bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of cytoreductive nephrectomy and systemic therapy in the management of tumor thrombus in patients with metastatic renal cell carcinoma.
Authors: Mittal Abhenil , Al-Ezzi Esmail Mutahar , Li Xuan , Wilson Brooke , Spiliopoulou Pavlina , Sridhar Srikala S. , Fallah-Rad Nazanin , Chung Peter W. M. , Hamilton Robert James , Hansen Aaron Richard
Published: February 2022

345

Background: Patients (pts) with metastatic renal cell carcinoma (mRCC) and tumor thrombus have historically been treated with cytoreductive nephrectomy (CN), however, their outcomes remain poor. Recent phase III data suggest the role for cytoreductive nephrectomy (CN) in mRCC is limited. To date, only case-reports have described thrombus response to systemic therapy. Here, we describe response and survival outcomes of de novo mRCC patients with thrombi treated with systemic therapy with or without CN. Methods: Pts with de novo mRCC at the Princess Margaret Cancer Centre were identified. Demographics, disease characteristics (including the presence of thrombus) and survival outcomes were collected. Progression free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan-Meier method (log-rank). Results: We identified 226 pts with de novo mRCC between 2002 and 2019. Pt demographics are listed in the table. In total, 157 pts underwent a CN and 69 received only systemic therapy. Of the total cohort, 64 pts (28%) had tumor thrombus at presentation (46 CN, 18 no CN). Of the 18 patients with tumor thrombus treated with only systemic therapy, 17 received first-line angiogenesis inhibitors and 1 had chemotherapy (medullary histology). Six (33%) had thrombus progression, 8 (44%) had stable disease and four (22%) had an objective response. Median PFS and OS for patients with and without tumor thrombus treated with systemic therapy only was not significantly different [5.3m (95% CI 3.6-11.7) vs 4.1m (95% CI 3.1-5.9)), p=0.33; OS: 12.1m (95% CI 8.8-27.7) vs 13.9m (95% CI 7.9-21.5), p=0.87). PFS for patients with tumor thrombus who had CN was similar to those treated with systemic therapy alone [8.4m (95% CI: 5.7-13.4) vs 5.3m (95% CI 3.6-11.7), p=0.57] but OS was significantly better favoring CN [29.4m (95% CI: 17.4-48.9) vs 12.1m (95% CI 8.8-27.7), p=0.01). Conclusions: In this largest series of patients with mRCC and thrombus treated with systemic therapy +/- CN, CN appears to plays an important role. More data is needed for patients with tumor thrombus treated with immunotherapy to confirm these findings and elucidate the role of surgery in those cohorts. Bias due to the retrospective study design is an important limitation.[Table: see text]
Efficacy of tyrosine kinase inhibitors (TKI) after combination ipilimumab plus nivolumab (I/N) in metastatic clear cell renal cell carcinoma (ccmRCC) patients: Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Kalirai Austin , Joy Isaiah , Ghosh Sunita , Kollmannsberger Christian K. , Hansen Aaron Richard , Thana Myuran , Graham Jeffrey , Heng Daniel Yick Chin , Castonguay Vincent , Bjarnason Georg A. , Breau Rodney H. , Kapoor Anil , Pouliot Frederic , Wood Lori , Basappa Naveen S.
Published: February 2022

346

Background: The use of I/N is a proven first-line option for patients with intermediate/poor IMDC prognostic criteria. The use of vascular endothelial growth factor inhibitors such as sunitinib have shown activity in the treatment of ccmRCC, but their effectiveness post I/N needs better characterization. This study aims to demonstrate the efficacy of sunitinib, and other TKI agents post I/N in ccmRCC in a real world setting. Methods: Patients with ccmRCC who had received I/N and were subsequently treated with TKI between Jan 1, 2011 and December 31, 2019 were identified from CKCis. Time to treatment failure (TTF – time from start of first subsequent TKI to discontinuation for any reason) and overall survival (OS) – time from first subsequent TKI to death) were calculated using the Kaplan-Meier method. Cox regression was performed to adjust for IMDC criteria. RECIST criteria was used to determine best overall response (ORR) of TKI radiographically. Results: 64 patients were treated with TKI post I/N. Characteristics and outcomes are listed in the table. Of the second-line TKI patients, 51 received sunitinib, 10 received pazopanib and 3 received other TKI. Reasons for second-line TKI discontinuation are: 28% toxicity, 34% progression, 7% other reasons while 31% remain on treatment. Median follow-up time was 12.9m. ORR for second-line TKI overall and second-line sunitinib was 30.0% and 29.4%, respectively. Conclusions: These data show that TKI are active after I/N in ccmRCC. TTF may underestimate PFS due to the large number of patients discontinuing treatment for toxicity and not progression. Efficacy of second-line TKI post I/N in this dataset is similar that of first-line sunitinib from recent randomized phase III trials, suggesting that there may be no significant loss of TKI activity after having received first-line I/N. Overall, these data support the use of TKI after I/N.[Table: see text]
Association of adrenal metastases with outcomes in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab in the GETUG-AFU-26 NIVOREN phase II trial.
Authors: Billon Emilien , Dalban Cécile , Oudard Stephane , Chevreau Christine , Laguerre Brigitte , Barthélémy Philippe , Borchiellini Delphine , Geoffrois Lionnel , Negrier Sylvie , Joly Florence , Thiery-Vuillemin Antoine , Gross-Goupil Marine , Rolland Frederic , Priou Frank , Mahammedi Hakim , Tantot Florence , Escudier Bernard , Chabaud Sylvie , Albiges Laurence , Gravis Gwenaelle
Published: February 2022

