bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural network analysis of tumor and germline profiling to predict survival of muscle-invasive bladder cancer following radical cystectomy: An analysis of the Cancer Genome Atlas (TCGA).
Authors: Sonpavde Guru P. , Sadler Layne , Ravi Arvind , Nassar Amin , Lerner Seth P. , Varambally Sooryanarayana 
Published: March 2023

546 Background: Following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), recurrence is suboptimally associated with pathologic stage. A prognostic model that incorporates information from comprehensive genomic and transcriptomic data from germline and tumor tissues will improve the selection of high-risk patients (pts) for adjuvant therapy and tailored surveillance. Methods: Pts with MIBC in TCGA who underwent RC (without neoadjuvant chemotherapy) and with whole exome sequencing (WES) of tumor + normal, and tumor RNA-Seq were eligible. Germline variants were called and annotated using GATK4 and Variant Effect Predictor (VEP). Only high and moderate VEP-Impact variants contributed to burdens. Given that recurrence is associated with 5-year survival, pts were required to have data for survival at a landmark of 5 years post-RC or may have died within 5 years of RC. Patients who died <4 months of diagnosis were excluded since they may have died from post-operative complications. Dead patients were propensity-matched against alive patients by pathologic stage, adjuvant chemotherapy, gender, race, age and smoking. A linear artificial neural network was trained to predict 5-year survival using Artificial Intelligence Quality Control (AIQC)-a deep learning experience tracker. The samples were divided into 3 equally distributed subsets of alive and dead pts. The algorithm was trained on 50% of the dataset, evaluated on 40% and tested on 10%. The remaining 39 dead pts were used for additional holdout validation. The accuracy (percentage of correct prediction of death or survival) was reported. Results: A cohort of 117 pts were evaluable for 5 year survival. The cohort included 39 survivors that satisfied inclusion criteria, and 78 dead pts that were propensity matched against them (one set of 39 dead pts for training & evaluation, and a second set of 39 dead pts as an additional holdout). The binary classification neural network was trained on 38 samples to predict survival based on their most differentiated: germline alteration burdens + tumor alteration burdens + tumor gene expression. The differentially mutated genes most important to the algorithm were: PTPRN(n-m), TECTA(t-m), BPIFB1(n-m), SORL1(n-m), SLC39A5(n-m), and RBBP6(n-h) [t=tumor/ n=normal tissue origin | m=moderate/ h=high VEP impact]. The algorithm was 97% accurate on the 38 training samples, and 94% accurate across the 79 evaluation (validation, test and holdout) samples. Conclusions: Neural network analysis of germline and tumor profiling was validated to optimally differentiate between dead and surviving pts at 5 years following RC for MIBC. Further validation and application of this promising algorithm may advance precision medicine by permitting the selection of the most appropriate pts with high-risk MIBC for adjuvant therapy.
Risk analysis of open vs. robotic assisted radical cystectomy.
Authors: Simhal Rishabh Kumar , Wang Kerith Ruoyao , Shah Yash , Simon Daniel P , Mark James Ryan , Shah Mihir S , Gomella Leonard G. , Chandrasekar Thenappan , Lallas Costas D. 
Published: March 2023

576 Background: Radical cystectomy (RC) is standard of care for muscle-invasive bladder cancer, but it comes with significant perioperative risk with half of patients experiencing major postoperative complications. Robot-assisted radical cystectomies (RARC) have aimed to decrease patient morbidity and have become increasingly adopted in North America. Currently, both open radical cystectomies (ORC) and RARC are frequently performed. To contribute to the existing literature using newly available data from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP), representing one of the most recent, largest multi-institutional studies, while uniquely accounting for a variety of factors including type of urinary diversion, cancer staging, and neoadjuvant chemotherapy. Methods: RC procedures performed between 2019-2020 were identified in NSQIP and the corresponding Cystectomy Targeted database. Cases in the ORC group were planned open procedures, and cases in the RARC group were robotic with intra- or extracorporeal diversions, including unplanned conversion to open cases for intention-to-treat. Chi-square and t-tests were performed to compare baseline demographics and operative parameters. Multivariate analysis was performed for outcomes including major complications, minor complications, and 30-day mortality, while adjusting for operative approach, medical comorbidities, functional status, age, race, sex, BMI, ASA-classification, preoperative labs, type of urinary diversion, pathological staging, prior pelvic surgery or radiation, need for preoperative transfusion, preoperative sepsis, emergent or elective surgery, and recent chemotherapy. Results: 4,022 RC cases were identified. Of these, 3,146 (78.2%) received planned ORC while 876 (21.8%) received RARC. Baseline demographics of the patients who received ORC versus RARC were largely similar, with no significant difference in age or medical comorbidities. RARC was associated with longer operative times and shorter hospital length of stay compared to ORC. On multivariate analysis, ORC was associated with a higher rate of 30-day mortality [OR 3.1; 95% CI 1.3-7.2; p=0.009], reintubation, cardiac arrest, superficial wound infection, bleeding requiring transfusion [OR 4.7; 95%CI 3.6 - 6.1; p<0.001], prolonged postoperative nasogastric tube use, rectal injury, and ureteral fistula or urine leak compared to RARC. Conclusions: In the NSQIP database, ORC is associated with higher rates of 30-day mortality and operative complications, most notably bleeding, compared to RARC. This study is unique in the size of the cohorts compared, the timeliness of the data (2019-2020), and the ability to control for factors, such as type of urinary diversion, pathological bladder cancer staging, and use of neoadjuvant chemotherapy.
