bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of microbiome and plasma cytokine dynamics to nivolumab response in metastatic renal cell carcinoma (mRCC).
Authors: Maia Manuel C. , Poroyko Valeriy , Won Haejung , Almeida Lorena , Bergerot Paulo Gustavo , Dizman Nazli , Hsu Joann , Jones Jeremy , Salgia Ravi , Pal Sumanta K. 
Published: February 2018

656 Background: Checkpoint inhibitors (CPI) represent a standard of care in mRCC. The relationship of the microbiome to benefit from CPIs has been suggested in clinical studies in melanoma (Wargo et al ASCO 2017). Here we provide updated evidence of association between microbiome composition, plasma cytokines and response to nivolumab in mRCC patients (pts). Methods: Stool and blood samples were prospectively collected from pts with mRCC at 3 time points relative to nivolumab treatment (baseline, week 4 and week 12) and used to assess gut microbiota composition in two different groups: responders (R; including complete/partial response and stable disease) and non-responders (P; primary progression). For stool analyses, microbial DNA was extracted, 16s rRNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina). Sequence reads were processed by Mothur software, assembled in OTUs, taxonomically annotated and used to construct dissimilarity matrices. Differentially abundant taxa were determined by METASTATS and compared between R and P. We further interrogated whether plasma cytokine profile was influenced by specific bacterial species. Results: Of 20 pts, 16 were evaluable for response. In preliminary analyses, 25,304 OTUs were attributed to 165 genera from 8 phyla. PCoA analysis reveals that the first two principal coordinates can explain 49.2% of data set variation. Subsequent k-means clustering shows an almost complete separation of microbiota in R and P groups (p = 0.07). The analysis of microbiota membership in P and R groups revealed 2 differentially abundant taxonomic units present above 1% abundance. Namely, Roseburia spp and Faecalibacterium spp were significantly elevated in R as compared to P (p < 0.05). Correlations between these bacteria and plasma cytokines will be presented at the meeting. Conclusions: Our results are the first to associate specific microbial genera to nivolumab response in mRCC, and this represents the first effort to combine analysis of the microbiome and serum cytokines. Manipulation of the stool microbiome as a means of modulating nivolumab response should be investigated.
Does treatment approach for small renal masses affect survival in patients 70 years old?
Authors: Hockman Lukas , Haden Tyler , Henderson Alex , Pokala Naveen 
Published: February 2018

658 Background: With the advent of modern imaging techniques small renal masses are being diagnosed more frequently. Many of these masses are benign, and those that are malignant are often low grade and rarely affect the survival. Surveillance is more commonly being advocated as an option for these masses. This study elucidates survival following different treatment approaches. Methods: SEER 18 data from 2004-13 identified 10,477 patients 70 years and older with renal cell carcinoma and tumors greater than or equal to 3 cm. Exclusion criteria included multiple primaries, distant metastasis and node positive disease. Data was collected on demographics, treatment patterns, overall survival and cancer specific survival. Kaplan-Meier analysis and Cox regression models were used to compare outcomes. Results: After exclusion 5084 patients remained. The mean age was 76.4 years. The mean tumor size was 2.3cm. Tumor laterality was right in 2610, left in 2467, bilateral in 2 and unspecified in 5. Racial analysis identified 84% of patients as white, 9% as black and 7% as other. Gender split was 51% male. Treatment methods included 791 ablations and 3324 surgical resections (radical or partial nephrectomy). The remaining 969 patients did not have treatment (surveillance). Survival was measured at 60 and 118 months. The overall survival was 75% and 54% respectively for ALL patients, 82% and 62% for ablation, 42% and 19% for surveillance and 82% and 62% for resection. Cancer specific survival was 97% and 96% for ablation, 83% and 74% for surveillance and 96% and 94% for resection. Surgical resection or ablation significantly improved survival at 5 and 10 years (p = < 0.0001). Multivariate analysis showed survival was affected by age and year of diagnosis, but not by tumor size. Conclusions: The significant difference in overall survival suggests appropriate selection of patients for surveillance based on medical comorbidities. Treatment with curative intent improves survival in patients with greater than or equal to 3 cm renal masses, even in patients 70 years and older, and must be offered to patients without significant comorbidities.
Drivers for treatment in an active surveillance cohort.
Authors: Gilbo Philip , Hamilton Mark , Potters Louis , Cox Brett Wayne 
Published: February 2018

