bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the discordance rate of HER2 expression by immunohistochemistry between primary and secondary prostate cancer biopsies.
Authors: Mabellos Joshua , Gill Puneet , Lap Coen Johannes Gerardus , Zara Rozalen Alexandra , Diao Guoqing , Liu Shanshan , Thomas Shrina , Subrahmanyam Ramesh , Nava Victor , Jain Maneesh Rajiv 
Published: June 2023

e17014 Background: Preliminary evidence suggests that human epidermal growth factor receptor 2 (HER2) expression may play a role in tumor cell proliferation in prostate cancer. Minner et al ( Clin Cancer Res, 2010) identified a prevalence of ~ 20% HER2 expression in prostate cancer. The aim of the study is to assess the prevalence and discordance rate of HER2 expression in prostate cancer patients with multiple prostate biopsies using immunohistochemistry (IHC) at a Veterans Affairs hospital. Methods: A single-center, retrospective chart review of at least 30 patients with prostate cancer that had two prostate biopsies based on data collected from the Computerized Patient Record System (CPRS) and Veterans Information Systems and Technology Architecture (VISTA). Demographic and laboratory data including age, race, Gleason score, and stage of cancer were collected under IRB-approved waivers for consent and HIPAA authorization. Formalin-fixed paraffin embedded (FFPE) prostate tumors were evaluated for IHC analysis by the Washington DC Pathology Department. HER2 expression was assessed using the VENTANA anti-HER2/neu (4B5) rabbit monoclonal primary antibody and scored as 0, 1+, 2+, and 3+. HER2 scores of 0 and 1+ to 3+ were categorized as HER2-negative and HER2-positive, respectively. The primary endpoints are the prevalence and discordance rate of HER2 expression in paired prostate samples. Results: In our predominately African American (94%) cohort of 32 patients with a mean age of 60 years, overall HER2 prevalence was 25% (n = 8) and 56% (n = 18) in the primary and secondary biopsies, respectively. The mean time between biopsies was 41 weeks and overall HER2 discordance was 56% (n = 18). Discordance from HER2-negative to HER2-positive was 38% (n = 12), while discordance from HER2-positive to HER2-negative was 6% (n = 2). The remaining discordance were from HER2-low to HER2-positive or vice-versa. The most common variance between primary and secondary biopsies was observed as +1 HER2 scoring category (n = 11). No significant associations were found between HER2 discordance and Gleason score or stage of cancer . Conclusions: In our cohort of patients with prostate cancer, HER2 expression was observed in 25% of initial biopsies and over 50% of secondary biopsies. Discordance of HER2 expression was found in over 50% of patients. A few patients had initial HER2-positive biopsies and subsequent HER2-negative biopsies. The majority of HER2 discordance involved patients who had initial HER2-negative biopsies and secondary HER2-positive biopsies with most showing +1 difference in IHC scores. This study could lead to the consideration of utilizing multiple prostate cancer biopsies to determine the eligibility for anti-HER2 therapy in future trials.
The association of HLA-DR and PD-L1 expression with clinical characteristics in prostate adenocarcinoma.
Authors: Tuerff Daniel , Muller Daniel J. , Lap Coen Johannes Gerardus , Liu Shanshan , Diao Guoqing , Antonio Martha , Nava Victor , Jain Maneesh Rajiv 
Published: June 2023

