bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of diet with survival of patients (pts) with metastatic cancer of the urothelium (mUC) and renal cell carcinoma (mRCC) on immune checkpoint blockade (ICB).
Authors: Guercio Brendan John , Ratna Neha , Gavrilov David , Duzgol Cihan , Akhlaq Mahnoor , Teo Min Yuen , Regazzi Ashley M , Kotecha Ritesh R , Funt Samuel A , Aggen David H , Voss Martin H , Carlo Maria Isabel , Laccetti Andrew Leonard , Feldman Darren R. , Shah Neil J. , Motzer Robert J. , Bajorin Dean F. , Rosenberg Jonathan E. , Iyer Gopa , Lee Chung-Han 
Published: June 2023

4598 Background: The gut microbiome is an emerging modifiable predictor of ICB efficacy. Diet impacts the gut microbiome and fiber intake is associated with longer progression-free survival (PFS) in advanced melanoma treated with ICB. Whether diet impacts ICB benefit in mUC or mRCC remains unknown. Methods: Using a prospective cohort design, baseline dietary data were collected from pts with mUC or mRCC initiating ICB at Memorial Sloan Kettering Cancer Center using the extensively validated Harvard Willett Food Frequency Questionnaire. Tumor mutational burden (TMB) was estimated by next generation sequencing (MSK-IMPACT). The primary endpoint was radiologist assessed PFS, with secondary endpoint of overall survival (OS). Fiber intake was stratified as high or low using the median intake in our cohort. Associations between fiber intake and clinical outcomes were assessed using Kaplan-Meier curves plus univariable (UV) and multivariable (MV) Cox proportional hazards regression. Models were adjusted for prior ICB exposure. Models for mUC controlled for TMB and Bellmunt risk factors. Models for mRCC controlled for histology (clear vs non-clear cell) and IMDC risk score. Results: From 2/2021-6/2022, 88 pts eligible for analysis were enrolled with median follow-up of 10.1 months (mo) (mUC n = 40; mRCC n = 48). Median fiber intake was 17.5 g/day (interquartile range 12.5-24.5). Among pts with mUC, high fiber intake (≥17.5 g/day) was associated with longer PFS (UV hazard ratio [HR] 0.56, 95% CI 0.26-1.19, p = .13; MV HR 0.39, 95% CI 0.16-0.93, p = .03). Similar trends were observed for mRCC. In subgroup analyses, PFS was numerically longer with high fiber intake among mUC pts on maintenance avelumab (median PFS 6.1 vs 3.0 mo, n = 14) and in pts with mRCC treated with first-line (1L) ipilimumab + nivolumab (median PFS 18.0 vs 5.7 mo, n = 14) and 1L ICB + tyrosine kinase inhibitor (median PFS not reached vs 5.1 mo, n = 21). Among pts with mUC on non-maintenance ICB, pts with high fiber intake had numerically higher PFS at 6 mo (38% vs 14%, n = 26). Conclusions: This pilot study indicates that high fiber intake is associated with longer PFS among pts with mUC on ICB. Trends towards longer PFS and OS with high fiber intake were observed among pts with mRCC. Analyses of the gut microbiome are underway to investigate mechanisms of action. [Table: see text]
Gender and postoperative surgical margin status in MIBC: An analysis of the National Cancer Database.
