bluuebunny/crossref_metadata_2025_split huggingface dataset:
Digital evaluation of tumor microenvironment immune markers pre- and post-neoadjuvant pembrolizumab in muscle-invasive bladder cancer (Pure-01 trial: An open label, single arm, phase II study).
Authors: Cattaneo Laura , Lagano Vincenzo , Carpenito Laura , Napolitano Caterina , Bersani Ilaria , Necchi Andrea , Nicolai Nicola , Paolini Biagio , Colecchia Maurizio , Milione Massimo , Pruneri Giancarlo , Mortarini Roberta , Anichini Andrea , Giannatempo Patrizia 
Published: March 2023

541 Background: PURE-01 trial enrolled 155 patients who received 3 cycles of pembrolizumab (IO) every 3 weeks before radical cystectomy. We compared tumor-microenvironment immune markers expression in pre- and post-IO TURB specimens in complete/major and non-responders to identify features associated with pathologic response. Methods: We evaluated pre-IO TURB samples of 18 complete responders (CR: ypT0), 6 major responders (MR: ypTa/ypT1) and 19 non-responders (NR: ypT2/ypT3, N0 or N+) and post-IO specimen of 7 CR, 3 MR and 14 NR. Immunohistochemistry analysis for lymphocytes (CD3, CD8, CD20), macrophages (CD68, CD163), immune checkpoints (PD1, PD-L1) and HLA molecule (MHC-I, HLA-DR, B2M) was performed. A semiquantitative count was made on all samples by 3 expert pathologists and a quantitative whole-slide digital evaluation was performed using QuPath (v.0.3) to assess cell density (cells per mm2) and expression of immune checkpoint and HLA molecules. Results: Semiquantitative count showed that seven markers (CD8, CD163, stromal or tumor PD-L1, HLA-DR and B2M on tumor cells) were significantly more expressed on TURB lesions from responders (CR + MR or CR only) compared to NR (N0 or N+) (p-value range: 0.001 to 0.048). In addition to such markers, patients achieving a CR, compared to NR, showed significantly higher expression of CD68 and CD163, of PD-1 on lymphocytes, as well as of tumor MHC-I molecules. Comparison of lesions from patients with CR vs MR revealed significant differences for CD3, CD163, PD-1 and MHC-I, all these markers being more frequently expressed on the former group compared to the latter. Digital pathology analysis confirmed this results on whole-slide evaluation showing higher density of CD8, CD163, PD-L1 and PD-1, and a higher expression B2M, MHC-I and HLA-DR (p-value range: 0.02 to 0.002) in responders. Moreover, N0 patients showed higher expression of PD-L1 and HLA-DR compared to N+ patients. Comparison of pre- and post-IO samples from NR patients showed an increased density of CD8 and CD20 cells (p-value: 0.04 and 0.01), and a decrease of CD163 and HLA-ABC (p-value: 0.003 and 0.02) expressing cells in the post-therapy samples. Conclusions: The tumor immune microenvironment of pre-therapy TURB lesions of patients achieving a complete or major pathologic response after neoadjuvant pembrolizumab shows significant enrichment for T cells and myeloid cells, for stromal or tumor PD-L1 as well as increased MHC-I expression on tumor cells compared to lesions from non responders. Post-IO surgical samples of NR patients showed downregulation of HLA-Class I antigens, in spite of increased CD8 and CD20 density. Clinical trial information: NCT02736266 .