e17017 Background: Prostate adenocarcinoma is the second most commonly occurring cancer in men, yet therapeutic progress in the past decade has stalled. Immune checkpoint inhibitors (ICI) are being successfully used for the treatment of multiple types of cancers and remain an appealing treatment option for patients with prostate adenocarcinoma. Unfortunately, only a small group of patients with prostate cancer appear to benefit from treatment with ICI. Both HLA-DR and PD-L1 have been identified as predictors of response to ICI in other malignancies. We investigated the prevalence of HLA-DR and PD-L1 expression in prostate cancer, and if there is a correlation with clinical characteristics. Methods: For this retrospective cohort study, 40 patients were randomly selected from a database of patients with prostate cancer seen at the Washington DC VA Medical Center between 2000 and 2022; 19 patients (47.5%) with metastatic disease at presentation and 21 patients (52.5%) presenting without metastatic disease. Clinical information was collected and included age at diagnosis, ethnicity, PSA at diagnosis, total Gleason score, and AJCC stage. Tissue samples of the primary tumors were retrieved and immunohistochemistry was performed for HLA-DR and PD-L1. Staining was independently scored by two experienced pathologists who were blinded to clinical information. Results: HLA-DR was found to be expressed in 14 patients (35%) with prostate cancer, whereas PD-L1 positivity was identified in 18 patients (45%). HLA-DR expression was not associated with metastatic disease, PSA at diagnosis, Gleason score, or AJCC stage ( p = 0.816, p = 0.314, p = 0.920, p = 0.458, respectively). In contrast, PD-L1 positivity was significantly associated with metastatic disease ( p = 0.028), a higher PSA at diagnosis ( p = 0.041), Gleason score ( p = 0.026), as well as AJCC stage ( p = 0.0438). No correlation was observed between HLA-DR positivity and positivity for PD-L1 ( p = 0.641). Conclusions: Both HLA-DR and PD-L1 are found to be expressed in tumor tissues of patients with prostate adenocarcinoma. Although HLA-DR expression was not associated with clinical characteristics, we did observe an association between PD-L1 positivity and advanced disease. This observation would be consistent with prior studies that have reported that PD-L1 expression in prostate cancer is correlated with clinic-pathologic features such as advanced stage of disease, castration resistance and poor overall survival. More studies are necessary to evaluate if PD-L1 could serve as prognostic or predictive biomarker in prostate adenocarcinoma.
Development and initial clinical testing of a multiplex assay evaluating histone modifier p300 acetylation in prostate cancer circulating tumor cells.
Authors: Jarrard David Frazier , Filon Mikolaj , Yang Bing , Schehr Jennifer L. , Singh Anupama , Bigarella Marcelo , Denu John M , Lang Joshua Michael 
Published: June 2023

e17020 Background: Histone modifying enzymes (HMEs) hold promise as targets for drug discovery in cancer. Histone acetyltransferases and histone deacetylases dictate the presence of acetyl marks, which regulate chromatin and transcriptional activation. We previously developed a novel ‘histone array on a chip’ to measure HME dysregulation associated with the development of castration resistant prostate cancer (CRPC) (ACS Chem Biol 2017). This approach identified decreased SIRT2 expression and increased p300 activity leads to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in CRPC xenografts. These alterations were subsequently validated in castration-resistant tissues (BMC Cancer 2017). The goal of the current study was to determine if circulating tumor cells (CTCs) could be used as a therapeutic biomarker to identify patients with altered p300 acetylation activity. Methods: Blood was collected from 11 CRPC and 3 hormone-sensitive patients with advanced PC under an IRB-approved protocol. PBMCs were isolated with Ficoll-paque PLUS, and lymphocytes were depleted using anti-CD45 magnetic beads. CTCs were then captured with EpCAM labeled coated magnetic beads. Bound cells were isolated with Exclusion-based Sample Preparation (ESP) technology. Bound cells were moved through staining and washing wells prior to imaging at 20x on a fluorescent microscope. Images were analyzed with NIS Elements software. Results: We initially optimized the staining of acetyl-p300, total p300, H3K18ac, and SIRT2 in single cell prostate cancer cell cultures. Exposure to A-485, a selective p300/CBP catalytic inhibitor, reduced levels of p300 and H3K18 acetylation confirming assay specificity. CTCs from patient samples were then captured by EpCAM antibody binding and target staining revealed clear expression of acetyl-p300, acetyl-H3K18, SIRT2, and CK (cytokeratin). No expression of CD45+ cells (lymphocyte exclusion) is noted. Acetyl-p300 displayed a strong positive correlation with its target acetylated H3k18 (Pearson’s r = 0.61), and SIRT2 expression showed robust negative correlation with H3k18 (r = -0.60). A distinct group of 6/11 (55%) of CRPC patients demonstrated altered expression. In one subject with an untreated CSPC sample and subsequent CRPC sample ( > 12mo) a loss of SIRT2 expression, increased p300 activity, and histone H3 hyperacetylation are associated with the transition from hormone-sensitive to CRPC. Conclusions: Acetyl-p300, H3K18ac, and SIRT2 increase in a subset of CTC from patients with CRPC. These biomarkers are associated with increased CBP/p300 activity. This biomarker suite could potentially be used for noninvasive monitoring of outcomes and predicting tumor responses to CBP/p300 acetylation inhibitors in clinical development.
Clinicopathological characteristics and survival outcomes for testicular choriocarcinoma and non-testicular choriocarcinoma: A SEER database analysis.
Authors: Alshwayyat Sakhr Abdulsalam , Ababneh Obada Ehab , Alshwayyat Tala Abdulsalam , Qaddoura Marwa Thaker , Soudi Maen Suliman 
Published: June 2023