348

Background: Glandular metastases (GMs) (adrenal, pancreas, thyroid, ovary, breast, or prostate) are rare in mccRCC. Several studies have observed significantly longer overall survival (OS) for GM patients treated with anti-angiogenic therapy. This study assesses outcomes from mccRCC treated with nivolumab with or without GMs. Methods: The GETUG-AFU 26 NIVOREN, phase II trial assessed the activity and safety of nivolumab in pts with mccRCC who failed antiangiogenic therapies (NCT03013335). Pts were stratified in two subgroups according to the presence of at least one GM. Specific analyzes were performed for pancreatic and adrenal metastases. Primary endpoint was OS, secondary endpoint were progression free survival (PFS) and overall response rate (ORR). Results: Between February 2016 and July 2017, among 720 patients treated by nivolumab 217 patients had GM (151: adrenal and 86: pancreatic metastases). Clinical characteristics were comparable between the two subgroups except for IMDC poor subgroup (19% vs 28%) and for Furhman grade IV (13.5% vs 23.4%) for GM and non GM respectively. Median time between metastatic disease and nivolumab was 3.2 years (y) vs 2 y for GM and non GM respectively and 2.8 vs 2.1 y with or without adrenal metastasis. There was no statistical difference in outcomes between pts with or without GMs. However, pts with adrenal metastases had worse OS (12-months survival: 64% vs 71.1%; HR 1.51 (1.19-1.92)); shorter PFS (6-months survival: 27.2% vs 36.6%; HR 1.29 (1.07-1.57)) and lower ORR (12.5% [7.6%; 19.0%] vs 23.2% [19.8%; 27.0%]; p = 0.005) than non-adrenal metastases. Conversely, patients with pancreatic metastases had significantly longer overall survival (12-months survival: 82.3% vs 67.9%; HR 0.59 (0.40-0.85)) in univariate analysis compared to non-pancreatic metastases. In multivariate analysis, only adrenal metastasis remained associated with dismal prognosis (Table). Conclusions: Adrenal metastasis is an independent poor prognostic factor for response and survival in the GETUG-AFU 26 NIVOREN phase II trial. Limited activity with nivolumab is observed for patients with adrenal metastases from mccRCC without difference with previous anti angiogenic therapy. Molecular characterization could help to identify the angiogenic profile of adrenal metastases. Clinical trial information: NCT03013335. [Table: see text]
Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcomes in patients with metastatic renal cell carcinoma (mRCC)?
Authors: Kumar Premsai , Zhang Yumeng , Li Jiannong , Manley Brandon J. , Chahoud Jad , Spiess Philippe E.
Published: February 2022

354

Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with < 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p=0.006) and more advanced age (median: 66 years vs 60 years, p=0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP and OS. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]
Assessing physician prescribing behaviors in first-line (1L) advanced renal cell carcinoma (aRCC): A case-based study.
Authors: Gajra Ajeet , Jeune-Smith Yolaine , Vaishampayan Ulka N. , Rupard Skyler
Published: February 2022

355

Background: Over the past decade, immune checkpoint inhibitors (ICIs) have become foundational to aRCC management. Tyrosine kinase inhibitors (TKIs) remain a mainstay, resulting in the potential for ICI/TKI combination regimens. Four ICI/TKI combinations (pembrolizumab/axitinib [PA], nivolumab/cabozantinib [NC], pembrolizumab/lenvatinib [PL], and avelumab/axitinib [AA]) have shown promising results compared to single-agent sunitinib in randomized clinical trials (KEYNOTE-426 [KN426], CheckMate 9ER [CM9ER], CLEAR, and JAVELIN RENAL 101 [JR101], respectively); national guidelines recommend them as 1L options. Further, an ICI-based regimen of nivolumab/ipilumumab (NI) is a treatment option for poor-risk RCC based on CheckMate 214 (CM214) results. We sought to understand how community oncologists perceive data from these trials and what aspects influence their clinical decisions. Methods: In May 2021, medical oncologists experienced in treating aRCC were presented with key results from these trials and 2 clinical vignettes. Treatment preferences and reasons for decisions were captured via an audience response system. Responses were aggregated and analyzed using descriptive statistics. Results: A total of 103 U.S. medical oncologists participated; most risk-stratify their patients with either IMDC (44%), MSKCC (34%), or both (14%). When presented with simulated case studies, most (76%) indicated they are not likely to order PD-L1 testing, yet 81% will treat with an ICI-based regimen. Participants are more likely to prescribe ICI/TKI over ICI/ICI (65% vs 47%) in favorable-risk aRCC. Yet in poor-risk RCC, they are more likely to prescribe ICI/ICI over ICI/TKI (52% vs 15%). Among ICI/TKI regimen, participants showed a small preference toward PA over NC for both the poor-risk (21% vs 20%) and intermediate-risk (30% vs 23%) patient case. In the favorable-risk case, PA was significantly preferred over NC, 46% vs 19%. Most participants were aware of the trial data (91% KN426, 82% CM9ER, 57% CLEAR, 96% CM214); and more found the data from CM9ER most compelling compared to KN426 and CM214 (32%, 29%, and 23%, respectively). The participants viewed trials that met primary or survival endpoints as strong. Major limitations in each trial commonly identified were trial design (KN426, 27%); short follow-up (CM9ER, 48%); short follow-up and no OS data (CLEAR, 39% and 38%, respectively), and high discontinuation rate (CM214, 42%). Conclusions: Providers typically will treat aRCC patients with ICI-based regimens regardless of PD-L1 status and are more likely to prescribe an ICI/TKI regimen for favorable-risk and an ICI/ICI regimen for poor-risk aRCC. Meeting primary endpoints is a strong influencer in providers’ decision-making. Given the nonsignificant difference in preference for PA over NC, further research is needed to assess factors influencing providers’ decisions.
Safety and differential clinical activity of nivolumab plus ipilimumab (nivo-ipi) in patients (pts) with non-clear cell renal cell carcinoma (nccRCC).
Authors: Alhalabi Omar , Wilson Nathaniel , Ajufo Helen , Lehner Michael , Hasanov Elshad , Campbell Matthew T , Shah Amishi Yogesh , Wang Jennifer , Jonasch Eric , Araujo John C. , Wang Jianbo , Gao Jianjun , Goswami Sangeeta , Msaouel Pavlos , Tannir Nizar M.
Published: February 2022

