bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of a phase II study of atezolizumab and bevacizumab in non-clear cell renal cell carcinoma (nccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (sccRCC).
Authors: McKay Rana R. , McGregor Bradley Alexander , Gray Kathryn , Steinharter John A. , Walsh Meghara K. , Braun David A. , Flaifel Abdallah , VanAllen Eliezer , Wei Xiao X. , Signoretti Sabina , Harshman Lauren Christine , Vaishampayan Ulka N. , Choueiri Toni K. 
Published: March 2019

548 Background: NccRCC and sccRCC have historically been underrepresented in clinical trials. Even with targeted therapy, most patients have inferior survival compared to clear cell renal cell carcinoma. The combination of atezolizumab and bevacizumab has demonstrated safety and efficacy in ccRCC. In this multicenter, phase II, open-label, single arm trial we evaluate the efficacy of atezolizumab and bevacizumab in patients with nccRCC and sccRCC with >20% sarcomatoid differentiation. Methods: Eligible patients had an ECOG performance status of 0-2 and may have received prior therapy. Prior PD-1/PD-L1 therapy was not allowed. Patients underwent a mandatory baseline biopsy and subsequently received atezolizumab 120 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. Patients remained on therapy until radiographic progression, unacceptable adverse events, or withdrawal. The primary end point was overall response rate (ORR) as determined by RECIST version 1.1. Results: 65 patients were enrolled of whom 52 had ≥1 response assessment and were included in this analysis. 36 patients had nccRCC (papillary n=14, chromophobe n=8, unclassified RCC n=3, collecting duct n=3, translocation n=3, other n=5), and 16 patients had sccRCC. 17 patients received prior systemic therapy, 16 of whom had nccRCC. The ORR was 31% in the overall cohort (Table 1). 10 patients (19%) developed grade 3 treatment-related adverse events (AEs), half of which were immune-related. There were no grade 4-5 AEs. Conclusions: In this study, we show that therapy with atezolizumab and bevacizumab was safe and demonstrated anti-tumor activity in nccRCC and sccRCC. Further analyses will report ORR by histologic subtype and PD-L1 expression status. Analysis of tissue and blood-based biomarkers of response are ongoing. Clinical trial information: NCT02724878. [Table: see text]
Novel predictive models of early death less than one year in patients with metastatic RCC treated with first-line tyrosine kinase inhibitors.
Authors: Kang Minyong , Joung Jae Young , Kim Tae Jin , Jeon Hwang Gyun , Jeong Byong Chang , Seo Seong Il , Jeon Seong Soo , Lee Hyun Moo , Sung Hyun Hwan 
Published: March 2019

552 Background: Although the IMDC model can provide useful information on overall survival outcomes in patients with metastatic renal cell carcinoma (mRCC), this model maybe invaluable in patients who experience early death less than one year after initial systemic therapy. Here, we aimed to develop a new prognostic model which can predict early death in patients with mRCC receiving first line tyrosine kinase inhibitors (TKI). Methods: We retrospectively evaluated a total of 498 patients treated with first line line TKI among 537 patients with mRCC at our institution. The primary endpoint was the rate of early death within 1 year after first line TKI administration. We selected statistically significant factors predicting early death by performing multiple logistic regression. Modified IMDC model 1 based on existing IMDC model and model 2 composed of new variables were generated. The prediction accuracy was evaluated by calculating the concordance index (C-index). Area under curve (AUC) and net reclassification index (NRI) using ROC curve analysis were used to compare the predictive power between the models. Results: Overall mortality was 59.0% (n = 294) in 498 patients, and early mortality was 19.7% (n = 98) within 1 year after first line TKI administration. The C-index of the IMDC model for early death was 0.655. Five variables were selected: previous nephrectomy, BMI, multiple metastases, previous metastasectomy and serum albumin level. The C-index of the model 1, which includes five new variables plus variables in the IDMC model, is 0.823, showing a significant improvement over the IDMC model. In model 2, hemoglobin and neutrophil levels were added in new five variables, and the C-index was 0.822. For the IMDC model, there was a significant NRI difference in both models 1 and 2, but no significant difference in NRI between models 1 and 2. (-0.0368 [95% CI = -0.1416 - 0.0681]; p = 0.491). Conclusions: In this study, we suggest modified IMDC models for predicting ‘early death less than one year in patients with mRCC treated with first line TKI. These novel models can provide better treatment strategies and counseling in patients with mRCC who were treated by first line TKI.
Impact of disagreement between the IMDC and MSKCC risk groups on prognosis in patients with metastatic renal cell carcinoma.
Authors: Hatakeyama Shingo , Tanaka Toshiaki , Ikehata Yoshinori , Fujita Naoki , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Masumori Naoya , Kitamura Hiroshi , Ohyama Chikara 
Published: March 2019

