bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating ether lipids in prostate cancer.
Authors: Horvath Lisa , Lin Hui-Ming , Huynh Kevin , Meikle Thomas , Joshua Anthony M. , Azad Arun , Tan Winston , Butler Lisa , Meikle Peter
Published: June 2023

e17009

Background: Decreased circulating levels of ether lipids (glycerophospholipids with an ether-linked fatty alcohol, e.g. plasmalogens) have been observed in obesity, diabetes and cardiovascular disease. In vitro and in vivo studies suggest that ether lipids are anti-inflammatory and protective against obesity. A recent landmark study revealed that ether lipids can kill cancer cells through ferroptosis. However, the role of ether lipids in prostate cancer has not been thoroughly investigated despite the known association of dysregulated lipid metabolism with poorer clinical outcomes. The aim of this study was to assess the relationship between the circulating profiles of ether lipids and clinical outcomes in localised and metastatic prostate cancer. Methods: The profiles of ~150 ether lipids (8 lipid classes) in plasma lipidomic data from localised prostate cancer (389 men in Australia) and metastatic castration-resistant prostate cancer (mCRPC)(2 cohorts –147 men in USA, 128 men in Australia) were analysed for associations with disease progression or overall survival (OS). Open-access genomic data of mCRPC tumours (108 men, CbioPortal) were analysed for aberrations in genes associated with ether lipid metabolism in relation to clinical outcome. Results: Previously in these study cohorts, we had identified men with poorer prognosis based on their plasma lipidome and our validated sphingolipid signature. These men with poorer prognosis have lower plasma levels of ether lipids than those with better prognosis (t-test p < 0.05, localised disease – 110 ether lipids, mCRPC – 54 ether lipids). Decreased plasma levels of up to 46 ether lipid species were associated with higher rates of clinical relapse in localised disease (hazard ratio (HR) range 0.37-0.73, p-value range 0.006-0.049), shorter radiological progression-free survival in mCRPC (HR range 0.35-0.73, p-value range 0.00009-0.049), and shorter OS in mCRPC (HR range 0.33-0.79, p-value range 0.000004-0.0497). Chromosomal loss of tumour GNPAT, an essential gene in ether lipid synthesis, was associated with shorter OS in mCRPC (HR = 1.36, 95% CI 1.02-1.81, p = 0.03). Conclusions: Lower circulating levels of ether lipids were associated with worse prognosis in localised and metastatic prostate cancer, suggesting that these lipids are protective against disease progression. Further research is required to understand the role of ether lipids in disease progression, and to determine if modulation of ether lipid levels through supplementation is beneficial.
The clinical value of homologous recombination deficiency score in prostate cancer.
Authors: Wang Yan , Qu Min , Dong Zhenyang , Hao Qing , Lin Guomin , Song Jinyi , Gao Xu
Published: June 2023

e17011

Background: Aberrations in homologous recombination repair (HRR) genes serve as biomarkers for guiding the treatment decision of PARP inhibitors in prostate cancer (PCa). Homologous recombination deficiency (HRD) score which directly shows the consequence of the loss of HRR function (genomic scars) may be a more reliable biomarker for identifying patients who are sensitive to PARP inhibitors. Methods: This study involved 50 patients with PCa, including mHSPC (n = 37), mCRPC (n = 11), and locally advanced PCa (n = 2). Tumor tissue specimens were collected for targeted next-generation sequencing for 406 cancer-related genes and HRD detection. HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. All the experiments were performed in OrigiMed, a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Results: The median HRD score was 34.5 (ranged from 14 to 64). With the median value as cutoff, the mutation rates of HRR were 32% (8/25) and 12% (3/25) in the high and low HRD score groups, respectively. BRCA2 mutations (P = 0.011), AR mutations (P = 0.032), RB1 mutations (P = 0.035) and altered HRR pathway (P = 0.017) were associated with high HRD scores. The mutation frequencies of AR and TP53 were significantly higher in mCRPC compared to mHSPC ( AR: 45.5% [5/11] vs 2.7% [1/37], P < 0.001; TP53: 63.6% [7/11] vs 24.3% [9/37], P = 0.027). A total of 9 patients carried HRR germline mutations (5 BRCA2, 1 BRIP1, 1 RAD50, 1 RAD51D, and 1 ATM). It was found that patients with BRCA2 germline mutations had a higher HRD score (median = 37) than those with other germline mutations ( BRIP1: 25, RAD50: 19, RAD51D: 35, ATM: 36). In the 6 patients who received HRD-related treatments (including cisplatin based chemotherapy or olaparib), 1 of the 2 patients with low HRD score had PSA progression after 251 days (the other one was lost to follow up), while no PSA progression was observed in the 4 patients with high HRD score with a median follow-up of 107 days (range: 40-274 days). A mCRPC case with high HRD score (37) and HRR wild-type who received second line docetaxel+cisplatin even achieved undetectable PSA. Another mHSPC patient with a high HRD score (37) and a BRCA2 germline mutation also had no detectable PSA after first-line docetaxel+cisplatin therapy. Conclusions: To our knowledge, this is the first study in China reporting the association of HRD score and platinum-based treatments in PCa. Our results supported the possibility that HRD score could be predictive for the efficacy of platinum-based chemotherapy.
X-linked inhibitor of apoptosis protein (XIAP) expression level analyzed by immunohistochemistry (IHC) as it relates to clinical and pathologic characteristics in prostate cancer.
Authors: Beckerman Jennifer Kate , Valburg Claire , Subrahmanyam Ramesh , Nava Victor , Zara Rozalen Alexandra , Diao Guoqing , Liu Shanshan , Antonio Martha , Jain Maneesh Rajiv
Published: June 2023

