bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathologic and radiographic outcomes following prostate cancer diagnosis aided by IsoPSA testing.
Authors: Benidir Tarik , Hofmann Martin , Lone Zaeem M , Weight Christopher , Klein Eric A. 
Published: February 2022

276 Background: IsoPSA is a structure-based assay previously demonstrated to outperform prostate specific antigen (PSA) and free-to-total PSA ratio in detecting clinically significant prostate cancer at the time of biopsy (Stovsky, Klein 2019). Herein we report pathologic outcomes in patients treated via radical prostatectomy (RP) whom had undergone IsoPSA testing prior to their diagnostic biopsy. We also explore IsoPSA status in the context of MRI dependent findings, including PIRADS scores and PSA density. Methods: We conducted a retrospective review of patients whom had undergone IsoPSA testing prior to biopsy and RP at our institution between 2019-2021. We also identified subsets of patients with pre-operative prostate MRI’s. Exploratory analyses were performed to determine associations between IsoPSA and adverse histologic (cribiform, intraductal status (CB/ID), grade group status) pathologic (extraprostatic extension, seminal vesicle involvement, surgical margins) and radiographic (PSA density, PIRADS, location) features. We examined these data points in a randomly selected control group of RP patients whom had not had IsoPSA testing. Student’s T-test, Mann Whitney U, Kruskal Wallis, were used where appropriate. Results: A total of 83 patients underwent RP following IsoPSA testing, with 72.2% (60/83) also undergoing pre-operative prostate MRI. The mean total PSA was 10.3 ng/dL, IsoPSA index was 10.2 and prostate size 46.8 cc. IsoPSA was significantly associated with PSA density (median IsoPSA of 9.9 vs 7.8 for PSA density > 0.15, <0.15 respectively, p < 0.001). The median IsoPSA index was higher when the dominant tumor was found in the transitional zone versus peripheral zone (12.7 vs 8.8 p = 0.011). IsoPSA trended towards but was not associated with PIRADS-v2 score (1-2 vs 3 vs 4-5) (p = 0.1). IsoPSA was not selectively associated with adverse pathological or histological features. Conclusions: IsoPSA has been shown to predict clinically significant disease on biopsy, and as such may improve the selection of men for such intervention. In our initial cohort, IsoPSA reliably identified patients with clinically significant disease without selecting for unique adverse pathologic/histologic features when compared to a control group. Radiographically, IsoPSA was significantly associated with elevated PSA density ( > 0.15), tumor location (TZ vs PZ), and trended towards significance with PIRADS v.2 score (p = 0.1. Further work is encouraged to explore its adjunctive benefit in correlation to MRI features.
Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC) in CheckMate 214: Five-year follow-up results.
Authors: Cella David , Choueiri Toni K. , Hamilton Melissa , Ejzykowicz Flavia , Blum Steven I. , Ivanescu Cristina , Motzer Robert J. 