Outcomes of patients with brain metastases from renal cell carcinoma treated with first-line therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Takemura Kosuke , Lemelin Audreylie , Ernst Matthew Scott , Wells Connor , Basappa Naveen S. , Szabados Bernadett , Powles Thomas , Davis Ian D. , Wood Lori , Kapoor Anil , McKay Rana R. , Lee Jae-Lyun , Meza Luis A , Pal Sumanta Monty , Donskov Frede , Yuasa Takeshi , Beuselinck Benoit , Gebrael Georges , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: March 2023

600 Background: The outcomes of patients with brain metastases from renal cell carcinoma (RCC) are not well characterized due to exclusion of these patients from clinical trials. Methods: Using the IMDC, patients with brain metastases from RCC at the initiation of first-line therapy were analyzed. Baseline patient characteristics, brain-directed local therapies, clinician assessment of best overall response as per RECIST 1.1, and overall survival (OS) were compared across first-line therapies, namely immuno-oncology (IO)-based combination therapy (IO/IO or IO/vascular endothelial growth factor (VEGF)) and anti-VEGF monotherapy (sunitinib or pazopanib). Results: The overall cohort of patients with brain metastases included 775 patients, consisting of 78/1298 (6.0%) and 697/8633 (8.1%) in the IO-based and anti-VEGF cohorts, respectively (p = 0.009). Among the baseline patient characteristics, only the proportion of patients receiving whole-brain radiotherapy differed significantly across the IO-based and anti-VEGF cohorts with proportions of 25.0% and 55.7%, respectively (p < 0.001). Best overall response in all disease sites was 3.4% complete response (CR), 25.9% partial response (PR), 39.7% stable disease (SD), and 31% progressive disease (PD) in the IO-based cohort, whereas it was 0.7% CR, 29.6% PR, 36.7% SD, and 33.0% PD in the anti-VEGF cohort (p = 0.223). The following factors were significantly associated with longer OS on multivariable analysis: IMDC favourable-/intermediate-risk (HR 0.49, 95% CI 0.37–0.65; p < 0.001), IO-based combination therapy (HR 0.51, 95% CI 0.29–0.92; p = 0.026), neurosurgery (HR 0.62, 95% CI 0.47–0.83; p = 0.001), and stereotactic radiosurgery (HR 0.64, 95% CI 0.49–0.84; p = 0.001). Conclusions: Patients with brain metastases receiving IO-based combination therapy may have longer OS than those receiving anti-VEGF monotherapy. Brain-directed local therapies including neurosurgery and stereotactic radiosurgery were associated with longer OS. [Table: see text]
Financial toxicity from first-line TKI plus IO therapies for advanced renal cell carcinoma.
Authors: Benjamin David Joseph , Rezazadeh Arash 
Published: March 2023

634 Background: Since the approval of sunitinib for the treatment of advanced renal cell carcinoma (RCC), the first-line treatment landscape has drastically altered with combination tyrosine kinase inhibitor (TKI) plus immunotherapy (IO) regimens. Despite improvements in survival, it remains unclear if these therapies are cost prohibitive for patients or hospitals compared to prior standard of care sunitinib. Methods: Approved TKI plus IO therapies were identified using the US FDA Oncology Announcements website and confirmed with NCCN Guidelines (Version 3.2023). Cost per unit was identified using public data (Lexicomp or manufacturer’s website). We calculated total cost of each treatment regimen using the cost per unit for each therapy and the median duration on treatment as reported in each combination therapy's clinical trial publication. Results: Average PFS benefit from combination TKI plus IO therapies was 8.1 months (range 4-14.7) in comparison with sunitinib. Average cost of TKI plus IO therapy was $443,839.32 compared with $199,541.44 for sunitinib therapy. Conclusions: Average increase in cost of TKI plus IO therapy compared to sunitinib was $244,297.88. For every month of PFS benefit with TKI plus IO combination therapy, there was on average $30,160.23 cost added per month. These increased costs may be prohibitive for many patients and hospitals, particularly in low- and middle-income countries (LMICs). [Table: see text]
Patient perceptions of benefits and risks of adjuvant therapy in renal cell carcinoma.
Authors: Battle Dena , Msaouel Pavlos , Pal Sumanta Monty , Vaishampayan Ulka N. , Staehler Michael D. 