e17012

Background: XIAP acts in both the extrinsic and intrinsic apoptotic pathways as an inhibitor of cell death, protecting cells from a range of triggers. Regulation due to apoptosis resistance may represent a targetable factor for therapeutic intervention in prostate cancer. This study focuses on XIAP as a biomarker and its expression in correlation with disease aggression. Methods: Expression levels of XIAP was analyzed by immunohistochemistry (IHC), graded 1 through 3 according to signal intensity, in radical prostatectomy samples from 90 patients with prostate cancer with a range of phenotypes including: indolent (A), locally advanced (B), progressive to metastatic (C) and de novo metastatic (D). Prognostic data was collected and Fisher’s exact statistical analysis was performed. Secondary analyses included a Fisher’s exact test with a pairwise comparison between individual disease grades and Gleason scores. Results: Higher XIAP protein expression levels on IHC correlated with disease grade and with total Gleason score (p = 0.0008 and p = 0.0002 respectively) by Fisher’s exact test analysis, indicating more aggressive disease phenotypes. Secondary results looked at a pairwise Fisher’s exact analysis comparing XIAP expression levels among disease grades (A-D) and Gleason scores. XIAP expression only significantly differed between those with grade A and D as well as between individuals with grades B and D (measured by Bonferroni-adjusted p-value of 0.003 and 0.018 respectively). Statistical significance was also achieved in XIAP expression levels when comparing among Gleason scores 6 and 8 (p = 0.025), 6 and 9 (p = 0.0125), as well as 7 and 9 (p = 0.030). Conclusions: This study demonstrates a correlation between XIAP expression levels by IHC and aggressiveness of disease, demonstrating clinical significance of XIAP as a prostate cancer biomarker. [Table: see text]
Total and anatomically contextualized quantitative 18F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression free survival in patients with prostate cancer.
Authors: Song Hong , Sjöstrand Karl , Duan Heying , Ferri Valentina , Mari Aparici Carina , Davidzon Guido , Franc Benjamin Lewis , Moradi Farshad , Anand Aseem , Iagaru Andrei
Published: June 2023

e17015

Background: PSMA PET has been widely adopted in restaging of prostate cancer at biochemical recurrence. We assess the clinical utility of quantitative parameters on 18F-DCFPyL PET/CT at biochemical recurrence and their association with the subsequent biochemical progression free survival (bPFS). Methods: This is a retrospective image analysis and longitudinal follow up of a prospective study evaluating 18F-DCFPyL PET in prostate cancer patients with biochemical recurrence after primary definitive treatment at Stanford Hospital. The 18F-DCFPyL PET images were quantitatively analyzed automatically by the aPROMISE application, a semi-automated analysis and structured reporting of PSMA PET/CT. aPROMISE uses deep learning to segment detailed anatomical information from the CT images and uses this information in combination with the PET image to detect and quantify candidates for prostate cancer lesions. The reader works in tandem with the software to vet the final list of lesions, from which the quantitative assessments and final report is created automatically. Based on the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. SUVmean, PSMA positive total tumor volume (PSMAttv) and aPSMA scores, a quantitative score for tumor burden measuring the interaction of tumor volume and uptake stratified by local tumors (aPSMA-miT), regional lymph nodes (aPSMA-miN) and distant metastases (aPSMA-miMa for extrapelvic metastases, miMb for bone metastases and miMc for other organ metastases) were obtained based on the miTNM classification. The association of these quantitative parameters with the subsequent bPFS was evaluated. Results: 134 patients (age 70.1 ± 7.6, range 51 -91 years; PSA 13.9 ± 98.5, range 0.12 – 1126 ng/mL) were included in the quantitative image analysis. aPROMISE detected nodal and/or bone metastases in 94 of 134 patients (70%) and only 12 of 134 patients (9%) had visceral disease. With median follow up of 37 months, 66 of 134 patients (49%) have progressed again biochemically after treatment. The bPSF was 25.8 ± 15.1 months. Quantitative analysis of 18F-DCFPyL PET found that the subsequent bPFS is significantly associated with aPSMA-miMb ( P < 0.001), PSMAttv ( P < 0.001), aPSMA-miN ( P < 0.01), aPSMA-miMa ( P < 0.05) but not with SUVmean or aPSMA-miMc. Conclusions: Total and anatomically contextualized quantitative image analysis of 18F-DCFPyL PET/CT at biochemical recurrence may be useful in predicting the subsequent bPFS. Studies in larger patient cohort is necessary to validate these findings. Given many patients were treated based on lesions found on 18F-DCFPyL PET/CT, clinical implication of this findings remains to be elucidated.
Analysis of androgen receptor dynamics through immunofluorescent staining of circulating tumor cells in castration-resistant prostate cancer.
Authors: Barnett Ethan , Gupta Santosh , Erazo Tatiana , Lam Ernest , Carbone Emily , Zanone Michelle , Nystrom Lucy , Gajar Ria N , Wenstrup Rick , Scher Howard I.
Published: June 2023