356

Background: Pembrolizumab monotherapy recently showed promising efficacy in nccRCC. The objective response rate (ORR) by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified RCC (McDermott, JCO 2021). However, combination immunotherapy data are limited in nccRCC. Methods: We retrospectively evaluated the efficacy and safety of nivo-ipi in pts with nccRCC treated at our institution. ORR and progression-free survival (PFS) were determined using RECIST. Overall survival (OS) was measured from therapy start to death or last follow up. Results: Between November 2017 and July 2020, 27 pts with nccRCC were treated with nivo-ipi at our institution; 25 pts (93%) received nivo-ipi as first-line therapy and 14 pts (52%) had prior nephrectomy. Histology subtypes included 13 (48%) papillary (4 with sarcomatoid features [SF]), 7 (26%) chromophobe (4 with SF), and 7 (26%) unclassified. Sites of metastases included lung in 52%, bone in 37%, and liver in 22% of pts. IMDC risk was favorable (8%), intermediate (48%) and poor (44%). ORR in all pts was 30%; 7 pts achieved a partial response (PR), and 1 patient achieved a complete response (CR). ORR by histology subtype was 54% for papillary, 14% for chromophobe, and 0% for unclassified (table). Clinical benefit (defined as PR, CR, or stable disease [SD] for > 6 months) was achieved in 62% for papillary, 57% for chromophobe, and 29% for unclassified. At a median follow-up time of 17.1 months, for all 27 pts, median PFS was 7.2 months, and median OS was 18.5 months. Median OS per each variant histology subtype was not reached in papillary, 25.7 months in chromophobe, and 7.4 months in unclassified. Median PFS per variant histology subtype was 11.8 months in papillary, 4.0 months in chromophobe, and 2.8 months in unclassified. Seven pts (26%) developed Grade ≥3 toxicity: pneumonitis (2), colitis (2), hepatitis (1), rash (1), and immune-mediated glomerulonephritis (1). Conclusions: In this small retrospective study, nivo-ipi was well-tolerated in pts with nccRCC and yielded high ORR and prolonged PFS in papillary RCC but disappointing efficacy results in chromophobe and unclassified RCC. Molecular studies are ongoing to understand the mechanisms of response and resistance to nivo-ipi in these tumor subtypes.[Table: see text]
Quantifying absolute benefit of adjuvant treatments in renal cell carcinoma: A systematic review and network-meta-analysis.
Authors: Sipra Qurat Ul Ain Riaz , Naqvi Syed Arsalan Ahmed , Islam Mahnoor , Asghar Noureen , Siddiqi Rabbia , Ikram Waleed , Singh Parminder , Xu Wenxin , Ho Thai Huu , Bryce Alan Haruo , Riaz Irbaz Bin
Published: February 2022

360

Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks (CIRs) were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]
Long-term PFS from TIVO-3: Tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC.
Authors: Atkins Michael B. , Verzoni Elena , Escudier Bernard , McDermott David F. , Hutson Thomas E. , Pal Sumanta K. , Porta Camillo , Asnis-Alibozek Aviva G. , Kasturi Vijay , Rini Brian I.
Published: February 2022