556 Background: As the clinical implication of the risk group disagreement between the risk models remains unclear, we aimed to investigate the impact of the risk group disagreement between the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models on prognosis. Methods: We retrospectively evaluated 176 patients with metastatic renal cell carcinoma (mRCC) who were treated with tyrosine kinase inhibitors as first-line therapy in five hospitals between October 2008 and August 2018. The risk group classification differences between the MSKCC and the IMDC models were evaluated using criteria of agreement (identical risk group in both the MSKCC and IMDC models) and disagreement (not identical risk group in both the MSKCC and IMDC models). The agreement of risk stratification between the MSKCC and IMDC models was evaluated using Cohen’s k coefficient. Oncological outcomes were compared between the agreement and disagreement groups. Results: The number of patients with agreement, upgrade, and downgrade was 135/176 (77%), 39/176 (22%), and 2/176 (1.1%), respectively. Of 41 patients with disagreement, reclassification from the MSKCC-intermediate to the IMDC-poor-risk group was most frequent (n = 34/176, 19%). The Cohen’s k coefficient for agreement of the two risk models was substantial with k value of 0.613 ( P < 0.001). Significantly poorer prognosis was observed in patients with disagreement than in those with agreement. Conclusions: Disagreement between the MSKCC and IMDC models may have a negative impact on prognosis in patients with mRCC. Further study is necessary to validate our findings.
Modeling of prognostication and differential genomic expression in the tumor microenvironment of clear cell renal cell carcinoma.
Authors: Lee Sunyoung S. , Kwon Seok Joon , Lee Dong Eun , Lee Seongwon , Baird Andrew , Park Shinyoung , Dolan Jillian , George Saby 
Published: March 2019

557 Background: Stroma in the tumor microenvironment (TME) influences prognosis and response to therapy. Few mathematical models exist to prognosticate patients (pts), based on mRNA expressivity in the TME. Methods: Clinical outcomes data and mRNA-seq of 533 pts with clear cell renal cancer were obtained from TCGA. Expressivity of 191 genes enriched in cellular and structural elements of TME and clinical data were analyzed via machine learning, multivariate nonlinear regression with confined optimization, and Kaplan-Meier (KM) analysis. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis in each stage (Table). P/G is the ratio of genes associated with poor (61 genes) to good (14) prognosis (refer to presentation). Based on RS, pts in each stage were clustered into 2 groups (high and low RS), showing 2 KM curves with p < 0.001 in each stage. Analysis of immune profiles in these 2 groups shows that in stage 1, expression of genes related to immune activation (IA) is not statistically different in high and low RS groups, but expression of genes related to immune inhibition (II) is higher in high RS group. In high RS groups of stage 2-4, IA genes are highly co-expressed with II genes. In high RS groups of all stages, expression of both IA and II genes increases as stage increases. In low RS groups, IA genes increase as stage increases, but II genes do not. Conclusions: Machine learning and mathematical modeling of RS and gene analysis show that IA genes are suppressed by high degree of II in high RS groups of advanced stages, contributing to worse prognosis. RS enables prognostication of pts encountered in the clinic, given genomic profiles. [Table: see text]
Treatment utilization trends and outcomes in renal liposarcoma (RLS): A National Cancer Database (NCDB) analysis.
Authors: Malla Midhun , Tripathi Abhishek , Zhang Ying , Patel Sanjay , Pareek Vipul 
Published: March 2019