e17021

Background: Prostate adenocarcinomas are initially dependent on the androgen receptor (AR) for growth and proliferation. Androgen synthesis inhibitors and AR antagonists are the most commonly used first line treatments in metastatic prostate cancer, but these agents are not curative and virtually all tumors progress to a castration resistant state often associated with AR amplification (ARamp) and overexpression. Small molecule AR degraders designed to overcome ARamp/overexpression and other AR alterations associated with resistance are now in clinical development. In parallel, it is important to identify and validate biomarkers that predict sensitivity and inform treatment selection. Methods: CTC samples collected at progression from 114 men with metastatic castration resistant prostate cancer were stained for CK, DAPI, CD45, and AR. AR cRatio (ratio between a cell’s immunofluorescent [IF] intensity and the median IF intensity across all cells) was quantified for each CTC. Low-pass whole genome sequencing (lpWGS) was performed on candidate CK-positive (CK+) CTCs to generate copy number profiles. Cohen’s kappa was used to evaluate the relationship between AR copy number and IF at the single cell level. Dynamics in high AR expressing (ARhigh) CTCs were analyzed separately in a longitudinal cohort of patients (n = 18) from whom CTCs were collected at baseline, early on-treatment (4-12 weeks), and at progression on their 1st AR signaling inhibitor (1L-ARSI). Results: lpWGS was performed on 726 CK+ CTCs, of which 23% (170) were ARamp and 27% (195) were ARhigh (AR cRatio ≥ 3). Fifty-six percent (96/170) of CTCs with ARamp were ARhigh. Overall, a fair agreement was observed between AR copy number and IF (76.1% agreement; k = 0.37, 95%CI = 0.29 – 0.44). At baseline prior to 1L-ARSI, the median CK+ CTC burden was 7.9 CTC/mL (IQR: 1.3 – 10.5). One or more ARhigh CTC was detected in 28% (5/18) of patients, but no patient had more than 0.7 ARhigh CTCs per mL of blood. ARhigh CTCs were not observed in early on-treatment samples. At progression, the median CTC burden was 2.3 CTC/mL (IQR: 0.9 – 9.45) and, despite lower CTC burden, the emergence of a substantial (≥1 CTC/mL) ARhigh CTC subpopulation was observed in 17% (3/18) of patients. In samples with ≥1 detected CTC, the mean AR cRatio was 1.106 and 1.777 at baseline and progression, respectively. Conclusions: AR protein can be measured in CTCs with IF staining and is supported by the agreement with data from lpWGS. ARhigh CTC subpopulations can be detected at baseline for 1L-ARSI, but these cells were all cleared from circulation after 4-12 weeks of therapy. In a subset of patients at progression, resistance appears at least partially attributable to selection for ARhigh CTC subclones. [Table: see text]
Awareness of testicular cancer and testicular self-examination in young adults, and the efficacy of education-based media.
Authors: Walt Aaron M. , Levy Micah , Chin Chih Peng , Liaw Bobby Chi-Hung , Palese Michael
Published: June 2023

e17022

Background: The prevalence of testicular cancer in adolescents and young adults creates a unique opportunity for education through social media. We investigated this populations’ baseline knowledge of testicular cancer (TC) and testicular self-examination (TSE) and identified the efficacy of various forms of media in educating young individuals. Methods: A survey was designed to assess participants’ baseline knowledge of TC and TSE. Participants were randomly shown one of three forms of educational media created by the Testicular Cancer Society and the National Cancer Institute. These were an infographic, a short (60 second) and a long (6 minute) video. Participants were then asked to correctly identify facts regarding TC and TSE. Baseline knowledge was analyzed by age (< 24 vs. > 25), and post-media knowledge was analyzed to determine the efficacy of each media form. Results: Responses from 328 participants were analyzed, with a mean age of 24.3 years, 40.9% male, 72.0% white, and 70.7% graduated college or a graduate program. Only 30.7% of participants reported being educated about TC, 25.9% correctly identified the 15-35 age group as having the highest prevalence of TC, and 26.3% correctly identified the TC survival rate as being 75-100%. The > 25-year-old group were significantly more likely to have heard of TSE (p < 0.001), performed a TSE if male (p = 0.043), encouraged males to perform TSE if female (p < 0.001) and correctly identify TC survival rate (p = 0.006) and treatability (p = 0.007). Long video viewers were significantly less likely to watch it in its entirety compared to infographic and short video viewers, and they were less likely to report an understanding of TSE compared to infographic viewers. Short video viewers were less likely to have properly identified the TC survival rate compared to both infographic (P < 0.001) and long video viewers (p = 0.001). Conclusions: Overall there is poor awareness and education regarding TC and TSE, with adolescents performing significantly worse than young adults. The infographic performed the best overall in completion and education about TC and TSE, with the short video performing similarly well, and the long video performing the worst. This suggests that easily dispersed and viewable forms of media may be the most effective tool for educating young people.[Table: see text]
Germline thrombophilia gene alterations and thrombosis rates among patients with advanced germ cell tumors treated with chemotherapy.
Authors: Brown Landon Carter , Robinson Myra M. , McCormack Michael Joseph , Steuerwald Nury , Symanowski James Thomas , Bose Rupali , Neelands Brittany , Akinyelu Tobi , Livasy Chad , Li Wencheng , Haynes Nathanael C. , Grigg Claud , Raghavan Derek , Clark Peter E , Patel Jai Narendra , Burgess Earle F
Published: June 2023

