bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
Platinum-based chemotherapy in patients with castration-resistant prostate cancer and hepatic metastases.
Authors: Von Amsberg Gunhild , Lunger Lukas , Darr Christopher , Strewinsky Nadja , Busenbender Tobias , Kaune Moritz , Tennstedt Pierre , Steinhelfer Lisa , Retz Margitta , Sauer Markus , Karimzadeh Amir , Bartel Timo , Herrmann Ken , Hadaschik Boris A. , Grünwald Viktor , Fendler Wolfgang P. 
Published: June 2023

e17063 Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and hepatic metastases face a dismal prognosis. In fact, the majority of phase 3 trials show no benefit of novel treatment modalities including Lutetium PSMA radioligand therapy (LuPSMA-RLT) in comparison with standard therapies for the subgroup of visceral metastases. In aggressive variant prostate cancer, the addition of platinum resulted in a clinically relevant improvement of progression free survival (PFS) and overall survival (OS). Whether adding platinum is also beneficial in unselected mCRPC patients with hepatic metastasis is unclear. Methods: We retrospectively analyzed mCRPC patients diagnosed with hepatic metastasis and treated with platinum-based chemotherapy or LuPSMA-RLT in three German centers (Hamburg, Essen, Munich). Patients with pure neuroendocrine prostate cancer were excluded. Survival rates and 95% confidence intervals (CI) were compared using the Kaplan Meier method and the logRank test. Results: A total of 84 mCRPC patients with hepatic metastasis who had received at least one platinum-based therapy and 32 patients treated with LuPSMA-RLT were evaluated. Median age at treatment initiation was 67 and 73 years. Patients had undergone a median of three treatment lines (83% ≥ 1 new hormonal agent (NHA); 87% ≥ 1 taxane based chemotherapy) before initiation of platinum based chemotherapy and a median of 4 treatment lines before LuPSMA-RLT. Median time to initiation of 1st platinum-based chemotherapy after diagnosis of liver metastases was 55 days. In total, 37% received carboplatin/cabazitaxel, 26% cisplatin or carboplatin/ etoposide, 11% carboplatin/docetaxel, and 26% other platinum-based combination therapies. In the platinum-treated group, 52.6% and 27% of the patients did not show progression at 3 and 6 months after treatment initiation as compared to 44.1% and 19.3% of the patients who received LuPSMA-RLT with a median PFS of 3.1 and 2.4 months, respectively. At 6 months 71.3% of the platinum-treated patients and 56.6% of the LuPSMA-RLT were alive. Overall, BRCA1/2 status was available for 53 of the platinum-treated patients, 15% of whom had a pathogenic alteration in either gene. This small subgroup was found to have a similar OS compared to the overall cohort. Conclusions: Platinum-based chemotherapy showed promising activity in mCRPC patients with hepatic metastasis. Given the high unmet medical need, platinum-based combination therapies should be further evaluated prospectively. [Table: see text]
Androgen receptor–specific CD8+ T cells with tumor cell cytotoxicity in patients with prostate cancer in Taiwan.
Authors: Huang Wilson , Lin Tzu-Ping , Huang William J. , Wu Chia-Jen 
Published: June 2023

e17069 Background: Classical androgen receptor (AR) target is the new “tumor-specific” antigen for prostate cancer vaccine development to delay progression and castration-resistant disease. HLA-A2-restricted AR ligand-binding domain (LBD) has been demonstrated to stimulate cytotoxic T lymphocytes (CTL) in HLA-A2+ prostate cancer patients. Although the prevalence of HLA-A2 serotype and LBD-specific CD8+ T cells among Caucasians are known, their frequencies in the Taiwan patients have not been established. In this study, we performed HLA-A2 genotyping, HLA-A2+ LNCaP stimulation of autologous T cell, and CTL tumor cell cytotoxicity from 25 castration-sensitive prostate cancer patients using blood samples collected from a single hospital center. Methods: 20ml whole blood samples are collected in EDTA tube from non-metastatic, castration-sensitive prostate cancer patients. PBMCs are subjected to HLA-A2 allele sequencing, separated by CD3 magnetic bead column, and expanded and activated ex vivo using CD3/CD8 polymeric beads. Autologous T cells are then isolated by CD8 magnetic bead column, stimulated by HLA-A2+ lentivirus-transduced LNCaP (AR+), and targeted against transduced (HLA-A2+) and non-transduced (HLA-A2-) LNCaP (AR+) by Chromium-51 Release Assay. We identified and correlated their frequencies with patient’s age at diagnosis, Gleason grades, PSA level, and family history. Results: A total of 25 blood samples were tested and analyzed for HLA-A2 genotype with 44% (11/25) positive for the HLA-A2 [28% (7/25) heterozygotes, 16% (4/25) homozygotes]. Among the 11 HLA-A2+ patients, 72% (8/11) were HLA-A*02:07 allele, 100% (11/11) CD8+ T cells were successfully stimulated with HLA-A2+ transduced LNCaP (AR+) and 45% (5/11) patients demonstrated HLA-A2+ AR-specific CTL tumor cell lysis. No clinical association with patient age (54-86 y.o.), Gleason grades (6-9), PSA level (3.84-62.8 ng/ml), and family history (1/25). Conclusions: In this single hospital center study, we observed a similar prevalence of HLA-A2 alleles in Taiwan prostate cancer patient cohort with a predominant HLA-A2*02:07 allele, and higher frequencies of HLA-A2-restricted CD8+ T cell stimulation and HLA-A2+ AR-specific tumor cell cytotoxicity. Our findings support the application of AR LBD as tumor antigen for prostate cancer vaccine development for Taiwan prostate cancer patients.
Efficacy of bi-weekly docetaxel in hormone-sensitive metastatic prostate cancer (mHSPC).
Authors: Lombana Quinonez Milton Alberto , Torres Ana Milena , Gonzalez Guido 
Published: June 2023

