bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of axitinib prior to partial nephrectomy to preserve renal function: An interim analysis of the PADRES clinical trial.
Authors: Hakimi Kevin , Campbell Steven , Nguyen Mimi , Rathi Nityam , Wang Luke , Rini Brian I. , Ornstein Moshe Chaim , McKay Rana R. , Derweesh Ithaar H 
Published: March 2023

683 Background: In renal cell carcinoma (RCC), partial nephrectomy (PN) is indicated for patients with solitary kidney, chronic kidney disease, or bilateral tumors. A subset of these patients, however, may have large and complex renal masses not initially suitable for PN. Neoadjuvant Tyrosine Kinase Inhibitor therapy has shown promising results in cytoreducing renal tumors and may permit PN in circumstances not otherwise feasible. Methods: This was a single arm phase II clinical trial of neoadjuvant axitinib in patients with complex (RENAL nephrometry score 10-12 and cT1b-cT3M0) biopsy-proven clear cell RCC with strong indications for partial nephrectomy (PN), and in whom radical nephrectomy may result in dialysis dependence. Axitinib 5 mg was administered orally twice daily for 8 weeks prior to surgery. Primary outcome was reduction in longest tumor diameter; secondary outcomes included tumor response (RECIST), change in RENAL score, feasibility of PN, change in estimated glomerular filtration rate (DeGFR), and post-surgical complications. Results: 26 patients were enrolled. 19 (73.1%) patients had ≥ clinical T3a staged tumors. Post therapy, 17 (65.4%) patients had ≥T3a staged tumors. Axitinib resulted in reductions in tumor size (7.7 vs. 6.3 cm, p<0.001) and RENAL score (11 vs. 10, p <0.001); 9 (34.6%) had partial response, and 17 (65.4%) stable disease by RECIST criteria. PN was successfully performed in 19 (73.1%); 24 (96.8%) achieved negative margins. Six (23.1%) had Clavien III-IV post-surgical complications. Median percentage DeGFR was 14.7%; one (3.8%) patient who had a radical nephrectomy had long-term dialysis dependence. Conclusions: Neoadjuvant axitnib resulted in significant reductions in tumor size and complexity, enabling PN in a cohort of complex renal masses, and with acceptable safety and functional preservation. Clinical trial information: NCT03438708 . [Table: see text]
Cabozantinib in combination with atezolizumab in non-clear cell renal cell carcinoma: Extended follow-up results of cohort 10 of the COSMIC-021 study.
Authors: McGregor Bradley Alexander , Agarwal Neeraj , Suárez Cristina , Tsao Kai , Kelly William Kevin , Pagliaro Lance C. , Vaishampayan Ulka N. , Castellano Daniel , Loriot Yohann , Xu Fiona , Andrianova Lana , Sudhagoni Ramu , Choueiri Toni K. , Pal Sumanta Monty 
Published: March 2023

684 Background: In the COSMIC-021 phase 1b study (NCT03170960) evaluating cabozantinib plus atezolizumab in advanced solid tumors, this combination therapy demonstrated encouraging clinical activity in patients with advanced non-clear cell renal cell carcinoma (nccRCC) with a median follow-up of 13 mo (Pal. JCO 2021). Results after extended follow-up in nccRCC are presented. Methods: Patients with advanced nccRCC and ECOG PS 0/1 who had ≤1 prior VEGFR-targeting tyrosine kinase inhibitor (TKI) were eligible. Prior treatment with TKIs targeting MET or immune checkpoint inhibitors was not allowed. Patients received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W until unacceptable toxicity or progression; dose reductions of cabozantinib (40 mg QD to 20 mg QD, then to 20 mg QOD) were permitted to manage adverse events. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by the investigator; other endpoints included safety, duration of response (DOR), PFS, and OS. Results: The study enrolled 32 patients with nccRCC (2 from dose escalation phase, and 30 from expansion phase of the study): median age, 62 y; male, 81%; ECOG PS 0/1, 75%/25%; histology, papillary/chromophobe/clear cell/other, 47%/28%/3%/22%; sarcomatoid feature, 13%; IMDC risk favorable/intermediate/poor, 50%/41%/9%; ≥3 tumor sites, 56%; tumor sites, lung/kidney/bone/liver, 50%/25%/16%/16%; prior nephrectomy, 63%; prior VEGFR TKI, 22%; 0/1 lines of prior therapy (locally advanced/metastatic setting), 81%/19%. As of July 21, 2022, median follow-up was 37.2 mo (range 32.1–58.5) with 5 (16%) patients remaining on study treatment. ORR by investigator was 31% (all PRs) and disease control rate was 94% (Table); median DOR was 8.1 mo. Median PFS was 9.3 mo (95% CI 5.5–12.3), and median OS was not reached (95% CI 23.0–NE). PFS and OS estimates at 12 mo were 34% and 84%, respectively; 24-mo estimates were 6% and 70%. Treatment-related AEs occurred in 97% (grade 3/4, 53%); the most common AEs included diarrhea (69%), palmar-plantar erythrodysesthesia (50%), fatigue (44%), dysgeusia (41%), hypertension (31%) and nausea (31%). One grade 5 treatment-related AE of pulmonary hemorrhage occurred. Treatment-related AEs leading to discontinuation of both study treatments occurred in 13% of patients. Conclusions: Extended 3-year follow-up reinforces the encouraging clinical activity of cabozantinib plus atezolizumab in advanced nccRCC with a manageable safety profile. Clinical trial information: NCT03170960 . [Table: see text]
The usefulness of meflin expression in cancer-associated fibroblasts as a predictive marker for immune checkpoint inhibitor in clear cell renal cell carcinoma.
Authors: Owaki Takayuki , Miyai Yuki , Naito Yushi , Sano Tomoyasu , Enomoto Atsushi 
Published: March 2023

699 Background: Tumor is composed of various cells, including not only cancer cells, but also immune cells, vascular endothelial cells and cancer associated fibroblasts (CAFs). CAFs generally work to promote cancer malignancy by secreting growth factors, promoting angiogenesis and producing extra cellular matrix. However, depletion of these CAFs accelerated tumor progression. Therefore, it is a common belief that there are two kinds of CAFs, cancer-promoting CAFs and cancer-restraining CAFs. Recently, our research group identified cancer-restraining CAFs expressing Meflin as a marker in pancreatic cancer. Furthermore, our research group reported that Meflin can be a good predictive marker for ICI in non-small cell lung cancer. This time, we performed a similar analysis for clear cell renal cell carcinoma (ccRCC), to confirm whether Meflin is universally a good predictive marker for ICI or not. Methods: This analysis was performed as a retrospective observational study and conducted in accordance with the Helsinki Declaration for Human Research and approved by the Ethics Committee of Nagoya University Graduate School of Medicine (approval number: 2020-0321).We identified 21 eligible patients with ccRCC who received ICI from 2017 to Mar 2019. We collected FFPE tissue and prepared 4–µm-thick slides for the analysis of Meflin expression by RNA in-situ hybridization (ISH). Then, we assessed the number of Meflin-positive CAFs and divided the patients into Meflin-high (15% and more CAFs express Meflin) and -Low groups, followed by the evaluation of the clinical outcomes, objective response rate (ORR) and overall survival (OS). Results: Patients were followed-up until the Aug 2022. 13 patients were divided into Meflin-high and 8 patients were divided into Meflin-low groups. Analysis revealed that 9 (69.23%) of 13 Meflin-high patients responded to ICI. In contrast, none (0%) of 8 Meflin-low patients showed any significant response (p-value: 0.0046). Furthermore, Kaplan–Meier survival analysis revealed, the Meflin-high group had a significantly favorable prognosis in OS (p-value:0.0137, hazard ratio 0.2959[0.06933 to 0.7097]). Conclusions: This analysis concluded that Meflin is a good predictive biomarker for ICI in ccRCC.