e17023

Background: Men with advanced germ cell tumors (GCT) treated with cisplatin-based chemotherapy are at high risk of venous thromboembolism (VTE). Validated predictors of VTE would allow development of targeted prophylactic anticoagulation strategies in this population. We hypothesized that a high genomic risk score from a previously identified panel of germline single nucleotide polymorphisms (SNPs) in thrombophilia genes would be associated with an increased risk of VTE within 6 months of chemotherapy initiation for GCT. Methods: Men with stage IIA or higher GCT who received 3-4 cycles of cisplatin-based chemotherapy were identified at two centers with available tissue for germline sequencing. High genomic risk was defined as having 4 or more risk alleles from an established 5 SNP germline panel composed of ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914). Univariable and multivariable logistic regression were used to evaluate the impact of genomic risk on VTE incidence within six months of chemotherapy initiation. Results: 123 patients were identified with 72% having non-seminoma histology and 28% categorized as IGCCCG intermediate or poor risk. The VTE rate was 26% (32/123), and the incidence of high genomic risk was 21% (26/123). Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5 – 3.5, p = 0.54). A multivariable model identified Khorana score, N3 status and elevated LDH as predictors for VTE (Table). The association between high genomic risk and VTE strengthened when adjusting for clinical variables, but remained non-significant, adjusted OR 2.1 (95% CI 0.7 – 6.5, p = 0.18). The optimal threshold to define high genomic risk in this cohort was 3 or more risk alleles, adjusted OR 2.5 (95% CI 0.9 – 6.8, p = 0.08). ABO (non-O blood type) was the only individual SNP significantly associated with VTE (p < 0.01). Conclusions: In this multi-institutional cohort, a previously established germline thrombophilia panel was not clearly associated with increased VTE risk among patients with GCT receiving chemotherapy. Khorana score, elevated LDH, clinical nodal stage, and non-O blood type were the strongest predictors of VTE. Exploratory analysis of the association between VTE risk and 76 additional SNPs is ongoing. Prospective studies of prophylactic anticoagulation are warranted in high-risk patients with advanced GCT undergoing chemotherapy.[Table: see text]
Clinical outcomes in patients with post-chemotherapy residual non-retroperitoneal (RP) disease in non-seminomatous germ-cell tumors (NSGCT).
Authors: King Jennifer , Ashkar Ryan , Kesler Kenneth , Althouse Sandra K. , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: June 2023

e17027

Background: In patients (pts) with metastatic NSGCT, the presence of teratoma in the primary tumor specimen or in the post-chemo RP lymph node dissection (RPLND) has previously been shown to have no impact on prognosis. We report clinical outcomes of pts based on pathology in primary tumor and from post-chemotherapy non-RP disease surgical resection. Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with metastatic NSGCT treated between 1990-2021 who completed first-line chemotherapy and had residual extra-RP disease in the absence of residual RP disease. Pts who had post-chemo non-RP surgical resection were included. Kaplan-meier methods were used to analyze progression-free survival (PFS) and overall survival (OS). Results: 131 pts met eligibility. Median age at diagnosis was 28.6 (range, 16.2-51.5). Primary site was testis in 130 pts (99%). Primary tumor predominant histology was embryonal (34.4%), mixed (26%), choriocarcinoma (14.5%), teratoma (11.5%), yolk sac (10.7%), seminoma (1.5%). Metastatic sites at diagnosis were lung (27.5%), brain (19.8%), RP (14.5%), liver (8.4%), mediastinal LN (7.6%), bone (7.6%). All pts with RP mets at diagnosis had normalization of RP nodes after chemo. All pts had surgical resection of non-RP disease. None had RPLND. IGCCCG risk was good in 56, intermediate in 23, and poor in 52 pts. Median pre-chemo AFP was 66.7 (0.9-467,000). hCG was 692 (0.5-500,000). First-line chemo was BEPX4 in 68, BEPX3 in 29, EPX4 in 10, VIPX4 in 8, and other in 16 pts. 76 pts (58%) had teratoma in the primary tumor. Median follow-up was 3.16yrs. 2-yr PFS for pts with teratoma in primary was 59% (95% CI 45-71) vs. 54% for pts without (95% CI 38-67); p = 0.42. 2-yr OS for pts with teratoma in primary was 85% (95% CI 73-92) vs. 70% for pts without (95% CI 54-81); p = 0.18. 2-yr PFS and OS based on pathology and location of non-RP site are listed in Table 1. Conclusions: The presence of teratoma in primary tumor and post-chemotherapy non-RP resections is not associated with worse PFS or OS in pts with metastatic NSGCT. [Table: see text]
Chemotherapy induced peripheral neuropathy (CIPN) and biomarkers of gut microbial translocation in long-term survivors of testicular germ cell tumors.
Authors: Chovanec Michal , Kalavska Katarina , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , De Angelis Valentina , Orszaghova Zuzana , Lesko Peter , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Vlkova Barbora , Pastorek Michal , Celec Peter , Mego Michal
Published: June 2023

