bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival in patients with prostate cancer and history of autoimmune disease.
Authors: Dedousis Demitrios , Zhang Annie , Vassiliou Anastasia , Cao Shufen , Yammani Deepthi , Kyasaram Ravi Kumar , Shanahan John , Keinath Melissa C. , Hsu Melinda Laine , Fu Pingfu , Dowlati Afshin , Garcia Jorge A. 
Published: June 2022

e17001 Background: Prostate cancer is thought of as an immunologically cold tumor, however a small proportion of patients treated with immunotherapy have impressive responses. Studies into the effect of autoimmune disease on risk of prostate cancer have yielded contradictory results and little is known about the survival of patients with concurrent autoimmune disease and prostate cancer. This study compared outcomes in patients with prostate cancer with and without autoimmune disease. Methods: This study was a retrospective analysis of patients from the SEER-Medicare databases from 2007-2014 with prostate cancer. Patients with a history of autoimmune disease were identified using ICD-9 codes. The effects of autoimmune disease on overall survival (OS) and cancer-specific survival (CSS) were estimated using multivariable Cox regression and Gray’s method respectively controlling the effects of age, race and chronic kidney disease (CKD). The cumulative CSS was estimated taking death as a competing risk. Results: The overall prevalence of investigated autoimmune diseases among the 172,061 patients with prostate cancer was 23.74%. The most common autoimmune diseases identified were rheumatoid arthritis (RA) (20.93%), psoriasis (2.43%) and ulcerative colitis (UC) (0.91%). In stage IV prostate cancer, OS (p = 0.018) and CSS (p < 0.001) were significantly higher in patients with autoimmune disease, with a median OS of 55 months compared to 48 months in patients without autoimmune disease. After adjusting for the effects of age, race, and CKD, autoimmune disease was still predictive of higher OS (HR: 1.41, 95% CI: 1.33 – 1.5, p < 0.0001) and CSS (HR: 1.30, 95% CI: 1.21 – 1.39, p < 0.0001). Patients with autoimmune disease and stage II and III prostate cancer had lower OS (p values < 0.0001) compared to patients without autoimmune disease. Conclusions: The study showed higher prevalence of RA, Crohn disease, UC, and systemic lupus erythematosus in patients with prostate cancer compared to cohorts of similar age ranges in the general population. History of autoimmune disease predicted significantly higher OS and CSS in patients with stage IV prostate cancer even when age, race and CKD were controlled for. It is possible that an improvement in OS with a history of autoimmune disease was evident in stage IV but not in stages II and III because anti-tumor autoimmune activity plays a larger role when prostate cancer effects regional lymph nodes or has distant metastases.
Racial differences in genomic profiling of prostate cancer at the durham veterans affairs medical center.
Authors: Labriola Matthew , Bitting Rhonda L. 
Published: June 2022

e17002 Background: Black men are underrepresented in precision oncology studies. Mahal et al. found that black men with metastatic PCa who had genomic profiling (GP) more commonly had mutations in DNA damage repair (DDR) and actionable genes, although only 8.5% of men in the study were black. [i] Here, we examine racial differences in GP in men with PCa at the Durham Veterans Affairs Medical Center (DVAMC). Methods: Men with PCa who had GP completed by Foundation Medicine at DVAMC from 2/2019-2/2022 were included. Reports were analyzed for mutations of interest. Biopsy site and patient demographics were extracted on chart review. Results: 155 men had GP at the DVAMC during the study period. Importantly 88 (57%) men were black and 67 (43%) were white. Sequencing was performed on the primary tumor (n = 80, 52%), metastatic site (n = 25, 16%), or circulating tumor (ct) DNA (n = 50, 32%). GP was performed on both tissue and ctDNA in 8% of patients, 58% had concordant findings. Racial differences in actionable mutations, DDR mutations, and mutations approved for PARP inhibitor use are noted in Table. The most commonly altered gene is TP53 (n = 59), more prevalent in black men (n = 36, 61%). ATM mutations are more common in black men, 10/14 (71%), however 85% of these are identified on ctDNA and n = 5 had an allele fraction of < 1% suggestive of clonal hematopoiesis of indeterminate potential (CHIP). In contrast, 8/9 (89%) of PIK3CA mutations and 25/36 (69%) of TMPRSS fusions were found in white men. Conclusions: Black men comprised a majority of the patients with PCa who had GP at the DVAMC. We found no statistically significant differences between black and white men in incidence of actionable mutations, DDR mutations, or mutations approved for PARP inhibitor use. PIK3CA alterations and TMPRSS fusions are enriched in white men, consistent with published literature, however, ATM and TP53 mutations are enriched in black men, discordant with findings from Mahal et al,raising the possibility that GP in veterans differs due to environmental exposures. ATM mutations are predominantly found in ctDNA, which may represent CHIP. Expansion of the above analysis could offer insight into racial differences in tumor biology.[Table: see text]
Early discontinuation of abiraterone acetate/prednisone (AA/P) in localized prostate cancer.