66 Background: Active Surveillance (AS) for Prostate Cancer (CaP) has become an established management option for patients (pts) with low-risk CaP. We examined the drivers of selecting treatment (tx) over time from a cohort of AS pts seen in a radiation oncology department. Methods: Pts seen in consultation with low-risk CaP were offered AS as one management option. A review of 2,545 pt charts with newly diagnosed CaP from 2010-2016 was undertaken with 794 (31.2%) meeting criteria for AS and ultimately 166 (20.6%) of those patients choosing AS within our department. 22 patients opted to discontinue surveillance before their confirmatory studies. Results: 145 pts elected AS and 66 (45.5%) ultimately required or chose tx. 138 (81.3%) of patients had Gleason 3+3, 28 (17%) had Gleason 3+4 and 3 (1.8%) had Gleason 4+3. The majority (96.4%) were T1c and 112 (67%) were characterized as having NCCN very low risk with a mean PSA of 5.38ng/mL (± 2.38ng/mL). Of the 66 pts who underwent tx, 36 (54.7%) were due to an increase in Gleason score or PSA rise, 14 (21%) electively decided against further AS, 6 (9%) for radiographic progression and 10 (15%) for other. Tx choices are presented in Table 1 with 54 pts (81%) choosing a radiotherapeutic (RT) intervention. The median time to initiate tx was 3.8 years from diagnosis. Conclusions: Men with low-risk CaP and eligible for AS elected AS 21% of the time with slightly less than half of the AS cohort converting to tx within 4 years. The main drivers for tx was either an increase in Gleason score or rise in PSA, followed by patient anxiety regarding diagnosis. Trends over time identified an increase in men electing AS but additional efforts are underway to educate pts on informed decision making and addressing diagnosis anxiety to maintain AS status. A significant proportion of patients chose a RT intervention, perhaps reflecting tx bias towards the physician performing the surveillance. [Table: see text]
Meta-analysis of randomized clinical trials (RCT) for the adjuvant treatment of high-risk clear cell renal carcinoma (RCC) with vascular endothelial growth factor receptor tyrosine-kinase inhibitors (VEGFR TKIs).
Authors: Almeida Daniel Vargas , Oliveira Cleyton Z. , Soares Andrey , Jardim Denis L , Bastos Diogo Assed , Maluf Fernando C. , Werutsky Gustavo , Monteiro Fernando Sabino M , Souza Vinicius Carrera , Fay Andre Poisl , Schutz Fabio A. B. 
Published: February 2018

660 Background: A significant proportion of RCC patients with localized disease will eventually recur after a curative intent nephrectomy. VEGFR TKIs have significantly improved the outcomes of patients with advanced disease. RCT are ongoing to evaluate the impact of adjuvant VEGFR TKI on clinical outcome of patients with RCC after definitive treatment . Results from 3 RCT have been already published, but data is controversial. Methods: PubMed databases were searched for articles published from January 1996 to October 2017. Eligible studies were limited to phase 3 RCT of US Food and Drug Administration-approved VEGFR TKIs that reported on patients with RCC treated in the adjuvant setting. Statistical analyses were conducted to calculate the summary hazard-ratio (HR) of disease-free survival (DFS), using 95% CIs by random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: A total of 4,096 patients from 3 RCT (ASSURE, S-TRAC and PROTECT trials) were included. 2374 patients were randomized to receive sorafenib, sunitinib or pazopanib, and 1722 to receive placebo. The summary HR of DFS for the overall population was 0.88 (95%CI 0.77-1.01; p = 0.0605). When evaluating the report of the ASSURE trial that included only clear cell RCC (n = 3222), the summary HR was 0.85 (95%CI 0.77-0.94; p = 0.0018) favoring adjuvant treatment. No evidence of publication bias was found. Conclusions: This meta-analysis failed to demonstrate a statistically significant improvement in DFS of RCC patients treated with adjuvant VEGFR TKI. However, a statistically significant improvement in DFS was observed when only patients with clear cell histology were evaluated. Longer follow-up of the ongoing trials is necessary in order to better evaluate the impact on overall survival.
Transforming growth factor–β signaling pathways in renal cell carcinoma are regulated by VHL status.
Authors: Ljungberg Borje , Mallikarjuna Pramod , Raviprakash Tumkur sitaram , Landstrom Marene 
Published: February 2018