362

Background: The TIVO-3 trial supported FDA-approval of TIVO in R/R advanced RCC, demonstrating significantly improved PFS over SOR in the primary independent review committee [IRC] analysis (HR: 0.672, 95% CI: 0.52-0.87). Long-term survival without disease progression (LT-PFS) is a clinically meaningful outcome among patients with R/R mRCC and ≥2 lines of prior therapy. We assessed the proportion of TIVO-3 patients living progression-free with R/R mRCC at 6-month intervals up to 4 years post-initiation of TIVO or SOR. Methods: Exploratory analysis of LT-PFS was calculated using investigator-assessment [INV] with a data cut-off of May 24, 2021. PFS hazard ratio and landmark values of LT-PFS at 6, 12, 18, 24, 30, 36, 42 and 48 months are reported. Results include the ITT population, with censoring for missing assessments and discontinuation without PD. Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for INV-PFS; odds ratios (ORs) are reported for landmark timepoints up to 36-months. LT-PFS across prespecified subgroups were analyzed descriptively. Results: 350 patients were randomized to TIVO (n=175) or SOR (n=175). INV PFS was superior with TIVO vs SOR (HR: 0.624, 95% CI: 0.49-0.79). Landmark LT-PFS rates up to 48-months are consistently higher with TIVO vs SOR, with 12% vs 2% and 7.6% vs 0% at 3- and 4-years, respectively (Table). Despite low numbers of patients at risk with extended follow-up, subgroups with ≥15% LT-PFS at 3-years include IMDC favorable risk, female gender, ECOG PS0, age ≥65 years, and region NA – all confined to the TIVO arm. Conclusions: INV PFS with long-term follow-up is consistent with primary IRC PFS. Patients treated with TIVO were up to 5X more likely to experience LT-PFS compared to SOR. A clinically relevant minority of patients are alive and progression-free on TIVO at 3- and 4-years. Clinical trial information: NCT02627963. [Table: see text]
Novel predictive biomarkers of response to immune checkpoint blockade with nivolumab ± ipilimumab in the TITAN-RCC phase 2 trial.
Authors: Grimm Marc-Oliver , Kesselmeier Miriam , Leucht Katharina , Schumacher Ulrike , Tunger Antje , Röber Nadja , Conrad Karsten , Sommer Ulrich , Baretton Gustavo Bruno , Scherag André , Albiges Laurence , Esteban Emilio , Barthélémy Philippe , Schmidinger Manuela , Busch Jonas , Pérez-Valderrama Begoña , de Velasco Guillermo , Duran Ignacio , Schmitz Marc , Wehner Rebekka
Published: February 2022

367

Background: Despite promising therapeutic efficacy of immune checkpoint inhibitors in renal cell carcionoma (RCC) response varies significantly between individual patients. Therefore, predictors of response are urgently needed. To identify novel predictive biomarkers, we explored the characteristics of blood-circulating immune cell subsets within the population of the TITAN-RCC trial (NCT02917772) applying a tailored approach with nivolumab (nivo) and ipilimumab (ipi). Methods: In TITAN-RCC, patients with intermediate and poor risk advanced clear cell RCC started nivo Q2W induction. Upon early progressive disease (PD, week 8) or non-response (stable disease or PD) at week 16, patients received 2-4 nivo+ipi “boost” cycles. Responders (complete or partial response) to nivo induction continued with maintenance but could receive nivo+ipi for later PD. Blood samples for biomarker analyses were taken at baseline, during nivo induction and nivo+ipi “boost” cycles. Samples from 198 RCC patients (105 first line, 93 second line) were analyzed by multi-parametric flow cytometry for frequency and phenotype of T cell, monocyte, myeloid-derived suppressor cell (MDSC) and dendritic cell (DC) subsets. Baseline data were associated to response upon nivo induction and data from samples taken prior to first “boost” to response to nivo+ipi. We applied uni- and multivariable logistic regression modelling to investigate the association between treatment response and immune parameters. Here we report on single marker models (adjusted for age and gender). Results: Higher percentages of blood-circulating 4-1BB+ CD4+ T cells (adjusted odds ratio (ORadj) 1.05, 95% CI 1.02-1.08), 4-1BB+ CD8+ T cells (ORadj 1.03, 95% CI 1.01-1.07) and LAG3+ CD4+ T cells (ORadj 1.03, 95% CI 1.01-1.05) were found in responders to nivo induction compared to non-responders. Moreover, in patients receiving nivo+ipi “boosts”, a higher proportion of PD-L1+ CD14+ monocytes (ORadj 1.22, 95% CI 1.06-1.58), PD-L1+ early-stage MDSC (ORadj 1.14, 95% CI 1.02-1.41) and PD-L1+ plasmacytoid DC (ORadj 1.08, 95% CI 1.01-1.17) was observed in responders compared to non-responders. Conclusions: We identified various immune cell-related parameters that are associated with increased or poor therapeutic efficacy in RCC patients which are currently investigated in multi-marker models. These parameters may represent novel predictive biomarkers for response to nivo±ipi in clear cell RCC. Clinical trial information: NCT02917772.
Validation of a 22-gene epithelial-mesenchymal transition (EMT) prognostic signature in clear cell renal cell carcinoma.
Authors: Cotta Brittney , Nallandhighal Srinivas , Stangl-Kremser Judith , Pham Trinh , Tosoian Jeffrey J. , Marchetti Kathryn , Berends Joel , Maruf Mahir , Tomlins Scott A. , Morgan Todd Matthew , Palapattu Ganesh S. , Adbulfatah Eman , Udager Aaron M. , Salami Simpa
Published: February 2022

