bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune profiling of advanced prostate cancer harboring homologous recombination deficiency.
Authors: Soleimani Maryam , Kung Sonia H.Y. , Saxena Neetu , Thi Marisa , Fazli Ladan , Nappi Lucia 
Published: February 2022

163 Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumour microenvironment (TME) associated with HRD is poorly understood. We used mPCa tumours of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumour immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n = 13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumour cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n = 104), and neoadjuvant hormone therapy treated (NHT) (n = 16) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations, BRCA1/2 were the most frequently identified ( BRCA1/2 n = 6, FANCC n = 1, FANCD2 n = 2, PALB2 n = 1, CDK12 n = 1, ATR n = 2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens rather than in the glandular epithelia. The HRD cohort had higher levels of A2aR, in TC and SL (p≤0.0001 for both). When compared to the untreated cohort, PD-L2 levels were higher in SL of the HRD cohort (p≤0.05) while lower in the TC (p≤0.01). Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort (p≤0.01). There were significantly lower levels of GAL9 in the TC of the HRD cohort compared to untreated (p < 0.0001) tumours. There were no differences in TIM-3 levels between the cohorts. Conclusions: Evaluation of stromal and tumour cell immune profiling indicates that compared to other subtypes, mPCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and high in PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable pathways which may render clinical benefit in this patient population.
Correlation of ABI1 and PTEN expression during prostate tumor progression.
Authors: Kotula Leszek , Hryniewicz-Jankowska Anita , Li Xiang , Augoff Katarzyna , Papp Csaba , Das Disharee , Kung Sonia H.Y. , Fazli Ladan , Jasmaspishvili Tamara , Berman David Monty , Zhang Fan , Porter Baylee , Sikorski Aleksander , Gleave Martin , Kuznetsov Vladimir , Bratslavsky Gennady 
Published: February 2022

172 Background: Mechanisms of tumor invasion are not well defined. PTEN, a key tumor suppressor frequently inactivated in epithelial cancers, acts as a central node that controls tumor invasion. Despite PI-3 kinase-phospho-Akt pathway activation resulting in enhanced tumor growth, prostate tumors with PTEN loss undergo p53-mediated senescence that restricts tumor invasion. Methods: ABI1 downregulation is associated with epithelial-mesenchymal transition in highly invasive prostate tumors; these tumors frequently loose PTEN; therefore we set to examine genetic interaction of ABI1 and PTEN using novel mouse model of prostate cancer. We analyzed the correlation of ABI1 and PTEN expression in human PCa tumor tissue. Results: Here, using Abi1/Pten KO mouse model we identified a novel mechanism that guards tumor invasion. In Pten-null tumors upregulation of Abi1 leads to sequestration of activated Src kinase. In the absence of Abi1, this regulation is lost leading to activation of non-canonical WNT-SRC-STAT3 axis and enhanced invasion through activation of MMP2 activity. This molecular mechanism explains progression of tumors with Pten loss from PIN to invasive carcinoma upon concomitant Abi1 inactivation. In human tumors with low Abi1 and Pten are associated with aggressive phenotype, biochemical recurrence and metastasis. Conclusions: ABI1 acts as failsafe mechanism in PTEN null tumors by restricting SRC-mediated tumor invasion. ABI1 might have a predictive value in clinical setting in context of PTEN levels.
Circulating tumor DNA responses to high-dose testosterone injections in CRPC patients.
Authors: Caputo Sydney , Jaeger Ellen B. , Fleming William , Manogue Charlotte , Huang Minqi , Lieberman Alex , Light Malcolm , Sussman Isabelle P. , Miller Patrick , Barata Pedro C. , Lewis Brian E. , Layton Jodi Lyn , Ledet Elisa M. , Sartor A. Oliver 
Published: February 2022