e17032

Background: Survivors of testicular germ cell tumors (GCT) may suffer from long-term treatment induced peripheral neuropathy. We hypothesized markers of gut microbial translocation after chemotherapy and/or radiotherapy may be contributing factors of peripheral neuropathy. Methods: GCT survivors (N = 194) from National Cancer Institute of Slovakia completed the EORTC QLQ Chemotherapy-Induced Peripheral Neuropathy (CIPN20) questionnaires during their annual follow-up visit at 10-year median (range 2-25). Biomarkers of gut microbial translocaion and dysbiosis (GMT) lipopolysaccharide (LPS), high mobility group box-1 (HMGB-1), d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Upon obtaining the scores from questionnaires per recommended guidelines, each score was correlated with biomarkers of GMT scored as as high or low (above and below median). Survivors were treated with orchiectomy only (N = 30), cisplatin-based chemotherapy (N = 135), radiotherapy to the retroperitoneum (N = 14) or both chemotherapy and radiotherapy (N = 10). Results: GCT survivors with higher vs lower plasma levels of HMGB-1 had worse overall CIPN20 score (median ± SD = 18 229.0 ± 13 644.2 vs 17 387.0 ± 5106.6 p = 0.048). Patients with higher vs lower plasma HMGB-1 also had worse motor function (9.0 ± 1.8 vs 8.0 ± 2.3, p = 0.036). Sensory and autonomy subscales of CIPN20 qestionaire did not show significant association with HMGB-1 (both P > 0.05). There was no significant difference in CIPN20 symptom burden associated with LPS, d-lactate and sCD14 (all P > 0.05). Conclusions: HMGB-1 may serve as a promising biomarker of CIPN20 in long-term cancer survivors. Proinflammatory pathways are suggested as underlying mechanism of CIPN. Furhter research and larger patient cohorts are needed to explore the pathogenesis of CIPN in GCT survivors.
Analysis of hospitalizations of patients with penile cancer: A national population-based study.
Authors: Kanemo Philip Onyekaoso , Akhiwu Ted , Olafimihan Ayobami Gbenga , Edigin Ehizogie , Ijeli Anthonia , Ibrahim Muhammad Bilal , Aihie Osaigbokan , Castillo Dan Ran , Riaz Muhammad Nauman
Published: June 2023

e17033

Background: Penile cancer (PC) is a rare malignancy that is more common in developing countries. However, recent studies have shown rising incidence-based mortality in the United States (U.S). National population data is scarce on reasons for hospitalizations, epidemiology, and hospitalization outcomes of patients with PC. Methods: Data were abstracted from the National Inpatient Sample (NIS) 2020 Database. T≥his database is the largest collection of inpatient admission data in the U.S. It is a 20-percent stratified sample of all discharges from U.S. community hospitals, excluding rehabilitation and long-term acute care hospitals. The numbers in the databases are weighted to optimize national estimates. Hospitalizations for patients with PC were obtained by searching for hospitalizations that contained the International Classification of Diseases (ICD)-10 code “C60” as a principal or secondary diagnosis. The principal diagnosis is the main reason for the admission, while any other diagnosis other than the principal, are secondary diagnosis. The reason for hospitalization (or principal diagnosis) was recorded in descending order of frequency based on the ICD-10 code organ system category and specific principal diagnosis. The total number of PC discharges, baseline demographic characteristics, hospital length of stay (LOS), and total hospital charges were recorded. STATA 16 was used for analysis. Since NIS contains de-identified data, Institutional Review Board (IRB) review was waived. Results: There were 32 million discharges included in the 2020 NIS database. Of those, 2,785 hospitalizations were for patients aged ≥18 years, who had either a principal or secondary ICD 10 code for PC. Patients were predominantly white (65.9%), mean age of 66.5 years, inpatient mortality of 4.7%, mean LOS of 6.1 days, and mean total hospital charge of 71,447 U.S dollars. The 7 most common reasons for hospitalization by ICD 10 code categories were neoplasm and hematological (35.9%), nonspecific (17.3%), infections (12.6%), injury & poisoning (7.1%), cardiovascular (6.4%), and Genito-urinary (4.3%). The 5 most common specific principal diagnoses for hospitalizations were malignant neoplasm of the penis (29.1%), admission for chemotherapy (12.7%), sepsis (2.7%), Malignant neoplasm of the glans penis (2.2%), secondary neoplasm of inguinal and lower limb nodes (1.8%). Conclusions: Hospitalized PC patients are mostly elderly white men. Infections, chemotherapy, and PC were the most common reasons for hospitalizations. Optimal management of underlying malignancy, prevention, and prompt treatment of infections in the outpatient is important in reducing hospitalizations of these patients.
Luminal and basal subtyping of circulating tumor cells and influence on outcomes in patients with metastatic castration-resistant prostate cancer.
Authors: Wang Jasmine Jiemei , Kim Minhyung , Teng Pai-Chi , Jan Yu Jen , Chen Jie-Fu , Zhu Yazhen , You Sungyong , Tseng Hsian-Rong , Posadas Edwin Melencio
Published: June 2023