Changes in planned disease management after piflufolastat F18 PET/CT in men with biochemically recurrent prostate cancer and low PSA levels: A secondary analysis of results from the CONDOR study.
Authors: Pouliot Frederic , Gorin Michael A. , Rowe Steven P. , Saperstein Lawrence , Denes Bela Stephen , DiPippo Vincent A. , Stambler Nancy , Morris Michael J. , Siegel Barry A. 
Published: March 2023

61 Background: Piflufolastat F 18 is a PSMA-targeted radiopharmaceutical approved in the US for imaging prostate cancer (PCa) patients both at the time of initial staging and at disease recurrence. In a phase 3 study of patients with biochemically recurrent (BCR) PCa, we reported that nearly two-thirds (63.9%; 131/205) of participants had a change in their intended disease management plan based on pre- and post-piflulfolastat F 18 PET/CT management questionnaires (MMQs) completed by the treating physicians. The clinical utility of piflufolastat F 18 scanning in men with very low/low PSA levels (<0.5 ng/mL) and a detection rate of ~36% has not been previously described. Here we report the changes in intended management in this subset of patients. Methods: Men ≥18 years of age with a rising PSA after definitive PCa therapy and negative or equivocal imaging were enrolled. A single ~9 mCi (333 MBq) dose of piflufolastat F 18 was administered followed by PET/CT from mid-thigh through skull vertex 1-2 hours later. Prior to scanning, the treating physicians completed a pre-PET MMQ to document the initial intended management plan for their patients based on available clinical information including baseline conventional imaging results. After PET, they completed a post-PET MMQ and recorded the management plan in light of PET findings. Treatment recommendations that differed from the pre-scan recommendations were reported as changes in the intended management plan. Results: 208 men (median PSA 0.8 ng/mL [range 0.17-98.45], n=202) underwent piflufolastat F 18-PET/CT. 200 evaluable patients had both a baseline PSA value and completed MMQs. Of 131 patients with a recorded change in intended management, 127 had an evaluable baseline PSA level. Of the 69 patients with baseline PSA levels ≤0.5ng/mL, 27 (39.1%) recorded a change in intended disease management based on positive (n=20) or negative (n=7) PET, including salvage local to systemic therapy (n=15); systemic to local therapy (n=3); observation to treatment (n=5); and treatment to observation (n=4). An additional 15 patients (21.7%) had recommended bidirectional change in management (e.g., salvage RT+ADT) and are excluded in this report. Specific treatment intensification/de-intensification plans are under investigation. Conclusions: The frequency of changes in intended disease management observed in BCR PCa patients with low baseline PSA levels (≤0.5ng/mL) was 39.1%. Both negative and positive PET/CT results impacted treatment recommendations and can provide useful and actionable information. Clinical trial information: NCT02981368 .
Evolution of systemic therapy from 2015 to 2019 for older patients in the United States with metastatic renal cell carcinoma.