Dissecting the molecular signatures underlying hybrid oncocytic tumors in Birt-Hogg-Dubé syndrome.
Authors: Wang Xiaoming , Mannan Rahul , Zhang Yupin , Hogan Margaret , King Dana , Chinnaiyan Anya , Chinnaiyan Arul , Dhanasekaran Saravana , Mehra Rohit 
Published: March 2023

707 Background: Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of renal tumors including the hybrid oncocytic tumors (HOT), renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC). HOT are known to exhibit morphological features overlapping between RO and CHRCC. The molecular underpinnings of HOT and the corresponding morphologic correlates remain poorly understood. Herein we aimed to understand the distinct molecular features underlying HOT and how the genomic phenotype differs from CHRCC. Methods: We performed next generation sequencing and single cell sequencing analysis to understand the clinico-pathologic aspects and tumor biology of HOT and CHRCC, including tumor development. This was followed by spatial transcriptome analysis of the distinct HOT tumor compartments, using nanoString GeoMX digital spatial profiler. The candidate biomarker expression was confirmed by immunohistochemistry (IHC) and RNA in situ hybridization (RNA-ISH), a unique gene expression visualization molecular technology. Results: We discovered unique gene expression signatures underlying the two distinct morphological patterns seen in HOT. FOXI1 and L1CAM show a striking mutually exclusive expression pattern in the two cellular populations seen within this tumor. The signature genes of RO like cells seen within HOT resembles the principal cells of the distal nephron seen in normal kidney; and the signature genes of the CHRCC like cells resembles the intercalated cells of the distal nephron. This suggests distal nephron as the cellular site of origin for HOT. We also nominated tumor specific biomarkers for HOT. Conclusions: We identified unique gene expression signatures which are definitional for HOT and nominated candidate diagnostic biomarkers to help distinguish HOT from other renal tumor subtypes with overlapping morphology. This finding would improve the diagnostic accuracy, assist familial genetic monitoring, and facilitate disease management.
Burden of surgeries and surgical complications in patients with Von Hippel Lindau (VHL) disease before and after treatment with belzutifan.
Authors: Wang Lin , Bensimon Arielle G. , Sundaram Murali , Xu Ruifeng , Lai Yizhen , Liu Yanfang , Mt-Isa Shahrul , Yang Danni , Freimark Jonathan , Song Yan , Jonasch Eric 
Published: March 2023

733 Background: VHL disease is a rare hereditary condition that causes abnormal tumor growth in multiple organs, including renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (Hb), pancreatic neuroendocrine tumors (pNET), and other tumors. Repeated surgeries are often required due to ongoing tumor recurrences and can lead to complications such as chronic kidney disease, pancreatic insufficiency, and neurological deficit. Belzutifan is a hypoxia-inducible factor inhibitor approved in the US for the treatment of VHL-associated RCC, CNS Hb, or pNET not requiring immediate surgery. This study aimed to quantify the annual rate and costs of VHL-related surgeries and surgical complications before and after belzutifan initiation. Methods: Surgeries were observed during the periods before and after belzutifan initiation in the single-arm phase 2 LITESPARK-004 trial (NCT03401788) among adults with VHL-RCC. Rates of RCC surgeries were obtained by fitting exponential survival models to: time from treatment initiation to the next renal surgery; and time (looking backward) from treatment initiation to the most recent renal surgery before treatment. Rates of surgeries related to other VHL manifestations were calculated as number of surgeries divided by person-years at risk, using all available post-treatment follow up (151 person-years; median [range] per patient: 29.2 [4.2-37.5] months) and equivalent person-years in the pre-treatment period. Complication risks per surgery and unit costs of surgeries and complications were obtained from a retrospective study on VHL within the Optum Clinformatics Data Mart (2000-2020). Annual per-patient costs of surgeries and complications were estimated in 2020 US dollars over the pre- and post-treatment periods from a US third-party payer perspective. Results: Among trial participants (N=61), the rate of RCC surgeries (surgeries/person-year) decreased 87% (0.108 to 0.014) after belzutifan initiation. The rate of other surgeries decreased 98% (0.265 to 0.007), with CNS Hb surgeries decreasing from 0.185 to 0.007, pNET surgeries from 0.013 to 0, adrenal lesion surgeries from 0.007 to 0, and retinal Hb surgeries from 0.060 to 0. Belzutifan was accordingly estimated to reduce per-patient average annual costs of surgeries and complications from $57,259 to $2,536. Conclusions: Healthcare costs of surgeries and surgical complications are substantial among patients with VHL-RCC. In a trial-based cost-consequence analysis, belzutifan was estimated to decrease annual surgery and complication costs by 96%, based on observed reductions in VHL-related surgeries. [Table: see text]
Treatment and survival of de novo metastatic prostate cancer in US veterans.