e17026 Background: Primary Choriocarcinoma (CC) is a rare germ cell tumor that can occur in males. The most common primary site in men is the testis. It can occur in extragonadal sites such as the mediastinum, retroperitoneum, lungs or brain. The clinical and prognostic differences between testicular CC and non-testicular CC are unclear. We aim to study the differences in clinical features, prognostic factors, and outcomes between the two subtypes of CC. Methods: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with pure CC between 2000 and 2018. Patients with a previous history of cancer or with other concurrent malignancies were excluded. These patients were divided into two groups: testicular and non-testicular CC. The clinicopathological features of each group were compared using chi-square tests. Kaplan-Meier estimator, log-rank tests, and Cox proportional hazard regression were used to identify prognostic factors over overall survival (OS) and cancer-specific survival (CSS). Results: The study included 363 patients, with 270 (74.4%) patients classified as having testicular CC and 93 (25.6%) as having non-testicular CC. The results showed that testicular CC was more likely to occur in white patients, be bilateral in distribution, have a smaller size, and be in more advanced SEER stages compared to non-testicular CC. Additionally, testicular CC patients were more likely to undergo surgical treatment, but not radiation. Testicular CC patients had a better OS and CSS (HR = 0.52, 95% CI: 0.38-0.71 and HR = 0.52, 95% CI: 0.37-0.71, respectively) compared with non-testicular CC. Our Cox multivariate analyses for OS and CSS identified the following independent prognostic factors for testicular CC: localized stage, surgery, tumor size ≥ 4cm, radiotherapy, and chemotherapy. Interestingly, the use of radiotherapy was actually associated with poor OS and CSS (HR = 1.8, 95% CI: 1.17-2.85 and HR = 1.7, 95% CI: 1.05-2.73, respectively). For non-testicular CC, the independent prognostic factors for OS and CSS were age ≥ 30 years, non-paired site, regional stage, surgery, and chemotherapy. Conclusions: Our study provides important insights into the differences between testicular and non-testicular CC. The use of radiotherapy is generally not recommended in testicular CC which might explain its bad prognostic effect as these patients might be naturally at higher risk of dying. However, the bad poor prognosis of patients using radiotherapy persisted even after controlling for other important prognostic factors. Further studies with larger sample sizes are needed to validate and build upon these findings, but our results provide a starting point for a better understanding of such rare cancer.
Doxorubicin, paclitaxel, and cisplatin (ATP) for refractory germ cell tumors.
Authors: Xiang Jenny Jing , Campbell Matthew T , Tu Shi-Ming , Araujo John C. , Nieto Yago , Lin John Kent , Xiao Lianchun , Shah Amishi Yogesh , Wang Jianbo 
Published: June 2023

e17028 Background: Patients with refractory germ cell tumor (GCT) have limited treatment options and poor prognosis. We describe our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) as an outpatient chemotherapy regimen for patients with refractory GCT. Methods: We performed a retrospective chart review of all patients who received ATP at our institution between August 2017 and August 2022. ATP consisted of doxorubicin 30 mg/m2, paclitaxel 100 mg/m2 over one hour, and cisplatin 30 mg/m2 every 2-3 weeks. We reviewed patient and disease characteristics including staging, histology, prior therapies, tumor marker and imaging responses. Progression free survival (PFS) and overall survival (OS) were respectively calculated from the first ATP dose date to disease progression/death and to death/last follow up. Results: A total of 39 patients with refractory GCT received ATP. Patients were 95% male, 54% white, with a mean age of 30 years (range 18-63). Prior to ATP administration, 92% of GCTs had elevated tumor markers, including 54% with elevated AFP, 56% with elevated HCG, and 18% with elevated both tumor markers. 8% of GCTs did not have elevated tumor markers at baseline. Further disease characteristics are described in table 1. Patients received a median of 2 lines of prior systemic therapies (range 1-6), including 97% with prior cisplatin-based regimens and 21% with prior high dose chemotherapy with stem cell rescue transplant. Patients received a median of 3 doses of ATP (range 1-8) with 31% for palliative intent and the rest as a bridge to transplant or other therapies. After ATP administration, 77% patients had decreased tumor markers, including 18% with tumor marker normalization. Of the 19 patients with imaging post-ATP, 53% had complete or partial response, 16% had stable disease, and 32% had disease progression. By December 2022, 79% patients had progression or death, with a median PFS of 3.8 months (95% CI: 1.94, 7.16) and median OS of 10.7 months (95% CI: 6.37, 32.69). 18% of patients experienced toxicities requiring admissions. Conclusions: Based on our retrospective single institution experience, ATP has clinical activity in refractory GCT and is associated with decreased tumor markers and imaging response in most patients. ATP is a convenient and feasible outpatient regimen and can be used in the salvage setting and as a bridge to other therapies. [Table: see text]
Bone metastasis in patients with germ-cell tumors: Analysis of survival outcomes and prognostic factors.
Authors: Hassoun Rebecca , King Jennifer , Althouse Sandra K. , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: June 2023

