bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of biochemical definition of cure after low-dose rate prostate brachytherapy.
Authors: Crook Juanita M. , Tang Chad , Thames Howard , Blanchard Pierre , Sanders Jeremiah , Ciezki Jay P. , Keyes Mira , Merrick Gregory Stephen , Catton Charles N. , Raziee Hamid , Stock Richard , Sullivan Frank , Anscher Mitch , Frank Steven J. 
Published: February 2020

322 Background: Prospectively collected outcome data for 14,196 patients with localized prostate cancer treated with LDR brachytherapy (BT) from 7 institutions were analyzed. For the 80% of patients with a 4 year PSA < 0.2 ng/ml, 99% were free of clinical failure at 10 years and 96% at 15 years. We sought to validate this result with 2 independent data sets from mature prospective clinical trials. Methods: In the initial analysis, patients were treated with either BT alone (61%), or in combination with external beam radiotherapy (EBRT:8%), androgen deprivation (ADT:22%) or both (9%). 42% were low risk, 50% intermediate (IR) and 8% high risk(HR). KM analysis was carried out using clinical failure (local, distant, regional or biochemical triggering salvage) as endpoints for each of 4 PSA categories: PSA<0.2 ng/ml, PSA >0.2 to < 0.5, PSA > 0.5 to < 1.0, and PSA>1.0 ng/ml. Results were compared to 12 year follow up data on a phase 2 trial of BT for IR prostate cancer (n=223; MDAnderson Cohort 1) and 10-year data from the BT arm of the phase 3 randomized ASCENDE RT trial (n=160, Cohort 2) for upper tier IR and HR prostate cancer. Results: The results of the initial KM analysis showed that for the 80% of patients with PSA < 0.2 ng/ml at 4 years, 99% were free of recurrence at 10 years (95% CI: 98.4-99.1) and 96% at 15 years (95% CI: 95-97). The association of treatment success with PSA range was highly significant (p<0.0005). Independent validation against BT alone in IR patients (Cohort 1) confirmed that 99% of patients with PSA at 4 years < 0.2 ng/ml were NED at 10 years (CI: 95.8-99.9). For the unfavorable IR and HR patients receiving 12 months ADT + pelvic EBRT and BT in ASCENDE-RT (Cohort 2), PSA < 0.2 ng/ml at 4 years was associated with 96.7% (CI: 89.9-98.9) being failure free at 10 years. Conclusions: As over 80% of patients achieve a PSA < 0.2 ng/ml at 4 years post-LDR BT, and this is associated with 97%-99% being disease free beyond 10 years, we suggest that this biochemical definition of cure be adopted for LDR brachytherapy patients with ≥ 4 years’ follow-up.
Association of black race with improved outcomes following definitive radiotherapy with androgen deprivation therapy for high-risk prostate cancer: A meta-analysis of eight randomized trials.