Authors: Schoen Martin W. , Etzioni Ruth Douglas , Knoche Eric Marshall , Graff Julie N , Sanfilippo Kristen Marie , Luo Suhong , Eisen Seth A , Montgomery Robert Bruce 
Published: March 2023

87 Background: Combination therapies using the androgen deprivation therapy (ADT) backbone have revolutionized treatment of metastatic hormone sensitive prostate cancer (mHSPC). Combinations include ADT plus docetaxel (DOC) or the androgen receptor targeting agents (ARTAs) abiraterone (AA), enzalutamide (ENZ), apalutamide (APA), and darolutamide (DAR). This study evaluates the utilization of these therapies in de novo mHSPC in a cohort of veterans and assesses recent overall survival (OS) of these therapies. Methods: Veterans were identified from 2012-2021 in the Veterans Affairs Prostate Cancer Data Core (VAPC) and oncology tumor registries using the initial pathological diagnosis of prostate cancer with SEER stage ‘distant’. All veterans had ADT initiated within 1 month prior and 3 months after diagnosis in VAPC. Additional therapies including DOC or ARTAs were collected from VAPC if initiated from 1 month prior to 4 months after ADT initiation. Data cut point was June 2022. Results: 5,006 patients with de novo mHSPC were identified with median age of 73.1 years (yrs), and 1338 (26.7%) identified as Black race. From 2012 to 2021, ADT alone was used in 3,569 (71.3%) of veterans, DOC in 438 (8.7%) and ARTAs in 999 (20.0%), wherein use of different ARTAs was AA in 783 (78.4%), ENZ in 204 (20.4%), APA in 10 (1.0%), and DAR in 2 (0.2%). Use of combination therapy for mHSPC increased from 3.1% in 2012-2013 to 61.2% in 2020-2021. Use of DOC peaked in 2016 and was used in 16.3% of veterans that year. Veterans treated with DOC were significantly younger (median 67.3 yrs, p<0.001) compared to veterans treated with ARTAs (73.1 yrs) or ADT alone (74.3 yrs). Veterans treated with combination therapies had longer median OS compared to ADT alone (37.2 vs. 29.3 months, p<0.001), with no significant difference between DOC and ARTA combinations (p=0.84). For 2,042 veterans with de novo mHSPC treated from 2018-2021, median OS of veterans treated with ADT+DOC (n=161, 35.3 months) and ADT+ARTA (n=849, 41.2 months) was longer than ADT alone (n=1,032, 29.3 months, p<0.001). There was no significant difference in median OS between DOC and ARTA combinations in this group (p=0.69). Conclusions: In veterans presenting with de novo mHSPC, use of initial combination therapy has increased, with the majority of veterans treated with ADT and an ARTA in 2020-2021. In this cohort, combination therapy was associated with longer OS compared to ADT alone and no significant differences were found between type of combination and OS. [Table: see text]
Identifying prostate cancer patient subgroups based on their preferences for key attributes of androgen deprivation therapies.
Authors: Collins Sean P. , Maculaitis Martine C. , Hauber Brett , Hunsche Elke , Kopenhafer Lewis , Nwokeji Esmond , Beusterien Kathleen M. 
