bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive profiling of renal medullary and collecting duct carcinomas.
Authors: Ho Thai Huu , Swensen Jeffrey , Ghazalpour Anatole , Hes Ondrej , Stanton Melissa L. , Joshi Monika , Sanati Souzan , Purnanada Priyanka , Arguello David , Reddy Sandeep K. , Gatalica Zoran 
Published: February 2017

572 Background: Renal medullary carcinoma (RMC) is an aggressive malignancy affecting predominantly young African Americans with sickle cell trait (SCT) or disease (SCD), while a pathologically similar collecting duct carcinoma (CDC) affects patients without sickle cell trait. Clinical responses to chemotherapy and IL-2 in RMC/CDC are poor and novel therapies are needed. Methods: 9 patients with RMC (ages 13-58 y. o., all male) and 15 patients (ages 26-74 y. o., M:F = 13:2) with collecting duct carcinoma (CDC) were studied. Expression of PD-L1 was evaluated with 2 monoclonal antibodies (SP142 and SP263) and tumor infiltrating lymphocytes (TIL) were evaluated for PD1 expression (MRQ-22 antibody) using immunohistochemistry (IHC). Additional studies included ALK protein expression (D5F3 antibody), gene translocation (break apart FISH), next generation sequencing (NGS), and microsatellite instability (MSI). Results: Cancer cell PD-L1 expression above the threshold ( ≥ 2+, ≥ 5%) was seen in 7/9 RMC and 5/13 CDC cases. Concordance between 2 PD-L1 antibodies was 94.4%. PD-1+ TIL were absent in 6/18 cases and variably present in 12/18 cases (from 1 to > 15 TIL/40x power field). No MSI was detected in any of the cases tested (0/6). No case expressed ALK protein, but one case of CDC showed ALK gene re-arrangement. Mutations were identified in SMARCB1, FH, TP53 (3x), ATM, BRCA2, CHEK2 (2x), NF2 (3x), SETD2, and CDKN2A. No mutations in VHL or KDR were detected. One patient with RMC (and SCT) achieved complete clinical remission after treatment with bevacizumab plus paclitaxel. Conclusions: RMC and CDC strongly express PD-L1 in the majority of cases (12/22), suggesting that these patients may benefit from targeting the PD-L1/PD1 interaction. The absence of MSI in these cancers indicates a different mechanism of PD-L1 upregulation from colorectal carcinomas. Consistent with our previous study that showed frequent activation of (pseudo)hypoxia-induced pathways in RMCs (Human Pathology 2011;42:1979), we describe a case of RMC successfully treated with anti-VEGF therapy.
Pazopanib for treatment of metastatic renal cell carcinoma with non-clear cell histology: Single-arm, open label, multicenter, phase II study.
Authors: Jung Ki Sun , Cho Jinhyun , Yoo Kwai Han , Park Se Hoon , Lee Jae-Lyun , Lee Se-Hoon , Lim Jae Yun , Kang Jung Hun , Lee Suee , Rha Sun Young , Lee Kyung Hee , Kim Ho Young , Lim Ho Yeong 
Published: February 2017

577 Background: Targeted therapy has shown remarkable treatment efficacy on the outcomes of patients with advanced renal cell carcinoma. However, this advance for treatment outcomes with targeted agents has been limited to patents with clear cell histology. The optimal treatment strategy for metastatic non-clear cell renal cell carcinoma (nccRCC) remains uncertained. Recently, several vascular endothelial growth factor inhibitors have shown efficacies for nccRCC. Thus, we designed a single-arm, open label phase II study to determine the efficacy and toxicity of pazopanib in patients with nccRCC. Methods: Patients with metastatic nccRCC except for collecting duct or sarcomatoid type received 800mg/day of pazopanib daily until progression of the disease or intolerable toxicity was observed. The primary objectives were progression free survival (PFS) and second objectives were overall survival (OS), treatment response and safety profiles. Results: A total of 29 eligible patients were enrolled from September 2012 to August 2014. The median age of the patients was 59 years (range, 30-77 years) and 21 patients were male. The median PFS was 8.3 months (95% CI, 4.0-12.6 months) and median OS was not reached (range, 1.5-34.7 months). Among all 29 patients, five patients (17.2%) are ongoing treatment without disease progression. Disease progression was observed in 16 patients (55.2%) during follow up period. Five patients (17.2%) experienced a treatment-related toxicity of grade 3 or more during the study and they stopped treatment in the end. Eight patients (27%) expired during follow up period but, there were no treatment-related deaths. Conclusions: This prospective phase II study showed that pazopanib demonstrated promising activity and tolerable safety in patients with nccRCC (ClinicalTrials.gov NCT01538238). Clinical trial information: NCT01538238.
Modeling patient variability in pazopanib-induced hepatotoxicity with iPSC-derived hepatocyte-like cells.
Authors: Choudhury Yukti , Toh Yi-Chin , Qu Yinghua , Xing Jiangwa , Poh Jonathan , Tan Hui Shan , Kanesvaran Ravindran , Yu Hanry , Tan Min-Han 
Published: February 2017