Published: March 2023

663 Background: Adjuvant treatment with the immune checkpoint inhibitor (CPI) pembrolizumab and the tyrosine kinase inhibitor (TKI) sunitinib are currently standard of care options for patients with high-risk localized renal cell carcinoma (RCC). However, treatment decisions need to be based on anticipated benefit, toxicity risk, and patient goals and values, particularly since multiple trials testing CPIs and TKIs in the adjuvant setting did not meet their primary endpoints. To improve patient selection and communication, we sought to assess how patients perceive the benefits and risks of adjuvant therapy. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists and patient advocates. The survey was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Out of 1,062 participants 639 patients self-identified with localized RCC and 223 patients had stage 3 RCC at initial diagnosis. 113 patients were offered adjuvant therapy by their doctor, 74 patients reported being treated with or having received treatment with adjuvant therapy (18% treated with TKI, 82% with CPI). Results: When asked to assess risk of recurrence, patients with stage 3 disease assessed their average personal risk to be 47%, 10% higher than what they reported their doctor assessed risk to be (37%). When asked to identify the most important factors related to adjuvant decision making, patients ranked risk of dying from cancer (76%) over severity of possible side effects (43%), chance of having side effects (35%), time required for treatment (24%), and cost of treatment (7%). 49% of patients offered adjuvant therapy believe that treatment reduces the risk of recurrent disease by more than 30% and 25% believe it reduces risk by more than 50%. Among patients receiving or having received adjuvant therapy, 46% completed adjuvant therapy, 17% stopped early due to side effects and 14% recurred while on therapy. Side effects were asymptomatic or mild in 38%, moderate without invasive intervention or hospitalization in 48% severe, requiring hospitalization in 8% and life-threatening in 7%. 22% of patients were told that their side effects would be life-long. Conclusions: Patients with high-risk localized disease estimate their recurrence risk to be higher than what their doctors assess their risk to be. When weighing decisions about adjuvant therapy, patients rank risk of dying from cancer over risks related to toxicity. An overestimation of benefits of adjuvant therapy is noted with one quarter of patients believing that adjuvant therapy will reduce their risk of recurrence by 50 percent or more. The findings highlight the importance of effective communication between patients and providers regarding the risks and benefits of adjuvant therapy to promote an informed and shared decision.
Frailty and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide.
Authors: Deol Ekamjit Singh , Luo Suhong , Sanfilippo Kristen Marie , Eisen Seth A , Schoen Martin W. 
Published: March 2023

71 Background: Abiraterone (ABI) and Enzalutamide (ENZ) are both treatment options for metastatic castration-resistant prostate cancer (mCRPC). However, both drugs have differing pharmacodynamics, so patient factors may selectively impact drug efficacy. Age-associated health deficits make older adults variably susceptible to disease under a syndrome termed frailty. The average age of initial prostate cancer diagnosis is age 66, and the average time to mCRPC progression is 11.7 years. Thus, frailty is an important patient factor to consider in mCRPC, and it may play a role in personalizing drug selection. Methods: Patients treated with ABI or ENZ for mCRPC from September 2014 to June 2017 were identified in the VA and followed until April 2020. Frailty was assessed using the VA frailty index, which looks at ICD-10, CPT, and HCPCS codes to assign a standardized frailty score between 0-1. Patients were categorized as frail if their VA-FI scores were > 0.2. The primary outcome was overall survival (OS) between the ABI and ENZ treatment groups. Cox regression models included age, race, body mass index, PSA, and total Charlson Comorbidity Index (CCI). For frail patients, a propensity score-matched cohort was also created by matching age, race, CCI, and total VA-FI between ABI and ENZ treatment groups. Results: Of the 5,822 patients identified, 57% were initially treated with ABI and 43% with ENZ. The ABI group had a lower mean VA-FI score of 0.192 compared to the ENZ group of 0.203 (p=0.004). Frail patients were older: mean 74.9 years vs. 76.1 years for non-frail (p<0.001). Frail patients had shorter survival than non-frail (18.5 vs. 26.6 months, p<0.001). In multivariable models, frailty was associated with increased risk of death (aHR 1.32, 95% CI 1.23-1.42). Among non-frail patients (n=3508, 60.3%), there was no significant difference in OS between ABI and ENZ treatment. Among frail patients (n=2314, 39.7%), patients treated with ENZ had a 3.5 month greater median OS than ABI (20.7 vs. 17.2 months, p = 0.0003 by log-rank). In frail patients, ENZ was associated with reduced risk of death (aHR 0.85, 95% CI 0.78-0.94). In a propensity matched cohort of 2070 patients, the enzalutamide treatment group had a 3.2 months greater median OS in the enzalutamide group than the abiraterone group (24.1 months vs. 20.9 months, p < 0.001). Conclusions: ENZ was associated with improved OS compared to ABI among frail veterans, but not among non-frail veterans. The improved survival remained significant in a propensity score-matched cohort and models including important covariates. Further assessment of the value of frailty in personalizing drug treatment is warranted to improve the care of older adults with advanced prostate cancer.