Published: March 2023

94 Background: Androgen deprivation therapies (ADTs) for prostate cancer (PC) vary in delivery mode, T (testosterone) surge occurrence, time to T recovery, adverse event profile, and costs. Data are limited on how men differ in their evaluation of ADT attributes. This study identified subgroups of men who vary in their preferences for key ADT attributes. Methods: A cross-sectional survey of US men aged >40 years, who had healthcare coverage for the past 3 years and self-reported a PC diagnosis, were recruited via healthcare research panels. Men were ineligible if they did not know/recall whether they had received ADT or were unable to complete the survey independently. Quotas ensured an approximate even split of ADT-experienced and ADT-naïve men. A discrete choice experiment assessed preferences for ADT attributes. In a series of choice tasks, men were presented with 2 ADT treatment profiles side-by-side and asked to select the one they prefer. Hierarchical Bayes models computed attribute level preference weights. Relative importance (RI), based on differences between the most and least favorable attribute level preference weight and standardized to sum to 100%, was estimated for each attribute; the higher the RI value, the more influential an attribute is to treatment choice. Latent class analysis (LCA) identified groups (Gs) of men with similar ADT preferences. Results: 304 men were included in the analyses, their mean age was 64.4±7.2 years, and 16.8% were African American. Mean PC duration was 5.4±4.8 years, 55.3% reported organ-confined PC, and 49.0% had prior ADT use. LCA identified 4 preference Gs. While impact on sexual activity was most important to G1, out-of-pocket (OOP) costs, mode of administration, and time to T recovery were choice drivers for G2. Mode of administration and OOP costs predominated in importance for G3 and G4, respectively. More than half of men in G1 and G3 were <65 years; G1, but not G3, included mainly men who planned to be sexually active. G2 and G4 were predominantly composed of men aged ≥65 years who often had Medicare insurance. Conclusions: Younger, sexually active men consider the potential impact on sexual activity when choosing PC therapy, while for older men administration burden or OOP costs are important choice drivers. Thus, ADT attributes often vary in salience to men and should be considered in shared PC treatment decision-making. [Table: see text]
Real world (rw) racial differences in treatment (tx) patterns and clinical outcomes among patients (pts) with mCRPC.
Authors: Barata Pedro C. , Du Ella X. , Yang Hongbo , Xu Chunyi , Guo Helen , Cui Caroline , Nazari Jonathan , Niyazov Alexander 
Published: March 2023

95 Background: Contemporary rw data is needed to describe the heterogeneity of the tx landscape among diverse pt populations. This study assessed rw tx patterns and clinical outcomes among US pts receiving tx for mCRPC. Methods: Data from pts with mCRPC initiating first line (1L) tx between 2016 and 2019 were abstracted from medical charts. Clinical characteristics and tx patterns stratified by race (White [W], Black [B], and Other [O]) were compared using descriptive statistics. Rw progression-free survival (rwPFS) and overall survival (OS) were analyzed using Kaplan–Meier method. A multivariate Cox model explored associations between race and rwPFS/OS, controlling for confounders. Results: 122 physicians contributed data from 260 charts (W n=127, B n=81, O n=52 pts). The median age was 69 years; 64 (25%) had ECOG score ≥2. Common sites of metastases (mets) were bone (73%) and lymph nodes (34%); median Gleason score (GS) was 8.0, with no significant differences in sites of mets or GS among B and W pts. Most common txs prior to mCRPC included androgen deprivation therapy (ADT) monotherapy (39%), chemotherapy (CT; 15%), and novel hormonal therapy (NHT; 9%). Prior to mCRPC, more B pts were offered tx intensification with NHTs or CT compared with W pts (35% vs 14%). NHT was the most common 1L mCRPC therapy, followed by CT (Table). Compared with W pts, more B pts were offered NHT (65% vs 59%, P=0.44) and CT (26% vs 20%, P=0.38) in the 1L setting. Adjusted median rwPFS on 1L tx was 43.7 months (mo; 95% CI: 27–not estimable [NE]). A longer rwPFS was observed for B vs W pts; median rwPFS NE (95% CI: 34.7–NE) vs 34.7 mo (95% CI: 21.0–NE), hazard ratio (HR)=0.58 (95% CI: 0.35–0.97; P<0.05). B pts had numerically greater OS vs W pts, HR=0.58 (95% CI: 0.31–1.1; P=0.09). Conclusions: In this rw study of pts receiving 1L tx for mCRPC, rwPFS was better compared with clinical trial data, particularly among B pts, who were more likely to receive life-prolonging txs in the 1L setting. These data suggest B pts might respond better to systemic therapies compared with W pts, and disparities observed in other settings may be attributed to access barriers. [Table: see text]
Final overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy (chemo) in untreated locally advanced or metastatic urothelial carcinoma (mUC) from the Phase 3 IMvigor130 study.