Authors: Kishan Amar Upadhyaya , Romero Tahmineh , Rettig Matthew , Garraway Isla , Roach Mack , Pisansky Thomas Michael , Michalski Jeff M. , Lee W. Robert , Jones Christopher U. , Rosenthal Seth A. , Feng Felix Y , Boutros Paul Christopher , Nickols Nicholas George , Mahal Brandon Arvin Virgil , Dess Robert Timothy , Tran Phuoc T. , Steinberg Michael L. , Elashoff David , Sandler Howard M. , Spratt Daniel Eidelberg 
Published: February 2020

327 Background: Though Black men with prostate cancer are more likely to have aggressive disease features than White men, race-specific differences in initial treatment responses in localized disease remains unknown. Methods: Individual patient data were obtained for 9259 patients (including 1674 [18.1%] Black men and 7585 [81.9%] White men) enrolled on eight randomized controlled trials evaluating definitive radiotherapy (RT) ± short-term or long-term androgen deprivation therapy (STADT and LTADT). The primary endpoints were biochemical recurrence (BCR), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Fine-Gray subdistribution HR (sHR) models were developed to evaluate the cumulative incidences of all endpoints after stratification by National Comprehensive Cancer Network risk grouping. A meta-analysis was done to estimate pair-wise comparisons of treatments within and between Black and White men, after adjusting for age, Gleason score, clinical T stage, and initial PSA. Results: Black men were more likely to have NCCN high-risk disease at enrollment (656/1674 [39.2%] vs 2506/7585 [33%], p<0.001). However, within the high-risk stratum Black men had lower 10-year rates of BCR (46.1% vs. 50.4%, p=0.02), DM (14% vs. 21.6%, p<0.001), and PCSM (4.9% vs. 9.8%, p<0.001). After adjusting for age and disease characteristics, Black men with high-risk prostate receiving RT+STADT had lower rates of BCR (sHR 0.73, 95% CI 0.62-0.86, p<0.001), DM (sHR 0.64, 95% CI 0.49-0.84, p=0.001) and PCSM (sHR 0.49, 95% CI 0.25-0.95, p=0.04). There were no differences in BCR, DM, or PCSM among men receiving RT+LTADT. The interaction between race and the impact of adding STADT to RT alone on BCR was statistically significant (p=0.003). Conclusions: Black men enrolled on randomized trials with long-term follow-up have higher risk disease at enrollment, but have better BCR, DM, and PCSM outcomes with RT-based therapy compared with White men, particularly with the addition of STADT.
Tumor cell intrinsic androgen biosynthesis by 3β-hydroxy steroid dehydrogenase (HSD3B1) to modulate radiosensitivity in prostate cancer cells.
Authors: Ganguly Shinjini , Balyimez Aysegul , Lone Zaeem , Hardaway Aimalie , Patel Mona , Davicioni Elai , Ornstein Moshe Chaim , Garcia Jorge A. , Stephans Kevin L. , Ciezki Jay P. , Tendulkar Rahul D. , Klein Eric A. , Sharifi Nima , Mian Omar Y. 
Published: February 2020

349 Background: Resistance to ADT is associated with a gain of function mutation in the 3β-HSD enzyme, which catalyzes extragonadal/intratumoral DHT synthesis. As androgen signaling is known to upregulate the DNA damage response (DDR), we investigated whether HSD3B1 genotype modulates DDR and radiosensitivity in PCa. Methods: We stably knocked down HSD3B1 in LNCaP, C42 and VCaP cell lines (which carry the protein stabilizing variant allele) and overexpressed the variant HSD3B1 allele in LAPC4 (harbors a WT allele which readily undergoes degradation). We examined the proliferative and clonogenic capacity of these cells in presence and absence of substrate, DHEA, followed by treatment with IR (400-800 cGy, single fraction). We studied DNA DSB formation and resolution kinetics using γH2AX foci formation in response to radiation. We also measured changes in mRNA expression of DDR response genes pre- and post-radiation. Results: Control shRNA transduced cell lines had increased cell proliferation (p<0.001) and clonogenic survival (2 logs at 800cGy single fraction radiation, p<0.001) in the presence of DHEA compared to HSD3B1 knockdown cells. Variant HSD3B1 cell lines were more radioresistant and exhibited more efficient γH2AX foci resolution at 24 hrs (p <0.05) in a DHEA dependent manner. We observe increased mRNA expression of DDR genes from specific repair networks including non-homologous end joining (PRKDC, XRCC4, XRCC5) and homologous recombination (RAD51, RAD54) in variant HSD3B1 cells. Transcriptional induction of DDR genes following radiation in presence of DHEA was significantly more pronounced in HSD3B1 variant cells, suggesting a more permissive chromatin context. Conclusions: Increased intracellular 3β-HSD drives transcription of NHEJ and HR genes, more rapid resolution of γH2AX foci, and radioresistance in prostate cancer. This work has therapeutic implications related to strategies for combined radiation and androgen directed therapy in localized and metastatic prostate cancer. Prospective validation of treatment strategies combining blockade of adrenal steroid precursor synthesis, ADT, and XRT in high risk disease is warranted.