e17034

Background: Luminal and basal subtyping using PAM50 classifier and the prostate cancer classification system (PCS) have been shown to predict outcomes and treatment response in prostate cancer (PCa). However, these genomic classifiers rely on the acquisition of tumor samples, which are usually not available in patients with metastatic castration resistant PCa (mCRPC). Circulating tumor cells (CTC) are tumors cells shed into bloodstream and can serve as surrogates of tumor. In this study, we aimed to subtype circulating tumor cells with PAM50 and PCS classifiers and evaluate their prognostic performance in mCRPC patients. Methods: A CTC RNA assay was developed by combining NanoVelcro microfluidic system for enriching CTCs and Nanostring nCounter system for PAM50 and PCS profiling of CTCs. The PAM50 and PCS genes were refined through a bioinformatic pipeline to ensure the specific profiling of CTCs. The classification and prognostic performance of the refined CTC-PAM50 and CTC-PCS gene panels were validated in GenomeDx GRID database. For the clinical study, 50 blood samples from mCRPC patients before the initiation of androgen receptor signaling inhibitors (ARSI) (n = 34) or taxanes (n = 16) were analyzed with the CTC RNA assay. Kaplan-Meier analysis and log-rank test were used to evaluate the association between CTC-PAM50/PCS subtypes and survival. Results: The refined CTC-PAM50 (36 genes) and CTC-PCS (40 genes) classifiers retained their original classification and prognostic performance in the GenomeDx GRID cohort. In the clinical study, the CTC RNA assay classified the 50 mCRPC patients into luminal A (n = 14), luminal B (n = 22), and basal (n = 14) by CTC-PAM50 classifier; and PCS1 (n = 5), PCS2 (n = 24), and PCS3 (n = 21) by CTC-PCS classifier. Overall, patients assigned as PCS1 subtype had shorter overall survival than other subtypes (hazard ratio [HR] = 4.8). In addition, basal or PCS1 subtype showed worse biochemical progression free survival than other subtypes (ARSI group: Basal: HR = 2.5; PCS1: HR = 6.9. Taxanes group: Basal: HR = 5.0; PCS1: HR = 7.2). Conclusions: Luminal and basal subtyping of CTCs is prognostic and provides a noninvasive method for molecular profiling mCRPC patients.
A phase Ib/II study of intermittent talazoparib plus temozolomide in patients with metastatic castration-resistant prostate cancer (mCRPC) and no mutations in DNA damage repair (DDR).
Authors: Autio Karen A. , Kyriakopoulos Christos , Xiao Han , Emamekhoo Hamid , Danila Daniel Costin , Devitt Michael Edward , Riedel Elyn , Jan Mehrin , Scher Howard I.
Published: June 2023

e17036

Background: Poly (ADP-ribose) polymerase (PARP) inhibition exhibits an enhanced cytotoxic effect in cancers with DDR alterations, but as monotherapy has little activity for those without DDR defects. A variety of combinatorial methods utilizing PARP inhibitors are under investigation to determine if a multimodal approach could benefit patients without DDR alterations. Supported by pre-clinical models, we hypothesized that the PARP inhibitor talazoparib in combination with the chemotherapy temozolomide could induce DNA damage leading to cell death and tumor response. Methods: This is a single arm Phase 1b/2 study of escalating doses of intermittent talazoparib (Day (D) 1-6) plus temozolomide (D2-8) in 28D cycles in patients with mCRPC without DDR mutations. Patients must have failed at least one androgen receptor signaling inhibitor and may have received chemotherapy in the hormone sensitive setting. Response is determined by a composite endpoint of overall response per RECIST v1.1, PSA50% decline, and CTC conversion from >1 to 0. Pharmacokinetic samples were collected, and the mTPI-2 method was used in escalation. Results: 13 patients were enrolled across 4 dose levels in escalation. The most common adverse events were anemia (any grade (Gr) 31%, Gr3 23%), thrombocytopenia (any Gr 54%, Gr3+ 30.7%), fatigue (Gr≤2, 62%), and nausea (Gr1 46%). There was one patient with a DLT (Gr3 neutropenic fever, Gr4 thrombocytopenia). The identified RP2D was talazoparib 1 mg (D1-6) and temozolomide 75mg/m2 (D2-8). 4 (30.8%) patients met the efficacy endpoint (3 CTC responses, 1 PR, 0 PSA50% decline). While there were no PSA50 responses, 2 (15.4%) patients had a PSA30% decline. Median duration on trial was 20 weeks with 4 (30.8%) patients on trial for ≥6mos, 2 of whom also met the efficacy endpoint. Conclusions: Hematologic toxicity was dose limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without DDR alterations. A reduction in CTCs to 0 was identified at several dose levels, and PSA30% declines were seen in 2 patients. With identification of the RP2D, enrollment in the Phase 2 study is currently underway. Clinical trial information: NCT04019327 .
Randomized placebo-controlled trial of intravenous vitamin C plus docetaxel in metastatic prostate cancer.
Authors: Paller Channing Judith , Zahurak Marianna , Heath Elisabeth I. , Kelly William Kevin , Hoimes Christopher J. , Taksey Jason David , Marshall Catherine Handy , Markowski Mark Christopher , Barata Pedro C. , Rudek Michelle A. , Nauroth Julie , Wang Lin , Durham Jennifer N. , Eisenberger Mario A. , Carducci Michael Anthony , Denmeade Samuel R. , Levine Mark
Published: June 2023