377

Background: Current predictors of metastatic progression after radical nephrectomy for localized clear cell renal cell carcinoma (ccRCC) include clinicopathologic features such as tumor stage and grade. The addition of molecular tumor characteristics in a prognostic score may improve risk stratification and patient selection for enhanced follow up strategies or adjuvant therapies. Methods: We retrospectively identified consecutive patients with ccRCC who underwent radical nephrectomy (RNx) for localized disease. Those who developed metastasis were identified. Whole-transcriptome mRNA sequencing of primary tumors was performed followed by gene set enrichment analysis (GSEA) for the most significant cancer hallmark pathways enriched in patients who did or did not develop metastasis. For each patient, the 22-gene epithelial mesenchymal transition (EMT) score was calculated (high vs. low), using cut-offs from a prior study using TCGA data. The prognostic impact of the EMT score was evaluated by performing multivariable cox-proportional hazard testing and Kaplan-Meier (KM) survival analysis. Results: We analyzed 82 patients with median age 62 years and median tumor size 6 ±2.9 cm. The median time to metastasis after radical nephrectomy for patients who developed metastasis (n = 12) was 18.2 months and 31.1 months for patients who did not develop metastasis (n = 70). We observed a significant enrichment of EMT, myogenesis, inflammatory response and hypoxia hallmark pathways in patients with metastasis vs. those without metastasis. Multivariable analysis controlling for relevant clinicopathologic features such as age, sex, tumor size, tumor stage etc. revealed high EMT score to be significantly associated with development of metastasis [hazard ratio (HR) 7.2; 95% CI 1.15-44.8; ]. Conclusions: Here we validate a prognostic 22-gene epithelial mesenchymal transition (EMT) score in patients treated with radical nephrectomy for localized ccRCC. Pending further studies, the EMT score may improve risk stratification and select patients for adjuvant therapy.
Characteristics and outcomes of patients managed with surgical resection of brain metastasis from renal cell carcinoma.
Authors: Drescher Max , Patel Sunil H. , Alam Ridwan , De La Calle Claire , Yerrapragada Anirudh , Bettegowda Chetan , Matoso Andres , Ged Yasser , Singla Nirmish
Published: February 2022

392

Background: For patients with metastatic renal cell carcinoma (mRCC), the presence of brain metastases (BM) confers a poor prognosis compared with alternative metastatic sites. Being an uncommon site of spread, granular data regarding BM in RCC is relatively sparse. We retrospectively reviewed the clinical features and outcomes of patients with surgically-resected BM from mRCC at our institution. Methods: Patients with mRCC and BM were identified within our institutional experience. Clinical and treatment data was obtained from electronic records. A diagnosis of mRCC to the brain was determined by pathological confirmation obtained via metastasectomy or rarely biopsy. Baseline patient demographics, clinicopathological disease characteristics and survival data were extracted. Overall survival (OS) was calculated from the date of BM intervention using Kaplan–Meier methods. Results: 54 patients were identified with surgically resected BM. Median age at RCC diagnosis was 58 years (IQR 49-67) and most patients were male (n = 39, 73%). 30 patients (56%) presented with de novo metastatic disease without any prior localized treatment, and most developed or presented with multiple metastatic sites. The most common histologic subtype was clear cell carcinoma (n = 51, 94%) and high grade disease was common (n = 39, 73%). The initial treatment of BM for the majority of patients was with neurosurgical resection (94%) followed by post-operative stereotactic radiosurgery (SRS) (87%) and systemic therapy (75%). For patients receiving systemic therapy, most received multiple agents (median 2, range 1-5). 32% of patients had received systemic therapy prior to developing BM. 19 patients (35%) received immune-checkpoint inhibitors. The median overall survival for patients from the date of neurosurgical intervention was 14.5 months (95% CI 9.2- 25 months). Conclusions: We present a large institutional series of patients with BM from mRCC treated with surgical resection. While BM remains a poor prognostic factor in mRCC, surgical resection in selected patients remains a viable strategy. Comprehensive molecular profiling of BM and their corresponding primary RCC tumors will shed light on biological tropism of this phenomenon and underscore prognostic and therapeutic implications.[Table: see text]
Comparison of quality of life (QoL) in survivors of testicular nonseminomatous germ cell tumor (NSGCT) with age-matched controls using EORTC QLQ-C30 questionnaire.
Authors: VARSHNEY ANKUR NANDAN , Raj Abhishek , Singh Prabhjot , Nayak Brusabhanu , KP Haresh , Sahoo Ranjit Kumar , Batra Atul
Published: February 2022

413

Background: Testicular NSGCT is typically diagnosed in young males, and is a highly curable cancer. Data pertaining to the quality of life of testicular NSGCT survivors are limited. Methods: Patients aged 18 or more years with a diagnosis of testicular NSGCT treated in a large tertiary care centre in New Delhi, India between January 2015 and July 2019 were eligible to participate. Patients had to be disease free for at least two years for QoL assessment using EORTC QLQ-C30 questionnaire. Raw scores were transformed as per the EORTC scoring manual. Controls were healthy age-matched adults recruited from the patient accompanying population. Results: We identified 55 survivors and 100 controls. Median age was 32 (range, 18-65) years and 58.2% of patients stage III disease, while the rest were equally divided in stage I and II. Chemotherapy was administered in 94% patients, while 25% had retroperitoneal lymph node resection for residual disease and relapse occurred in 11%, who were treated with salvage chemotherapy and resection of the residual disease. Emotional, social and global scores were significantly lower in survivors as compared to controls. Among symptom scales, fatigue, pain, dyspnoea, insomnia, appetite loss, and financial difficulty were significantly increased in patients as compare to survivors (Table). On a multivariate analysis, neither stage of disease nor treatment were found to be associated significantly with QOL scores. Conclusions: Survivors of testicular NSGCT have lower emotional, social and global functioning and a higher symptom burden. Since NSGCT affects young males, aggressive measures may be needed to improve the QoL in such patients.[Table: see text]
Association of nonseminomatous testicular germ cell tumors with teratoma-free primaries with disease relapse and overall survival.
Authors: Paffenholz Pia , Landwehr Georg , Seidel Christoph Alexander , Poch Annika , Cathomas Richard , Pfister David , Heidenreich Axel
Published: February 2022