Published: February 2022

307 Background: Nivolumab + ipilimumab (N+I) demonstrated durable, long-term survival in the phase 3 CheckMate 214 trial as first-line treatment for intermediate/poor (I/P)-risk patients (pts) with aRCC. After a minimum follow-up of 5 years, N+I maintained superior overall survival and response benefits vs sunitinib (S) in both I/P-risk pts and across all randomized pts. We report the HRQoL results from the 5-year follow-up. Methods: Pts were randomized 1:1 to receive N 3 mg/kg + I 1 mg/kg every 3 weeks (wks) for 4 cycles followed by N 3 mg/kg every 2 wks or S 50 mg/d orally for 4 wks (6-wk cycle). HRQoL was assessed using the FKSI-19, FACT-G, and EQ-5D-3L instruments at baseline (BL) and on day 1 of wks 1 and 4 of the first 2 cycles, on day 1 of wks 1 and 5 of the next 2 cycles, and on day 1 of wk 1 of subsequent cycles. The analyses included mixed-model repeated measures (MMRM) for change from BL across 59 months (while on-treatment) and time to confirmed deterioration (TCD). Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). Results: 1096 pts were randomized to N+I (I/P-risk: 425; favorable [F]-risk: 125) and S (I/P-risk: 422; F-risk: 124). In the overall and I/P-risk populations, N+I pts reported improved mean FKSI-19 total scores over time compared with a decline observed with S. Overall changes from BL through 59 months favored N+I over S with significant differences between arms observed for all outcomes (Table). Median TCD was significantly longer with N+I vs S for all FKSI-19 scores, as well as FACT-G total and physical domains for both populations ( P < 0.05). Pts in the N+I arm were 76% (odds ratio [95% CI]: 0.24 [0.16–0.35]) and 73% (0.27 [0.18–0.40]) less likely to be notably bothered by side effects than pts in the S arm in the total and I/P-risk populations, respectively. Conclusions: Pts reported HRQoL benefits with N+I vs S. Treatment with N+I showed a decreased risk of being bothered by treatment side effects and of experiencing clinically meaningful deterioration in HRQoL in contrast with S. These results suggest that the superior efficacy of N+I over S comes with the additional benefit of improved long-term HRQoL. Clinical trial information: NCT02231749. [Table: see text]
Efficacy and safety of lenvatinib (LEN) plus pembrolizumab (PEMBRO) versus sunitinib (SUN) in the East Asian subset of patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial.
Authors: Rha Sun Young , Choueiri Toni K. , Matveev Vsevolod B. , Alyasova Anna , Hong Sung-Hoo , Alonso Gordoa Teresa , Gurney Howard , Bjarnason Georg A. , Buchler Tomas , Pedrazzoli Paolo , Takagi Toshio , Park Se Hoon , Lee Jae-Lyun , Perini Rodolfo F. , He Cixin , McKenzie Jodi A. , Eto Masatoshi 
Published: February 2022

338 Background: In the phase 3 CLEAR trial that included patients with aRCC, LEN + PEMBRO demonstrated significant improvements in progression-free survival (PFS; hazard ratio [HR] 0.39; 95% CI 0.32, 0.49; P < 0.001), overall survival (OS; HR 0.66; 95% CI 0.49, 0.88; P = 0.005) and objective response rate (ORR; odds ratio 4.35; 95% CI 3.16, 5.97) vs SUN. Here we report the efficacy and safety results of the East Asian population subset of the CLEAR trial. Methods: Patients with aRCC and no prior systemic therapy were randomized (1:1:1) to receive 1 of 3 treatments including LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W and SUN 50 mg PO QD (4 weeks on/2 weeks off). Randomization was stratified by geographic region and MSKCC prognostic groups. This analysis compares the efficacy and safety of LEN + PEMBRO vs SUN in the East Asian subset of the CLEAR trial including patients from Japan and the Republic of Korea. The primary endpoint was PFS; secondary endpoints included OS, ORR and safety. An independent review committee assessed tumors per RECIST v1.1. Median PFS and OS were calculated using the Kaplan-Meier method; HR and 95% CI were estimated by a stratified Cox model. Odds ratios were estimated by a stratified Cochran-Mantel-Haenszel test. Results: Of the 1069 patients randomized, 75 patients in the LEN + PEMBRO group and 65 patients in the SUN group were from East Asia. PFS was improved with LEN + PEMBRO vs SUN (median 22.1 vs 11.1 mo; HR 0.38, 95% CI 0.23, 0.62). Median OS was not reached for both arms; the HR for OS comparing LEN + PEMBRO vs SUN was 0.71, 95% CI 0.30, 1.71. ORR was improved with LEN + PEMBRO vs SUN (65.3% vs 49.2%; odds ratio 2.14, 95% CI 1.07, 4.28). Grade ≥3 treatment emergent adverse events (TEAEs) occurred in 88.0% of patients in the LEN + PEMBRO group and in 79.7% of patients in the SUN group. The incidences and types of TEAEs were generally similar to the overall CLEAR population and were manageable with dose adjustments and appropriate concomitant therapies. Conclusions: Efficacy results for patients in the East Asian subset of the CLEAR trial were consistent with the results of the overall population. The safety profile of LEN + PEMBRO in the East Asian subset was also generally consistent with that of the overall population. Clinical trial information: NCT02811861. [Table: see text]
A phase II study of talazoparib and avelumab in VHL deficient clear cell renal cell carcinoma.