661 Background: To evaluate the role of pVHL in the regulation of the TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC, and to evaluate the expression pVHL and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival. Methods: Snap frozen tissue samples from 143 ccRCC, and 56 non-ccRCC patients were examined by Western blot. Two ccRCC cell lines were utilized for in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Based on the median pVHL level the ccRCCs were divided into pVHL-low and pVHL-high. Results: Non-ccRCCs and pVHL-high ccRCCs expressed similar levels of pVHL. Expression of the ALK5-FL and ALK5-ICD, TGF-βRI, were significantly higher in ccRCC compared with non-ccRCC while pSmad2/3 and PAI-1did not differ. In non-ccRCC patients, expressions of ALK5-FL, ALK-5-ICD, pSmad2/3, and PAI1-1 did not associate to clinicopathological parameters and survival. In the ccRCC pVHL-high, expression of ALK5-ICD and PAI-1 associated significantly only to tumor stage and patients survival. Contrastingly, in ccRCC pVHL-low, ALK5-FL, ALK5-ICD, pSmad2/3 and PAI1 all associated to tumor stage and size, and patient’s survival. In-vitro studies on ccRCC cell lines, A498 and ACHN, revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked polyubiquitination thus negatively controlling TGF- β induced invasiveness of cells. Conclusions: The pVHL status regulates the TGF-β signaling pathway as well as the aggressiveness of tumors and survival of the ccRCC and non-ccRCC patients.
Impact of tumor size on survival outcome in metastatic renal cell carcinoma patients (mRCC) treated with targeted therapy.
Authors: Xie Wanling , DiNatale Renzo , Hakimi A. Ari , Donskov Frede , Porta Camillo , Reaume M. Neil , Basappa Naveen S. , Hansen Aaron Richard , Rini Brian I. , Beuselinck Benoit , Bjarnason Georg A , Srinivas Sandy , Brugarolas James , Rha Sun Young , Wood Lori , Lalani Aly-Khan A. , Bosse Dominick , Duquette Audrey , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: February 2018

667 Background: Recent research suggested that patients (pts) with small renal masses (4cm or less) were at low risk of disease recurrence after surgery. The impact of tumor size on survival in mRCC patients treated with targeted therapy (TKI) is unclear. Methods: Two cohorts were identified from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Cohort 1 pts had initial nephrectomy for M0 RCC and subsequently developed metastasis during follow-up. Cohort 2 pts presented with de novo metastasis with or without cytoreductive nephrectomy. Cox regression was performed to assess the associations of primary tumor size (≤4 vs > 4cm) and overall survival (OS) on first line TKI, adjusted for histology, sarcomatoid features, tumor stage, number of metastasis, IMDC risk groups and age at TKI initiation. Results: 4089 pts with mRCC treated with first line TKI had primary tumor size data available. Patient characteristics were generally balanced between tumor size groups (≤4 vs > 4cm), except pts with ≤4cm tumors were more likely to have single metastasis (29% vs 18%, p = 0.001) and less likely to have IMDC poor risk (32% vs 39%, p = 0.04) in pts from cohort 2. For pts from cohort 1, tumor size at initial nephrectomy did not impact OS after TKI initiation (p = 0.689). However, in pts presenting with de novo metastasis (cohort 2), small primary tumors were associated with improved OS after TKI initiation, but only in T1-2 tumors (Table). Conclusions: Tumor size impacts survival outcome with targeted therapy in mRCC patients presenting with de novo metastasis and T1-2 disease. This may need to be taken in consideration in clinical trial designs. [Table: see text]
Immunologic profile and prognostic significance of tumor-infiltrating lymphocytes in renal cell carcinoma.
Authors: Khan Amir Ishaq , Jansen Caroline Stewart , Wilkinson Carlisle Jennifer , Melnick Kevin Richard , Kim Kyu Seo , Hosseinzadeh Fares , Prokhnevska Nataliya , Bilen Mehmet Asim , Master Viraj A. , Kissick Haydn T. 
Published: February 2018