Influence of caseload on survival of patients (pts) with localized prostate cancer (PC) after definitive radiation therapy (DRT).
Authors: Sadeghi Sarmad , Lara Primo , Tsao-Wei Denice D. , Aron Monish , Pinski Jacek K. , Quinn David I. , Gill Inderbir , Barzi Afsaneh 
Published: February 2020

357 Background: We recently reported a significant all-cause mortality risk reduction associated with higher annual caseload for radical prostatectomy (RP)- (PMID 31398279). Here we explore this relationship in DRT. Methods: National Cancer Database (NCDB) was used to investigate outcomes of DRT in the United States. Beam radiation (BR), radioactive implant (RI) and both (BRRI) were included in analysis. Using overall survival (OS) as primary outcome, the relationship between facility annual caseload (FAC) for all PC pts and facility annual caseload (FARC) for those requiring DRT were examined using Cox model. Four volume groups (VG) were defined as VG1: <50th, VG2: 50th-74th, VG3: 75th-89th and VG4: top 10 percentile of caseload. Results: Between 2004 and 2014, 355,247 pts underwent DRT. At a median follow up of 70.1 (95% CI: 1.0 - 143.1) months (mo), the median OS was 137.3 mo (136.9, 138.1). Using FAC/FARC, 19/14, 27/24, 24/26, and 30/37 % of pts were treated at VG 1 through 4, respectively. For FARC, median OS was 136.8 mo (134.9, 142.2+) for VG1 and 139.7 (137.7, 141.8+) mo for VG4, adjusted hazard ratio (aHR) 1.06 (1.03-1.09), p <0.001. For FAC, median OS was 135.4 (134.1, 138.7) mo for VG1 and not reached for VG4, aHR 1.13 (1.09, 1.16), p <0.001. In subgroups, FARC aHR for VG1 vs VG4 were 1.20 (1.16-1.25) for BR, 0.99 (0.93-1.05) for RI, and 1.15 (1.02-1.31) for BRRI. These numbers for FAC were 1.10 (1.06, 1.14), 1.12 (1.05, 1.19), and 1.24 (1.12, 1.39), respectively. Conclusions: There is a statistically significant OS advantage to DRT at a high annual caseload facility. This effect is more pronounced for BR and is influenced more noticeably by facility all PC caseload rather than DRT.[Table: see text]
Treatment timing in localized high-risk prostate cancer treated with radiation and androgen deprivation therapy.
Authors: Hasan Shaakir , Lazarev Stanislav , Gorovets Daniel , Garg Madhur , Press Robert H. , Choi Isabelle , Simone Charles B. 
Published: February 2020

359 Background: Data regarding the impact of overall treatment time in prostate radiotherapy predate the dose escalation era and is absent in high risk disease. We hypothesize that delays in initiating androgen deprivation therapy (ADT) and in completing fractionated radiotherapy (XRT) correlate with worse outcomes in high risk prostate cancer. Methods: Using the National Cancer Database, we identified 9,611 cases of localized high risk prostate cancer, defined as Grade groups 4 and 5 (Gleason 8-10), PSA < 40, and T1-T3N0M0, treated with conventionally fractionated XRT (74-81 Gy, median 78 Gy) and ADT between 2010-2014 with at least 12 months follow-up (median 40). Receiver operating characteristic (ROC) analyses determined a-priori values for days to initiation of treatment (ADT or XRT) and number of “missed” treatment days (number of days beyond the minimum required to complete XRT). Multivariable regression models with propensity matching conveyed the relative impact of these timing parameters on survival. Results: The median time from diagnosis to treatment intervention was 63 days and median missed XRT treatment days was 2.2. The greatest difference in survival was seen when intervention was initiated beyond 74 days from diagnosis (HR=1.21, P=0.045) and when more than 3 XRT treatment days were missed (HR=1.27, P=0.006). Only missed treatment days correlated with survival as a continuous variable (HR=1.028, P<0.001) on multivariable analysis. On a multivariable regression model propensity-matched for missed treatment days, independent predictors for worse survival include older age, higher comorbidity score, dose below 78 Gy, grade group 5, and PSA > 20. Greater than 3 missed treatment days remained an independent predictor; adjusted HR = 1.23 (P=0.002). The lone predictors of missed treatments was African American race (OR=1.21). Conclusions: Although outcomes in prostate cancer are not typically thought to be associated with treatment time, our study, the largest such analysis to date, revealed a strong independent correlation between timely completion of XRT and survival in high risk disease. The association between survival and time to initiating ADT was not nearly as strong.