Authors: Asif Samia , Schissel Makayla , Teply Benjamin A. 
Published: June 2022

e17003 Background: Data from STAMPEDE trial supporting systemic therapy intensification with long course AA/P was first presented in 2017. Overall survival benefit was confirmed in 2021. Our institution proceeded with early adoption of addition of 24 months of AA/P to ADT and radiotherapy (RT) in patients with high-risk localized or regional prostate cancer in 2017. In STAMPEDE, only 17% patients discontinued AA/P prior to completion of planned course. Outside of a clinical trial, whether patients adhere to this intense combination therapy that is associated with toxicities and expense is unknown. We hypothesized that adherence to long course AA/P in real-world practice in definitively treated prostate cancer would be poor. Methods: We performed a retrospective study for patients with clinically localized prostate cancer treated with AA/P combined with standard ADT and RT who had at least 6 months of follow-up data. Primary endpoint was rate of early discontinuation (prior to the 24mo) of AA/P. Secondary outcomes included rates of RT completion and disease recurrence and toxicity of intensive therapy. Reasons for early discontinuation were analyzed. Fisher's Exact, Chi-square analysis and Mann-Whitney tests were used to compare variables. SAS 9.4 was used for statistical analysis. Results: We identified 77 patients who met inclusion criteria, including 2 (2%) with high-risk, 30 (39%) with very high-risk, 19 (25%) with regional risk and 26 (34%) with locally recurrent disease after prostatectomy. AA/P was discontinued in 29 (38%) patients prior to completion of 24mo. Among those with early discontinuation, median duration of AA/P was 12.1 mo [0.1-21.7] and median duration of ADT was 17 mo[3.5-32.2]. Common reasons for early AA/P discontinuation included refractory hypokalemia (n = 4), diarrhea (n = 3), heart failure and fluid retention (n = 2 each) and quality of life deterioration (n = 8). Other reasons included hepatotoxicity, arrhythmia, osteoporotic fracture and financial toxicity (n = 1 each). All patients completed definitive RT. Only 1 of 77 patients had disease recurrence and had discontinued AA/P after 14 mo. A statistically significant association between age at diagnosis and treatment completion was noted(p = 0.01); each 1-year increase in age was associated with 9.4% decrease in odds of completing AA/P. Median age at diagnosis in those completing vs not completing AA/P was 65 vs 71 years. Conclusions: Very high rates of early discontinuation of AA/P were observed among patients with localized prostate cancer receiving definitive RT. Patients were less tolerant of toxicity in adjuvant setting compared to in a clinical trial or advanced disease. Shorter durations of AA/P appeared more acceptable but whether similar benefit is derived with a truncated course of AA/P is unknown. Future studies need to explore an optimal duration of AA/P that will reduce toxicity without compromising survival benefit.
Oncologic outcomes of primary retroperitoneal lymph node dissection (RPLND) for stage II seminoma: Indiana University experience.