673 Background: Renal cell carcinoma (RCC) has been shown to be a genetically and morphologically heterogeneous cancer. As studies show the significance of tumor-infiltrating lymphocytes (TIL) in cancer, it is critical to examine how the phenotype of TILs manifests in RCC. Such analysis may help explain the role of the immune landscape in developing resistance and its contribution to the high treatment failure observed in immunotherapy for RCC. This study compares the immune phenotype of primary tumors, venous tumor thrombi (VTT), and metastases, as well as multiple sites within primary tumors, and investigates whether inter- and intra-tumoral immune heterogeneity is present in RCC. The association of TIL levels and clinical prognosis will also be assessed and compared with current RCC prognostic scores. Methods: Our cohort included 15 VTT and 6 metastases (3 adrenal, 2 bone, 1 liver) with 20 matched primary tumors, as well as 25 non-metastatic primary tumors. The RCC tissue was collected and digested into single cell suspensions. Suspensions were stained for TIL surface markers and processed using flow cytometry. The data was analyzed to capture %CD8+ and %CD4+ in total tumor. The %CD28+ and %PD1+ of CD8+ cells were measured to describe the co-stimulatory and co-inhibitory receptor expression, respectively. Clinical data was obtained to calculate the Mayo Stage, Size, Grade, and Necrosis (SSIGN) and UCLA Integrated Staging System (UISS) scores for each patient and to evaluate recurrence. Results: Immunologic concordance was observed in all measured parameters (%CD8+, %CD4+, %CD28+, and %PD1+) for primary tumors and VTT, for primary tumors and their metastases, and for different sites within 10 primary tumors. In our overall cohort, %CD8+ was found to be inversely associated with recurrence (p = 0.02). Furthermore, %CD8+ was not significantly associated with patient Mayo SSIGN and UISS scores. Conclusions: Despite the genetic and morphologic heterogeneity seen in RCC, immunologic concordance was observed for both inter- and intra-tumoral analysis. The association between %CD8+ and recurrence presents a novel and objective immune-based prognostic factor for RCC, independent of Mayo SSIGN and UISS scores.
Tumor contact surface area as a predictor of functional outcomes after partial nephrectomy.
Authors: Suk-Ouichai Chalairat , Wu Jitao , Dong Wen , Hajime Tanaka , Caraballo Elvis , Remer Erick M. , Li Jianbo , Isharwal Sudhir , Campbell Steven C. 
Published: February 2018

675 Background: New baseline GFR is a major factor for cancer survivorship after renal cancer surgery. Parenchymal mass preservation is the predominant factor associated with functional outcomes after partial nephrectomy (PN). Contact surface area (CSA) between the tumor and parenchyma may impact parenchymal preservation and predict functional outcomes after PN. We evaluated CSA as a predictor of parenchymal mass and function preserved by PN. Methods: 419 patients managed with PN had necessary studies to evaluate preoperative and postoperative parenchymal mass and renal function within the operated kidney. Patients with multifocal renal masses were excluded. Parenchymal mass in the operated kidney and CSA were measured using contrast-enhanced CT < 2 months prior and 3-12 months after PN. CSA was calculated using mathematical formula: 2πrd, where r = radius and d = intraparenchymal depth of tumor. Pearson correlation evaluated relationships between CSA and parenchymal mass or GFR preservation. Multivariable linear regression assessed predictors for GFR preservation. Conceptually, the formula for CSA should function best for exophytic tumors, while predictive value for endophytic tumors may not be as strong. Results: Median tumor size and R.E.N.A.L. were 3.5 cm and 8, respectively. Median global/ipsilateral GFR preserved were 89%/79%, respectively. Median ipsilateral parenchymal mass preserved was 85% and significantly higher for exophytic masses (87% vs 83%, p = 0.001). Median CSA was 22.8cm2 and significantly less for exophytic masses (19.8cm2 vs 24.6cm2, p = 0.02). CSA associated modestly with both ipsilateral GFR and mass preserved ( r= 0.25 and 0.36, respectively, both p < 0.001). On multivariable analysis, CSA associated with ipsilateral GFR preserved for exophytic masses (p = 0.011), but not for endophytic ones (p = 0.27). Limitations include retrospective design. Conclusions: CSA associates with parenchymal mass and function saved after PN, although its utility appears to be greatest for exophytic rather than endophytic tumors. Further study will be required to validate the utility of CSA in different clinical settings.
Outcomes of metastatic chromophobe renal cell carcinoma (ChRCC) with sarcomatoid features (SF).
Authors: Ged Yasser , Knezevic Andrea , Chen Yingbei , Redzematovic Almedina , Carlo Maria Isabel , Lee Chung-Han , Feldman Darren R. , Patil Sujata , Motzer Robert J. , Voss Martin Henner 
Published: February 2018