Authors: Kotecha Ritesh , Lee Chung-Han , McHugh Deaglan Joseph , Dadoun Chloe , Knezevic Andrea , Carlo Maria Isabel , Feld Emily , Shapnik Natalie , Shah Neil J. , Feldman Darren R. , Motzer Robert J. , Voss Martin H 
Published: February 2022

347 Background: VHL inactivation may lead to impairments in the DNA damage response pathway and increased replication stress, which consequently can increase the genomic instability of clear cell renal cell carcinoma (RCC). Other molecularly driven RCC subtypes including FH and SDH deficient RCC show impaired DNA repair through oncometabolite accumulation. Synthetic lethality with PARP inhibitors (PARPi) has been suggested in preclinical models, and PARPi may potentiate the effects of immune checkpoint blockade (ICB) therapy. Methods: We conducted a single center, investigator-initiated phase II trial to evaluate combined PARPi + PD-L1 inhibition in two genomically selected advanced RCC cohorts: 1) VHL altered RCC; 2) FH, SDH-RCC and renal medullary carcinoma. For Cohort 1, patients had to have previously been treated with VEGFR TKI and ICB therapy with maximum 3 prior lines of therapy. Patients received talazoparib 1mg daily plus avelumab 800mg IV every 14 days. The primary endpoint was objective response rate (ORR) by iRECIST, and secondary endpoints included progression-free survival (PFS), safety and tolerability. Results from Cohort 1 are reported here. Results: From 2019-2021, 10 advanced RCC patients were enrolled per the first stage of a Simon 2-stage design for cohort 1. The median age was 63 years (R: 42-71), and median number of prior therapies was 2 (R: 1-3). All patients had VHL loss detected by tissue NGS sequencing via MSK-IMPACT, and 3/10 (30%) of patients had co-occurring somatic or germline alterations in DDR specific genes. No objective tumor responses were seen, and the disease control rate was 60% (6/10) with those patients achieving stable disease as best response. All patients experienced disease progression and the median PFS was 3.6 months (95% CI 1.4-4.9). Adverse events were in keeping with reported toxicities for individual agents without emerging safety signals. Conclusions: This is the first clinical study of combination PARPi and ICB therapy in advanced clear cell RCC. In our cohort of VHL deficient TKI/ICB refractory RCC, the study did not meet its pre-defined efficacy threshold to continue enrollment, and our results do not support further study of this regimen in this population. Exploratory efforts to evaluate this treatment approach in other biomarker selected populations of RCC, including cohort 2 of this study, are ongoing. Clinical trial information: NCT04068831.
Final analysis of a non-interventional study on cabozantinib in patients with advanced renal cell carcinoma after prior checkpoint inhibitor therapy (CaboCHECK).