173 Background: Some proportion of men with CRPC have favorable responses to high doses of testosterone (HDT) and some do not. Genomic determinants of these responders and non-responders are poorly understood. Herein ctDNA predictors of response are assessed using a responder/non-responder analysis. Methods: All men with CRPC had been pretreated with abiraterone, enzalutamide, or both. A ctDNA test was obtained prior to high doses of testosterone (administered as a dose of 400 mg IM testosterone cypionate every 3-4 weeks). Guardant 360 was used to analyze ctDNA (with an allelic fraction cut-off of > 0.5%) to ascertain the presence or absence of pathogenic mutations. Lower allelic fractions were not analyzed. Responders had a PSA decline of 50% or more (N = 16), non-responders received at least two doses of testosterone but never had any PSA decline at all (N = 20). All patients were treated at Tulane Cancer Center. Results: AR amplifications were more commonly detected (p = 0.036) pre-treatment in the ctDNA of responders (5/16) as compared to non-responders (1/20). No differences were found in those with common AR mutations; T878A was detected in 2/16 responders and 2/20 non-responders, L702H was detected in 1/16 responders and 2/20 non-responders. No differences were seen with regard to TP53 mutations, 6/20 non-responders and 7/16 responders. Non- AR/non- TP53 mutations were not distinct in the two groups but trended (P = 0.15) toward being more common in non-responders (5/16 in responders versus 11/20 non-responders). Pre- and post- ctDNA analyses were conducted in 5/6 patients for those with AR amplification at baseline. In all 5 of these patients, the degree of AR amplification diminished after testosterone injections. Conclusions: In this analysis of CRPC patients who were responders and non-responders to 400 mg testosterone cypionate q 3-4 weeks (post-abiraterone and/or enzalutamide), only AR amplifications in ctDNA were predictive of response. In all measured patients, the degree of AR amplification in the ctDNA diminished after testosterone injections.
Analysis of the role of PI3K-AKT and DNA damage repair (DDR) genomic biomarkers as predictors of clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Gagnon Richard , El Hallani Soufiane , Lee-Ying Richard M. , Kolinsky Michael Paul , Khalaf Daniel Joseph , Cook Sarah , Vasquez Catalina , Samuel Divya , Lewis John D , Faridi Rehan , Borkar Minal , Heng Daniel Yick Chin , Alimohamed Nimira S. , Ruether Joseph D. , Gotto Geoffrey , Fairey Adrian S. , Bismar Tarek A. , Yip Steven 
Published: February 2022

175 Background: Clinically relevant outcomes in nmCRPC treated with androgen receptor-axis-targeted therapies (ARAT) may be inferior in patients with tumors harboring mutations bypassing androgen receptor signalling. This final update of a retrospective, multicenter analysis explores the association between genomic mutations in the PI3K-AKT and DDR signalling pathways with ARAT treatment outcomes in nmCRPC patients. Methods: Relevant clinical endpoint were collected for high-risk nmCRPC patients treated with an ARAT at APCaRI affiliated cancer centers, including median metastasis-free survival (MFS), overall survival (OS), PSA decline ≥ 50% (PSA50), and second progression free survival (PFS2). Archival tumor tissue was accessed for next generation gene sequencing, examining for genomic alterations in 500 genes, including those involved in the DDR and the PI3K-AKT signalling pathways. Comparison of outcomes of patients with DDR and PI3K-AKT pathway mutations was conducted using Cox proportional hazards regression using wildtype cases as the reference group, adjusting for PSA doubling time and pelvic lymphadenopathy. Results: Of the 37 patients included, 30 (82%) received apalutamide, 5 (13%) received darolutamide, and 2 (6%) received enzalutamide. 10 patients (27%) had PI3K-AKT pathway mutations (4 PTEN, 3 PIK3Ca, 2 PIK3C2G, 1 PIK3C2b), 8 patients (22%) had DDR gene mutations (3 ATM, 2 CHEK1, 1 BRCA2, 1 CDK12, 1 CHEK2, 1 FANCD2, 1 FANCL), and 1 patient (3%) had 2 MLH1 mutations (microsatellite instability). Of those who had subsequent treatment, 1 received enzalutamide and 5 received abiraterone. Patients with PI3K-AKT pathway mutations had significantly shorter MFS (4.8 mo; HR 4.2; 95% CI 1.2 – 15.0; p = 0.025). Those with DDR mutations had a trend towards shorter MFS (23.3 mo HR 3.7; 95% CI 0.71 – 13.4; p = 0.134). OS data remains immature. 4 (11%) patients did not achieve PSA50, including a patient with 2 MLH1 mutations. Conclusions: This final analysis demonstrates that nmCRPC with PI3K and DDR signalling pathway mutations have poor clinical outcomes when treated with ARAT, likely secondary to decreased reliance on the androgen receptor signalling pathway. These results highlight the potential value of exploring targeted therapies, such as PARP or AKT inhibitors in patients with these mutations.
Patient derived tumor xenograft study with CDK4/6 inhibitor plus AKT inhibitor for management of metastatic castrate resistant prostate cancer.
Authors: Kase Adam McLain , Tan Winston , Gleba Justyna , Miller James , Meurice Nathalie , Petit Joachim , Copland John A. 
Published: February 2022