Impact of overall survival (OS) as a function of facility caseload on feasibility of referral of radical prostatectomy (RP) to higher volume facilities.
Authors: Ahmadi Hamed , Barzi Afsaneh , Lara Primo , Quinn David I. , Klein Eric A. , Gill Inderbir , Sadeghi Sarmad 
Published: February 2020

363 Background: We recently reported a significant all-cause mortality (ACM) risk reduction associated with higher annual caseload for RP (PMID 31398279). Four volume groups (VG) were defined as VG1: <50th, VG2: 50th-74th, VG3: 75th-89th and VG4: top 10 percentile of caseload. The adjusted OS difference between VG1 and VG4 at 90th percentile survivorship reached 13.2 months, HR 1.30 (p<0.0001). Here we explore this economics of referral to VG4. Methods: Using a Markov model, we designed 4 scenarios (Sc) where 100,000 RPs were performed. In Sc 1 all RPs were performed at VG1; in Sc 2, 3 & 4, all RPs were performed at VG2, 3 &4 respectively. Subjects were followed for up to 20 years after RP. Survival and costs of care for each Sc were recorded. Probabilities of PSA recurrence (PSAR), development of metastatic disease (Met), cancer specific mortality (CSM) and ACM were adjusted for each VG according to the published HRs. Savings resulting from fewer recurrences, avoidance of salvage radiation therapy (SRT) and management of fewer Met were calculated. Standard discounting at 3% were applied to costs and benefits. Survival benefit and costs savings associated with making referrals from VG1, VG2, or VG3 centers to VG4 center were calculated. Using a willingness to pay (WTP) of $50K per life years gained (LYG), the maximum referral costs (MRC) were calculated. Results: Referral from a VG1 to a VG4 center was associated with highest OS benefit of 720 LYG at 20 years of follow up per 1000 referrals (PKR). Within a WTP of $50K, MRC of up to $37K was cost effective- Table. Conclusions: Given the survival benefit associated with performing RP at facility with high annual caseload, significant resources could be allocated to making a referral possible while still remaining within cost effectiveness boundaries.[Table: see text]
The efficacy and safety of radical prostatectomy and radiotherapy in high-risk prostate cancer: A systematic review and meta-analysis.
Authors: Wang Zhipeng , Ni Yuchao , Chen Junru , Sun Guangxi , Zhang Xingming , Zhao Jinge , Zhu Xudong , Zhang Haoran , Zhu Sha , Dai Jindong , Shen Pengfei , Zeng Hao 
Published: February 2020

369 Background: The optimal treatment for patients with high-risk prostate cancer (PCa) remains debate and selection of patients to receive proper therapy is still an unsettled question. This systematical review was to compare the effectiveness of prostatectomy (RP) and radiotherapy (RT) in patients with high risk prostate cancer (PCa) and to select candidates for optimal treatment. Methods: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched for eligible studies. We extracted hazard ratios (HRs) and 95% CI of included studies. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS); the secondary outcomes were biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS) and clinical recurrence-free survival (CRFS). The meta-analysis was performed using Review Manager 5.3. Subgroup analyses were conducted according to GS, T stage and RT types. Quality of life (QOL) was compared with these two treatments. Results: A total of 25 studies were included. Overall, RP showed more survival benefits than RT on CSS (P=0.003) and OS (P=0.002), while RT was associated with a better BRFS (P=0.002) and MFS (P=0.004). Subgroup analyses showed RT was associated with similar or even better survival outcomes compared to RP in patients with high GS, high T stage or received external beam radiotherapy plus brachytherapy (EBRT+BT). As for QOL, RP was associated with poorer urinary and sexual function but better performance in the bowel domain. Conclusions: RP could prolong the survival time of patients with high risk PCa; however, RT could delay disease progression, and combined RT (EBRT+BT) even brought better CSS and similar OS than RP. RT might be the prior choice for patients with high T stage or high GS. RP could lead to poorer urinary and sexual function, while brought better performance in the bowel domain.
