bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical evaluation of teleglenastat (CB-839) in prostate cancer.
Authors: Lam Elaine T. , Su Lih-Jen , Salzmann-Sullivan Maren , Nordeen Steven K. , Flaig Thomas W. 
Published: March 2023

378 Background: Glutaminase (GLS) levels are upregulated in prostate cancer [PMID: 28138303, 16897757]. The androgen receptor signaling pathway enhances the expression of SLC43A1, SLC1A4 and SLC1A5 (amino acid and glutamine transporters) in prostate cancer cells [PMID: 22007000, 24052624, 28507054]. We evaluated prostate cancer data from The Cancer Genome Atlas and found that GLS expression correlates with Gleason sum. We performed in vitro and in vivo experiments to evaluate the effect CB-839, a glutaminase inhibitor (GLS1 > GLS2), as monotherapy and in combination with other agents. Methods: We evaluated glutamine dependence of 3 prostate cancer cell lines [parental LNCaP (P0, hormone-sensitive), LNCaP-derived castrate resistant (CRPC) variant (P1, PMID: 34575033), and PC-3 (CRPC)] using media with and without glutamine, as well as clonogenic assays in regular media with BPTES (GLS1 inhibitor as a control) and CB-839. Combinatorial treatment and dose response studies were performed with CB-839 plus enzalutamide (ENZ), everolimus (EVE), or olaparib (OLA). We used NOD SCID female nude mice carrying P1 and PC3 prostate tumor xenografts to evaluate effects of CB-839 monotherapy, CB-839 + EVE, and EVE monotherapy. Results: P0, P1, and PC-3 all exhibited glutamine dependence. In glutamine-deplete media, all tested cell lines formed < 50% of colonies from baseline. Clonogenic assays with BPTES showed IC50 of 2-6 uM. CB-839 showed single agent activity in vitro with IC50 = 1 uM (P0), IC50 = 2 (P1), and IC50 < 0.1 uM (PC-3). The IC50 of CB-839 + ENZ in P1 cells was < 4uM CB-839 + 2uM ENZ. CB-839 + OLA showed no additive effect as OLA alone was very active (IC50 < 100 nM) in P1 cells. CB-839 + EVE showed single agent and synergistic effect (IC50 < 4 uM CB-839 + 0.05 uM EVE) in both P1 and PC-3 cells. In P1 tumor xenografts, treatment response was seen in CB-839 monotherapy, EVE monotherapy, and CB-839 + EVE treatment arms. In PC-3 xenografts, treatment response was seen in all groups, with greater effect in the EVE monotherapy and CB-839 + EVE treatment groups compared with CB-839 monotherapy. Conclusions: CB-839, EVE, and CB-839 + EVE all demonstrated activity in P1 and PC-3 castrate resistant prostate cancer tumor xenografts. Additive or synergistic activity was difficult to assess with combination therapy since each drug was effective as monotherapy. Additional studies are needed to evaluate the role of EVE monotherapy or CB-839 + EVE in prostate cancer. Research Sponsors: NCI CTEP UM1 Supplement CA186688-04, NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30. [Table: see text]
A phase 2 study of ibrutinib as neoadjuvant therapy in patients with localized prostate cancer.