176 Background: Despite androgen deprivation therapy, prostate cancer will develop resistance known as castrate resistant prostate cancer (CRPC). Androgen signaling is associated with pathways that influence cell proliferation and survival via cell cycle regulation. AR signaling results in inactivation of Rb tumor suppressor by way of AKT and reduction in intrinsic CDK4/6 inhibitors. Since PTEN loss is found in 40% of mCRPC and AKT pathway is a mechanism of CDK4/6 inhibitor resistance, we hypothesize adding an AKT inhibitor to a CDK4/6 inhibitor will have synergistic activity while delaying CDK4/6 inhibitor resistance. Preclinical xenografts have been shown to recapitulate patient response, therefore, can be used to guide clinical trials using novel combinations. Methods: We have established patient derived tumor xenograft models (GUR-017M, TMA-027 and PRJ-88T) from patients with mCRPC with each having a unique genomic alteration profile. In the clinical setting, GUR-017M was resistant to abiraterone, enzalutamide, cabazitaxel and had exposure to docetaxel. TMA-027 and PRJ-88T were resistant to enzalutamide. We combined a CDK4/6 inhibitor with an AKT inhibitor and treated each of these patient tumors in NOD-SCID mice for a total duration of 40 days. Mice were implanted and separated into 4 groups (placebo, CDK4/6 inhibitor, AKT inhibitor and CDK4/6 + AKT inhibitor) with 10-13 mice in each group. Tumor volumes were measured twice a week. For GUR-017M, abemaciclib (50 mg/kg) was combined with MK2206 (120 mg/kg) and was compared to each placebo and each single agent alone. For TMA-027, palbociclib (50 mg/kg) was combined with ipatasertib (50 mg/kg). After 40 days, tumors were harvested for immunohistochemistry analysis. PRJ-88T was grown as 3D spheroids in ultra-low attachment plates and treated with palbociclib + ipatasertib (10 uM-100uM) to evaluate for synergy. Results: GUR-017M and TMA-027 showed significant delayed tumor growth compared to placebo or either single agent alone. In the GUR-017M group, the final mean tumor volume for the combination group was 149 mm3, compared to 377 mm3 (abemaciclib), 358 mm3 (MK2206) and 527 mm3 placebo group, representing a percent decrease compared to control by 72%, 29%, and 32%, respectively. For TMA-027, the final mean tumor volume for the combination group was 102 mm3, compared to 259 mm3 (palbociclib), 416 mm3 (ipatasertib), and 402 mm3 placebo group, representing a percent decrease compared to control by 75%, 36%, and 4%, respectively. PRJ-88T 3D spheroids showed synergy with palbociclib + ipatasertib. In vivo experiments using PRJ-88T are in progress. Conclusions: The preclinical results show combining CDK4/6 inhibitors with AKT inhibitors is a promising treatment strategy and provides the basis for a clinical trial in patients with mCRPC.
Waning efficacy of COVID-19 vaccination at six months in patients (pts) with genitourinary malignancies.
Authors: Zengin Zeynep Busra , Meza Luis A , Malhotra Jasnoor , Salgia Sabrina , Ely Jennifer , Hsu Joann , Kelley Erin , Mead Heather , Dizman Nazli , Chehrazi-Raffle Alex , Govindarajan Ameish , Muddasani Ramya , Chawla Neal Shiv , Dorff Tanya B. , Lyou Yung , Karczewska Ewa , Trent Jeffrey M. , Salgia Ravi , Altin John , Pal Sumanta K. 
Published: February 2022