559 Background: RLS is an extremely rare neoplasm with only few case reports documented in the literature. Due to the rarity of this disease, level 1 evidence guiding optimal patient management is lacking. Utilizing the NCDB, we analyzed the current treatment patterns and outcomes in patients with RLS in the United States. Methods: The NCDB was queried from 2004- 2015 for patients diagnosed with T1-4N0-1M0 RLS. Baseline patient characteristics were summarized using descriptive statistics. Impact of baseline demographic, clinicopathologic variables and treatment on overall survival (OS) was evaluated using univariate (UV) and multivariable (MV) cox proportional hazards analysis. Results: 136 patients diagnosed with non-metastatic RLS between 2004- 2015 were included in this analysis. Median age at diagnosis was 64.7 years. Males and females had equal preponderance (50% each). 89% (n = 121) were Caucasian, while only 6% were African American. T staging was based on AJCC 8th edition. 20% of patients had T1 disease, 17% had T2, while T3 and T4 stage was present in 26% and 37% of cases respectively. Only 7% (n = 10) had lymph node (LN) involvement. Dedifferentiated RLS was the most common histology (44%). 59% (n = 80) had radical nephrectomy, 12% (n = 17) had partial nephrectomy, and 17% had nephrectomy NOS. Adjuvant radiation and chemotherapy were used in 15% (n = 20) and 3.6% (n = 5) of patients respectively. Median OS was 41 months (20-76 mos). On UV analysis age ≤ 70 years and sex had a statistically significant effect on OS (HR: 0.387 and 0.549, p < 0.001 and 0.04 respectively). On MV analysis adjusting for age and sex, female patients had a significantly improved OS compared to males (47 vs 36.7mos, HR-0.45, CI: 0.250-0.804 p < 0.05). Conclusions: RLS is a rare and aggressive malignancy with poor outcomes even at localized stage. Age at diagnosis and sex had a statistically significant impact on OS. Given the lack of prospective data, our study provides insights into the prognosis of this rare disease. Additional studies are needed to better guide the optimal management of this rare disease.
The effect of loss of SETD2 on mitochondrial dysfunction in clear cell renal cell carcinoma.
Authors: Hapke Robert , Beckermann Katy , Rathmell Kimryn , Haake Scott Mattox 
Published: March 2019

567 Background: SET domain-containing protein 2 ( SETD2) is among the most commonly mutated genes in clear cell renal cell carcinoma (ccRCC). Classically, SETD2 modulates chromatin structure via the methylation of lysine 36 on histone H3. However, histone-independent functions of SETD2 are emerging. We sought to discover novel SETD2-dependent changes to the cellular lysine methylation landscape during kidney cancer tumorigenesis. Methods: In this study, we used HKC human proximal tubule kidney cell lines, the likely nephrogenic region of origin for ccRCC. The proteomes of wild type (WT) and SETD2-knock out (KO) cells were labeled using stable isotope labeling by amino acids in cell culture (SILAC). Proteins were trypsinized and lysine-methylated peptides were immunoprecipitated. Relative abundance of lysine-methylated peptides and total peptides were calculated in the WT and SETD2-KO using nano-liquid chromatography/tandem mass spectrometry (LC/MS-MS). Results: > 30,000 peptides were quantified, including > 50 lysine methylated peptides. We observed decreased lysine methylation of eukaryotic elongation factor 1A1 (eEF1A1), including K165 trimethylation (K165me3) and K318 monomethylation (K318me1). eEF1A1 is classically known for delivery of aminoacyl-tRNA to the ribosome, and its function is modulated via the lysine methyltranferases eEF1AKMT1-4. eEF1AKMT3 is responsible for trimethylation of K165, and expression of this enzyme was decreased in SETD2-KO cells. In addition, we observed significant decrease in expression in proteins of the electron transport chain (ETC) complex 1 in SETD2-KO cells yet normal gene expression, suggesting a translational defect. Functionally, SETD2-KO cells are characterized by decreased cellular oxygen consumption rate and increased mitochondrial mass, suggestive of ETC dysfunction. Conclusions: We observe decreased expression of eEF1AKMT3 in SETD2-KO cells, resulting in decreased K165me3 of eEFA1A, decreased translation of ETC proteins, and mitochondrial dysfunction. As mitochondrial dysfunction is commonly observed in RCC, we expect this represents a novel mechanism of SETD2-mediated tumorigenesis.
Is cytoreductive nephrectomy necessary in metastatic renal cell carcinoma with primary kidney tumor in situ treated by sunitinib: Real-world data from a single Chinese center.
Authors: Xu Wen-Hao , Qu Yuan-Yuan , Wang Hong-Kai , Zhang Hai-Liang , Ye Dingwei 
Published: March 2019