Authors: Grünwald Viktor , Boegemann Martin , Rafiyan Mohammad-Reza , Niegisch Guenter , Schnabel Marco Julius , Flörcken Anne , Maasberg Michael , Maintz Christoph , Zahn Mark-Oliver , Wortmann Anke , Hinkel Andreas , Casper Jochen , Darr Christopher , Hilser Thomas , Schulze Matthias , Sookthai Disorn , Schoenherr Caroline , Ivanyi Philipp 
Published: February 2022

357 Background: Data for cabozantinib after IO-combinations in metastatic renal cell carcinoma (mRCC) remain scarce. We therefore evaluated safety and effectiveness of cabozantinib after failure of IO-based therapies. Methods: Data from patients (pts) with mRCC and cabozantinib treatment after IO-based therapy was retrospectively collected from medical records. Primary endpoint was the incidence of serious adverse events (SAEs). Response rate was assessed clinically (CRR) and/or according to RECIST 1.1. Overall Survival (OS) and Progression Free Survival (PFS) were assessed from start of therapy and data were compared for pts with starting dose of 60 mg (cohort A) vs < 60 mg (cohort B) in a post-hoc analysis. Descriptive statistics and KM-plots were utilized, where appropriate. Results: This final analysis (cut off 08-Oct-21) assessed 56 eligible pts (71.4% male) with median age of 66 yrs. 87.5% (n = 49) had previous nephrectomy. 66.1% (n = 37) had clear cell RCC. 89.3% (n = 50) had ≥2 previous lines. ECOG ≤1 was 33.9% (n = 19). IMDC factors were 0 in 2 (3.6%), ≥1 in 21 (37.5%), missing in 31 pts (55.4%). 62.5% (n = 35) started at reduced dose. 55.4% (n = 31) required dose reductions and 1.8% (n = 1) discontinuation. Median treatment duration was 6.1 months (m). PR was 10.7% (n = 6), SD 19.6% (n = 11), PD 12.5% (n = 7) and missing in 57.1% (n = 32). Median OS and PFS were 15.34 m (95% CI 8.94, 20.93) and 6.34 m (95% CI 5.29, 8.25) in the ITT, 10.48 m (95% CI 6.01, 34.14) and 6.51 m (95% CI 2.99, 10.87) in cohort A and 16.46 m (95% CI 9.56, 23.33) and 6.34 m (95% CI 4.86, 8.71) in cohort B, respectively. All grade AEs and grade 3-5 AEs were 87.5% (n = 49) and 44.6% (n = 25) in the ITT, 95.0% (n = 19) and 55.0% (n = 11) in cohort A and 85.7% (n = 30) and 40.0% (n = 14) in cohort B. SAEs were reported in 21.4% (n = 12) of pts, which were 30.0% (n = 6) of cohort A and 17.1% (n = 6) of cohort B. Treatment related SAEs were reported in 10.7% (n = 6) of pts, which were 15.0% (n = 3) in cohort A and 8.6% (n = 3) in cohort B. Conclusions: Cabozantinib directly after IO therapy was safe and feasible. No new safety signals were reported. A reduced starting dose was frequently utilized and was not associated with adverse outcomes. Our data supports the use of cabozantinib after IO-failure. Major limitation was the retrospective nature of our study.[Table: see text]
Targeting an IL-6/JAK/STAT/PIM1 pathway in renal cell carcinoma.
Authors: Meza Kimberly Stephanie , Holder Sheldon L. 
Published: February 2022

376 Background: Renal cell carcinoma (RCC) is the most common cancer of the kidney and accounts for over 430,000 new cases worldwide and 179,000 deaths each year. PIM1 overexpression is associated with poor clinical outcomes in patients with RCC. PIM1 is a constitutively active effector serine/threonine kinase with roles in tumor progression including cell proliferation, apoptosis, invasion, and migration. Yet, the mechanisms that underlie PIM1 expression and its function in RCC are not fully understood. Previous studies have implicated the cytokine IL-6 as an activator of STAT3 and stimulator of PIM1 expression in pancreatic cancer. The aim of the present study is to explore expression of PIM1 in RCC and identify potential signaling pathways that influence PIM1 expression. Methods: To evaluate the contribution of PIM1 expression in RCC we first established baseline PIM1 levels across four RCC cell lines (786-O, 769-P, CAKI-1, and RCC-4). Next, we quantified the presence of IL-6 in cell culture supernatants for each cell line using an ELISA assay. IL-6 signals through the JAK/STAT pathway, consequently we then used immunoblotting to determine whether ruxolitinib, a JAK1/2 inhibitor, would affect PIM1 expression. Finally, we examined cell viability post-ruxolitinib therapy using an MTS assay. Results: Our results show that 769-P, 786-O, and CAKI-1 but not RCC-4 cells overexpress PIM1 relative to normal renal proximal tubule epithelial cells. Results from the ELISA assay show that 786-O, CAKI-1, and to a lesser degree RCC-4 cells secrete IL-6 into their media. Interestingly, 769-P cells had little to no IL-6 present in their media. Based on these differences we sought to understand what effect inhibiting JAK may have on PIM1 expression. After treating cells with ruxolitinib, we found that 786-O and CAKI-1 cells show a time and dose dependent decrease in PIM1 levels whereas 769-P cells did not. To understand if these differences correlate with cell viability, we performed an MTS assay after treating cells with ruxolitinib. Preliminary results show that at 8hr post-treatment, CAKI-1 but not 769-P cells display a time and concentration dependent loss of cell viability. Conclusions: Our initial studies suggest that differential expression of PIM1 among RCC cell lines may be linked to autocrine IL-6 secretion. In CAKI-1 cells JAK inhibition decreases PIM1 expression and cell viability. In the context of 769-P cells with high PIM1 expression but low IL-6 secretion levels, JAK inhibition did not affect cell viability. These data suggest that in 769-P cells there exists a non-IL-6 dependent mechanism stimulating PIM1 expression. Further investigation is required to elucidate the contexts of these PIM1 regulatory pathways in order to develop IL-6/JAK/PIM1 targeted anti-cancer strategies in RCC.