e17070 Background: In pts with mHSPC, docetaxel in a three-week schedule is associated with better overall survival (OS) vs androgen suppression alone, principally in pts with high tumor volume(HV). In pts with mCRPC stage, biweekly docetaxel demonstrated greater efficacy and a better toxicity profile. There are few published data about the use of bi-weekly docetaxel in pts with mHSPC. Methods: Pts with mHSPC and treated with bi-weekly docetaxel from January 2014 to December 2020 at The Comprehensive Cancer Center Clinica de Occidente in Cali-Colombia, were retrospectively identified. We collected relevant variables from electronic medical records. Our primary objective was to determine the efficacy in OS and the incidence of febrile neutropenia (FN). We performed Kaplan Meier, and cox regression analysis with relevant variables. Results: 69 pts were included, with a mean follow-up time of 45 months. Median age was 72y, 82% had ECOG PS 0/1, 74% grade group 4-5, 23% visceral metastases, and 93% de novo metastatic disease. The median OS was 51 months, and 39% at 5 years. In HV and de novo metastatic pts, the median OS was 49 months. The median time to development of mCRPC was 34 months. 35% of the patients had a PSA < 0.2ng/mL at month 6. In the univariate analysis, pts with HV (HR 10.49 95% CI 1.43-76.50, P = 0.0005), PSA > 0.2ng/mL (HR 4.43 95% CI 2.09-9.41, P = 0.0000), imagen objective response rate (ORR) (HR 1.47 95% CI 1.09-1.95, P = 0.0156) and PS ECOG > 0, (HR 3.3 CI95% 1.31-8.45, P = 0.003) had worse OS. Neither histologic grade 5 (HR 1.07, P = 0.8), visceral metastases (HR 1.2, P = 0.57), or de novo metastatic disease (HR 0.84, P = 0.74) were significantly associated. In the multivariate analysis, only PSA of > 0.2ng/mL at 6 months remained significantly [Table 1]. FN was detected in 3.2% of patients. Conclusions: We report the study with the largest number of patients and follow-up time (median 42.5 months) in patients with mCSPC who used biweekly docetaxel in addition to standard androgen suppression. The outcomes are similar, indirectly compared, to those reported in the CHAARTED study in OS, specifically in the de novo high-volume metastatic subgroup (CHAARTED 48 months, current study 49 months), better time to CRPC (20 months CHAARTED, 34 months current study), and with a lower incidence of FN (6% CHAARTED, 2% current study). None of the pts used primary granulocyte colony-stimulating factor prophylaxis. The use of biweekly docetaxel in this scenario offers high efficacy with less toxicity. Randomized studies are strongly recommended to confirm these results. [Table: see text]
Additional cycles of docetaxel in combination with androgen deprivation therapy (D-ADT) in metastatic hormone-sensitive prostate cancer (mHSPC): Efficacy and feasibility analysis.
Authors: Aydogdu Can , Urban Florian , Tamalunas Alexander , Berg Elena , Götz Melanie , Rodler Severin , Unterrainer Lena , Heinemann Volker , Stief Christian G. , Casuscelli Jozefina 
Published: June 2023