422

Background: As the characteristics and outcome of non-seminomatous testicular germ cell tumours (NSGCT) with teratoma-containing primaries are still under debate, this study aims at evaluating recurrence-free and tumor-specific survival in this cohort of patients. Methods: We performed a retrospective analysis including 218 patients with metastatic NSGCT as a registry study within the "German Testicular Cancer Study Group". We analysed patient characteristics as well as follow-up of all included patients, being treated from 2000 to 2021. Results: Of the eligible 218 patients with NSGCT, 92 (42%) of all orchiectomy specimens had teratoma-containing primaries, while 126 (58%) were teratoma-free. Kaplan-Meier estimates revealed that 28% of all patients relapsed during a median follow-up of 58 months [35-112] with a median time to relapse of 10 months. Teratoma-containing and teratoma-free NSGCT did not show a significant difference regarding the occurrence of relapse, however, teratoma-containing NSGCT had a significantly lower rate of early relapses ( < 24 months) compared to teratoma-free NSGCT (57% vs. 82%, p = 0.035). 14% (30/218) of all patients died due to their disease with a median time to death of 15 months, however median overall survival was not reached. There was no difference regarding the tumour-specific survival between teratoma-containing NSGCT and teratoma-free NSGCT when looking at the entire cohort of patients (11% vs. 16%, p = 0.299). However, in the group of intermediate or poor IGCCCG prognosis patients, tumour-specific survival was significantly worse in patients teratoma-free NSGCT compared to teratoma-containing specimens (16% vs. 35%, p = 0.040). Furthermore, patients with intermediate or poor IGCCCG prognosis showed a higher tumour-related mortality in pure teratoma-free primaries compared to patients with pure teratoma in the orchiectomy specimens (28% vs. 14%, p = 0.070). Here, pure embryonal carcinoma showed the highest relative mortality (80%). Conclusions: In our study, NSGCT patients with teratoma-containing primaries showed a significantly lower number of early relapses as well as a reduced tumour specific survival in intermediate and poor prognosis patients compared to teratoma-free NSGCT. Especially pure embryonal carcinoma patients revealed the highest rate of mortality. Consequently, treating physicians should be aware of these patients portending a dismal prognosis.
Optimization of serum miR-371a-3p for the detection of chemotherapy-naïve minimal residual germ cell tumor.
Authors: Lafin John T. , Amini Armon , Konneh Bendu , Savelyeva Anna , Piao Jin , Nuno Michelle , Scarpini Cinzia , Howard Jeffrey , Gerald Thomas , Jia Liwei , Coleman Nicholas , Murray Matthew , Frazier Lindsay Lindsay , Amatruda James F. , Bagrodia Aditya
Published: February 2022

423

Background: Currently used serum tumor markers exhibit middling sensitivity and specificity for the detection of germ cell tumors (GCTs). Circulating miRNAs, particularly miR-371a-3p, have exhibited strong performance characteristics in the pre-orchiectomy setting. However, the ability of miR-371a-3p to detect chemotherapy-naïve occult disease is less clear. We previously reported in a small cohort of patients that miR-371a-3p outperforms conventional markers in the context of chemotherapy-naïve minimal residual disease. Here, we expand upon that experience and further refine the assay, including the recommendation of an indeterminate range. Methods: We examined over 250 assays to compare performance between classification based on raw Cq, Cq normalized to miR-30b-5p (∆Cq), or relative quantification to normal serum (RQ). We prospectively collected pre-surgical serum samples and clinical information from GCT patients undergoing primary retroperitoneal lymph node dissection (RPLND) at our institution. Patients were classified based on histology as “Control” (pure teratoma or no GCT) or “GCT”. RNA was extracted from these samples, and miR-371a-3p (target) and miR-30b-5p (reference gene) were detected by qPCR. Performance was assessed by calculation of sensitivity, specificity, and area under the ROC curve (AUC). Results: Sensitivity, specificity, and AUC did not significantly change based on thresholding metric (Cq, ∆Cq, or RQ). We found a 25% chance that any given control sample would return a false positive result, and to combat this, estimated an indeterminate range of Cq 28-35. Repeating any indeterminate sample once improved performance. We then compared the performance of this updated process to a simple binary threshold in a cohort of patients with occult disease. 32 patients were enrolled in the study (15 Control, 17 GCT). 12 samples were indeterminate on first run (6 Control, 6 GCT). 8 remained indeterminate on a second run, all of which harbored teratoma or viable GCT. Inclusion of a second run prevented 3 false positives, improving specificity from 86% to 100% and yielding a sensitivity of 92% and AUC of 0.96 (95% CI: 0.89-1). Conclusions: The use of Cq instead of RQ to classify results for the miR-371a-3p test would eliminate the need for a normal sample in each run without injuring assay performance. In the context of chemotherapy-naïve minimal residual germ cell tumor, consideration of an indeterminate range may improve the performance of the miR-371a-3p test.
Association of household net worth with healthcare utilization in 90-day window after radical cystectomy using real-world data.
Authors: Washington Samuel L. , Lonergan Peter Eoin , Odisho Anobel Y. , Meng Maxwell , Porten Sima P.
Published: February 2022