Authors: Bamias Aristotelis , Davis Ian D. , Galsky Matt D. , Arranz Arija Jose Angel , Kikuchi Eiji , Grande Enrique , Garcia del Muro Xavier , Park Se Hoon , De Giorgi Ugo , Alekseev Boris , Mencinger Marina , Izumi Kouji , Puente Javier , Li Jian-Ri , Bene-Tchaleu Fabiola , Mariathasan Sanjeev , Lee Chooi Peng , Bernhard Sandrine , De Santis Maria 
Published: March 2023

LBA441 Background: Two interim OS analyses from IMvigor130 demonstrated non-statistically significant OS benefit with atezo monotherapy (Arm B) vs placebo + platinum (investigator [INV] choice of carboplatin or cisplatin [carbo or cis])/gemcitabine (plt/gem; Arm C) in patients (pts) with PD-L1–high (IC2/3) mUC, as well as a favorable safety profile vs chemo (Galsky Lancet 2020, Davis AACR 2021). Exploratory data showed clinical benefit with atezo monotherapy in cis-ineligible pts with IC2/3 tumors. Here, we report the final OS analysis from IMvigor130 Arms B and C. Methods: Pts were randomly assigned 1:1:1 to Arm A (atezo + plt/gem; not reported here), B or C. Due to the statistical testing hierarchy, no formal comparison of OS (co-primary endpoint) in Arm B vs C was performed in ITT and IC2/3 pts. ORR and DOR, both per INV-assessed RECIST 1.1 (secondary endpoints), and safety were assessed. Subgroup analyses of OS in cis-ineligible pts and disease control rate (DCR, confirmed CR, PR or [SD ≥6 mo]) were exploratory. Results: As of data cutoff Aug 31, 2022, time since last pt randomly assigned was 49 mo. OS data (Table) did not show benefit for ITT pts, while an HR of 0.56 (0.34, 0.91) was seen in the cis-ineligible IC2/3 subgroup. In the ITT population, the 24-mo OS rates were 34% in Arm B and 32% in Arm C. ORR was 24% (87/359; 38% DCR) in Arm B and 44% (158/356; 59% DCR) in Arm C; median DOR was 29.6 and 8.1 mo, respectively. In cis-ineligible IC2/3 pts, ORR was 40% (20/50) in Arm B and 33% (14/43) in Arm C. Median DOR was not evaluable in Arm B and 6.2 mo in Arm C. Of safety-evaluable pts, 57 of 354 in Arm B (16%) and 312 of 389 in Arm C (80%) had a Gr 3/4 treatment-related AE (TRAE); 3 (1%) and 4 (1%), respectively, had a Gr 5 TRAE. Gr 3/4 AEs of special interest occurred in 36 pts (10%) in Arm B and 17 (4%) in Arm C. Conclusions: The final OS analysis was consistent with previous data. Atezo monotherapy continued to show better tolerability vs chemo with no new safety concerns. These exploratory data support the benefit-risk ratio of atezo monotherapy vs chemo for first-line cis-ineligible IC2/3 mUC. Clinical trial information: NCT02807636 . [Table: see text]