Overall survival (OS) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) receiving bicalutamide (BIC) followed by enzalutamide (ENZA) or abiraterone (ABI).
Authors: George Daniel J. , Tagawa Scott T. , Lechpammer Stanislav , Russell Dave , Hong Agnes , Mardekian Jack , Huang Ahong , Wang Li , Janjan Nora , Ramaswamy Krishnan 
Published: February 2020

40 Background: The objective of this study was to evaluate real-world OS in men with chemotherapy-naïve mCRPC treated with first-line ENZA or ABI or sequencing to these agents after treatment with BIC ( > 90 d). Methods: A retrospective analysis was performed using the Veterans Health Administration (VA) database. Men with mCRPC and ≥ 1 pharmacy claim for ABI or ENZA (1st claim date = index date) following surgical or medical castration and with no chemotherapy treatment 12 months pre-index date were identified from 01APR2014 to 31MAR2017. Men had continuous VA enrollment for ≥ 12 months pre- index date and were followed until death or study end. Cox proportional hazards regression models examined the impact of treatment on OS, and the impact of first using BIC ( > 90 d) vs first-line use of ABI and ENZA on OS. Adjusted Kaplan-Meier analysis was conducted to graphically describe OS. Results: This study included 1229 ENZA- and 1945 ABI-treated men with mCRPC with mean ages of 74 and 73 y, respectively. Median follow‐up was 548 and 572 d, and median OS was 892 and 786 d, respectively. ENZA and ABI were first-line treatment in 1068 and 1628 men, but BIC ( > 90 d) was first used before sequencing to ENZA or ABI in 161 and 317 men, respectively. Median duration of BIC treatment was similar in men subsequently treated with ENZA or ABI (251 v 246 d, respectively). Compared with first-line ABI, use of ABI following BIC led to shorter OS (hazard ratio [HR] = 1.30; 95% CI 1.11 -1.52). Compared with first-line ENZA, use of ENZA following BIC resulted in a nonsignificant effect on OS (HR = 0.92; 95% CI 0.72-1.19). In the Cox analysis, ENZA-treated men had longer OS compared with ABI-treated men (HR = 0.84; 95% CI 0.76-0.94). Conclusions: Use of BIC ( > 90 d) before sequencing to ENZA did not negatively effect OS, however BIC before ABI impacted OS adversely in men with chemotherapy-naïve mCRPC. There are significant differences in OS favoring ENZA compared with ABI regardless of prior BIC. Real-world observational data are nonrandomized, and markers for disease severity/volume are not available in the claims database. Further research is required to confirm these findings.
Thoracic radiotherapy for renal cell carcinoma metastases.