444

Background: Radical cystectomy (RC) remains the gold standard for muscle invasive bladder cancer yet confers significant healthcare costs. Prior work on the impact of costs commonly relied on comparisons by insurance status (yes/no) and income, a partial proxy for net worth, ie one’s net economic standing or value of financial assets minus liabilities. Few have examined the relationship between net worth and encounter type. Methods: We identified commercially insured Black, White, Asian, and Hispanic patients who underwent radical cystectomy between January 1, 2007 to April 10, 2021 in The OptumLabs Data Warehouse, a longitudinal, real-world data asset with de-identified administrative claims and electronic health record data. Demographics and costs included household net worth, health plan costs, out of pocket costs, and total healthcare costs accrued from index admission to 90 days after. Multivariable logistic regression models were generated for each encounter type [acute inpatient, emergency department (ED), outpatient, and office visit]. Odds ratios (OR) are presented with 95% confidence intervals (CI) and p-values. A p value of <0.05 was deemed statistically significant. Results: The study cohort was comprised of 141,903 patients (2.4% were Black, 11.4% Hispanic, and 8.1% Asian). Household net worth categories were near evenly distributed amongst the study cohort. Acute inpatient encounters harbored the greatest health plan (mean $24,642.80, SD $57,218.41) and out of pocket costs (mean $1,428.24, SD $2108). Office visits conferred the lowest health plan costs (mean $1,126.78, SD $4,119.12) while ED visits had the lowest out of pocket costs (mean $181.88; SD $399.65). Black patients harbored increased odds of an acute inpatient encounter (HR 1.22, 95% CI 1.16-1.29) and ED encounter (HR 1.20, 95% CI 1.14-1.27) while Asian (HR 0.76, 95% CI 0.69-0.85, p<0.001) and Hispanic (HR 0.74, 95% CI 0.69-0.78, p<0.001) patients had lower odds of an outpatient encounter. Increasing household net worth was associated with decreasing odds of acute inpatient or ED encounters, and greater odds of an office visit. Conclusions: Our study is the largest cohort of commercially insured patients to examine variations in healthcare utilization by net worth in the 90 days after radical cystectomy. Those with lower net worth harbored greater risk of an acute inpatient encounter (and higher medical costs) while those with the greater net worth had greater odds of office visits (and lower costs). Greater financial flexibility (i.e., net worth) continues to confer differences in healthcare utilization (and lower healthcare costs), even within a commercially insured population. Household net worth provides a more comprehensive assessment of patients’ financial flexibility than income alone and functions as proxy for healthcare access and privilege that could not be directly measured.
Longitudinal analysis of bladder cancer-specific mortality trends in the United States.
Authors: Kamran Sophia C. , Ghosh Anushka , Goldberg Saveli , Chino Fumiko , Efstathiou Jason A.
Published: February 2022

445

Background: Bladder cancer is the most common malignancy of the urinary system. Advances in diagnosis, imaging, and treatments have led to improvements in bladder cancer management. Recent data demonstrate decreasing bladder cancer-specific mortality (BCSM) rates between 2014-2018 for both males and females, however, these trends have not been further examined by race, ethnicity, or geographical location. Using a comprehensive dataset of BCSM over 2 decades, we sought to evaluate differences in BCSM rates overall and by sex, race, ethnicity, location and urbanization category in the United States (US). Methods: Age-adjusted mortality rates for bladder cancer (ICD10 code 67) were obtained for males and females of all ages in the US from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database. BCSM rates from 1999-2019 were estimated using linear regression. BSCM trends were evaluated by sex, race (White vs. Black), ethnicity (Hispanic vs. Non-Hispanic), urbanization category, and census region. BCSM rates were compared by F-test. Data analysis was performed using SAS 9.4. All p-values are based on a two-sided hypothesis test with values < 0.05 considered statistically significant. Results: From 1999-2019, age-adjusted BCSM rate overall has decreased linearly by (-)0.0073 per 100,000 population/year (p < 0.05). Evaluating by sex, both female [(-)0.131] and male [(-)0.022] BCSM rates decreased yearly (p < 0.05). By ethnicity, male Hispanic and female Non-Hispanic patients had significantly decreasing BCSM rates [(-)0.021 and (-)0.011, respectively, p < 0.05]. White patients had a slightly decreasing rate of BCSM [(-)0.0003, p = NS] while Black patients had an increasing BCSM rate [(+)0.022, p < 0.05] – the difference between the two rates was significant (p < 0.0001). BCSM rates were significantly decreasing in all census regions (Northeast, Midwest, South, Midwest, p < 0.05). BCSM rate in micropolitan (rural) regions has increased yearly [(+)0.006], and rate differences between rural vs large fringe metro (suburban) and vs small metro (population < 250,000) categories, both with significantly decreasing BCSM rates, were statistically significant (p = 0.03 and p = 0.047, respectively). Conclusions: Using comprehensive data on BCSM in the United States over two decades, we demonstrate that the overall mortality rate from bladder cancer has been decreasing. However, when disaggregating age-adjusted BCSM by sex, race, ethnicity, census regions, and urbanization categories, significant differences in mortality rates are found including worsening mortality for Black patients, demonstrating that improvements in BCSM are not equitable across variables. Further evaluation of these trends is important to understand how to target specific populations to improve BCSM and overall outcomes for all patients with bladder cancer.
Vesical Imaging-Reporting and Data System (VI-RADS).
Authors: Ikuma Shunsuke , Kimura Go , Mikami Hikaru , Yanagi Masato , Endo Yuki , Takeda Hayato , Akatsuka Jun , Toyama Yuka , Kondo Yukihiro
Published: February 2022