e17050

Background: Some phase I/II trials showed that combining high dose IV vitamin C with chemotherapies decreased toxicities and improved QoL in advanced cancers, while others failed to show benefits. While grade ¾ AEs are not typically a co-primary endpoint, they are a measure of cumulative toxicity. We investigated whether high-dose IV vitamin C could improve prostate-specific antigen (PSA) response rate and mitigate docetaxel toxicities in patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving docetaxel. Methods: Patients were randomized (2:1) to receive docetaxel (75mg/m2 IV every 3 weeks) plus IV vitamin C (1g/kg) or placebo twice a week. The primary endpoints were PSA50 response by24 weeks and adverse events (AEs) of fatigue, nausea, bone pain, and anorexia. Secondary endpoints included overall survival (OS) and QoL measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Results: 50 patients were randomized, 47 received therapy (treatment N = 32, control N = 15), 3 untreated (withdrawal, elevated creatine, low hemoglobin). The median age was 74 years (range 45-85) and ECOG 1. The median PSA was 108.3 ng/mL (range: 0.3, 2102.3). The median number of chemotherapy cycles was 6 (IQR 3-8). The study was suspended after the pre-specified interim analysis for primary endpoints showed futility. The PSA50 response was 41% for treatment and 33% for control (P = 0.44). Grade 1-2 and grade 3-4 prespecified AEs occurred in 69% and 6% of treatment group patients versus 60% and 0% of control group patients (one-sided Cochran Armitage test, P =0.90). Diarrhea (72% vs 19%) and anemia (47% vs 25%) and neutropenia (22% vs 19%) are more frequent in the Vit C group. Compared with the control group, treatment group patients showed a trend towards shorter median OS. FACT-P was not significantly different at any timepoints. Conclusions: Initial concurrent high-dose IV vitamin C with docetaxel did not improve PSA response, toxicity, or clinical outcomes. MCRPC patients receiving docetaxel should be advised against seeking concurrent high-dose IV vitamin C. Clinical trial information: NCT02516670 .
Understanding testing for and treatment of homologous recombination repair (HRR)-mutated metastatic castrate-resistant prostate cancer (mCRPC): A quality initiative by Integra Connect (IC) PrecisionQ.
Authors: Thomas Roby Antony , Gart Mike , Blanc Simon , Choksi Rushir J.
Published: June 2023

e17052

Background: In May of 2020, the approval of two Poly (ADP-ribose) polymerase inhibitors (PARPi) changed the landscape for treatment among patients (pts) with HRR mutations (HRRm) in mCRPC. The University of Pittsburgh Medical Center (UPMC) conducted a quality initiative (QI) with IC PrecisionQ to assess the rates of HRR testing, HRR positivity, and study the rates of PARPi use in HRRm patients with mCRPC. This QI included clinical interventions to optimize testing and treatment in these patients. We aim to show the improvement in HRR testing and rates of treatment with PARPi after implementation of the QI, in patients with HRRm mCRPC at UPMC. Methods: Using the de-identified IC PrecisionQ database, 223 UPMC pts with mCRPC were selected by medical chart curation as baseline group. Patients in the baseline group had received treatment between 5/1/2020 to 9/30/2021 that were confirmed as mCRPC. The baseline data was reviewed with UPMC clinical leadership, discussed among a physician roundtable, and HRR testing rates were shared among providers. Post-baseline, we evaluated 152 mCRPC pts who started a new line of therapy between 1/1/2022 to 12/31/2022 to assess HRR testing rates and use of PARPi in eligible mCRPC pts. The presence of one or more HRR genes was used to determine testing rates. Descriptive analyses were performed and a two-proportion z-test was used for comparisons of HRR testing in patients with mCRPC and treatment with a PARPi in HRRm mCRPC pts. Results: The average age at diagnosis was 67 years, 47% of patients had a Gleason score of > = 8, and 62% were stage IV. The rate of HRR testing at baseline was 52% (116 of 223). The results post baseline and intervention showed an increase in HRR testing to 69% (105 of 152) of mCRPC patients who started a new line of therapy in 2022 (p < 0.01). At baseline, 60% (21 of 35) of HRRm pts were treated with a PARPi after prior NHA treatment compared to 68% (19 of 28) post baseline and intervention (p > 0.05). Among all HRR mCRPC tested pts, there was a 30.9% (84/272) positivity rate, of which 11.4% were BRCA1/2 positive (30/262) and 10.5% were ATM positive (26/247). Not all patients tested for HRR were tested for all genes. Conclusions: This quality initiative to improve testing and identification of HRR mutations in patients with mCRPC led to a 33% relative increase in HRR testing. Quality initiative programs are critical to transforming cancer care and moving the field closer toward individualized, precision medicine.
Real-world genetic testing patterns in metastatic prostate cancer in Latin American (LATAM) population.
Authors: Angel Martin , Freile Berenice , Rodriguez Andres , Cayol Federico , Manneh Kopp Ray , Rioja Patricia , Losco Federico , Bernal Vaca Laura , Penaloza Jose Mauricio , Zapata Muñoz Maycos Leandro , Neciosup Silvia P. , Sade Juan Pablo
Published: June 2023

