterone (T) and PCSK9, and the impact of E2 replacement therapy in women and T replacement and ablation therapy in men on circulating PCSK9. Methods We conducted a cross-sectional study to examine the correlation between serum T (in males) and E2 (in females) and serum PCSK9. We also conducted interventional studies to examine the effect of hormonal therapy on serum PCSK9 levels. Results In men, (1) serum T does not correlate with circulating PCSK9 or with LDLC in the basal state, (2) T replacement therapy does not have any effect on circulating PCSK9, and (3) T ablation therapy has mixed results. In women, (1) E2 correlates inversely with circulating PCSK9 and directly with serum LDLC, but (2) E2 replacement therapy does not have any effect on circulating PCSK9. Conclusions We demonstrate differences between men and women in the relationship of their major sex hormones with circulating PCSK9. In men, circulating PCSK9 is not related to or affected by T except for a possible effect during T ablation therapy. In women, E2 is inversely related to circulating PCSK9 but the lack of effect of E2 therapy on circulating PCSK9 suggests that the E2-related differences in PCSK9 levels may be the result of differences in receptor-mediated PCSK9 clearance through E2-induced changes rather than production of PCSK9. The studies were registered with ClinicalTrials.gov NCT00848276 . [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Caesalpinia pyramidalis Tul. (Fabaceae), known as “catingueira”, has been used in folk medicine in the treatment of various disorders such as gastritis, heartburn, indigestion, and stomach ache. However, the gastroprotective properties of this species have not yet been studied. Materials and methods: The ethanol extract of Caesalpinia pyramidalis inner bark was used in rats via oral route, at the doses of 30, 100, and 300mg/kg. The antiulcer assays were performed using the ethanol- and nonsteroidal anti-inflammatory drug-induced ulcer models. Gastric secretion parameters (volume, pH, and total acidity) were also evaluated by the pylorus ligated model, and the mucus in the gastric content was determined. The anti-Helicobacter pylori activity of the ethanol extract of Caesalpinia pyramidalis was performed using the agar-well diffusion and broth microdilution methods. Results: The ethanol extract (30, 100, and 300mg/kg) produced dose dependent inhibition (P<0.01) on the ulcer lesion index, the total lesion area, and the percentage of lesion area in the ethanol-induced ulcer model. The ethanol extract (30, 100, and 300mg/kg) also reduced (P<0.001) the ulcer index in the indomethacin-induced ulcer model. In the model ligature pylorus, the treatment with Caesalpinia pyramidalis ethanol extract failed to significantly change the gastric secretion parameters. However, after treatment with the ethanol extract of Caesalpinia pyramidalis (30, 100, and 300mg/kg), there was a significant increase (P<0.05) in mucus production. The ethanol extract showed anti-Helicobacter pylori activity, with inhibition halos of 12.0±1.7mm at 10,000μg/mL. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of the ethanol extract were of 625 and 10,000μg/mL, respectively. Conclusions: Collectively, the present results suggest that the ethanol extract of Caesalpinia pyramidalis displays gastroprotective actions, supporting the folkloric usage of the plant to treat various gastrointestinal disturbances. [Copyright &y& Elsevier]

Purpose/objective(s): Quality Assurance (QA) is an integral part of the delivery of Radiotherapy (RT). Peer review (PR) is an essential component of the QA process mandated by Cancer Care Ontario (CCO). The COVID-19 pandemic has caused significant disruptions to cancer care worldwide. We aimed to investigate PR rates across all regional cancer centers in Ontario during the pandemic.Materials/methods: Using a provincial database maintained by CCO, PR data regarding completed curative and palliative RT courses were reviewed from December 2014 to November 2020. Peer reviews reported completed in March 2020 onward were considered to be completed during the pandemic. The monthly PR rates of 2019 were used as a baseline comparator. Wilcoxon signed-rank test (two-tailed) was used to determine significance in PR rates and courses of RT delivered. A P-value of < 0.05 was considered significant.Results: A total of 24,936 radical courses and 18,759 palliative radiotherapy courses were completed in Ontario during the first 8 months of the pandemic. We found no difference in the average number of RT courses the year prior compared to during the pandemic for radical (3117/month vs 3382/month, P = 0.078) or palliative courses (2344/month vs 2227/month, P = 0.195). PR rates of radical RT were significantly decreased compared to the previous 12-month time period 86.1% vs 88.5% (95% CI: 0.6%-4.6% P = 0.014). Palliative RT also had a decrease in PR from 61.7% to 56.6% (95% CI:1.4%-7.2%, P = 0.016). In the 2 immediate months following March 2020, there was a decrease of PR rates with radical RT PR rates nadiring at 83% and palliative RT nadiring a 53% PR rate, the lowest since April 2016 and January 2018 respectively. This trend quickly reversed and PR rates increased in subsequent months. Analysis by disease site indicated a significant decrease compared to the prior year in disease site-specific PR rates for radical courses within breast (87.8% vs 90.3%, P = 0.16) and gynecologic (76.9% vs 84.1%, P = 0.049) disease sites respectively. Lung, Head and Neck, Gastrointestinal and CNS sites had no significant differences in PR rates when compared to the preceding year.Conclusion: Peer review rates had an initial decrease across regional cancer in both radical and palliative intent radiation. Overall, peer review rates remain modestly lower than the period immediately preceding the pandemic. All centers still maintained a high rate of PR during the initial 8 months of the COVID 19 pandemic. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Standard clinicopathologic variables including T-category, Gleason grade, and prostate-specific antigen (PSA) guide the management of localized prostate cancer. The prognostic and predictive performance of these variables has been assessed primarily in retrospective cohorts without standardized quality assurance. Given the substantial heterogeneity in oncologic outcomes for men with localized prostate cancer, we hypothesized that standard clinicopathologic variables have inherent limitations. We therefore sought to assess their performance in a meta-analysis of 10 phase III randomized trials.Materials/methods: Individual patient data was obtained from 10 radiotherapy-related RCTs (NRG/RTOG 9202, 9408, 9413, 9910, 0126; EORTC 22863, 22961, 22991; DART 01/05 GICOR, and Ottawa 0101). The cohort was split 2:1 into training and validation cohorts. In the training set, multivariable cox regression and random forest models were developed. Concordance indices (c-indices) and bootstrapped 95% confidence intervals were calculated for models based on age, performance status, T-category, Gleason score, and PSA. Interactions with androgen deprivation therapy (ADT) treatment effects were also tested. Endpoints included distant metastasis (DM), metastasis-free survival (MFS), and overall survival (OS).Results: A total of 10,535 patients were included. The training cohort (n = 7382) was used to develop an optimized clinicopathologic model. Using the locked-model in the validation cohort (n = 3153), the 10-year c-index was 0.70 (95% CI: 0.66-0.74), 0.61 (0.59-0.63), and 0.61 (0.59 - 0.63), for 10-year DM, MFS, and OS, respectively. Similar results were obtained using random forest models. In trials testing the addition of short-term (ST) ADT, or those testing the addition of long-term (LT) ADT, there was no evidence of treatment effect modification by any variable for any endpoint (all P-interaction > 0.05). There was, however, significant heterogeneity in the absolute benefit derived from ADT intensification; the empirical 10-year absolute DM risk reduction with LT ADT over ST ADT ranged from 4.1% to 18.0% depending on modelled baseline risk.Conclusion: In this large cohort with long-term follow-up and trial-level quality assurance, models based on standard clinicopathologic variables had limitations in accurately estimating prognosis. The proportional benefit of ADT use was consistent, but the absolute magnitude of benefit varied greatly by predicted baseline risk of DM. Incorporation of genomic prognostic information into risk stratification to better estimate absolute ADT benefit are needed and ongoing (NCT04513717). [ABSTRACT FROM AUTHOR]

Purpose/objective(s): While health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localized prostate cancer (LPCa). In this exploratory analysis, we report the association of baseline HR-QoL metrics with overall survival (OS) and risk of late radiation-induced toxicity in men with LPCa treated with combination of radiotherapy (RT) and androgen deprivation therapy (ADT).Materials/methods: This is a secondary analysis of a phase III randomized controlled study conducted in two tertiary cancer centers. LPCa patients with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. HR-QoL scores were estimated using European Organization for Research and Treatment of Cancer QoL questionnaire. A multi-state Markov model was used to determine the association of baseline HR-QoL metrics with OS and a multilevel multivariable Cox regression to determine the association with incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P-value < 0.025 was considered as statistically significant. Conditional approach was used to calculate 15-year adjusted OS for patients with and without financial difficulty and patients with and without dyspnea at baseline.Results: Overall, 393 patients with baseline HR-QoL data were included in this analysis - 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio [HR]: 1.020, 95% confidence intervals [CI]:1.010-1.030, P = 0.02), and dyspnea (HR: 1.020, 95% CI:1.003-1.030, P = 0.01) were associated with inferior OS. Adjusted OS for patients with and without financial difficulty at baseline was 15.5% and 45.7%, respectively (P < 0.01). Adjusted OS for patients with and without baseline dyspnea was 21.2% and 46.6%, respectively. Baseline dyspnea was associated with higher incidence of grade ≥3 toxicity (HR: 1.020, 95% CI: 1.010-1.030, P = 0.023).Conclusion: In a cohort of LPCa patients treated with RT and short-term ADT, a 10-point increase in baseline financial difficulty or a 10-point increase in baseline dyspnea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnea, we noted an 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity. These findings underscore the importance of integrating these baseline patient-reported metrics in selecting patients, making informed treatment-decisions, and optimizing overall outcome in men with localized prostate cancer. [ABSTRACT FROM AUTHOR]