bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration analysis of single-cell multi-omics in the prostate cancer ecosystem.
Authors: Bian Xiaojie , Wang Wenfeng , Abudurexiti Mierxiati , Yao Zhu , Zhang Min , Ye Ding-Wei , Wang Jianhua 
Published: June 2023

e17046 Background: Prostate cancer (PCa) is characterized as a extensive heterogeneous disease with the complex cellular ecosystem in the tumor microenvironment (TME). However, the content of how heterogeneity is shaped by tumors and stromal cells or vice versa remains poorly understood. Methods: Single-cell RNA sequencing, spatial transcriptomics and bulk ATAC-sequence from a series of human PCa and normal control were integrated. Results: We identified a stemness subset of club cells marked with SOX9highARlow expression, which enriched significantly after neoadjuvant androgen-deprivation therapy (ADT). Furthermore, a subset of CD8+CXCR6+ T cell, functioned as effector T cell, was observed to be markedly reduced in the malignant PCa patients. Notably, immunosuppressive microenvironment in advanced PCa was associated with infiltration of regulatory T cells (Tregs), which is potentially induced by FAP+ fibroblasts (cancer-associated fibroblasts, CAFs subset). Moreover, for spatial transcriptome analysis, we comprehensively utilized machine learning and computational intelligence to identify cellular diversity of prostate and cell-cell communication with each other in situ.Importantly, we also depicted macrophage and neutrophil state transition under different biological conditions in vivo. Conclusions: We delineate the cellular heterogeneity in the stage-specific PCa microenvironment at single-cell resolution, uncover their reciprocal crosstalk with disease progression and these results will be helpful in exploring potential target for PCa therapy.
Phenotypic differences related to homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) treated in routine care settings in the United States (US).
Authors: Sillah Arthur , Adeboyeje Gboyega , Lee Liam , Gart Mike , Saunders William M. , Wang Brandon , Dave Poras , English Sandy , Blanc Simon 
Published: June 2023

e17047 Background: Recent evidence suggests mutations in HRR genes predict clinical benefit from treatment with PARP inhibitors in patients (pts) with mCRPC. Little is known about the prevalence, clinical and prognostic phenotypes associated with HRR-mutated (HRRm) mCRPC pts receiving routine oncology care in the US. We assessed HRRm positivity rate and described difference in phenotypic factors between HRRm+ and HRRm- mCRPC patients receiving routine care in community oncology settings. Methods: In this retrospective cohort study, we identified biologically male pts with mCRPC, ≥18 years, who received HRRm testing and on systemic anti-cancer treatment from 5/1, 2020 – 3/31, 2022, from the Integra Connect database, an electronic medical record (EMR) and claims database of US cancer pts in community oncology. We defined 2 cohorts based on their HRRm status (defined by the presence of an alteration in at least 1 of the following genes: BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). We described age and race (at diagnosis), cancer stage and Gleason score (at staging), and line of therapy (LOT), Eastern Cooperative Oncology Group (ECOG) performance status, prostate-specific antigen (PSA) values and microsatellite instability (MSI) status using values closest to mCRPC diagnosis. HRR tests were stratified by germline, ctDNA, and solid tumor. Results: The study cohort comprised 376 HRRm-tested pts: by ctDNA only – 29%, germline only – 16.2%, solid tissue only – 18.4% and > 2 testing types – 33.5%. 96 had HRRm+ mCRPC (25.5%). Median (IQR) age at diagnosis for both cohorts was 67 (43-89) years and there were no statistically significant differences in age, race, stage, Gleason score, PSA value, LOT or ECOG by HRRm status. HRRm+ rates by ctDNA, germline, and solid tissue testing were 26.6%, 13.1% and 21.7%, respectively. Of the 126 patients with > 2 testing types, HRRm+ rate was 30.9%. A higher, but not statistically significant, proportion of HRRm+ pts had Gleason scores 9-10 compared to HRRm- pts (54.8% vs 48.6%). Of HRRm- pts, 10.2% had MSI-H status compared to 6.5% in HRRm+ pts. Conclusions: In this real-world cohort of HRR gene-tested pts with mCRPC, we observed a 25.5% HRRm+ rate, which suggests the prevalence for HRR mutation is significant enough to warrant testing for all pts with mCRPC. Further research is needed to examine the impact of these findings on overall survival and other clinical outcomes.
Lu-PSMA-617 in combination with third-line therapy for castration-resistant prostate cancer: A systemic review and meta-analysis.
Authors: Akbar Usman Ali , Ali Fatima , Vikash Sindhu , Khalid Saad , Farooqui Sabeeh , Aman Aleena , Qazi Shaheryar , Muhibullah - , Qadeer Abdul , Rehman Mohammad Ebad Ur , Zubair Rameesha , Ashraf Muhammad Aizaz , Shabbir Muhammad Asad , Ahmed Muhammad Ihsan , Khalid Alina 
Published: June 2023