Authors: Nawaf Cayce Ben , Peng Bo , Reimers Melissa Andrea , Weimholt Cody , Slane Kathryn , Oppelt Peter John , Frankel Jason , Figenshau Robert S. , Kim Eric H , Andriole Gerald L. , Fong Lawrence , Pachynski Russell Kent 
Published: March 2023

387 Background: Treatment of localized prostate cancer (PCa) with surgery or radiotherapy remains suboptimal with failure rates of 35-40%. Bruton’s Tyrosine Kinase (BTK) is seen elevated in PCa tissues compared to normal prostate tissue. Malignant B-cell density has been correlated with higher risk of aggressive PCa and mitigating that through the BTK has been proposed in mouse models. Ibrutinib is a potent BTK inhibitor which targets B-cell signaling pathways, has an established safety profile, and has been shown to inhibit in vivo prostate tumor growth pre-clinically. Therefore, we hypothesized that ibrutinib will augment anti-tumor immune responses through inhibiting tumor-intrinsic growth via blocking BTK B-cell signaling pathways, while also inducing favorable T-cell profiles in localized PCa. Methods: We performed a neoadjuvant clinical trial (NCT02643667) studying ibrutinib in PCa. Eligible patients had localized PCa with no prior treatment, and deemed suitable for undergoing a radical prostatectomy. Patients received 840mg/day oral ibrutinib for 28 days followed by a radical prostatectomy 7-12 days later. Patients were assessed 4 weeks after surgery. The primary objectives are to assess safety of ibrutinib and characterize B and T cell infiltration. Correlative pre- and post- treatment tissue and blood samples were collected; BTK and PD-L1 expression in tumor and immune-infiltrating immune cells will be examined, and BCR and TCR clonality and diversity will be evaluated. Results: 22 patients were registered and underwent treatment to date. 4 patients had early termination of ibrutinib treatment with 3 due to adverse effects and 1 due to discovery of surgically unresectable disease. A total of 21 of 22 patients received radical prostatectomies. There were no intra-operative complications attributed to ibrutinib. The treatment was generally well tolerated with 7.1% grade 3 treatment related adverse effects. 2% experienced a grade 4 treatment adverse effects of hepatic dysfunction. The most common grade 1-2 adverse effects were diarrhea (8.2%), fatigue (7.1%), and anemia (6.1%). The median follow-up time was 23.9 months. Median overall survival and median failure free survival have not been reached and the two-year milestone is 100%. Sample collection is complete and immune correlative analyses are ongoing. Safety/tolerability, clinical outcomes, and preliminary correlative data will be reported. Conclusions: This is the first clinical trial of ibrutinib in PCa, and lays the foundation for larger future studies. Clinical trial information: NCT02643667 .
Biochemical recurrence (BCR) surrogacy for clinical outcomes after radiotherapy for adenocarcinoma of the prostate (BCRSCRAP): A meta-analysis from MARCAP Consortium.
Authors: Roy Soumyajit , Romero Tahmineh , Steigler Allison , Denham James William , Joseph David John , Michalski Jeff M. , Feng Felix Y , Bolla Michel , de Reijke Theo M. , Maingon Philippe , Sydes Matthew R. , Dearnaley David P. , Incrocci Luca , Heemsbergen Wilma , Nabid Abdenour , Souhami Luis , Zapatero Almudena , Sun Yilun , Spratt Daniel Eidelberg , Kishan Amar Upadhyaya 
Published: March 2023

391 Background: Event-free survival, a PSA-driven endpoint, was shown to not be surrogate endpoint for overall survival (OS) in the ICECAP two-stage meta-analytic approach. However, time to biochemical recurrence (TTBCR) in NRG/RTOG 9202 met Prentice criteria for surrogacy. We performed an individual patient data (IPD) meta-analysis of 11 randomized controlled trials evaluating RT dose escalation, ADT use, and adjuvant ADT prolongation to evaluate the surrogacy of time to BCR (TTBCR), censoring for non-prostate cancer deaths, using both approaches to evaluate surrogacy. Methods: This individual patient level meta-analysis was performed using data from the MARCAP consortium, and 11 radiotherapy trials were included. TTBCR was defined as time to developing a BCR or experiencing prostate cancer-specific mortality (PCSM), with censoring at time of other-cause death or loss to follow-up. Landmark analyses were used to test the Prentice criteria for surrogacy. For patient level correlation between TTBCR and OS, we applied a bivariate Copula model to estimate the Kendall’s τ. For trial level correlation of the treatment effect on TTBCR and true endpoints, a weighted linear regression model was applied between the effects of treatment (natural log of hazard ratio [log-HR]) on OS versus TTBCR using a weightage that was inverse variance of BCR log-HR estimate. Results: Based on Prentice criteria, BCR at the landmark time point of 48 months was associated with increased risk of mortality in trials that compared treatment intensification with adjuvant ADT prolongation (HR 2.18 [95% CI 1.95-2.42]), the addition of ADT (HR 1.38 [1.25-1.54]), and RT dose escalation (HR 2.12 [1.83-2.46]) on uni- and multi-variable analyses. At the patient level, there was a low to moderate level correlation between BCR and OS with Kendall’s τ of 0.34 and a R2 of 0.55 for correlation of treatment effect on TTBCR and OS. At the trial level, there was a poor correlation between treatment effect on TTBCR and OS (R2=0.16). Conclusions: This IPD meta-analysis demonstrates that while BCR is prognostic, it is not a surrogate endpoint for OS in localized prostate cancer for patients treated with a diverse array of radiotherapeutic strategies. This highlights the importance of other cause mortality in prostate cancer. Our results highlight the differences in interpretability of Prentice criteria and the two-stage meta-analytic approach and suitability of endpoints for clinical trial design.
Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
Authors: Spiess Philippe E. , Li Roger , Grivas Petros , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Danziger Natalie , Ross Jeffrey S. , Jacob Joseph M , Bratslavsky Gennady 
Published: March 2023

4 Background: TMB has emerged as a major biomarker of efficacy in immune checkpoint inhibitor (ICPI) therapies in the neoadjuvant, adjuvant and metastatic disease setting in a wide variety of malignancies, but not in PSCC. Methods: 397 clinically advanced (local major recurrence and/or metastatic disease) PSCC underwent hybrid capture-based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Trinucleotide mutation signatures were evaluated (Alexandrov, et al. 2013). Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and excluding whole-arm and whole-chromosome events. TMB was categorized into three cohorts: <10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and >20 muts/Mb (very high). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) and defined as tumor proportion score (TPS) >1. The presence of HPV16/18 was determined by next generation sequencing (NGS). Statistical comparisons were corrected for multiple comparisons using the Bonferonni method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases in this study. The mean age of PSCC with very high TMB at 70.1 yrs was older than for TMB low at 63.4 yrs (p=.08). There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% of the TMB 10-19 and 11.8% of the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs TMB low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than in the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than the TMB low PSCC (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for the TMB low, 50.0% for the TMB high and 58.8% for the TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels revels significant differences in biomarkers for the near 15% of cases that have TMB >10 muts/Mb. Further study of TMB as a biomarker in ICPI-based clinical trials for advanced PSCC appear warranted.
Comparison of serum miR-371a-3p assay performance by digital droplet PCR and reverse transcriptase quantitative PCR in patients with malignant germ cell tumor.
Authors: Nuno Michelle , Lafin John T. , Scarpini Cinzia , Savelyeva Anna , Wang Zhaohui , Gagan Jeffrey , Jia Liwei , Lewis Cheryl , Murray Sarah , Cheng Yun , Margulis Vitaly , Woldu Solomon L. , Strand Douglas , Coleman Nicholas , Amatruda James F. , Frazier Lindsay Lindsay , Murray Matthew , Bagrodia Aditya 
Published: March 2023

426 Background: MicroRNAs have shown promise as potential germ cell tumor (GCT) biomarkers. In particular, previous work has shown miR-371a-3p alone may serve as a biomarker for GCTs, demonstrating higher sensitivity than current biomarkers. Quantitative reverse transcriptase PCR (RT-qPCR) has been commonly used to measure circulating levels of miR-371a-3p. More recently, miR-371a-3p has also been measured using digital droplet PCR (ddPCR), which has the potential advantage of absolute quantification. Here, we compared the performance of miR-371a-3p as quantified by RT-qPCR and ddPCR. Methods: Patient samples from the University of Texas Southwestern (UTSW) Medical Center and the University of Cambridge (UoC) were evaluated using both RT-qPCR and ddPCR, as per current protocols (RT-qPCR) or as per standard manufacturer’s recommendations (ddPCR). A range of clinical scenarios (pre-orchiectomy, chemotherapy-naïve RPLND) were intentionally selected. We compared the performance of the two assays using receiver operating characteristic (ROC) curves and area under the curve (AUC) values. We also determined an optimal threshold for each procedure by maximizing the Youden Index and compared the corresponding estimated sensitivity and specificity. Results: Data were available for 69 patients. Among these patients, 35 (50.7%) had malignant GCT (MGCT) and 34 (49.3%) had either non-MGCT (n=26) or no tumor (n=8). Patients with non-MGCT or with no tumor were considered controls. Cq values were generally lower among patients with MGCT and the number of positive droplets was higher compared with controls. The AUC was 0.96 when using RT-qPCR and 0.82 when using ddPCR to classify patients based on circulating miR-371a-3p. The optimal threshold for ddPCR was determined to be 17.5 positive droplets with a corresponding estimated sensitivity of 71% and 100% specificity. For RT-qPCR, the optimal threshold was determined to be Cq=28.52, with a corresponding estimated sensitivity of 83% and specificity of 100%. Conclusions: RT-qPCR was more sensitive in identifying MGCT patients in our current cohort when compared with ddPCR. Further investigations are required to optimize PCR methodology, particularly for ddPCR, and determine whether e.g., tumor volume and/or clinical context affects ddPCR performance. [Table: see text]
Co-primary endpoint analysis of HCRN GU 16-257: Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer (MIBC).