Authors: Tachibana Isamu , Alabd Andre , Piroozi Alex , Mahmoud Mohammad , Kern Sean , Tong Yan , Masterson Timothy A. , Adra Nabil , Foster Richard , Hanna Nasser H. , Einhorn Lawrence H. , Cary Clint 
Published: June 2022

e17012 Background: Stage II seminoma is typically treated with radiotherapy or chemotherapy based on NCCN guidelines. Primary RPLND has demonstrated efficacy as first-line therapy for retroperitoneal (RP)-only disease. Our aim was to study recurrences of patients undergoing primary RPLND for Stage IIa or IIb seminoma to identify clinicopathologic factors affecting outcomes. Methods: Using our prospectively maintained database, we identified patients that had primary RPLND for seminoma from 2014-2021. All patients had at least 6 months of follow up. Patients were clinical stage IIa or IIb at the time of surgery and underwent open RPLND. We used Kaplan-Meier analysis for recurrence free survival (RFS) and compared clinicopathologic factors. Results: We identified 67 patients that underwent RPLND for RP only seminoma. Table shows the clinical characteristics of patients experiencing recurrences (median follow up - 22.4 months) and excludes 2 patients that had adjuvant chemotherapy. The 2-year RFS rate was 80.2%. Eleven patients (16.4%) experienced recurrences. Kaplan Meier analysis demonstrated improved survival in patients that had an RPLND after 12 months of surveillance (p = 0.02). Fifty-six patients were presumably cured with surgery alone at time of last follow-up. No patients died of testis cancer. One patient had a recurrence within the surgical field. Two patients had contralateral recurrences that may have been cured with bilateral RP template dissection. Seven patients that had a bilateral template dissection had disease on the contralateral side, of which 4 patients had visible nodes on pre-operative scans. In total, 9 out of 67 patients had disease on the contralateral side suggesting that bilateral RP template could confer higher cure rates. Recurrences were successfully treated with BEPx3 (9 pts), Redo RPLND then BEPx3 (1 pt), BEPx3 then High Dose chemotherapy (1 pt), and EPx4 (1 pt). Conclusions: Primary RPLND for low volume RP disease is effective with over 80% chance of surgical cure. Recurrences were cured almost exclusively with induction chemotherapy. Patients with delayed RP only recurrences had improved surgical success. Further investigation in larger trials may help standardize bilateral templates in seminoma and surveillance protocols in the post-operative setting. [Table: see text]
Phase II study of disulfiram (D) and cisplatin (P) in refractory germ cell tumors (GCTs).
Authors: Mego Michal , Svetlovska Daniela , Schmidtova Silvia , Kalavska Katarina , Obertova Jana , Palacka Patrik , De Angelis Valentina , Lesko Peter , Orszaghova Zuzana , Rejlekova Katarina , Reckova Maria , Sycova-Mila Zuzana , Mardiak Jozef , Chovanec Michal , Kucerova Lucia 
Published: June 2022

e17013 Background: Multiple relapsed/refractory GCTs patients have extremely poor prognosis, therefore, new treatment strategies are warranted. Previously, we showed, that cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory germ cell cancer. Methods: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. All patients were pretreated with at least 2 cisplatin-based therapies (median 4, range 2 – 7); 6 tumors (50.0%) were absolutely refractory to cisplatin and 9 patients (75.0%) had visceral non-pulmonary metastases. Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in the this report. Results: Median age was 36 years (range: 29 – 48 years). Median number of treatment cycles was 2 (range 1 – 6). During a median follow-up period of 3.1 months (range: 1.3 – 13.9), all (100%) patients experienced disease progression and died. None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival (PFS) was 1.4 months, 95% CI (0.7 – 1.5 months), and median overall survival (OS) was 2.9 months 95% CI (1.5 – 4.7 months). Disease stabilization for at least 6 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. Conclusions: This study failed to achieve its primary end point and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory germ cell tumors. Clinical trial information: NCT03950830.
Genomic landscape and homologous recombination repair (HRR) genes analysis in Chinese prostate cancer (PCa) patients.