e17029 Background: Bone metastasis (BM) is uncommon in patients with germ-cell tumor (GCT). There is lack of data regarding optimal treatment approach. We report the outcomes and prognostic factors in 99 pts with BM treated at our institution. Methods: We identified 99 pts with GCT and BM treated at Indiana University between year 1986-2021. Kaplan-Meier methods were used for progression free survival (PFS) and overall survival (OS) analysis. Results: Median age was 31.5 (range, 13.1-58.8). Primary tumor histology was non-seminoma in 77 and pure seminoma in 22. Predominant histology was seminoma in 26, yolk sac tumor 23, mixed 16, embryonal ca 12, teratoma 10, choriocarcinoma 9. Other mets sites included lungs in 68, RP LNs in 63, liver in 34, brain in 19. BM location was spine in 73, pelvic bones in 22, humerus/femur in 14, ribs in 10, sternum/clavicle in 7. Median pre-chemo AFP was 438 (range, 1-75,414) and hCG 80 (range, 0.7-1,700,000). 1L chemo was BEP x4 in 46, VIPx4 in 10, BEP x3 + EP x1 in 8, EP x4 in 8, BEP x3 in 7, VIPx3 in 1, and other in 19. Histology of BM resection for those who underwent surgery was viable non-teratoma GCT in 6, teratoma in 1, malignant transformation of teratoma in 3, and necrosis in 3. 28 had radiotherapy to symptomatic BM. 80 (82.5%) pts progressed after 1L chemo and 46 (53.5%) progressed after 2L chemo. With median f/u from diagnosis of 5.7 years, 5 yr PFS was 17.8% (95% CI 10.3-27.0) and 5 yr OS was 59.9% (95% CI 47.9-70.0). For pts with pure seminoma, 5 yr PFS was 29.8% (95% CI 12.4-49.5) and 5 yr OS 83.1% (95% CI 55.7-94.3). For non-seminoma: 5 yr PFS was 14.6% (95% CI 6.9-25.1) and 5 yr OS 52.2% (95% CI 38.4-64.2). Multivariable analysis indicated that pts with concurrent liver and/or brain mets had worse OS. Conclusions: Outcomes of pts with GCT and BM are inferior than what is expected based on IGCCCG risk categories. Pts with concurrent liver and/or brain mets have particularly worse OS outcomes. [Table: see text]
Real world utilization and outcomes of immunotherapy regimens in metastatic castration resistant prostate cancer (mCRPC).
Authors: Ganta Teja , Anker Jonathan Forrest , Miller Eric James , Tsao Kai , Oh William K. 
Published: June 2023

e17038 Background: While immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm in many cancers, their efficacy in mCRPC is limited. Ongoing research suggests distinct subpopulations of mCRPC may derive benefit or that combinatorial regimens including ICIs may overcome treatment resistance. This single-center retrospective study aims to describe real-world utilization patterns of ICIs for patients with mCRPC and assess the treatment effects. Methods: The EHR database was queried for patients with PC who were treated with an ICI outside of a clinical trial. Additional data were obtained from chart review and the cancer registry. Patients were excluded if ICI was given for another cancer type, non-metastatic disease, or as a component of small-cell lung cancer regimens. Kaplan-Meier curves were used to estimate time to events. Results: 31 patients are included in the study. From years 2016 to 2022, 13 patients received ICI alone. Starting in 2019, 18 patients received ICI combined with cabozantinib (C). ICI+C had PSA response rate (RR) of 50%, median duration of treatment (DOT) of 5.5 months, and median overall survival (OS) of 8 months (Table 1). 3 of these patients received therapy for ≥ 12 months. ICI alone had a RR of 0%. 94% of patients who received ICI+C were not a candidate for CONTACT-2 (NCT04446117). Conclusions: Oncologists continue to use ICI for mCRPC. While noncomparative, ICI+C demonstrated favorable activity over a historical cohort of ICI alone. Ongoing clinical trial participation is vital for patients with mCRPC; however, off-label prescribing may provide additional access to treatment options. [Table: see text]
Dual inhibition of PARP and ATR induces homologous recombination repair deficiency and leads to synthetic lethality in prostate cancer with CDK12 alteration.
Authors: Akamatsu Shusuke , Kamiyama Yuki , Sunada Takuro , Hikami Kensuke , Fukui Tomohiro , Mizuno Kei , Sumiyoshi Takayuki , Goto Takayuki , Kobayashi Takashi , Sasanuma Hiroyuki 
Published: June 2023