e17051 Background: Prostate cancer is the second most common cancer and the sixth leading cause of cancer death among men worldwide. Lu-177 viptriplet, also known as lutetium-177-PSMA-617, is a highly targeted form of radioligand therapy that aims to shrink prostate cancer tumors and slow their progression. It is also recommended as a treatment option by the American Society of Clinical Oncology (ASCO) for patients with prostate-specific membrane antigen (PSMA) positive PET/CT-positive castration resistant prostate cancer (CRPC) who have progressed on at least one prior line of androgen receptor pathway inhibitors (ARPI) and at least one prior line of chemotherapy. However, the evidence on its effectiveness with third-line chemotherapy is scarce. We aim to evaluate the efficacy of Luma-PSMA plus third-line chemotherapy in CRPC. Methods: We conducted a comprehensive literature search in PubMed, PMC, Scopus, and Embase using relevant keywords to identify articles related to Luma-PSMA and third line chemotherapy for prostate cancer from inception to Jan 30, 2023. Three independent reviewers screened the articles for eligibility and extracted data on outcomes such as overall survival (OS), PSA decline > 50%, and partial remission. We used Raveman 5 software to perform a statistical analysis and calculated the odds ratio with a 95% confidence interval for each outcome. Results: A total of 11 studies were included in our analysis with 787 patients. Pooled analysis of studies demonstrated an overall survival after Lu-PSMA-617 therapy plus third line chemotherapy as compared to standalone chemotherapy in castration resistant prostate cancer to be 13.15 months (95% CI = 10.66 – 15.65, P = < 0.001, I2= 69.93%). Pooled prevalence of prostate specific antigen (PSA) decline > 50% was determined to be 49.5% (95% CI = 44.2 – 54.7, P = 0.162 I2= 33.27%) and partial remission was observed in 39.7% patients (95% CI = 28.5 – 50.9, P = 0.952 I2= 0%). Conclusions: Our meta-analysis suggests that Lu-PSMA-617 therapy plus third-line chemotherapy may improve overall survival and PSA response in patients with CRPC compared to chemotherapy alone. However, the quality of evidence is limited by heterogeneity and risk of bias. More high-quality randomized trials are needed to confirm the efficacy and safety of this combination therapy. [Table: see text]
Use of poly (adp-ribose) polymerase inhibitors (PARPi) in metastatic castration resistant prostate cancer (mCRPC) patients stratified by homologous recombination repair mutations.
Authors: Thomas Roby Antony , Vasudevan Anupama , Blanc Simon , Choksi Rushir J. , English Sandy , Aton Lindsay , Tierno Marni Brisson , Gart Mike 
Published: June 2023

e17053 Background: Approval of the PARPi in May 2020 caused a paradigm shift in the treatment of mCRPC patients with homologous recombination repair (HRR) mutations. Gaps remain in the optimal prescribing of PARPi in eligible patients, with negative consequences on clinical outcomes. The goal of this study was to look at PARPi prescribing practices in patients with HRR mutations overall and by sub-mutation. Methods: The Integra Connect PQ-deidentified real-world database was used, comprising over 1 million cancer patients across 275 sites of care, of which 80% were community practices and 20% academic settings. We performed medical chart reviews and identified 261 patients with HRRm mCRPC that received therapy between 5/1/2020 to 1/24/2023. We segmented patients into BRCA-positive with or without other HRR mutations, ATM positive without BRCA mutations and with or without other HRR mutations, and other HRR mutations without BRCA or ATM mutations. We compared utilization of PARPi in HRRm patients by sub-group. Descriptive statistics were used to assess proportions of utilization of PARPi treatment among HRRm patients. Proportions were compared using the two-proportion z-test. Results: Among HRRm mCRPC patients with prior next-generation hormonal agent (NHA) treatment, the use of PARPi is 61% (158 of 261). Among HRRm mCRPC patients who received PARPi after prior NHA treatment, 76% (78 of 103) were in the BRCA positive group, 62% (48 of 78) in the ATM positive group and 40% (32 of 80) in the other HRR mutations positive group. Patients in the BRCA positive group were more likely to receive a PARPi than those in either the ATM or other HRR mutations group (p < 0.01). Patients harboring ATM mutations were more likely to receive a PARPi than patients with non-BRCA HRR mutations (p < 0.01). Conclusions: This real-world study shows an opportunity to increase rates of PARPi treatment in patients with HRRm mCRPC across all HRR gene mutations. mCRPC patients with BRCA and ATM mutations were more likely to receive PARPi than those with other HRR mutations.
The association between antibiotics administration and outcomes in men with chemotherapy-naive metastatic castration-resistant prostate cancer: Secondary analysis of two randomized clinical trials.
Authors: Ni Xudong , Wei Yu , Ye Ding-Wei , Zhu Yao 
Published: June 2023