Authors: Galsky Matt D. , Daneshmand Siamak , Lewis Sara C , Chan Kevin G. , Dorff Tanya B. , Cetnar Jeremy Paul , Mamtani Ronac , Kyriakopoulos Christos , Gogerly-Moragoda Mahalya , Izadmehr Sudeh , Yu Menggang , Zhao Qianqian , Jun Tomi , Mehrazin Reza , Sfakianos John P. , Pal Sumanta Monty 
Published: March 2023

447 Background: Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients with MIBC but efforts to advance this paradigm have been complicated by a lack of (a) prospective studies, (b) rigorous approaches to assess and define clinical complete response (cCR), and (c) integration of novel therapies. Methods: Eligible patients were cisplatin-eligible with cT2-T4aN0M0 urothelial bladder cancer. Patients received 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder biopsies. Patients achieving a cCR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab q2 weeks x 8 followed by surveillance. Patients not achieving cCR were recommended to undergo cystectomy. Coprimary endpoints included (1) cCR rate and (2) association between cCR and 2-year outcomes. The key secondary endpoint was the impact of pre-specified baseline genomic alterations on outcomes. Additional biomarkers to refine patient selection were also explored. Results: Between 8/2018-11/2020, 76 patients were enrolled at 7 sites (male 79%, median age 69; cT2 = 56%, cT3 = 32%, cT4 = 12%). Median follow-up is 27 months. 72/76 patients underwent clinical restaging and a cCR was achieved in 33/76 (43%; 95% CI: 32%, 55%). One cCR patient opted for immediate cystectomy (ypTaN0M0). Outcomes are summarized in the Table. Baseline ERCC2, ATM, FANCC, or RB1 alterations were not, but tumor mutational burden ≥ 10 mutations/mb was, significantly associated with the composite endpoint of ypT0 (immediate cystectomy) or 2-year bladder-intact metastasis-free survival (BIMFS). On landmark analysis, VI-RADS (Vesical Imaging–Reporting and Data System) score (3-5 versus 1-2) on restaging MRI (central blinded review) was associated with inferior BIMFS (HR 4.5; p = <0.01) and MFS (HR 19.3; p <0.01). Circulating tumor DNA data will be presented at the meeting. Conclusions: TURBT followed by gemcitabine, cisplatin, plus nivolumab achieves stringently defined cCR in a substantial subset of patients with MIBC. ≥2-year bladder-intact survival is achieved in the majority of patients with a cCR. Clinical trial information: NCT03558087 . [Table: see text]
Incidence and survival in patients with urachal carcinoma: Cancer registry analysis between 2008 and 2019.