678 Background: ChRCC makes up 5-10% of RCC subtypes and is generally thought to confer favorable prognosis. Presence of SF on histologic review can occur in any RCC subtype and is considered a hallmark of aggressive disease. We assessed outcomes in a cohort of patients (pts) with metastatic ChRCC and SF (sChRCC). Methods: Baseline clinical features and details on treatment were collected for pts with newly diagnosed metastatic sChRCC evaluated at Memorial Sloan Kettering Cancer Center (MSKCC) between 2002-17. Overall survival (OS) was calculated for all patients and time to treatment failure (TTF) for those who received first-line therapy at MSKCC. Next generation sequencing (NGS) with MSK-IMPACT was performed in a subset of pts. Results: 27 pts with newly diagnosed metastatic sChRCC were identified; other clinical features are summarized below ( table). 2 pts never received first line therapy based on poor performance status. 16 were treated at MSKCC and received a median of 2 lines of systemic therapy. First line agents included sunitinib (n = 6), pazopanib (n = 2), temsirolimus (n = 2), everolimus + bevacizumab (n = 2), sunitinib + gemcitabine (n = 2) and interferon alpha (n = 2) with median TTF of 2.1 months (0.9-14.5). Across the entire cohort (n = 27), median OS was 7.9 months (95% CI 4.2-11.2) with estimated 1 year OS rate of 25%. By comparison, a cohort of 67 pts with metastatic ChRCC lacking SF also treated at MSKCC 2002-17 achieved median OS of 38.1 months, (HR 4.6; 95% CI: 2.6-8.3; p < 0.001). In the 6 sChRCC pts with NGS analysis, TP53 (n = 4), PTEN (n = 2) and CHEK2 (n = 2) were the most frequently altered genes. Conclusions: Outcome for pts with metastatic sChRCC was poor in contrast to pts with ChRCC lacking SF. The lack of benefit observed across various classes of systemic agents warrants study of underlying biology and novel agents. [Table: see text]
Statin use and risk of renal cell carcinoma in three prospective cohort studies.
Authors: Wilson Kathryn M. , Sanchez Alejandro , Graff Rebecca E. , Signoretti Sabina , Choueiri Toni K. , McDermott David F. , Cho Eunyoung , Preston Mark A 
Published: February 2018

679 Background: Evidence on statin use and incidence of renal cell carcinoma (RCC) is mixed. Previous results from the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) found a suggestive protective effect in women but not in men (Liu et al, Cancer 2012). We conducted an updated analysis of statin use and risk of total and fatal RCC in the NHS, HPFS, and NHS 2 cohorts, with more than twice as many cases. Methods: We examined the associations between statin use and risk of RCC from 1990 to 2016 in HPFS (men), 1994 to 2016 in NHS (women), and 1999 to 2015 in NHS 2 (women). Information on statin use was collected every two years. We used Cox proportional hazards models, adjusting for known and suspected risk factors, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for use of statins and risk of total and fatal RCC, RCC by stage at diagnosis, and clear cell RCC. We pooled results across cohorts using a random effects model. Results: We documented 661 cases of RCC (310 in HPFS, 255 in NHS, 96 in NHS 2), of which 132 (20%) were fatal. Of the 661 cases, 458 (69%) were clear cell. The pooled multivariable HR for total RCC was 1.01 (95% CI 0.84-1.21) for current statin use, updated over time. Current use was not associated with risk of fatal, advanced (stage T3 or higher), or localized (stage T1 or T2) disease. There were no associations between duration of statin use and risk of RCC; compared to never users, those with less than four years of total use had an HR of 0.91 (95% CI 0.71-1.18), and those with four or more years of use had an HR of 1.03 (95% CI 0.84-1.27). Among men, statin use was associated with increased risk of clear cell RCC (HR for current use: 1.48, 95% CI 1.04-2.11; HR for 4 or more years of use: 1.58, 95% CI 1.05-2.36). Statins were not associated with risk of clear cell RCC in women (HR for current use: 0.77, 95% CI 0.58-1.03; p-value for heterogeneity across cohorts = 0.02). Conclusions: Overall, statin use was not associated with risk of RCC in three large, prospective cohorts of US women and men. Statin use was associated with increased risk of clear cell RCC among men.