Authors: Chow Ryan Dz-Wei , Long Jessica B. , Hassan Sirad , Wheeler Stephanie B. , Spees Lisa , Leapman Michael , Hurwitz Michael E. , McManus Hannah Dzimitrowicz , Gross Cary Philip , Dinan Michaela Ann 
Published: March 2023

610 Background: Immune checkpoint inhibitors (IOs) and oral anti-cancer agents (OAAs) have demonstrated survival improvements in randomized trials of patients with metastatic renal cell carcinoma (mRCC). IOs were approved as second-line mRCC therapy in 2015 (nivolumab), followed by first-line approval in 2018 (ipilimumab/nivolumab). Real-world changes in overall treatment rates and IO usage have not been examined in patients over 65, who are often underrepresented in trials. Disparities in mRCC outcomes have persisted in the era of these novel therapies, raising the question of whether receipt of IOs and OAAs varies by race and ethnicity. Methods: We conducted a retrospective cohort study of Medicare beneficiaries over age 65 diagnosed with mRCC from 2015 through 2019 who were enrolled in fee-for-service Medicare Parts A, B, and D from 1 year prior to diagnosis through 1 year after presumed diagnosis or until death. We identified our cohort using diagnosis codes for primary or secondary kidney malignancy. We queried claims from 2014-2020, identifying receipt of IO, OAA, or other systemic therapies in the 2 months before through 1 year after diagnosis. Patients that received both IOs and OAAs were categorized as IO if both therapies were started within 60 days; otherwise, patients were categorized by the first therapy received. We assessed trends in treatment from 2015-2019, stratifying by race and ethnicity to compare non-Hispanic White (NHW) patients with Hispanic, Black, Asian, Pacific Islander, American Indian, Native Alaskan, or Other patients (grouped as non-NHW due to limited sample sizes). Results: We identified 15,407 patients who were diagnosed with mRCC between 2015-2019 and met study criteria. Non-Hispanic White patients comprised 84% of our sample. Receipt of IOs increased from 4% of patients in 2015 to 37% in 2019 ( P < .001). Among NHW patients, IO treatment receipt increased from 4% in 2015 to 38% in 2019 ( P < .001); for non-NHW patients, IO receipt grew from 3% in 2015 to 31% in 2019 ( P < .001). OAA usage decreased over time, from 31% of all patients in 2015 to 11% in 2019 ( P < .001). The percent of NHW patients treated with any systemic therapy increased from 51% in 2015 to 60% in 2019 ( P < .001), while there was no significant change for non-NHW patients (51% in 2015 to 54% in 2019; P = 0.27). Conclusions: Among Medicare beneficiaries, receipt of IO therapy for mRCC increased from 2015-2019. Receipt of any systemic therapy significantly increased over time for NHW patients, but not for non-NHW patients. [Table: see text]
CARINA interim analysis: A non-interventional study of real-world treatment sequencing and outcomes in patients with advanced renal cell carcinoma initiated on first-line checkpoint inhibitor-based combination therapy.
Authors: Nathan Paul D. , Allison Jennifer , Charnley Natalie , Michael Agnieszka , Moore Kathryn , Sharma Anand , Klair Bhupinder , Perrot Valérie , Larkin James 
Published: March 2023

626 Background: First-line (1L) checkpoint inhibitor (CPI)-based combinations have become standard of care for patients with advanced renal cell carcinoma (aRCC). Data are required to inform optimal sequencing of aRCC therapies. CARINA is a non-interventional study of treatment sequencing and outcomes in patients with aRCC initiated on 1L CPI-based combination therapy. We report the results of a pre-planned interim analysis. Methods: We reviewed electronic prescribing records from participating UK specialist centers to identify patients (aged ≥ 18 years) with aRCC who received 2L therapy after 1L CPI-based combination therapy. The primary objective was to determine the treatment pathway for patients with aRCC who initiated treatment with a CPI-based combination and received subsequent therapy. Secondary objectives included treatment duration and objective response rate (ORR). Outcomes were evaluated for all patients (enrolled population [EP]) and for the patient subgroup who received 2L cabozantinib. Results: In total, 129 patients were eligible for inclusion in this interim analysis of the EP (mean [SD] age at diagnosis, 60.0 [9.9] years; 75.2% male; 77.3% clear-cell aRCC). Of these patients, 82.9% received 1L ipilimumab + nivolumab (Ipi + Nivo, n = 107) and 17.1% received axitinib + avelumab (Axi + Ave, n = 22); median (95% CI) duration of 1L treatment was 10.2 (9.1–17.1) weeks, ORR was 18.4%. The most commonly prescribed 2L therapies after Ipi + Nivo were cabozantinib (74.8%) and sunitinib (13.1%); the most commonly prescribed 2L therapies after Axi + Ave were lenvatinib + everolimus (45.5%) and cabozantinib (31.8%). Median (95% CI) duration of all 2L therapies was 23.6 (14.0–28.3) weeks, and median duration of 2L cabozantinib was 28.1 (20.1–37.1) weeks. ORR to 2L therapy was 30.4% for the EP, and 38.8% for the subgroup of patients who received 2L cabozantinib. Conclusions: In this interim analysis, the most commonly prescribed 2L therapies were cabozantinib and sunitinib after Ipi + Nivo, and lenvatinib + everolimus and cabozantinib after Axi + Ave. Antitumor response with 2L cabozantinib was observed after prior CPI-based therapy. Clinical trial information: NCT04957160 .