453

Background: The VI-RADS has been widely used as diagnostic criteria for MRI to predict muscle-invasive of bladder cancer (MIBC). The aim of this study is to evaluate the diagnostic performance of VI-RADS in our hospital and the clinicopathological features of true positive (TP), false positive (FP), true negative (TN), and false negative (FN) cases to identify possible factors for misdiagnosis. Methods: Of the 286 patients who underwent TURBT at our hospital from January 2019 to October 2020, we selected 129 consecutive cases who had performed preoperative enhanced mpMRI and diagnosed as urothelial carcinoma pathologically. We defined VI-RADS score ≥4 as positive for MIBC. The clinicopathological features of TP, FP, TN, and FN groups were retrospectively analyzed and compared. Chi-square test and Mann–Whitney U test were used for the test between the two groups. Results: VI-RADS score in MIBC cases were 2 cases for ≤3 and 22 for ≥4, and in non-MIBC cases 91 cases for ≤3 and 14 for ≥4. The diagnostic performance of VI-RADS for MIBC was 92% for sensitivity, 87% for specificity, 61% for positive predictive value, 98% for negative predictive value, 88% for accuracy and the area under the curve (AUC) was 0.89. There were no statistical differences of age and %male cases between TP (22 cases), FP (14), TN (91) and FN (2) groups. Pathological features of the (TP, FP, TN, FN) groups were shown (table). TP had significantly larger tumor size than the other three groups, and higher %G3, %tumor necrosis and %variant+ than FP and TN. FP group had significantly larger tumor size than the TN. Conclusions: VI-RADS showed high diagnostic performance in predicting MIBC. Our study showed that larger tumor size was a significant factor for overestimation, suggesting the need for improved accuracy in cases with large tumor size.[Table: see text]
Impact of FDA label change on immunotherapy for metastatic urothelial cancer (mUC) and subsequent changes in mortality.
Authors: Vader Daniel , Parikh Ravi Bharat , Li Haojie , Imai Kentaro , Hubbard Rebecca A. , Mamtani Ronac
Published: February 2022

459

Background: In May 2017, atezolizumab and pembrolizumab (IO) received accelerated approval for first-line treatment of cisplatin-ineligible patients with mUC, irrespective of PDL1 test status. In June 2018, the FDA and EMA restricted IO to cisplatin-ineligible patients with PDL1 positive tumors based on early review of data from confirmatory trials which suggested decreased overall survival in patients with PDL1 negative tumors treated with IO. We assessed the impact of the FDA label change on clinical outcomes of mUC patients in routine care. Methods: We conducted a controlled interrupted time series analysis using the US Flatiron Health electronic health record-derived de-identified database. The study sample included patients from 280 cancer clinics nationwide diagnosed with mUC and compared patients potentially impacted by the label change (cisplatin ineligible patients initiating first-line IO or carboplatin-based chemotherapy) to a comparator group who would have been unaffected by the label change (patients initiating first-line cisplatin-based chemotherapy) from 01 April 2017 to 17 May 2018 (pre-label change) and 20 June 2018 to 01 March 2020 (post-label change), excluding a 30-day wash out period encompassing the time-period between the initial FDA safety alert (18 May 2018) and the official FDA label change (19 June 2018). We used Cox regression to estimate adjusted pre-/post-label change related mortality differences in patients receiving carboplatin-chemotherapy or IO, accounting for secular changes in survival through comparison with the cisplatin comparator group. Results: The study included 829 patients with mUC initiating treatment in the pre-label change period (582 IO or carboplatin, 247 cisplatin) and 1,184 patients in the post-label change period (849 IO or carboplatin, 336 cisplatin), respectively. The use of IO, carboplatin, and cisplatin was similar across time-periods (pre-label change: 44.4%, 25.8%, and 29.8%; post-label change: 48%, 23.6%, 28.4%); while PD-L1 testing increased (6.6% to 28.1%). In adjusted models, there were no differences in survival in any of the groups following the FDA label change policy (table). Conclusions: The U.S. FDA label restriction on first-line immunotherapy was associated with increased PD-L1 testing but was not associated with changes in treatment patterns or improved mortality among patients with mUC.[Table: see text]