Risk of secondary malignancies after pelvic radiation: A population-based analysis.
Authors: Salib Andrew , McPartland Connor , Mark James Ryan , Lallas Costas D. , Trabulsi Edouard John , Gomella Leonard G. , Chandrasekar Thenappan 
Published: February 2022

478 Background: Radiation therapy (RT) is an integral component of the multimodal therapy of pelvic malignancies, either as primary treatment or in combination with surgical resection. In addition to local treatment effects on nearby pelvic organs, RT has been established to be a risk factor for delayed secondary malignancies. In this study, we examine the rate of any secondary malignancies following RT for primary pelvic malignancies, with a specific emphasis on secondary pelvic malignancies Methods: Using the SEER (Surveillance, Epidemiology, and Ends Results) database, we retrospectively examined 2,102,192 patients with primary pelvic malignancies (prostate, bladder, uterine, rectal, cervical). For each disease site, we compared the rate of all secondary malignancies in radiated patients to non-radiated patients. Secondary malignancies were then stratified as pelvic and non-pelvic, in order to determine the local effect of RT on malignancy risk. Results: A total of 2,102,192 patients were examined (1,189,108 prostate, 315,026 bladder, 88,809 cervical, 249,535 uterine, 259,714 rectal). A total of 113,322 patients developed secondary malignancies after RT (Table), with 26,299 developing secondary pelvic malignancies after RT (18,411 prostate, 1,026 bladder, 1,410 cervical, 2,179 uterine, 3,273 rectal) (Table). The overall relative risk (RR) of RT on developing a secondary malignancy was 1.79 (1.77-1.80 CI, P<0.0001), particularly in patients with prostate (RR 2.57), uterine (RR 1.24) and cervical cancer (1.09). The overall RR of RT on developing a secondary pelvic malignancy was 2.09 (2.06-2.13 CI, P<0.0001), particularly in patients with bladder (RR 6.90), prostate (RR 2.74), and uterine cancer (RR 1.21). Conclusions: Radiation treatment for pelvic malignancies increases the risk of developing secondary malignancies over the patient’s lifetime. Further work needs to done to identify at risk populations.[Table: see text]
A prospective phase II trial of neoadjuvant nivolumab plus gemcitabine/cisplatin chemotherapy in muscle-invasive urothelial carcinoma of bladder.