Authors: Gordon Olivia French , Whalen Michael Joseph 
Published: June 2023

4599 Background: Women with muscle-invasive bladder cancer (MIBC) continue to experience persistent disparities in health outcomes despite accounting for less than 1/3 of newly diagnosed bladder cancer cases. Multiple studies have acknowledged the aggressive profile of female bladder cancer. This study aims to identify tangible areas to intervene and improve the delivery of oncologic care. Methods: The National Cancer Database (NCDB) was queried from 2004-2017 to conduct a retrospective cohort analysis of men and women with MIBC (cT2a-T4). N=41,037 patients with MIBC were reviewed, (30,313 male; 10,724 female). The primary endpoints were OS and surgical margin status. Logistic regression was performed to determine whether female sex conferred differential impact on surgical margin status when controlling for baseline clinical stage, age, receipt of neoadjuvant chemotherapy (NAC), Charleson-Deyo Comorbidity Classification (CDCC), and facility type. Cox proportional hazards assessed the impact of age, gender, margin status, CDCC and NAC on OS. Results: Logistic regression showed that sex, age, baseline clinical stage, CDCC, facility type and NAC were significant predictors of surgical margin status (p<.001). Female sex was found to have a 14.4% higher probability of having positive residual margins (HR 1.144 (95% CI: 1.07-1.23), p<.001). When adjusting for age, margin status, CDCC and NAC, Female gender (OS HR 1.063 (95% CI: 1.03-1.09), p<.001), positive microscopic margins (OS HR 2.0 (95% CI: 1.90-2.10), p<.001) and positive macroscopic margins (OS HR 2.62 (95% CI: 2.40-2.90), p<.001) independently portended poorer OS and necessitated increased adjuvant XRT (p<.001). Unexpected demographic findings included a significantly greater number of females than expected with a median household income <$38,000 (p= 0.047) and a greater number of females in the upper quartile of patients without a HS diploma (p<.001). The median days from diagnosis to definitive surgical treatment was significantly lower compared to males (58 vs 67 days; p<.001). Conclusions: Women with MIBC faced obstacles to getting treatment (less education and lower median income). Despite these hurdles they may be more proactive with their health as seen by a shorter time from diagnosis to the surgical table. However, this proactivity has yet to pay off as women undergoing surgical treatment for MIBC were significantly less likely to have clear margins post-operatively. The urologic community must mirror female patient’s proactivity and further investigate the gender disparity in surgical treatment of MIBC. [Table: see text]
Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): An international multicenter retrospective study.
Authors: Hadaschik Boris A. , Eiber Matthias , Weber Manuel , Ravi Kumar Aravind , Calais Jeremie , Czernin Johannes , Ilhan Harun , Saad Fred , Kretschmer Alexander , Brookman-May Sabine D. , Mundle Suneel , Small Eric Jay , Smith Matthew Raymond , Perez Rivera Paola M. , Hope Thomas A. , Herrmann Ken , Hofman Michael S , Fendler Wolfgang P. 
Published: June 2023

5010 Background: PSMA-PET was positive for distant metastases (39% distant nodes, 24% bone, 6% visceral organ) in >50% of nmCRPC pts who were nonmetastatic by conventional imaging (Fendler et al. CCR 2019). However, the prognostic impact of PSMA-PET disease extent and its association with oncologic outcomes is unknown. We assessed the prognostic utility of PSMA-PET disease extent in nmCRPC pts defined by conventional imaging for OS and new metastases-free survival (nMFS). Methods: 200 pts (6 centers) with nmCRPC by conventional imaging and prostate-specific antigen doubling time (PSADT) ≤10 mo and/or ISUP grade group ≥4 underwent PSMA-PET. Clinical course and treatment management after PSMA-PET imaging were recorded for 4-9 y. Pt characteristics and PSMA-PET disease extent were analyzed retrospectively. OS and PSMA-PET nMFS (time from primary PSMA-PET to appearance of new distant metastases by PSMA-PET or death) were analyzed for pt subgroups based on disease extent by univariate Cox regression. Results: Median OS was 74 mo, similar to the SPARTAN study of nmCRPC pts (74 mo; Smith et al. Eur Urol 2021). Polymetastatic disease (≥5 distant lesions by PSMA-PET) was associated with shorter OS (median 61 mo vs not reached [NR]) and shorter PSMA-PET nMFS (HR 1.8, 95% CI 1.1-2.9; median 38 vs 60 mo; p=0.021). Any metastatic disease by PSMA-PET and whole-body PSMA tumor volume were not prognostic for OS and PSMA-PET nMFS (all p>0.05). Initial pN1 status was associated with shorter OS (median 55 mo vs NR), but not with PSMA-PET nMFS (p>0.05). Baseline age, baseline Gleason grade ≥8, prior radiotherapy (RT), and PSA and PSADT at time of primary PSMA-PET were not associated with outcomes (all p>0.05). Management after PSMA-PET imaging was mostly local/targeted therapy in pts with no visible/locoregional disease (40/30%) and androgen receptor signaling inhibition therapy in pts with nodal/bone distant metastases (35/43%). Conclusions: Polymetastases (>5) by PSMA-PET and initial pN1 status were significantly associated with worse OS. PSMA-PET disease extent provides a potential novel additional risk stratification for pts with nmCRPC without distant metastasis based on conventional imaging. Further validation is needed to prove its independent prognostic value. Clinical trial information: NCT01946204 . [Table: see text]
Do bone scans over-stage disease compared to PSMA PET? An international multicenter retrospective study with blinded independent readers.