e17055

Background: Prostate cancer (PC) clinical course is variable. It was thought that BRCA1 and BRCA2 mutations were associated with only a small proportion of PC cases. However, recent genomic analysis has revealed that germline or somatic inactivating mutations in genes involved in the homologous recombination (HR) pathway of DNA repair collectively occur in as much as 20%-25% of advanced PC. Referring to the metastatic castration resistant PC (mCRPC) the somatic mutations were recently reported to be up to 12,7% for BRCA2 and 2% for BRCA1. PC is the most frequent tumor among LATAM men. The incidence of de novo metastatic PC is higher in LATAM than other parts of the world, and demographic changes in the region have increased disease burden. However, region-specific information about genomic profiling of this tumor is scant. This study aims to describe the genomic profile patterns of PC, either presenting as metastatic hormone treatment–naive prostate cancers, or locoregional tumors that later evolve to metastatic disease in LATAM pts. Methods: A retrospective observational cohort design was used. The study sample included patients with a confirmed PC diagnosis with adenocarcinoma histology, from 8 academic centers in 3 countries between 1st January 2020 and 30th November 2022 whom had been molecularly tested. Results: Of 185 pts tested, 183 had metastatic PC. Somatic evaluation was done in 49.5% of the pts, while 66.48% have germline test, 13% pts were tested by both methods. Forty-two (22.7%) pts were tested in the metastatic sensitive castration scenario, instead 141 (76.2%) were mCRPC. Actionable mutations were detected in 21 pts (11.35%), being the most frequents PTEN and BRCA2. The median tumor mutational burden was 5 (IQR 0-2.52). No mutation in the following clinically relevant genes were found in our pts: BRCA1, RAD51C, RAD51D, RAD54, PALB2 and BRIP1 (Table1). Between pts with actionable mutations, 27.3% had high volume disease, with a median Gleason score of 9 (IQR 8-9) and de novo metastatic setting in 40.9%. Despite that 25.9% of our pts have a VUS (Variant of unknown significance), only 7 pts (3.8%) access to oncology genomic counseling. Conclusions: In our region, the percentage of actionable mutations found in this population appears to be lower than that reported in studies from other regions of the world, but remarkably the mutations detected are different. This data shows the importance to have mutational data of the population of each region what is heterogeneous among themselves and with respect to other regions of the world. [Table: see text]
Efficacy of PARP inhibitors in patients with metastatic castration resistant prostate carcinoma: A meta-analysis of phase III randomized controlled trials.
Authors: Patel Rushin , Oyenuga Mosunmoluwa , Onyechi Afoma , Chitkara Akshit , Sartaj Sara , Mohamed Mohamed G , Patel Zalak , Patel Mrunal
Published: June 2023

e17060

Background: PARP inhibitors effectively treat several solid tumors, regardless of the presence of BRCA mutations. Patients with castration-resistant metastatic prostate cancer become refractory to androgen deprivation therapy. PARP inhibitors were recently approved for use in prostate cancer, and have opened new avenues in prostate cancer treatment research. Methods: We systematically searched multiple databases using pre-specified search terms. We included only phase III RCTs comparing PARP inhibitors versus standard of care in patients with castration-resistant biopsy-proven metastatic prostate cancer. The outcomes studied were radiologically guided progression-free survival (PFS) and overall survival (OS). We used a random effects model via RevMan 5.4 software for statistical analysis. Results: 3 phase III RCTs met the inclusion criteria with a total of 1606 patients (PARP inhibitors = 867 patients, standard of care = 739 patients). Compared to the standard of care, PARP inhibitors showed significantly higher PFS [HR = 0.62( 95% CI, 0.49-0.78) P < 0.0001]. There was no statistically significant difference in OS [HR = 0.85( 95% CI, 0.69-0.1.04) P = 0.11] between the two groups. Conclusions: The use of PARP inhibitors in patients with castration-resistant metastatic prostate cancer is associated with improved progression-free survival. No significant difference was observed in overall survival between the two groups. There is a need to study the cost-benefit analysis of using PARP inhibitors as they do not show any improvement in overall survival. [Table: see text]
Accuracy of a simplified sequencing and bioinformatics platform on genetic variant detection in patients with prostate cancer.
Authors: Kapoor Deepak A. , Anderson Ann E. , Anderson Jonathan
Published: June 2023

e17061

Background: Consensus guidelines suggest that genetic testing is clinically indicated for prostate cancer (PCa) patients who meet certain family history, stage and histopathological grade criteria. Current next generation sequencing (NGS) diagnostics rely on capital and maintenance intensive sequencers which require highly trained technical personnel to operate. This may restrict availability of testing where specimen transport or access to personnel/capital is limited. We sought to compare results obtained using a simpler sequencer coupled with a bioinformatics platform which requires minimal maintenance and capital cost with those from more traditional NGS equipment. Methods: We compared results in detection of 10 genes recommended by NCCN PCa guidelines (ATM, BRCA1, BRCA2, CHEK2, MLH1, MSH2, MSH6, PALB2, PSM2, and HOXB13) between the Oxford Nanopore Technologies MinION to the Illumina NextSeq sequencer. All samples were sequenced in a depth greater than 50x. Bioinformatics for the Illumina sequencer was performed using Illumina’s TruSight Hereditary Cancer panel. As the MinION reads long DNA fragments, and cancer diagnostics is focused on short exon sequencing, we used the CorrSeq Dx by Foresee Genomics to create long DNA molecules consisting of several tandem repeats of short DNA fragments separated by sequences recognized by automated bioinformatics software. Statistical analysis was performed using Cohen’s kappa test. This IRB-exempt study was conducted in accordance with the Declaration of Helsinki. Results: We detected using 380 variants in 13 patients on the Illumina platform and 379 (3 false negatives, 2 false positives) variants on the same patients using the MinION sequencer with CorrSeq Dx assay. The positive predictive value and sensitivity for the simplified platform was 99.5% (375/(375+2)) and 99.2% (375/(375+3)), respectively. The demonstrated accuracy of the simplified process was 99.9% (Cohen's kappa > 0.99). Conclusions: Thisl data suggests that a simpler sequencing solution with appropriate bioinformatics could allow clinical laboratories with limited technical and capital resources to perform germline and possibly somatic testing in-house; use of this technology may also serve to reduce costs for labs currently performing these tests. While some labs or clinics can outsource their NGS diagnostics if such commercial options are available, these options may not be possible where transport of specimens is logistically difficult or if access to technology is limited. A simpler process for NGS testing could improve access to guideline-based care in both remote and economically disadvantaged areas, resulting in better treatment outcomes as well as increased global healthcare equity. Further testing of this technology in prostate cancer as well as other disease states is warranted to fully understand its potential impact on patient care.