The Lung Immune Prognostic Index (LIPI) stratifies prognostic groups and correlates with gut microbiota (GM) in patients with advanced renal cell carcinoma (RCC).
Authors: Silva Carolina Alves Costa , Zoppi Silvia , Reni Anna , Piccinno Gianmarco , Lahmar Imran , Cerbone Luigi , Carril-Ajuria Lucía , Colomba Emeline , Flippot Ronan , Sow Cissé , Segata Nicola , Escudier Bernard , Zitvogel Laurence , Albiges Laurence , Derosa Lisa 
Published: March 2023

719 Background: The LIPI score has been reported as an independent prognostic factor in RCC patients treated with immune checkpoint inhibitors (ICI) or tyrosine kinase inhibitors (TKI). Here, we aimed to correlate LIPI score and GM composition in patients with RCC. Methods: We prospectively collected fecal samples of all comers RCC patients who started a 1st or beyond line therapy (standard or clinical trial) in the NCT0457446 at Gustave Roussy. Neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were obtained from routine blood tests. Shot gun metagenomic sequencing (MGS) data were analyzed by multivariate and pair-wise/fold ratio . Clinical benefit ratio (CBR, complete response + partial response + stable disease, RECIST1.1) and overall survival (OS, from treatment start) were evaluated. Multivariate analysis (MVA) for OS included age, gender, therapy line, IMDC, histology, hypoalbuminemia. Results: From February 2016 to July 2021, 160 patients were screened and 102 were included. Median age was 61 years (22-89), patients were mostly males (75%) and clear cell histology (90%). Patients were treated in 1st (15%), 2nd (53%) and beyond (32%) lines. Treated with ICI monotherapy (65%), followed by TKI or mTOR (20%) and ICI combination (19%). IMDC was 32% good (G), 54% intermediate (I) and 14% poor (P) and LIPI was 69% G, 25% I and 6% P. Median OS was 42.9, 17.7 and 8.3 months in patients with LIPI G, I and P, respectively (p<0.0001) . Among IMDC risk groups, IMDC G + LIPI G had better OS compared to other subgroups (p=0.017), and those with IMDC P + LIPI P had the worse OS. Overall, LIPI G had higher rates of CBR than I+P LIPI (74% vs 50%; p=0.0158). At MVA, LIPI was independently associated with OS (HR 6.25, 2.02-24.34; p=0.0187). Overall, Parabacteroides merdae and Veillonella parvula were enriched in LIPI I+P, while LIPI G harbored Faecalibacterium prausnitzii. In patients treated with ICI monotherapy, LIPI I+P were enriched with Bacteroides spp ( P. merdae, Phocaeicola vulgatus), and LIPI G had an overrepresentation of Ruminococcaceae unclass bacterium. Conclusions: We report the first MGS study correlating LIPI score and GM composition in RCC patients. LIPI score correlates with clinical outcomes (OS and CBR) and helped to better-stratified IMDC risk groups. Patients LIPI G harbor health-related commensals, while I and P groups are associated with harmful ones. LIPI score could represent a clinically relevant score to stratify mRCC patients. Clinical trial information: NCT04567446 .
Alliance A031902 (CASPAR): A randomized phase (ph) 3 trial of enzalutamide with rucaparib/placebo in first-line metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rao Arpit , Heller Glenn , Ryan Charles J. , VanderWeele David James , Lewis Lionel D , Tan Alan , Watt Colleen , Chen Ronald C. , Kohli Manish , Barata Pedro C. , Gartrell Benjamin Adam , Grubb Robert , Dueck Amylou C. , Wen Yujia , Morris Michael J. 