Authors: Fendler Wolfgang P. , Hope Thomas A. , Jiang Fei , Thompson Daniel , Barbato Francesco , Juarez Roxanna , Hernandez Pampaloni Miguel , Auerbach Martin S. , Gupta Pawan , Benz Matthias R. , Calais Jeremie 
Published: June 2023

5011 Background: PSMA positron emission tomography (PET) has a higher accuracy than computed tomography (CT) and bone scans to stage patients with prostate cancer. However, we do not understand how to apply clinical trial data based on conventional imaging to patients staged using PSMA PET. Therefore, we aim to evaluate the ability of bone scans to detect osseous metastases using PSMA PET as a reference standard. Methods: In this multicenter retrospective diagnostic study, 167 patients with prostate cancer, who were imaged with bone scan and PSMA PET performed within 100 days were included for analysis. Each study was interpreted by three blinded readers, and the results of the PSMA PET were used as the reference standard. Endpoints were positive predictive value (PPV), negative predictive value (NPV) and specificity for bone scans. Additionally, inter-reader reproducibility, positivity rate, uptake on PSMA PET, and number of lesions were evaluated. Results: 167 patients were included in the study, with 77 at initial staging, 60 in the BCR/CSPC setting and 30 in the CRPC setting. BS findings for metastatic disease validated by PSMA PET were tabulated. In all patients, the PPV, NPV and specificity for bone scans were 0.73 [0.61,0.82], 0.82 [0.74,0.88] and 0.82 [0.74,0.88]. In patients at initial staging, the PPV, NPV and specificity for bone scans were 0.43 [0.26,0.63], 0.94 [0.85,0.98], and 0.80 [0.68,0.88]. At initial staging 13/23 (57%) of positive bone scans were false positive. Inter-reader agreement for bone disease was moderate for bone scans (Fleiss k, 0.51) and substantial for the PSMA PET reference standard (Fleiss k, 0.80). Conclusions: In this multicenter retrospective study, the PPV of bone scans was low in patients at initial staging with majority of positive bone scans being false positives. This suggests that a large proportion of patients considered low volume metastatic by bone scan actually have localized disease. [Table: see text]
Final results from phase I study of PSCA-targeted chimeric antigen receptor (CAR) T cells in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Dorff Tanya B. , Blanchard Suzette , Martirosyan Hripsime , Adkins Lauren , Dhapola Gaurav , Shishido Stephanie , Wagner Jamie R , Stiller Tracey , D'Apuzzo Massimo , Kuhn Peter , Forman Stephen J. , Priceman Saul 
Published: June 2023

5019 Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of mCRPC. Prostate Stem Cell Antigen (PSCA) is highly expressed on the surface membrane in mCRPC and with limited expression on normal tissues. We are completing a phase I study of PSCA-targeted 4-1BB-co-stimulated CAR T cell therapy in mCRPC. Methods: CAR T cells were manufactured at City of Hope’s cGMP facility. Patients (pts) were required to have disease progression after at least 1 androgen receptor targeted therapy but there was no limit on other prior treatments. The primary objective was to define the dose limiting toxicities (DLT) as well as to describe preliminary bioactivity and activity. CAR T persistence and cytokine levels were evaluated by flow cytometry and Luminex. Circulating tumor cells (CTC) were measured by an unselected assay (Kuhn). Results: 14 pts were treated, median age 69, median baseline PSA 88. 12(86%) had previously been treated with chemotherapy; 9 received two taxanes and 3 docetaxel only. 79% of screened pts had PSCA expression >2+ in >80% of cancer cells. Two of 6 pts encountered DLT (grade 3 cystitis) at 100M + lymphodepletion (LD) chemotherapy. The protocol was amended to reduce the LD dose to 300 mg/m2 cyclophosphamide D1-3. No DLTs occurred in 5 pts treated in the modified LD 100M cohort. Cytokine release syndrome (CRS), best response by RECIST, CAR T cell expansion and persistence are presented by dose level in the table. CAR T expansion was greater with LD than without. PSA declines were seen, as well as radiographic improvement, though RECIST response was limited to stable disease (SD) by concurrent bone metastases. Cytokine peaks were higher in patients with anti-tumor effect noted. CTC decreases in both marrow and peripheral blood were seen, associated with PSA declines. Conclusions: PSCA-CAR T cells have anti-cancer activity in mCRPC with DLT of cystitis. LD was required for greater expansion and activity; lower dose LD improved toxicity without clear negative impact on expansion. Clinical trial information: NCT03873805 . [Table: see text]
Longitudinal transcriptome profiling of localized hormone-sensitive tumors in treatment-naïve ENACT patients with prostate cancer with and without enzalutamide (ENZA).