185 Background: Short-term effectiveness of COVID-19 vaccination is widely demonstrated, but the emerging real-world data suggest that immunity may wane over-time (Levin et al. NEJM 2021). Herein we aimed to explore the long-term efficacy of the COVID-19 vaccination among pts with genitourinary cancer. Methods: In this study, pts with genitourinary malignancies (prostate, kidney, and bladder cancers) who had not received COVID-19 vaccination were included. Blood samples were collected prior to and after one dose of either an adenovirus- or mRNA-based COVID-19 vaccine at the 2- and 6-month timepoints. Additional blood samples from pts receiving systemic treatment were collected at 3 consecutive therapy cycles following vaccination. Antibody titers were assessed using the SCoV-2 Detect IgG ELISA assay and results were reported as immune status ratios (ISR). T-cell receptor (TCR) repertoire sequencing was performed using the MiXCR software (MiLabs) and custom strips were used to assess TCR abundance and homology clustering. Results: A total of 183 pts were enrolled, and 136 pts provided baseline blood samples. Among these, 59 (8:51 F:M) provided samples for both the 2- and 6-month timepoints by the 10/6/2021 data cut-off. In this subset of pts, median age was 66 (range 48-85) and 33 (55.9%), 25 (42.4%), and 1 (1.7%) pts had prostate, kidney, and bladder cancer, respectively. A majority of the pts (93.2%) were on systemic treatment with 23.7% on immune checkpoint inhibitors, 18.6% on targeted agents, and 1.7% on chemotherapy. The most commonly administered vaccines were BNT162b2 (61.0%) followed by mRNA-1273 (37.3%) and Ad26.COV2.S (1.7%). The mean (±standard deviation) ISR values at baseline and 2 months were 0.68±1.59 and 6.62±1.75, respectively. At the 6-month timepoint, mean ISR was 5.46±1.61; this was significantly lower than the 2-month antibody titers (p < 0.0001), and reflects a reduction of 17.6%. Further data on TCR sequencing will be presented at the meeting. Conclusions: To our knowledge, this is the first data assessing the long-term serologic outcomes of COVID-19 vaccination in pts with cancer. Our data suggest waning immunity over time in cancer pts. Strategies to prolong host immunity against SARS COV-2 (e.g., booster vaccination) are likely warranted.
Aspartyl (Asparaginyl) β-hydroxylase (AABH) as a serum biomarker for prostate cancer, to identify prostate cancer, regardless of PSA level.
Authors: Moshiri Mahmood , Moshiri Arsha , Pashaei Hamed , Moshiri Kiarash , Nazari Reza , Monhemi Hassan 
Published: February 2022

226 Background: Prostate Cancer (PC) is the most common form of cancer in men in the United States. In their lifetime, approximately 1 out of every 6 American men will develop PC. The chances of developing PC increase dramatically after age 50 with more than 72% of cases occurring in individuals over 65 years of age. Methods: We have investigated the use of aspartyl (asparaginyl) β-hydroxylase (AABH) as a cancer biomarker. We have developed a sandwich ELISA for its detection. Here this assay was utilized to screen sera from patients with prostate cancer and PSA values in various ranges. Results: AABH levels were assessed in sera from 263 individuals with PC and 73 men over 50 years of age not known to have cancer. The levels of AABH in the two groups were > 3.00 ng/ml and < 3.00 ng/ml, respectively. The overall sensitivity and specificity of the test were 97.5% and 96%. AABH and PSA levels were also compared. The AABH values and sensitivities in individuals with PC and PSA values in the ranges < 2 ng/ml, 2-4 ng/ml and > 4 ng/ml were > 3.00 ng/ml, 99% (n = 115); > 3.00 ng/ml, 98% (n = 64) and > 3.00 ng/ml, 95% (n = 114). Conclusions: The present study of AABH indicates that cancer group can be clearly distinguished from normal healthy controls. Moreover, the study indicates that AABH might be used to identify disease in individuals with questionable PSA values. These results support to the establishment of routine screening of serum AABH as a means to detect those who need referral for prostate biopsy. The use of AABH testing may enhance current prostate cancer screening practices by both identifying individuals with low but suspicious PSA values who should be recommended for biopsy and reducing the number of false biopsies indicated by positive PSA tests. Serum AABH levels are significantly elevated in individuals with prostate cancer. Using a cutoff value of 3ng/ml, overall sensitivity of the assay for prostate cancer is 97%. The test has a specificity of 96% in healthy men over 50 years of age. AABH is elevated in prostate cancer tissue but NOT in normal prostate or in Benign Prostatic Hyperplasia (BPH). Serum AABH levels are NOT correlate with PSA levels.
Preoperative PI-RADS scores are associated with prostate cancer upstaging on surgical pathology.
Authors: Pockros Benjamin , Stensland Kristian D. , Parris Molly , Frankenberger Edward , Canes David , Moinzadeh Alireza 
Published: February 2022