e17074 Background: Several phase III trials have assessed efficacy and safety of 6 cycles of docetaxel combined to androgen deprivation therapy (D-ADT) in metastatic hormone-sensitive prostate cancer (mHSPC). This is the current standard of care for a subgroup of patients. We aimed to assess whether treatment beyond 6 cycles of docetaxel prove to be more effective than the standard of care. Methods: We retrospectively collected data from patients with histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease treated at a large tertiary care center. All patients with mHSPC were treated in first-line with D-ADT (75 mg/m2) intravenously on the first day of each 21-day cycle. A subset of patients was treated beyond the standard of 6 cycles. Clinical and pathological variables were examined, as were treatment-related toxicities; progression free survival on D-ADT (PFS1), progression free survival on subsequent therapy (PFS2) and overall survival (OS) were calculated from start of treatment to progression or death by log-rank test. Results: Between 2015-2023 a total of 108 mHSPC patients were treated and observed for a median time of 13.8 months. Mean age was 66.2 years (range 46.9-82.7), and 75.0% had GS≥8, 65.7% a CHAARTED high-volume and 69.4% LATITUDE high risk disease. 72 pts. were treated with ≤ 6 cycles (D-ADTstand) (4.2% 1-2 cycles; 95.8 % ≥3 cycles; mean 5.2 cycles) and 36 were treated with > 6 cycles docetaxel (D-ADTadd) (27.8% 7-8 cycles; 72.2% ≥9-10 cycles, mean 9.2 cycles). Frequency of toxicities did not differ in the groups. No significant differences were observed in median PFS1 (10.3 vs. 13.4 mos.) and PFS2 (6.3 vs. 6.6 mos.). Median OS in the D-ADTstand group was 39.8 mos., median OS in the D-ADTadd group was not yet reached. Conclusions: While more than 6 cycles of D-ADT in mHSPC proved to be feasible without significant additional toxicity, efficacy is not superior compared to the standard of 6 cycles. Overall survival data is not mature yet, but the benefit of more chemotherapy upfront is debatable and leverages further studies in light of the upcoming triplet combinations in mHSPC, that presumably will render doublet D-ADT obsolete in future. [Table: see text]
Prognosis stratification by a mutational signature in metastatic prostate cancer.
Authors: Zhang Gejun , Liu Huanhuan , Qin Jiayue , Cao Shanbo 
Published: June 2023

e17079 Background: Metastatic prostate cancer (mPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis. Classification of patients with similar mutation profiles may help identifying subgroups of patients outcomes. However, classification based on somatic mutations is challenging due to the sparseness and heterogeneity of the data. Methods: A retrospective study was performed to identify the prognosis-related somatic mutations of mPC in 453 MSK-IMPACT, 1945 MSK-MET and 93 The Cancer Genome Atlas (TCGA) database. Cox regression were performed to screen out prognostic genes. Results: In the MSK-IMPAC cohort, a total of 35 genes were related with overall survival (OS). We selected genes mutated in at least 4 patients, leaving 6 genes (APC, ZFHX3, NCOR1, ASXL2, ARID1A, JAK1genes). We then recruited this mutation and formed a total number of 6-gene signature. Compared with the wildtype group, the OS of mutated signature was markedly lower, with p = 0.033. Similarly, the mutated signature harbored a lower OS than that in the wildtype group in the MSK-MET cohort (p = 0.001). In mutated signature cohorts, the five most frequently mutated genes were APC(45%), TP53 (42%), ZFHX3 27%), FOXA1(14%), and PTEN (13%). Dissimilarly, the five most frequently mutated genes were TP53 (43%), FOXA1 (10%), PTEN (9%), SPOP (7%), and CDK12 (7%) in wildtype cohorts. Furthermore, patients with mutated signature had higher WNT pathway (47.5% vs 14.8%), PI3K pathway (38.8% vs 12.0%), and NOTCH pathway (19.42% vs 6.0%) than those in the patients without mutated signature. Conclusions: These data underline the potential value of using somatic mutations to accurately stratify mPC patients into clinically actionable subgroups.
Real-world baseline characteristics and first-line (1L) treatment (Tx) in patients (pts) with de novo metastatic castration-sensitive prostate cancer (mCSPC) by disease volume.
Authors: Freedland Stephen J. , Hong Agnes , El-Chaar Nader N. , De Hoedt Amanda Marie , Kim Janet , Ramaswamy Krishnan , Gu Lin , Polascik Thomas 
Published: June 2023