Published: March 2023

TPS277 Background: Despite a growing number of treatment options for first-line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Co-inhibition of androgen receptor (AR) and PARP is a promising therapeutic strategy that leverages synthetic lethality induced by impaired double-strand DNA repair. Two phase III studies have shown improvement in radiographic progression-free survival (rPFS) in HRR-mutant pts with abiraterone + PARPi combinations vs abiraterone alone. However, the results in HRR-wild type pts are conflicting, with only one of the studies demonstrating a benefit with the abiraterone + PARPi combination. ENZ + RUCA has shown an acceptable safety profile & no significant drug-drug interactions (S-DDI) in a phase 1b trial. This allows its evaluation in mCRPC. Methods: CASPAR (A031902) is a phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue is available). Treatment will be continued until disease progression and crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. Hierarchical co-primary endpoints are overall survival (OS) and rPFS. The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA testing for HRR gene alterations. Enrollment began in July 2021 & the study is available for participation to all US-NCTN sites. Clinical trial information: NCT04455750 .
PRIMARY2: A phase III, multi-centre, randomised controlled trial investigating the additive diagnostic value of [68Ga]Ga-PSMA-11 PET/CT in men with negative/equivocal MRI in the diagnosis of clinically significant prostate cancer.
Authors: Buteau James Patrick , Moon Daniel , Fahey Michael T , Roberts Matthew , Thompson James , Murphy Declan G. , Papa Nathan , Mitchell Catherine , Kasivisvanathan Veeru , Stricker Phillip , O'Brien Jonathan , Counter William , Sharma Gaurav , Agrawal Shikha , Ho Bao , Yeung Theresa , De Abreu Lourenço Richard , Dhillon Haryana M. , Hofman Michael S , Emmett Louise 
Published: March 2023

TPS397 Background: Multi-parametric magnetic resonance imaging (MRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa), with superior diagnostic accuracy compared with transrectal ultrasound guided prostate biopsy alone. PRIMARY demonstrated significant improvement in sensitivity (97% vs 83%) and negative predictive value (91% vs 72%) with the addition of [68Ga]Ga-PSMA-11 PET/CT (PSMA PET/CT) vs MRI alone. Furthermore, 38% of patients with PI-RADS 2 or 3 were true negative on PSMA PET/CT, a population which may potentially benefit from avoiding transperineal prostate biopsy (TPPB). We hypothesize that the addition of PSMA PET/CT is non-inferior to MRI for the detection of sPCa in men with PI-RADS 2-3 disease, while providing the advantages of reducing unnecessary biopsies and limiting to targeted-only TPPB. Methods: This multi-centre, two-arm, randomized controlled, phase III trial will recruit 660 men with high clinical suspicion of sPC. Participants will be randomized in a 1:1 ratio in permuted blocks, stratified by center. In the experimental arm, participants will undergo a pelvic PSMA PET/CT. Local and central reviewers will interpret independently, based on the PRIMARY Score. Participants with a positive result will undergo targeted-TPPB, whereas those with negative PSMA PET/CT will avoid biopsy. In the control arm, all participants undergo template-TPPB. Patients will continue follow-up for subsequent clinical care for up to two years post-randomization. Key eligibility criteria include an MRI result of PI-RADS 2 with at least one red flag [PSA density >0.1, abnormal digital rectal examination (DRE), strong family history, BRCA mutation, PSA >10, PSA doubling time <36 months, PSA velocity >0.75/year], or PI-RADS 3, having never undergone a prostate biopsy, <cT3 on DRE, and PSA ≤20 ng/mL. The co-primary objectives are to estimate the percentage difference in sPCa between the experimental and control arms, and the percentage of participants who avoid TPPB in the experimental arm. The primary endpoints will be analyzed on the intention-to-treat principle. The main secondary objectives are the percentage difference between arms in insignificant prostate cancer, in complications following biopsy, in health-related quality of life, generalized anxiety, cancer worry, as well as the health economics impact. Patient enrolment began in March 2022, with recruitment expected to take 36 months. Clinical trial information: NCT05154162 .