Authors: Liu Jianhua , Lu Jiantang , Wang Jian , Hu Yuan , Li Binbin , Zhong Xuefeng , Huang Mengli 
Published: June 2022

e17020 Background: HRR gene mutations have been proven to be effective biomarkers for PARP inhibitor (PARPi) therapy in metastatic castration resistant PCa. The epidemiological data of genomic variation and the characteristic of HRR gene alterations in Chinese population is still insufficient. Methods: Tumor tissue samples (including surgical and biopsy samples) and blood samples from 250 pathologically confirmed PCa patients were collected and analyzed using next generation sequencing (733-gene panel). Tumor mutation burden (TMB) was defined as total number of somatic non-synonymous mutations in coding region. Homologous recombination deficiency (HRD) was evaluated by the sum of the loss of heterozygosity, telomeric allelic imbalance and large-scale state transition. Somatic or germline alterations (including copy number reduction, CNV-loss) of HRR pathway genes were classified as HRR-altered positive. Results: In total, the top three alteration frequency somatic genes were FOXA1 (24.9%), TP53 (15.2%) and MYC (13.6%) while the top three alteration frequency germline genes were DPYD (17.1%), UGT1A1 (13.2%) and SLX4 (4.3%). In HRR pathway genes, the top three alteration frequency somatic genes were CDK12 (9.7%), ATM (4.7%) and BRCA2 (3.9%) while the top three alteration frequency germline genes were BRCA2 (3.1%), PALB2 (1.9%) and BRCA1 (1.6%). 25.6% (64/250) cases carried HRR gene alterations. Among HRR-altered positive cases with HRD score, only 8.9% (4/45) carried more than one HRR gene alteration and most carried a single HRR gene alteration (40.0% [18/45] in CDK12, 17.8% [8/45] in ATM or BRCA2, 11.1% [5/45] in BRCA1 and 2.2% [1/45] in PALB2 or FANCA). 61 HRR gene alterations were detected in these 45 cases and the commonly alteration types of HRR genes were single base substitution (47.5%, 29/61). The alteration type of CNV-loss (14.8%, 9/61) was only detected in somatic samples. The HRD score of HRR-altered group was significantly higher than wild group (median HRD socre, altered-type vs. wild-type = 23.5 vs. 19.0, P= 0.0097). And there was no significant difference in HRD score between CNV-loss and other alteration types. Moveover, the TMB level of HRR-altered group tended to be higher than wild group (median TMB, altered-type vs. wild-type = 4.5 vs. 2.8 Muts/Mb, P= 0.5). Conclusions: The results illustrated the molecular characteristics of HRR gene in Chinese PCa and indicated that HRR gene alterations (including CNV-loss) were associated with higher HRD score. These data provide further evidence for the clinical management of PARPi personalized therapy.
Effectiveness and durability of benefit of mTOR inhibitors (mTORi) in a real-world cohort of metastatic prostate cancer (mPCA) patients with PI3K pathway alterations.
Authors: Eule Corbin , Flaig Thomas W. , Wong Katy Ann , Graf Ryon , Lam Elaine T. 
Published: June 2022

e17034 Background: Alterations in the PTEN/PI3K/AKT/mTOR pathway are prevalent in prostate cancer, as frequent as 41% by prospective comprehensive genomic profiling (CGP) (PMID: 31218271). The use of mTORi in unselected patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) has limited efficacy in inducing a PSA response or clinical response. In this retrospective study, we evaluated the clinical effectiveness of mTORi specifically in mPCA pts with tissue assessed PI3K pathway alterations. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine mPCA clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (̃800 sites of care). We evaluated treatment data for pts with mPCA from October 2014 to February 2020 and selected all pts who received mTORi therapy. Unique patients who received mTORi therapy were included if they had PI3K pathway alteration by tissue CGP. Demographic and clinical data were extracted and analyzed for PSA response and time to next treatment (TTNT) on mTORi therapy. Results: In a cohort of 2301 mPCA pts with 7208 evaluable treatment lines in the database, there were 20 pts who underwent mTORi treatment. After excluding 1 pt who had liquid CGP and 2 pts who did not have PI3K pathway alterations, we included 17 mPCA pts with tissue assessed PI3K pathway alterations who received mTORi treatment. Pts had a median age of 72y (IQR 68.0, 76.0) and were heavily pretreated (11 pts, 64.7% on 4th- or later-line therapy). Two pts (11.8%) were treated in first-line metastatic hormone-sensitive prostate cancer (mHSPC) setting and the remaining 15 pts (88.2%) had mCRPC. All 15 mCRPC pts received prior novel hormone therapy (NHT), and 10 pts (58.8%) were previously treated with a taxane. The PI3K pathway alterations included PTENdel (10 pts, 58.8%), AKT1mut (4 pts, 23.5%), PTENmut (2 pts, 11.8%), and dual PTENmut and PIK3CAmut (1 pt, 5.9%). Most (15 pts, 88.2%) were treated with everolimus (EVE) monotherapy; 1 pt received EVE + abiraterone (EVE/ABI); 1 pt had EVE + docetaxel (EVE/DOC). The median pre-treatment PSA (14 pts available) was 148.9 ng/dL (range 1.16, 3430). Among 10 pts with on treatment PSA available, 3 pts had PSA decrease at ̃ week 12 (range -0.1%, -44.0%) and 5 patients had PSA decrease overall. Only 1 pt (with PTEN homozygous deletion) had a PSA response with nadir -95.1% and TTNT of 7.5 months (mo). The median TTNT was 3.62 mo (range 0, 8.52). Interestingly, the ABI/EVE pt had PSA nadir -17.2% and TTNT 2.0 mo; the EVE/DOC pt had nadir of -21.9% and TTNT 7.5 mo. Conclusions: The clinical use of mTORi in patients with prostate cancer is low overall. In this small cohort of mPCA pts with tissue assessed PI3K pathway alterations, mTORi therapy was not effective with few PSA responses and short duration of therapy.