Authors: Stewart Glenn , Breen William , Stish Brad J. , Park Sean Sunghun , Olivier Kenneth R. , Costello Brian Addis 
Published: February 2020

409 Background: For patients with metastatic renal cell carcinoma (RCC), metastasis-directed local therapies can delay progression and need to initiate/switch systemic therapy. We examined our experience treating lung or mediastinal metastases from RCC with radiotherapy (RT). Methods: We reviewed patients with lung or mediastinal metastases from RCC treated with RT. Overall survival (OS) and local control (LC) was measured from the start of RT using the Kaplan-Meier method. Results: Seventy-one patients were treated with RT for 89 lung or mediastinal metastases. Median follow-up was 2.0 years (range 0.02-11.4 years) after RT for surviving patients. Most patients were male (n=53, 74.6%). Median age was 58.4 years at initial diagnosis. Histology was most frequently clear cell carcinoma (n=62, 89.9%). At the time of treatment, 18 patients (25.4%) had 1-3 metastases, and the remainder (74.6%) had 4 or more metastases. Forty-one patients (57.5%) received systemic therapy prior to thoracic radiation. Initial systemic therapy was most commonly sunitinib (45%) or pazopanib (32.5%). Median time from starting systemic therapy to initiation of radiation was 2.0 years. Fifty-eight lung metastases and 31 mediastinal metastases were treated with a median 5 fractions (range 1-40), to a median total dose of 4800 cGy (range 400-7000), with a median fraction size of 500 cGy (range 150-2000). Thirty-three lesions were treated with concurrent systemic therapy, which was most commonly nivolumab (n=16). Of 89 treated lesions, 11 (12%) had local tumor recurrence, at a median of 1.6 years (range 0.4-2.9 years) after initiation of radiation. 1, 3, and 5 year MC (metastasis control) were 96.6%, 83.5% and 67.9%, respectively. Nine patients were treated with radiation in order to delay initiation of systemic therapy. Of these, 3 eventually received systemic therapy, initiated at a median 2.5 years after radiation. At last follow-up, 41 patients (57.7%) had died. Median OS was 2.6 years. Survival at 1, 3, and 5 years was 65.2%, 48.5%, and 38%, respectively. Conclusions: Radiation achieves high metastasis control rates for lung and mediastinal metastases from RCC, potentially delaying the need for systemic therapy.
Serum microRNA-371a-3p levels to predict viable germ cell tumor in chemotherapy-naïve patients undergoing retroperitoneal lymph node dissection.
Authors: Singla Nirmish , Lafin John T. , Woldu Solomon L. , Lotan Yair , Lewis Cheryl , Majmudar Kuntal , Savalyeva Anna , Kenigsberg Alexander P. , Kapur Payal , Margulis Vitaly , Strand Douglas , Murray Matthew , Amatruda James F. , Bagrodia Aditya 
Published: February 2020

417 Background: Serum microRNAs are candidate biomarkers for diagnosing and monitoring germ cell tumors (GCTs). The ability of miRNA to inform treatment in low-stage chemotherapy-naïve patients is unexplored. We sought to evaluate the performance characteristics of serum miRNA levels to predict viable GCT in chemotherapy-naïve patients undergoing primary retroperitoneal lymph node dissection (RPLND). Methods: We prospectively collected presurgical serum samples and clinicopathologic characteristics from consecutive chemotherapy-naïve GCT patients undergoing primary RPLND from 2016-2019. Serum miRNAs (-367-3p/-371a-3p/-372-3p/-373-3p/-375) were isolated and quantified. RPLND histopathology was categorized as benign, viable GCT, or teratoma; miRNA levels were compared among groups. Performance characteristics, including receiver operating characteristic (ROC) curves, assessed the discriminative ability of each miRNA signature to predict viable GCT. Results: 24 patients with stage I-II GCT underwent RPLND, revealing viable GCT in 11 (46%), teratoma in 3 (13%), and benign pathology in 10 (42%) patients. miR-371a-3p was the most discriminatory serum miRNA for viable GCT, exhibiting ~13,000-fold increase in expression over teratoma or benign pathology. On ROC analysis, miR-371a-3p had AUC = 0.965, with sensitivity and specificity of 100% and 92%, respectively. The AUC for other serum miRNAs in predicting viable GCT were 0.874 (miR-367-3p), 0.846 (miR-372-3p), and 0.720 (miR-373-3p). These serum miRNAs were not predictive of pure teratoma. Potential limitations include small cohort size and no post-RPLND sera for comparison. Conclusions: Serum miRNAs, particularly miR-371a-3p, can accurately differentiate small-volume viable GCT from benign processes or teratoma in patients with negative serum tumor markers undergoing primary RPLND. If validated, these data suggest a basis to implement precision medicine strategies in treating patients with early-stage GCT.