570 Background: To evaluate the role of cytoreductive nephrectomy (CN), which was an indispensable treatment in metastasis renal cell carcinoma (mRCC), compared with cytokine treatment, we assessed the survival benefit of CN in patients with mRCC treated by sunitinib in targeted therapy era. Methods: This retrospective study compared the progression-free survival (PFS) and overall survival (OS) between mRCC patients who did or did not undergo CN. We screened out and enrolled patients from April 2006 to November 2013 as suitable candidates for CN with primary kidney tumor in situ. Logistic regression models were used to measure the effects of the clinical and pathological covariates. The Kaplan-Meier method and log-rank test were performed to evaluate the possible survival differences between two groups. Results: Atotal of 70 patients were assigned to undergo CN followed with sunitinib and 48 received sunitinib alone. According to the survival analysis, the median PFS was 8.38 months and the median OS was 15.48 months, with 109 deaths observed. There were no significant difference between CN-sunitinib group and sunitinib-alone group in both PFS(7.2 versus 11.6 months, 95% confidence interval, 5.3 to 11.8; P= 0.525) and OS (16.7 versus 15.2 months, 95% confidence interval, 12.0 to 18.9, P= 0.839). However, stratified analysis revealed that PFS and OS might decrease after CN in the subgroups of patients with IMDC prognostic criteria of high-risk disease (PFS: 4.4 [95% CI, 3.5 to 5.3] vs. 6.3 [95% CI, 5.3 to 7.2]months, P= 0.002; OS: 8.8 [95% CI, 7.0 to 10.6] vs 9.9 [95% CI, 10.0 to 11.8] months, P= 0.011) and those with lymphatic metastasis (PFS: 4.4 [95% CI, 2.9 to 6.0] vs. 6.6 [95% CI, 2.1 to 11.2] months, P< 0.001; OS: 8.8 [95% CI, 6.9 to 10.7] vs 9.9 [95% CI, 7.1 to 10.7] months, P= 0.006). Conclusions: Cytoreductive nephrectomy may offer no survival benefits in those mRCC patients with primary kidney tumor in situ, and moreover, sunitinib-alone therapy perhaps contributes longer PFS and OS for the patients with IMDC high-risk disease and those with lymphatic metastasis.
Prognostic impact of neutrophil-to-lymphocyte ratio in renal cell carcinoma: A systematic review and meta-analysis.
Authors: Mollica Veronica , Di Nunno Vincenzo , Gatto Lidia , Santoni Matteo , Cosmai Laura , Porta Camillo , Massari Francesco 
Published: March 2019

572 Background: Several clinical scores have been adopted in clinical practice for the prognostic estimation in patients with Renal Cell Carcinoma (RCC). Neutrophil-lymphocytes ratio (NLR) has shown to be a reliable and economic parameter associated with prognosis however its role has not been fully understood. Methods: We performed a systematic review and meta-analysis according to PRISMA guidelines to evaluate the prognostic value of NLR in terms of overall and progression free survival (OS/PFS) in both metastatic and non metastatic patients with RCC. We applied the inverse variance technique for the meta-analysis of the HRs and due to the intrinsic heterogeneity of the data we adopted a Random Effects model. 24 studies were selected for the final analysis, 21 for the comparison of NLR and OS and 15 for the comparison of NLR and DFS/PFS. Results: In overall population higher NLR resulted in worst OS benefit with a pooled HR of 1.80 (95% confidence interval of 1.61 – 2.00, I2 45%.) as well as in non metastatic (pooled HR of 1.57, 95% CI 1.27-1.94, I2 39%) and metastatic patients (2.05, 95% CI 1.74-2.41, I2 0%). Moreover, NLR resulted in worst PFS in overall population (pooled HR 1.69, 95% CI 1.42-2.01, I2 81%), in non metastatic (HR 1.52, 95% CI 1.23-1.87, I2 53%) and metastatic (HR 1.95, 95% CI 1.43-2.64 I2 90%). Conclusions: According to our results NLR ratio is a variable correlated to prognosis in RCC patients. The low level of heterogeneity among studies included suggests that it has a strong association with patients’ survival. Thus it appears as an attractive, dynamic and economic biomarker which could be adopted to further subdivide prognostic classes into even more accurate groups of prognosis in order to choose the best treatment strategy possible. Further prospective studies are needed to confirm our findings.
Exploratory endpoints in a FARETES study of the efficacy of testosterone in metastatic renal cell carcinoma (mRCC) patients.
Authors: Tsimafeyeu Ilya , Borisov Pavel , Zukov Ruslan , Zakurdaeva Kristina , Bondarenko Anastasia , Tishova Yulia 
Published: March 2019