Authors: Ross Ashley , Shore Neal D. , Davicioni Elai , Zhao Xin , Elsouda Dina , Liu Yang , Proudfoot James A. , Hairston John , Russell David , Iwata Kenneth K. , Schaeffer Edward M. 
Published: June 2023

5026 Background: The ENACT trial (NCT02799745) randomized men with low- or intermediate-risk prostate cancer to 12 months of ENZA monotherapy followed by active surveillance (AS) for 12 months or to AS alone. Men were followed longitudinally, including by serial genome-wide expression profiling. Of 258 genomic signatures evaluated from baseline samples, increased Decipher genomic classifier score was prognostic for progression on AS; androgen receptor activity (AR-A) and PAM50 subtypes were associated with clinical benefit from ENZA, as previously reported. Here we present transcriptomic changes over time for men undergoing AS and those treated transiently with ENZA. Methods: Gene-expression profiling was performed via the Decipher GRID platform (Veracyte, Inc.) on 131 ENACT patient samples (ENZA, n=57; AS, n=74) collected at prespecified time points (screening, 12 months, and 24 months). Predefined GRID signatures were assessed for correlation with biological and clinical characteristics, including immune activity, treatment sensitivity, metastatic risk, and molecular subtypes. Statistical analysis was conducted by Cox proportional hazards models and logistic/linear regression; longitudinal changes were assessed by linear mixed-effects models. Results: Analysis of 12-month longitudinal samples showed significant transcriptomic changes in patients treated with ENZA, including markers of AR-A downregulation, decreased regulatory T-cell suppression, and increased immune activation. Many of the transcriptomic signature changes that occurred during ENZA treatment, including immune marker changes, were transient and returned to baseline values by 24 months following ENZA treatment discontinuation at 12 months. Conclusions: This exploratory biomarker analysis provides valuable data on transcriptomic changes in patients undergoing AS and those exposed to ENZA followed by cessation of treatment. Longitudinal analysis data provided insights into progression of early disease in the AS arm and possible strategies for extending ENZA activity beyond progression. Immune modulation with ENZA treatment may provide further insights for exploration of immunotherapy strategies. Clinical trial information: NCT02799745 .
Predicting absolute benefit in risk of metastasis of androgen deprivation therapy added to radiation therapy in patients with newly diagnosed prostate cancer using Prolaris.