Authors: Kim Hongsik , Kim Ryul , Hong Joohyun , Kwon Ghee Young , Kim Chan Kyo , Park Won , Song Wan , Sung Hyun Hwan , Jeong Byong Chang , Hong Jung Yong , Park Se Hoon 
Published: February 2022

494 Background: To assess the efficacy and safety of the combination of nivolumab plus gemcitabine/cisplatin in neoadjuvant setting of muscle-invasive urothelial carcinoma of bladder (MIBC). Methods: In this prospective phase II trial (CRIS, KCT0003804), eligible patients had cT2-T4a N0 MIBC, cisplatin-eligible, and to be planned radical cystectomy. Patients received nivolumab 3 mg/kg on days 1 and 15, cisplatin 70 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1, 8 and 15. Study treatment was repeated every 28 days up to 3 or 4 cycles, depending on the surgery schedules. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (<ypT1), disease-free survival (DFS) and safety. Results: Between Sep 2019 and Oct 2020, 51 patients were enrolled. The majority of patients (96%) completed the planned (median, 3; range 1 to 4) cycles of nivolumab plus gemcitabine/cisplatin without significant toxicities. The most commonly observed adverse events included fatigue, nausea and pruritus. Among the 49 patients who completed study treatment, 12 patients refused surgery but were treated with concurrent chemoradiotherapy. Radical cystectomy was performed in 34 (69%) patients. Pathologic results revealed 12 pCR (ypT0, 35%), 4 ypTis, 3 ypTa, 3 ypT1, and 12 ypT2/T3. Preoperative PD-L1 (22C3 TPS>1%) did not correlate with pCR or pathologic downstaging rates. With a median follow-up of 19 months (95% CI, 17 to 20), 12 patients experienced disease recurrence and median DFS was not reached. Conclusions: Neoadjuvant nivolumab plus gemcitabine/cisplatin was feasible and provided meaningful pathologic responses in patients with MIBC. Clinical trial information: KCT0003804.
ABLE: Phase 2, single-arm, two-stage study of nabpaclitaxel with anti-PD1/PDL1 in advanced urothelial cancer.
Authors: Tsung Irene , Green Edward , Palmbos Phillip Lee , Reichert Zachery R , Vaishampayan Ulka N. , Smith David C. , Caram Megan Veresh , Yentz Sarah Elizabeth , Daignault-Newton Stephanie , Sloan Zachery , Hurley Laura , Alva Ajjai Shivaram 
Published: February 2022

502 Background: Anti-PD/PDL1 immune checkpoint inhibitor monotherapy is standard in select PDL1 expressing advanced urothelial cancer (aUC) and platinum-refractory aUC. Nab-paclitaxel (NAB) previously showed encouraging activity in platinum-refractory aUC. We conducted a single-arm trial of the combination of NAB and pembrolizumab in platinum-refractory or cisplatin-ineligible aUC. Methods: Eligible patients (pts) had RECIST 1.1 measurable urothelial cancer, grade ≤1 neuropathy, and ECOG PS 0-2. Study therapy consisted of NAB at starting dose of 125 mg/m2 IV on days 1 and 8 and pembrolizumab 200 mg IV on day 1 in 21-day cycles until progression, intolerable toxicity, death, or consent withdrawal. Continuing NAB after 6 cycles was optional. NAB starting dose was reduced to 100 mg/m2 after planned interim analysis on the first 17 subjects. Primary endpoint was overall response rate (ORR) by RECIST 1.1. Secondary endpoints included safety/toxicity, progression free survival (PFS), overall survival, complete response proportion, duration of response (DOR), and duration of therapy (DOT). Results: Between 2/2018 and 4/2021, 36 response evaluable pts were enrolled; 11 of upper tract origin, 32 men, mean age 71.5 years (range 52 – 88), 25 pure urothelial, 15 platinum-refractory, 21 cisplatin-ineligible by Galsky criteria, and ECOG PS was 0, 1 or 2 in 9, 20, and 7 pts, respectively. Unconfirmed best ORR was 58.3% (95% CI: 42-74) including 3 CR and 18 PR, confirmed ORR 50% (18/36); 31/36 pts experienced some tumor shrinkage. Median DOR was 19 weeks (95% CI: 15.6-34.8), and median PFS 5.4 months (95% CI: 4.6-7.9). Pts received a median of 6 cycles (range 1-14) with median DOT 4.2 months (range 0.6-9.6). Grade ≥3 adverse events (AE) occurred in 25 pts including fatigue (n = 6), anemia (n = 6), peripheral neuropathy (n = 3), and oral mucositis (n = 3); 6 discontinued treatment due to AEs. Ten pts had immune mediated AEs including 1 with encephalitis. Archival tumor NGS revealed TMB ≥10 in 5/21 available. Conclusions: The combination of NAB and pembrolizumab exhibited promising activity in advanced urothelial cancer with no unexpected toxicity. Clinical trial information: NCT03240016.