Authors: Darr Christopher , Möller Lennart , Schürger Niklas , Szarvas Tibor , Reis Henning , Stang Andreas , Hadaschik Boris A. , Kajüter Hiltraud , Grünwald Viktor 
Published: March 2023

480 Background: Urachal carcinoma (UrC) is a rare and poorly studied cancer without evidence-based treatment strategies. Due to the low prevalence of this cancer, only sparse data on its incidence and survival are available. Therefore, we analyzed the incidence and survival rates of patients with UrC in North Rhine-Westphalia (NRW), a state of the Federal Republic of Germany. Methods: UrC (ICD-O-3: C67.7) diagnosed between 2008 and 2019 were identified via the NRW Cancer Registry (population 18 million) and classified according to Mayo-staging and T-category. Mayo stage was based on the TNM classification. We calculated age-standardized incidence rates using the European standard and Kaplan-Meier overall survival (OS). Age was stated as mean and standard deviation (SD). Results: A total of 121 UrC patients were described, of which men were more frequently affected at 57%. The distribution for women was 43%. The mean age was 61.1 (SD: 15.5) years for men and 58.8 (SD: 15.3) years for women. The overall age-standardized incidence rate was 0.43 per 1.000.000 person-years, which was 0.5 for men and 0.37 for women. 85.1% had adenocarcinomas, 6.6% urothelial carcinoma, 4.1% unspecified cancer, 2.5% epithelial carcinomas, 0.8% squamous cell carcinomas or others, respectively. The 5-year OS rate were 60.4% (CI-95%: 48.9%; 74.7%) for men and 41.7% (CI-95%: 28.8%; 60.2%) for women. According to TNM classification, 33% of the patients presented with T1-2, 29.8% with T3-4, while for the Mayo staging a distribution of 17.4% for stage I-II and 13.2% for stage III-IV was shown. Data regarding T-category and Mayo-satging were available in 63.6% (44 patients) and 30.6% (84 patients), respectively. The 5-year OS was 73.3% (CI-95%: 59.3%; 90.6%) in T1-2, 37.2% (CI-95%: 23.6%; 58.6%) in T3-4. and 69.3% (CI-95%: 47.6%; 100%) and 25.6% (CI-95%: 9.89%; 66.49%) in Mayo stage I-II and III-IV, respectively. Conclusions: UrC is a rare cancer and OS rate in NRW were comparable to historical data. The prognosis was stage-dependent and identified poor outcome in patients with advanced disease. Our data underscored the role of proper staging and diagnosis for future clinical studies that investigate optimal treatment strategies.
A SEER-Medicare based quality score for patients with synchronous and metachronous metastatic upper tract urothelial carcinoma and its association with cost of care and survival.
Authors: Joyce Daniel D , Shan Yong , Stewart Courtney A. , Chamie Karim , Boorjian Stephen A. , Williams Stephen B. , Sharma Vidit 
Published: March 2023

482 Background: Population-based studies evaluating outcomes exclusively for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and often only capture patients with de novo (synchronous) metastases as opposed to those who progress to metastatic disease (metachronous). We sought to evaluate the outcomes and costs associated with mUTUC and employ a novel methodology to identify both synchronous and metachronous mUTUC patients using claims data. Additionally, we created a guideline-based quality score to improve quality of care in this space. Methods: Using the SEER-Medicare database we identified patients aged 66 years and older diagnosed with mUTUC between 2004 and 2012. Achievement of the following quality criteria was assessed: 1) cancer-specific survival greater than 12 months; 2) receipt of systemic therapy; 3) receipt of hospice/palliative care. Kaplan-Meier survival curves and Cox proportional hazard models were used to compare overall survival between quality scores (0 vs. ≥1) and synchronous vs. metachronous mUTUC. Total healthcare and Medicare Part D out-of-pocket costs within two years of diagnosis were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. Results: Of the 1,223 patients identified, 381 (31.2%) and 842 (68.8%) had synchronous and metachronous mUTUC, respectively. At least one quality criterion was met in 40.2% of patients. Notably, only 54 patients (4.4%) received palliative care services. On multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41–0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47–0.98), were less likely to achieve at least one quality criterion. Patients meeting quality criteria had longer survival compared with patients who did not meet criteria (HR:0.52, 95%CI: 0.46–0.59). Meeting at least one quality criterion was independently associated with increased costs ($94,677, 95%CI: 87702–101652 vs. $63575, 95%CI: 59598–67552) on multivariable regression analysis. Conclusions: Less than half of mUTUC patients met at least one quality criterion. Quality score achievement was associated with longer overall survival at a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.