574 Background: In multicenter randomized phase 2 study (FARETES) we showed that male patients with mRCC receiving targeted therapy had significantly less fatigue and better symptom control with testosterone undecanoate (T) (MASCC 2018, LBA004). Here we described exploratory endpoints in FARETES study. Methods: Sixty male patients with clear cell mRCC, normal PSA level, low testosterone level and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either T (Nebido, 1,000 mg) and targeted therapy or targeted therapy alone (control group). T was injected intramuscular deeply on Day 1 of a new treatment cycle. Exploratory endpoints included rate of adverse events (AE) of targeted therapy, duration of targeted therapy, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of the data cutoff on October 17, 2018, median (range) follow-up was 15.2 (9.9 -16.5) months. No unexpected toxicity of T was observed. Grade 3-4 targeted therapy-related AE occurred in 11 (37%) and 3 (10%) patients in the control group and T group, respectively. Discontinuation due to AE was observed in 3% (1/30) of patients in the T group and in 17% (5/30) of patients in the control group. ORR and PFS were significantly better in the T group (all P < 0.05, Table). Median OS was not reached in either group. Clinical trial information: NCT03379012. Conclusions: T therapy could decrease rate of serious AE of targeted therapy. Male mRCC patients receiving T had longer duration of targeted therapy, better PFS and ORR. Larger trials are needed to evaluate efficacy of T in this group of patients.[Table: see text]
Concordance between PD-L1 assays for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC).
Authors: Zhu Jason , Labriola Matthew , Cheris Sachica , Liu Xin , Perkinson Kathryn , Su Zuowei , McCall Shannon , Huang Jiaoti , Gupta Rajan , Armstrong Andrew J. , George Daniel J. , Zhang Tian 
Published: March 2019

577 Background: Immune checkpoint inhibitors (ICIs) are now standard of care for mRCC and mUC patients (pts). PD-L1 status is gaining importance as a predictive biomarker, particularly for cisplatin-ineligible mUC. Four different PD-L1 assays vary in thresholds of PD-L1 positivity dependent on tumor type, with limited concordance studies. Given real-world limitations in PD-L1 testing, concordance between assays are needed to distinguish positive (pos)/negative (neg) results and treatment selection. We undertook comparisons of Dako 28–8 and Ventana SP142 assays in mRCC and Dako 22C3 and Ventana SP263 assays in mUC. Methods: 32 patients with mRCC and 18 patients with mUC who had received ICI therapy at Duke Cancer Institute were identified. FFPE archival tumor samples for pts with mRCC were evaluated with Dako 28–8 and Ventana SP142 PD-L1 immunohistochemistry (IHC) assays. For pts with mUC, FFPE archival tumor samples were evaluated with Dako 22C3 and Ventana SP263 PD-L1 IHC assays. Scoring was validated by two pathologists using the scoring system for each assay. PD-L1 status was subsequently correlated to best RECIST response (objective response rate (ORR) defined as stable disease or better)). Results: The majority of mRCC cases (29/32, 91%) were concordant between Dako 28-8 and Ventana SP142 assays (8 cases pos and 21 cases neg), with 3 discordant cases (1 case pos for Dako 28-8 but neg for Ventana SP142 and 2 cases neg for Dako 28-8 but pos for Ventana SP142). The majority of mUC cases (17/18, 94%) were also concordant between Dako 22C3 and Ventana SP263 assays (2 pos cases and 15 neg cases), with 1 indeterminate Dako 22C3 test due to background lymph node. In mRCC, the ORR for PD-L1 pos cases was 45% (5/11) versus 33% (8/24) for PD-L1 neg cases. In mUC, the ORR for PD-L1 positive cases was 50% (1/2) versus 31% (5/16) for PD-L1 neg cases. Conclusions: There was strong concordance between PD-L1 tumor/immune cell assays chosen for comparison in both mRCC and mUC with similar performance characteristics. Although PD-L1 positivity enriches for response to ICIs, many patients respond who are PD-L1 negative. PD-L1 status could be used interchangeably for the majority of cases when selecting treatment in mRCC and mUC.