228 Background: Prostate Imaging Reporting and Data System (PI-RADS) scores can help identify clinically significant prostate cancer and improve patient selection for prostate biopsies. However, the role of PI-RADS scores in patients already diagnosed with prostate cancer remains unclear. The purpose of this study was to evaluate the association of PI-RADS scores with prostate cancer upstaging. Upstaging on final pathology is a surrogate for biochemical recurrence, morbidity, and mortality. Methods: All patients from a single high-volume institution who underwent a prostate multiparametric MRI and radical prostatectomy between 2016-2020 were included in this retrospective analysis. Univariable and multivariable analyses were conducted to investigate potential associations with upstaging events, defined by pT3, pT4, or N1 on final pathology. A logistic regression model and receiver operative characteristic curves were constructed for the prediction of upstaging events based on PI-RADS score, prostate-specific antigen density (PSA-D), and biopsy Gleason grade groups. Results: 294 patients were included in final analysis. Upstaging events occurred in 137 (46.5%) of patients. On univariable analysis, patients who were upstaged on final pathology had significantly higher PI-RADS scores (OR 2.34 95% 1.64 - 3.40, p < 0.001) but similar PSA-D (OR 2.70 95% 0.94 – 8.43, p = 0.188) compared to patients who remained pT1 or pT2 on final pathology. On multivariable analysis, PI-RADS remained independently significantly associated with upstaging, suggesting it is an independent risk predictor for upstaging. Lymph node metastasis only occurred in patients with PI-RADS 4 or 5 lesions (n = 15). Our model using PSA-D, biopsy Gleason grade, and PI-RADS had a predictive AUC of 0.69 for upstaging events, an improvement from 0.59 using biopsy Gleason grade alone. Conclusions: PI-RADS scores are independent predictors for upstaging events and may play an important role in forecasting biochemical recurrence and lymph node metastasis. PI-RADS scores could improve shared decision making and help set expectations with patients. Modern nomograms should be updated to include PI-RADS to predict lymph node metastases and the likelihood of biochemical recurrence more accurately.[Table: see text]
Successful same-day discharge for robot-assisted radical prostatectomy: A systematic review and meta-analysis.
Authors: Uy Michael , Millan Braden , Jones Conor , Sands David , Matsumoto Edward , Bay Benjamin , Shayegan Bobby 
Published: February 2022

238 Background: In the current era of enhanced recovery after surgery (ERAS), same day discharge (SDD) following robot-assisted radical prostatectomy (RARP) is emerging as the standard of care. In order to implement a safe and efficient SDD pathway, it is imperative to appropriately select candidates and have established discharge criteria. We conducted a systematic review and meta-analysis to summarize published pathways, as well as to evaluate the differences in peri-operative characteristics, complication/readmissions rates, and satisfaction/cost data, between in-patient (IP) RARP versus SDD-RARP. Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was prospectively registered with PROSPERO (CRD42021258848). A comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Google Scholar, and conference abstract publications was performed comparing outcomes between IP-RARP and SDD-RARP. A leave-one-out sensitivity analyses was performed to control for heterogeneity and risk of bias. Results: A total of 14 studies (eight prospective and six retrospective cohort studies) were included with a pooled population of 3795 patients, including 2348 (61.9%) IP-RARPs and 1447 (38.1%) SDD-RARPs. SDD pathways varied, though many commonalities were present in patient selection (minimal comorbidities and lived close to the hospital [≤ 50-150 km]), peri-operative recommendations (judicious intra-operative intravenous fluids and short-acting narcotics), and post-operative management (immediate ambulation and diet, and non-narcotic analgesia). When compared to IP-RARP, SDD-RARP had no differences in ≥ Grade 3 Clavien–Dindo complications (RR: 0.4, 95% CI 0.2, 1.1, p = 0.07), 90-day readmission rates (RR: 0.6, 95% CI 0.3, 1.1, p = 0.10), or unscheduled ED visits (RR: 1.0, 95% CI 0.3, 3.1, p = 0.97). Cost savings per patient ranged between $367-2109 (USD), and overall satisfaction was high between 87.5-100%. Conclusions: Same day discharge following RARP is both feasible and safe, with comparable complication and readmission rates to IP-RARP. Additionally, SDD offers healthcare cost-savings with high patient satisfaction rates. Data from this study will further inform the uptake and development of future SDD pathways in contemporary urological care such that it may be offered to a broader patient population.