Financial toxicity in patients with metastatic renal cell carcinoma on combination therapy.
Authors: Staehler Michael D. , Ebrahimi Hedyeh , Vaishampayan Ulka N. , Rodler Severin , Pal Sumanta Monty , Battle Dena 
Published: March 2023

651 Background: Combination therapy based on immunotherapy (IO) alone or in combination with oral tyrosine kinase inhibitors (TKI) has become the standard of frontline therapy in metastatic renal cell carcinoma (RCC). We sought to ascertain real world data on financial implications in RCC patients on combination therapy. Methods: An online survey was administered by Kidney Cancer Research Alliance (KCCure), a non-profit patient advocacy group, between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Multiple responses from the same patient were prohibited via anonymized IP address tracking. Select questions were directed at questions related to financial concerns as well as the validated 11-item COST measure and out-of-pocket spending patterns related to supplement purchases. Pearson’s correlation (r) and Kendal’s tau test were used to analyze the COST questionnaire, financial burden and hardship. Significance levels were 2 tailed. Results: 289 responders were on combination therapy (IO+IO or IO+TKI) (M:F, 145:143). Median age was 61 (range 19-89). 177 pts answered the COST questionnaire. Patients identified themselves as white (91%), living in the US (86.8%) and had a bachelor's degree or beyond (52.9%). 21.1%, 46.1%, and 32.6% lived in urban, suburban, and rural locations. The approximate annual household income was <50.000US$ in 17%, <100,000US$ in 41% and >200,000US$ in 15%. 61% had private insurance, 27% were on Medicare/Medicaid and 0.6% were uninsured. 14% reported that it was difficult or very difficult to pay their premiums. 31% were retired and 24% not able to work. 28% reported that their medical situation has not reduced their income at all and 26% claimed that their disease reduced their income very much. Significant financial, medical, behavioral, psychological and emotional hardship was reported by 15%, 26%, 12%, 19% and 24% of the patients respectively. The monthly out of pocket costs were independent of type of therapy with 50% of the patients reporting spendings of <50US$. 36% reported high out of pocket costs are a barrier to care. 44% have received financial support through a manufacturer or a foundation.22.4% of responders reported spending >$100/month on supplements, and 8.3% reported spending >$250/mo. Median COST score was 22 (range 4-36). COST score was significantly correlated to age, NCCN distress score, time since diagnosis and supplement intake (p<0.05). Conclusions: Systemic therapy imposes financial hardship on patients but does not seem to be worse with combination therapy in RCC. Route of administration is not influencing financial hardship. Patients are willing to pay for out supplements if their treatment is not causing financial harm.
Effect of RRx-001 on nephrotoxicity of cisplatin/etoposide in patients with solid tumors.
Authors: Abrouk Nacer , Cabrales Pedro , Oronsky Bryan , Caroen Scott , Reid Tony R. 