High exosomal PD-L1 expression in relation to lymph node progression in metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (abi) or enzalutamide (enza).
Authors: Conteduca Vincenza , Del Re Marzia , Scarpi Emanuela , Crucitta Stefania , Gurioli Giorgia , Restante Giuliana , Cucchiara Federico , Lolli Cristian , Brighi Nicole , Schepisi Giuseppe , Casadei Chiara , Ulivi Paola , Beltran Himisha , Danesi Romano , De Giorgi Ugo 
Published: June 2022

e17038 Background: Programmed death-ligand 1 (PD-L1) has been recently found in tumor-derived exosomes and associated with progressive disease (PD) ( Poggio, Cell 2019). In localized prostate cancer, PD-L1 tumor expression has been shown to be a biomarker for node-positive patients (pts) ( Petitprez, Eur Urol Focus 2019) but its role in mCRPC is largely unexplored. We aimed to determine the potential of PD-L1 exosomal expression to predict lymph nodal PD in mCRPC receiving abi or enza. Methods: In a biomarker prospective study (REC 2192/2013), exosomes were isolated from plasma samples collected before first-line therapy with abi/enza between December 2014 and October 2018. RNA was extracted for analysis of PD-L1 by digital droplet PCR ( Del Re, Prostate Cancer Prostatic Dis 2021). Results: In our cohort of 55 node-positive mCRPC pts (median age: 76 years, range 47-89), the amount of exosomal PD-L1 expression (pts dichotomized in “high” and “low” as below or above median PD-L1/ACTB ratio = 0.0052) was associated with radiographic response after the first 3 months abi/enza therapy [high PD-L1 vs low PD-L1: 8 (25.8%) vs 0 (0%) PD, 23 (74.2%) vs 18 (75%) stable disease, and 0 vs 6 (25%) partial/complete response] (p = 0.0009). We observed an overall median progression-free survival (PFS) of 14.3 months [95% confidence interval (CI) 8.6-not reached] shorter in high PD-L1 compared to low PD-L1 10.6 (6.5-23.4) vs not reached [hazard ratio (HR) 3.1 (95% CI 1.1-8.5), p = 0.023]. In multivariable analysis including exosomal PD-L1 and androgen receptor (AR) variant 7, AR copy number gain detected in plasma, neutrophil lymphocyte ratio (NLR), lactate dehydrogenase, exosomal PD-L1; AR-V7 and AR gain were independent predictors of nodal PFS (HR 5.8, 95% CI 1.4-24.2, p = 0.01, HR 3.2, 95% CI 1.1-9.2, p = 0.03 and HR 12.9, 95% CI 2.3-73.2, p = 0.004), whereas AR-V7, AR gain, NLR > 3 were independent predictors of OS (HR 4.9, 95% CI 1.8-13.1, p = 0.001, HR 4.4, 95% CI 1.1-17, p = 0.02, and HR 3.2 95% CI 1.1-9.4, p = 0.03, respectively). Moreover, a trend of a worse OS was reported in high PD-L1 compared to low PD-L1 pts (HR 2.6, 95% CI 0.9-7.5, p = 0.07). Conclusions: In mCRPC pts treated with ARSI, exosomal PD-L1 expression may be considered as a predictive biomarker of lymph nodal response, playing a potential role in individualized disease monitoring and treatment combining between ARSI and immunotherapy. Larger evaluation of treatment decisions based on exosomal PD-L1 expression is now required.