e17081 Background: Intensification of androgen deprivation therapy (ADT) using novel hormonal therapies (NHT) has been established as a new standard of care for pts with mCSPC. Tx intensification still remains suboptimal, and data in de novo mCSPC pts is limited. Moreover, prior studies utilized claims data and so could not assess the impact of disease burden on Tx intensification. This study assessed baseline characteristics and 1L Tx patterns in pts with high-volume (HV) vs low-volume (LV) de novo mCSPC. Methods: This retrospective study used the Veterans Affairs Informatics and Computing Infrastructure to identify adult men who had ≥1 ICD code for prostate cancer and de novo mCSPC diagnosed between February 2018 and June 2020 confirmed by clinical chart review and initiated either ADT alone, ADT + first-generation non-steroidal anti-androgens [NSAA], or ADT+NHT. Index date was defined as ADT initiation date. The volume of disease was defined as HV or LV per the CHAARTED trial criteria (presence of visceral metastasis and/or ≥4 bone metastases, with ≥1 metastasis beyond the pelvis and vertebral column). Clinical data was hand abstracted from the medical record. Baseline characteristics and 1L Tx were analyzed descriptively. Results: Of the 380 de novo mCSPC pts reviewed, 57% had HV and 43% had LV disease. Mean age of pts was similar between HV and LV cohorts, 74.5 vs 75.2 years, respectively. In addition, the proportion of Black vs White pts in the HV and LV cohorts was similar, 34% and 35% were Black, and 66% and 65% were White, respectively. At index date, HV pts had higher median prostate-specific antigen (153.1 ng/mL vs 73.8 ng/mL) and alkaline phosphatase (192.0 IU/L vs 106.0 IU/L) vs LV pts. HV pts were less likely to have diabetes and cardiovascular comorbidities than LV pts (Table); however, the distribution of Charlson Comorbidity Index score was similar between cohorts (mean [SD]: 4.4 [3.1] vs 4.2 [3.1]). Among the pts with bone metastases only, HV pts had higher proportion (65%) of “too numerous to count” bone metastases vs LV pts (9%). While ADT+NHT use was slightly more common among HV pts (35%) vs LV pts (27%), in both HV and LV cohorts, ADT±NSAA was the most common 1L Tx (Table). The median 1L Tx duration was shorter in the HV pts compared with the LV pts (286 vs 358 days). Conclusions: The results showed that Tx intensification was underutilized in de novo mCSPC pts, even among those with HV, pointing toward an unmet need among pts with de novo mCSPC regardless of disease burden. [Table: see text]
Survival of de novo metastatic hormone sensitive prostate cancer in US Veterans based on treatment and PSA at diagnosis.
Authors: Babar Arslan , Montgomery Robert Bruce , Riekhof Forest , Etzioni Ruth Douglas , Al masalmeh Nada , Knoche Eric Marshall , Sanfilippo Kristen Marie , Schoen Martin W. 
Published: June 2023

e17091 Background: Combinations of androgen deprivation therapy (ADT) plus docetaxel (DOC) or androgen signaling agents (ASIs) (i.e. abiraterone, enzalutamide) improve survival in de novo metastatic hormone sensitive prostate cancer (mHSPC). In several trials, the benefit of combination therapy is greatest in patients with a high volume of disease. We sought to study the treatment and survival of US of veterans with mHSPC and stratify by PSA level at diagnosis during a time when different types of combination therapy was available. Methods: Veterans from 2018-2021 were identified with a pathologic diagnosis of prostate cancer with SEER stage ‘distant’. All veterans had ADT initiated within 1 month prior and 4 months after diagnosis. Combination therapy was determined if DOC or an ASI was initiated from 1 month prior to 4 months after ADT. Highest PSA level within 3 months of diagnosis was collected and patients with a PSA of ≥100ng/mL were included in PSA≥100. To avoid immortal time bias, all veterans had to survive 4 months after biopsy to be included. Baseline differences were compared using ANOVA and log-rank testing was used for time to event analyses. Results: 2,227 patients with de novo mHSPC were identified with mean age of 74.0 years (yrs), and 575 (25.8%) identified as Black race. From 2018 to 2021, ADT alone was used in 1,157 (52.0%) of veterans, DOC in 189 (8.4%) and ASIs in 881 (39.6%). Veterans treated with DOC were significantly younger (median 67.7 yrs, p < 0.001) compared to veterans treated with ASIs (72.9 yrs) or ADT alone (75.8 yrs). Veterans treated with combination therapies had longer median OS of 40.9 months (mos) compared to 32.9 mos for ADT alone (p < 0.001) with no difference within the combination treatment groups (p = 0.63). There was a trend for veterans with PSA≥100 to receive combination therapy (50.0% vs. 46.0%, p = 0.058). For 1,071 veterans with PSA≥100, median OS of veterans treated with combination therapy (n = 536, 37.4 mos) was longer than ADT alone (n = 535, 27.5 mos, p < 0.001). There was no differences in DOC combination treatment (n = 100, 37.9 mos) and ASI (n = 436, 36.6 mos) treatment groups (p = 0.37). Veterans with PSA≥100 had shorter OS compared to PSA < 100 (31.2 vs. 42.5 mos, p < 0.001). Conclusions: In veterans with de novo mHSPC, initial combination therapy was associated with longer survival than ADT alone. There were no differences in survival between DOC and ASI combinations observed in the entire population nor in veterans with PSA≥100. Further studies including tumor genetics or response to treatment may help guide treatment in mHSPC. [Table: see text]