Published: March 2023

657 Background: RRx-001 is a small molecule anticancer agent that preclinically protects non-malignant tissues, but not tumors, against the cytotoxicities of chemotherapy and radiation. In a completed, multicenter Phase 2 trial, QUADRUPLE THREAT, patients with previously platinum-treated extrapulmonary small cell cancer (SCC), high-grade neuroendocrine carcinoma (HGNEC), non-small cell lung cancer (NSCLC), and genitourinary cancer (GUC) received 4 mg IV RRx-001 followed by etoposide plus cisplatin or carboplatin (EP). In addition to overall survival (OS), and progression-free survival (PFS), this study also evaluated the possible prevention of nephrotoxicity by RRx-001. Methods: 90 patients with SCC, HGNEC, NSCLC, and GUC that previously received ≥2 lines of therapy including a platinum doublet were treated with 4 mg RRx-001 IV once per week. At progression, RRx-001 was discontinued and 40 patients were re-challenged with IV etoposide 80-100 mg/m2 (Days 1, 2, and 3) and cisplatin 60-80 mg/m2 on Day 1 for 4-6 cycles. The co-primary endpoints were PFS and OS. For all patients, serum creatinine (Cr), blood urea nitrogen (BUN), and electrolytes were determined prior to, during and after each treatment cycle. Results: After 2 cycles of chemotherapy, no patients experienced BUN elevations above 20 mg/dL and creatinine beyond 1.5 mg/dL. After four cycles of chemotherapy, 36/40 (90%) patients experienced no elevations of BUN above 20 mg/dL and creatinine above 1.5 mg/dL and none of the patients experienced > Grade 2 elevations of creatinine. 1/40 (2.5%) patients experienced Grade 3 hypomagnesemia (0 Grade 4). 3/40 (7.5%) patients were dose reduced or withdrawn from the trial due to platinum-related adverse events. No patients experienced renal-related serious adverse events (SAEs). One patient experienced a renal failure SAE, which was not drug related. The cumulative OS and PFS median of all the tumor types were 8.6 and 6.4 months, respectively. Conclusions: 20%-35% of patients develop acute kidney injury after cisplatin administration. Based on published clinical literature, approximately 33% of patients experience kidney injury just days following initial treatment (p = 0.0034, two-sided chi-square test comparing our study nephrotoxicity of 10% (4/40) in the first four cycles against 33% historical rate), and 20% of patients taking high-dose cisplatin experience severe renal dysfunction. The nephrotoxic effect of cisplatin is cumulative. In this heavily platinum-treated population, none of the patients were ineligible to receive cisplatin as scheduled because their serum creatinine levels had failed to return to < or = 1.5 mg/dL. RRx-001 pretreatment did not affect the antitumor effects of EP as assessed by PFS and OS. This dose of RRx-001 warrants further evaluation as a nephroprotectant that reduces the cumulative renotoxic effects of cisplatin but not its antitumor efficacy. Clinical trial information: NCT02489903 .
Evaluation of the safety and effectiveness of cryoablation in the treatment of renal angiomyolipoma related to tuberous sclerosis complex: The Cryo-TSC.
Authors: Kashiwagi Eiji , Hatano Takashi , Shimiz Kanichiro , Takamoto Atsushi , Tomita Koji , Osawa Takahiro , Sakuhara Yusuke , Hongo Fumiya , Hirota Tatsuya , Ushijima Yasuhiro , Asayama Yoshiki , Miki Jun , Kiyomi Fumiaki , Egawa Shin , Nasu Yasutomo , Shinohara Nobuo , Ukimura Osamu , Nakano Shuji , Arai Yasuaki , Eto Masatoshi 
Published: March 2023

669 Background: Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease. Approximately 60%–80% of patients with TSC have bilateral angiomyolipoma (AML). Cryotherapy is one treatment option for renal tumors, but the safety and efficacy of cryotherapy for TSC–AML is not clear. We planned this study to establish the safety and efficacy of cryotherapy for TSC–AML. Methods: This was an open-label, single-arm phase II study to evaluate the safety and efficacy of cryotherapy for TSC–AML of 4 cm or less in diameter in patients at least 16 years old. The exclusion criteria were an inability to withdraw from mTOR inhibitor and failure to maintain rest during cryotherapy. mTOR inhibitors were withdrawn at least 7 days prior to cryotherapy and discontinued during the study period. Cryotherapy was performed using Cryohit (Galil Medical LTD, USA). Safety was assessed at 1, 2, 6, and 9 months after cryotherapy, and efficacy was assessed at 3 and 9 months after cryotherapy. The efficacy of cryotherapy was evaluated according to the modified RECIST or RECIST criteria. The primary endpoint was the disease control rate, and secondary endpoints included the overall response rate, safety, renal function, quality of life, and need for additional treatment. Results: The disease control and overall response rates were 100% and 93.3%, respectively. After 9 months of follow-up, the median creatine level was slightly increased by 0.06 mg/dL. Quality of life was stable, and no additional treatment was needed. Three Grade 3 adverse events (hematuria, chronic kidney disease, and aspartate aminotransferase elevation) were observed in three patients. Conclusions: Cryoablation is a safe and effective treatment option for TSC–AML. Clinical trial information: jRCTs072200039 .