e17042 Background: CDK12 is considered as a gene involved in homologous recombination repair (HRR); however, recent clinical trials have shown poor benefit of poly(ADP-ribose) polymerase(PARP) inhibitors in prostate cancer (PCa) patients with CDK12 alterations. Since CDK12 is the third most commonly altered gene in the HRR pathway in PCa, development of a new treatment strategy is urgently needed. Methods: To understand the biological consequence of CDK12 alteration, CDK12 was knocked out in LNCaP using CRISPR-Cas9 system to generate CDK12KO cells. Cell growth and cell cycle were evaluated as well as HRR efficiency. Downstream genes were evaluated by RT-PCR and western blots. Combination therapy by a PARP inhibitor and ATR inhibitors were tested using two lines of patient derived xenografts (PDX) established from tissues of patients with deleterious CDK12 variants. Three different ATR inhibitors were tested to confirm reproducibility. Results: In LNCaP, CDK12 knockout enhanced cell cycle progression until the M phase, however, cell cycle was stalled at the M phase with accumulation chromosomal aberration, suggesting that rapidly progressive CDK12 altered tumors clinically encountered harbor a mechanism of escaping the M phase checkpoint without DNA repair. γH2AX was accumulated in CDK12KO after treatment with CPT11, consistent with impaired HRR in CDK12 KO cells. Analysis of HRR associated genes showed that in PCa, CDK12 knockout leads to transcriptional downregulation of ATM but not the other HRR associated genes. Expression patterns of downstream genes after double strand break (DSB) induction in CDK12 and ATM knockout cells suggested that in PCa, CDK12 regulates HRR through regulation of ATM. Since synthetic lethality of PARP and ATR inhibition has been reported in ATM deficient PCa, 2 PDX lines with CDK12 alterations were administered the combination therapy. Tumor growth suppression and accumulation of γH2AX in tumor tissue was observed when treated by the combination therapy, but not with either drug alone. Either drug alone or in combination did not affect the growth of a PDX established from a tissue of a patient with wild-type CDK12. Conclusions: In PCa, CDK12 acts through transcriptional regulation of ATM, and combination treatment with PARP inhibitor and ATR inhibitor could be a potential treatment strategy in PCa with CDK12 alteration.
Real-world data for predictors of PSA response to Lu177-PSMA-617 in metastatic castration resistant prostate cancer.
Authors: Hassoun Rebecca , Tann Mark , Sims Justin , Auxier Ashleigh , Althouse Sandra K. , King Jennifer , Adra Nabil 
Published: June 2023

e17044 Background: Lu177-PSMA-617 (Lu177) therapy is effective in a subgroup of patients with metastatic castration resistant prostate cancer (mCRPC). We evaluated PSA responses in subgroups of pts with mCRPC. Methods: Pts with mCRPC who progressed after androgen receptor pathway inhibitor (ARPI) and taxane chemotherapy (or who have refused chemotherapy) were treated with Lu177. Pts with ≥6 weeks follow-up after start of Lu177 therapy were included. Baseline clinical/molecular characteristics and PSMA PET parameters were analyzed and association with PSA30 response was evaluated. Results: 45 pts were included. Median age 71.7 (range, 58-90). At baseline PSMA PET: 37 pts had PSMA + disease in bone, 28 lymph nodes, 5 lungs, 4 liver, and 1 brain. 14 pts had 1 prior ARPI, 31 pts had ≥2 prior ARPI. 5 pts had no prior taxane regimen, 18 had 1 prior taxane, 14 had 2 prior taxanes and 8 had ≥3 taxane regimens. 10 pts had prior PARP inhibitor. With a median follow-up of 2.8 months (1.4-6.1) from starting Lu177 therapy, 21 (46.7%) pts achieved a PSA30 response, and 18 (40.0%) pts achieved a PSA50 response. 24 (53.3%) pts achieved any confirmed PSA response. Grade≥3 toxicity occurred in 3 pts. Conclusions: There is a trend with higher PSA30 and PSA50 response to Lu177 with higher SUVmean, less prior taxane exposure, and in pts with homologous recombination repair mutations (HRR). [Table: see text]