e17054 Background: The associations of antibiotics with overall survival (OS) and radiographic progression-free survival (rPFS) in trials in chemotherapy-naive metastatic castration-resistant prostate cancer remain unclear. Methods: COU-AA-302 (NCT00887198, n = 1088) and ACIS (NCT02257736, n = 982) patients were stratified by antibiotics administration. Since there was evidence of a threshold phenomenon, the association of duration of antibiotics administration and OS was assessed using a segmented linear regression model. Kaplan–Meier survival analysis was used to compare OS and rPFS. Hazard ratios were calculated using a multivariable Cox proportional-hazard model. Results: Using segmented linear regression models, we selected ≥30 days as the threshold for antibiotics administration in clinical trials. In COU-AA-302 Abiraterone + Prednisone (AAP) subgroup, antibiotics administration was associated with prolonged OS (50.4 vs. 33.8 months, HR0.57, 95%CI 0.38–0.84, P = 0.004) and prolonged rPFS (27.7 vs. 12.8 months, P = 0.0095). In COU-AA-302 Placebo + Prednisone (PLA) subgroup, antibiotics administration was also associated with prolonged OS (50.4 vs. 29.0 months, HR0.41, 95%CI 0.26–0.63, P < 0.001) and prolonged rPFS (16.46 vs. 5.72 months, P < 0.001). Antibiotics administration also improved patients’ outcomes in ACIS. In ACIS Apalutamide + Abiraterone + Prednisolone (AAAP) subgroup, antibiotics administration was associated with prolonged OS (43.3 vs. 27.3 months, HR0.68, 95%CI 0.54–0.85, P < 0.001) and prolonged rPFS (30.5 vs. 18.2 months, P < 0.001). In ACIS Placebo + Abiraterone + Prednisolone (PAAP) subgroup, antibiotics administration was also associated with prolonged OS (45.4 vs. 30.2 months, HR0.62, 95%CI 0.50–0.78, P < 0.001) and prolonged rPFS (23.4 vs. 13.4 months, P < 0.001). Conclusions: Within the limitations of post-hoc sub-analyses, antibiotics administration is associated with prolonged OS and rPFS in men with chemotherapy-naive metastatic castration-resistant prostate cancer. Further pharmacological researches and prospective clinical trials are needed to increase the indications for these drugs to benefit prostate cancer patients.
Tolerability of lutetium-177–PSMA-617 in men with prostate cancer and baseline cytopenia.
Authors: Abdelrazek Ahmad S , Mahmoud Ahmed , Johnson Geoffrey , Johnson Derek R , Bach Corrie R , Orme Jacob , Rodrigo Rodrigues Pessoa , Nabavizadeh Reza , Thorpe Matthew , Kwon Eugene D. , Kendi Ayse T. , Childs Daniel S 
Published: June 2023

e17057 Background: Results from the VISION trial (NCT03511664) led to the approval of lutetium-177 (177Lu)–PSMA-617 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This trial excluded patients with baseline cytopenias, thus safety in this frequently encountered patient population is unknown. We aimed to use real-world data to describe the tolerability of radioligand therapy in those with poorer bone marrow reserve. Methods: We retrospectively reviewed the records of all patients, who received a first dose of 177Lu–PSMA-617 at Mayo Clinic in the interval of April 26, 2022, to December 1, 2022. Patients were categorized as having poor marrow reserve on the basis of pre-treatment hematologic parameters, including: (1) an anemia cohort with hemoglobin (Hg) less than 9 g/dL, (2) a thrombocytopenia cohort with platelets (Plt) less than 100 x 109/L, (3) a leukopenia cohort with white blood cell count (WBC) less than 2.5 x 109/L, and (4) a multiple cytopenia cohort. These were exclusionary parameters from the VISION trial. Longitudinal laboratory data and clinical outcomes were collected and analyzed using descriptive statistics. Results: At data cutoff, 185 patients had received one or more doses of 177Lu, including 26 (14%) with at least one baseline cytopenia prior to their first cycle of treatment. In total, there were 19 (73%) patients with anemia, 3 (12%) with thrombocytopenia, 2 (8%) with leukopenia, and 2 (8%) with multiple cytopenias at baseline. The median number of cycles received thus far is 3, including 14 (54%) who are still receiving therapy and 12 (46%) who have permanently discontinued treatment. Median longitudinal changes in blood counts for the anemia cohort are presented in Table 1. Reasons for treatment discontinuation include: toxicity (n = 2), disease progression (n = 5), death (n = 4), or other (n = 1). Dose reductions or treatment delays for worsening myelosuppression were utilized in 3 (12%) and 5 (19%) patients, respectively. Transfusions of packed red blood cells or platelets were required for 16 (62%) patients. A total of 6 (23%) received care in the emergency department or were hospitalized. Conclusions: Treatment discontinuation for toxicity was rare among men with mCRPC and baseline cytopenias, while receiving 177Lu; however, these patients have an overall poor prognosis. [Table: see text]
The expression of PKM1 and PKM2 in benign and cancerous prostatic tissues.
Authors: Li Lin , Cheng Siyuan , Yu Xiuping 
Published: June 2023