Authors: Tward Jonathan David , Lenz Lauren , Gutin Alexander , Clegg Wyatt , Finch Rob , Cohen Todd 
Published: June 2023

5030 Background: Most patients would defer using androgen deprivation therapy (ADT) with radiation therapy (RT) when the number-needed-to-treat (NNT) exceeds 25 persons to prevent 1 from developing metastasis, corresponding to an absolute benefit of 4%.1 However, no tools for estimating personalized NNT or absolute benefit from ADT exist. We aimed to quantify personalized absolute benefit and NNT for persons receiving ADT added to single modality RT. Methods: The clinical cell-cycle risk (CCR) score combines the University of California, San Francisco’s Cancer of the Prostate Risk Assessment and the cell cycle progression molecular score to accurately assess prostate cancer aggressiveness. The effect of ADT added to RT was modeled using a 10-year risk of metastasis as a function of continuous CCR score for patients treated with RT alone. The relative benefit of ADT added to RT to reduce distant metastasis was modeled using published data from The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) which utilized several prospectively randomized RT±ADT trials.2 The average absolute benefit was calculated for patients with CCR scores above and below a prespecified multimodality treatment threshold (MTT) using the distribution of scores in a cohort of patients commercially tested by Myriad Genetics. Results: The commercially tested cohort consisted of 56,485 patients spanning all National Comprehensive Cancer Network risk categories (33.7% very low/low risk, 29.8% favorable intermediate risk, 25.6% unfavorable intermediate risk, 11.0% high/very high risk), with 87.2% having CCR scores at or below the MTT and 12.7% with CCR scores above the threshold. The average absolute benefit of ADT treatment was 0.86% (NNT=116) for patients with CCR scores below the MTT and 8.2% (NNT=12) for patients with CCR scores above the MTT. Patients with CCR scores at precisely the MTT had a predicted absolute benefit of 3.7% (NNT=27). Conclusions: The Prolaris test can accurately predict an individual's benefit of adding ADT to RT, and the risk threshold is consistent with patient attitudes about when to use or omit ADT. 1. Spratt DE, Tward JD: IJROBP 108:899-902, 2020. 2. Kishan AU, Sun Y, Hartman H, et al. Lancet Oncol 23:304-316, 2022.
Prevalence of mismatch repair deficiency in a large prospective prostate cancer cohort.
Authors: McNevin Ciara S. , Mohammed Nur Mutaz , O'Brien Cathal , McGovern Brianan , McFadden Julia , Baird Anne-Marie , Cadoo Karen Anne , Barr Martin P , Gray Steven G. , Keogh Anna P. , Sheils Orla , Sutton Lesley Ann , Flanagan Sinead , Mucci Lorelei A , Stopsack Konrad H. , Finn Stephen P. 
Published: June 2023

5031 Background: Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are predictive biomarkers for immunotherapy response. The best approach to identify patients with such tumors is unclear in prostate cancer. Methods: This study included men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). The highest-grade/index lesions of tumor tissue from radical prostatectomy (95%) or transurethral resections of the prostate were mounted in triplicate on tissue microarrays. Immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2 was performed, with scoring as MMR-deficient requiring a visible staining in a non-tumor internal positive control of the same case. For validation, a polymerase chain reaction-based MSI assay (Idylla MSI Test, Biocartis) was performed on tumor DNA of MMR-deficient cases and a selection of MMR-intact cases. Results: The study included 1016 men with prostate cancer. Tumor stage was predominantly pathologically localized (71% stage pT1/2, 18% T3a/b) with a full distribution of Gleason scores, including 20% Gleason score 6 (grade group 1), 36% 3+4 (grade group 2), 23% 4+3 (grade group 3), 8% 8 (grade group 4) and 13% 9-10 (grade group 5). MMR tumor scoring could be performed for MLH1 in 747 cases (75% of those with tumor tissue), for MSH2 in 903 cases (90%), for MSH6 in 708 cases (74%), and for PMS2 in 703 cases (72%). The remaining tumors were unevaluable due to lack of non-tumor tissue necessary as an internal positive control. Of the 903 tumors evaluable for MSH2 protein loss, 4 tumors had loss of MSH2 (prevalence 0.4%, 95% confidence interval [CI] 0.2–1.1%), and 3 of 708 evaluable tumors had concomitant loss of MSH6 (prevalence 0.4%, 95% CI 0.1–1.2%). No tumor had loss of MLH1 or PMS2. The MMR-deficient tumors had Gleason scores of 3+4, 8 (two cases), and 9–10. Tumor DNA of 1 of the 4 MMR-deficient tumors met the manufacturer’s cut-off for MSI-high; two additional MMR-deficient cases had non-zero repeats, with good reproducibility between tumor cores and technical replicates. One MSH2-deficient tumor and 6 DNA samples from 3 MMR-intact cases had repeat scores of zero. Conclusions: In this nationwide prospective study, MMR deficiency was rare in primary, surgically treated prostate cancer. This low prevalence contrasts with hospital-based studies of MMR deficiency and MSI that may have represented tumors with certain clinical features. The low prevalence and the need for an internal positive control for reliable scoring calls into question to what extent immunohistochemistry-based screening for MMR deficiency on limited tissue specimens, such as prostate biopsies, is routinely feasible.