e17058 Background: Prostate cancer (PCa) is the most diagnosed cancers in American men. After androgen deprivation therapy (ADT) fails, there is an increase in the aggressive neuroendocrine (NE) phenotype. Currently, there is no effective treatment for NE prostate cancer (NEPC). The metabolic reprogramming, one of the cancer hallmarks, regulates PCa progression and therapy resistance. However, the energy metabolism in NEPC has not been well studied yet. Pyruvate kinase (PK), catalyzing the final step of glycolysis, has PKM1, PKM2, PKL and PKR four isoforms. PKL and PKR are expressed in the liver and erythrocytes, respectively. Alternative splicing of PKM results in two isoforms, PKM1 and PKM2, which are expressed in most tissues. In prostate adenocarcinoma, loss of PKM1 promotes PCa progression whereas loss of PKM2 suppresses tumor growth. However, the expression pattern of PKM1 and PKM2 in NEPCa remains largely unknown. Methods: Immunofluorescence (IF), immunohistochemistry (IHC), Western blot and RT-qPCR were conducted to examine the expression of PKM1 and PKM2 in both murine and human prostatic tissues. The bioinformatics analysis was done using the publicly available RNA-Seq data obtained from the cBioportal, the Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia websites (CCLE). Results: TRAMP is a widely used PCa mouse model. TRAMP mice develop prostatic intraepithelial neoplasia (PIN) and the tumors progress into NEPC following castration. We found that PKM1 expression was detected in normal prostate but not in the PIN lesions. In the TRAMP NEPC tumors, PKM1 expression was detected in the NE areas but not in the adjacent PIN lesions. Compared with the adjacent PIN, NEPC cells displayed lower PKM2 expression. Further, we examined the expression of PKM1 and PKM2 in human prostatic tissues including benign prostatic hyperplasia (BPH), low-grade adenocarcinomas (AdPCa), high-grade AdPCa, and NEPC. We found that in BPH, basal epithelial cells express both PKM1 and PKM2. In PCa, PKM1 was robustly expressed in the stromal cells but its expression was absent in the cancer cells in majority of the specimens examined except a small number of samples where low level of PKM1 was detected in the cancer cells. However, PKM1 expression was detected in 9 out of 12 NEPC samples and colocalized with NE marker chromogranin A. This co-expression was also detected in the NE cells scattered on the prostate adenocarcinoma tissues. As for PKM2, its expression was detected in all the samples examined. However, different from previous report, PKM2 expression levels did not correlate with cancer grade in this cohort. Conclusions: PKM1 is expressed in the basal epithelial cells of benign prostates, a small subset of prostate adenocarcinomas, and 75% NEPC tumors. PKM2 is expressed throughout prostate development, in both benign and cancerous prostate. However, PKM2 expression does not correlate with tumor grade.
Racial and income characteristics and the burden of illness among metastatic prostate cancer patients.
Authors: Poolakkad Sankaran Satheesh kumar , Epstein Joel Brian , Adjei Boakye Eric , Alam Naheed , Pili Roberto 
Published: June 2023

e17064 Background: The incidence of metastatic prostate cancer has increased dramatically between 2010 and 2017 in the United States. Since the racial and ethnic mix of the population of the United States (U.S.) have changed between the years 2010 and 2020–it is extremely important to understand its effects on prostate cancer outcomes. Therefore, we investigated the burden of illness across racial groups and income levels among patients diagnosed with metastatic prostate cancer. Methods: This study utilized the U.S. 2017 National Inpatient Sample database to identify hospitalizations with a primary diagnosis of prostate cancers. We evaluated associations between race and income levels, and the burden of illness (total charges and length of stay (LOS)) adjusting for patient and clinical factors with multivariable generalized linear models. Results: A total of 63,880 metastatic prostate cancer patients were included in the study, and the median [IQR] age was 74 [66, 82]. There were 65.6% Whites, 20.6% Blacks, 7.7% Hispanics, and 6.1% Asians and Others. Blacks had a higher prevalence in the age group 45-55 (34.2%), when compared to 55-64 (29.8%), or > 65 (17.6%) age group. There were only 10% Blacks and 4.9% Hispanics living in high-income neighborhoods, whereas this was 75.5% for Whites. In the adjusted analysis, compared to the Whites, Hispanics (1.43; 95%CI-1.29- 1.57), and Asians and Others (1.39; 95%CI- 1.25- 1.56) had a higher total charge; and compared to Whites, Blacks had a higher LOS (1.28; 95%CI-1.15-1.44). Compared to high-income neighborhoods, those living in the 26th to 50th percentile had a lower total charge (0.86; 95%CI- 0.78-0.94). Compared to the > 65 years age group, the 44-55 age group had a lower total charge (0.73; 95%CI-0.61-0.89). Compared to patients with Medicare, those with Private Insurance (0.87; 95%CI- 0.80-0.94) and Self-pay and Others (0.73; 95C%CI-0.62–0.86) had a lower total charge. And when compared to non-elective admissions, elective admissions had a higher total charge (1.44; 95%CI-1.29- 1.59). Conclusions: Hispanics and Asians and Others had a higher burden of illness, and Blacks had a higher LOS. Patients who reside in lower income neighborhoods had lower total charges. Understanding prostate cancer outcomes by race and income is crucial to designing strategies to improve access to care.
Personalized precision combination therapies based on potential actionability and coalterations and therapeutic opportunities for CDK12-mutated prostate cancer.
Authors: Li Hong Zheng , Wang Haitao 
Published: June 2023

e17068 Background: Translational studies have reported that CDK12 aberrations in metastatic castration-resistant prostate cancer (mCRPC) are related to homologous recombination (HR) deficiency and focal tandem duplications(FTDs), characterized by gene fusions and fusion-induced neoantigens (FINAs). In prostate cancer,CDK12 aberrations as a biomarker have been reported associated with poor prognosis, whether hormonal and taxane therapies as well as to PARP inhibitors. Herein, we aimed to molecularly, pathologically, and clinically characterize CDK12-aberrant mCRPC. Methods: Clinical data and molecular analyses are collected from the mCRPC patients treated in our center. Thirty-two patients with prostate cancer underwent soft tissue biopsy or sufficient ctDNA(Circulating Tumor DNA) for NGS and confirmed the CDK12 aberrations. Twenty-eight patients had advanced to the stage of mCRPC, and twenty-seven of them had exhausted standard treatment.All of the twenty-seven patients consented to the individualized therapiees based on NGS.PSA50 response rate and progression-free survival(PFS) are used to describe clinical features and outcomes to various individualized therapies, including sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) and PD-1/PD-L1 inhibitors monotherapy or combined with other off-label drugs. Results: Of the 32 patients with CDK12-aberrant prostate cancer, 19(59.4%) had detected biallelic CDK12 alterations. At diagnosis,17 (68%) patients' PSA≥100ng (only 26 patients retained the PSA data), 27 (93.1%) had Gleason grade group 4-5(only 29 patients retained the pathology),16(51.6%) had lymph node metastasis, 16(51.6%) had bone metastasis.13 patients received PARPi combine NHT(Novel hormone therapy) or not after NHT therapy resistance,only 1 patient PSA response reached PSA50.9 patients received PARPi combine temozolomide,2 reached PSA50,1 patient's liver metastases were significantly reduced ang reached PR.In that five patients,4 of 5 were monotherapied by PARPi.21 patients accepted PD-1/PD-L1 combined with PARPi or other off-label drugs based on the NGS or not.Four patients accepted immune monotherapy,only 1 reached PSA50. In the remaining 17 combined treatment patients, PSA50 responses were noted in 23.5%. What is noteworthy is that,4 of 16 happened HPD(hyperprogressive disease) with clinical manifestations such as rapid increase of PSA and significant decrease of ECOG score. Conclusions: CDK12-aberrant mCRPC is an aggressive subtype and have worse prognosis to PARPi. PARPi combine with temozolomide may be a effective therapeutic schedule. Along with NGS development,more therapeutic drugs are available to us to benefits for patients.But immunotherapy is questionable to CDK12-aberrant mCRPC because of the lower response rate and higher risk of HPD.