578 Background: The tyrosine kinase inhibitor drug, pazopanib, is commonly prescribed as a first-line treatment option for metastatic renal cell carcinoma (mRCC). Administration of pazopanib can produce severe hepatotoxicity with elevated transaminases and bilirubin levels. The idiosyncrasy of hepatotoxicity suggests individual patient-factors as the key predisposition. Patient-derived induced pluripotent stem cells (iPSCs) bearing individual genetic and other signatures, were interrogated as a novel cell-based approach to model inter-patient drug response variability. Methods: iPSC lines were generated from five mRCC patients who exhibited positive (n = 3) or negative (n = 2) clinical hepatotoxicity to pazopanib. The iPSC lines were differentiated into functional hepatocyte-like cells (HLCs), which were then dosed with pazopanib. Differential cellular viability changes among hepatotoxicity-positive and -negative lines were assessed. To gain insight into the mechanism of idiosyncratic hepatotoxicity, a comparison of transcriptomic changes in HLCs after pazopanib treatment was also done, with accompanying functional assays to investigate mechanisms of toxicity. Results: iPSCs were successfully generated from five patients and could be robustly differentiated into HLCs with uniformly high degrees of hepatocyte function. HLCs from patients with clinical hepatotoxicity exhibited higher in vitro toxicity to pazopanib compared to HLCs from patients without hepatotoxicity (p < 0.01). However, all HLCs showed similar toxicity to known hepatotoxicants. Analysis of transcriptomic changes showed differential early-stress response among pazopanib-sensitive HLCs and suggested oxidative stress as a mechanism of pazopanib toxicity, which was verified by the observed depletion of intracellular glutathione levels in HLCs. Conclusions: We have a developed a novel cellular platform using iPSC-derived HLCs that can recapitulate phenotypes corresponding to clinical variation in pazopanib-induced hepatotoxicity. Furthermore, the patient-derived HLCs are ideal tools for the investigation of specific mechanism of hepatotoxicity.
Efficacy and safety of sequential use of everolimus in patients with metastatic renal cell carcinoma previously treated by bevacizumab with or without interferon therapy: Results from pooled analysis of AVATOR, CHANGE, and TRAIN studies.
Authors: Thiery- Vuillemin Antoine , Guillot Aline , Steiner Thomas , Herrmann Edwin , Syrigos Konstantinos N. , Kelkouli Nadia , Cattaneo Agnese , Nguyen Thierry 
Published: February 2017

585 Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. It gained approval based on the results of the RECORD-1 trial, which included patients with metastatic renal cell carcinoma (mRCC) whose disease progressed after receiving vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Bevacizumab is a monoclonal antibody targeting angiogenesis that is approved in patients (pts) with mRCC. AVATOR was the 1st study to explore the sequential use of bevacizumab followed by everolimus but with limited number of pts. Methods: In order to further explore this sequence pooled data from the AVATOR, CHANGE and TRAIN studies were analysed retrospectively. All pts had mRCC and were previously or currently treated with everolimus after failure of bevacizumab ± IFN. The primary end point was everolimus time to progression (TTP). Secondary end points were related to the overall survival (OS) of patients receiving the drug sequence, everolimus treatment and safety. Results: 89 pts were included in the analysis. Median age was 68 years [18-90]. At everolimus initiation ECOG was 0-1 for 72% pts and 16% were classified as poor prognosis from Heng classification. Exploring the duration of second-line everolimus treatment, 32% of patients received less than 3 months of everolimus and 35% received at least 6 months of treatment. At the time of data analysis, 20 pts (24%) were still receiving everolimus. Pts receiving everolimus after bevacizumab experienced a median TTP of 6 months [95%CI 4 - 14]. Median OS was not reached for everolimus second-line therapy. At 36 months after the start of first-line therapy, 60.4% of pts were still alive. All grades of common adverse events were consistent with the known safety profile of everolimus. Conclusions: The larger size of this cohort confirms the signal previously seen with AVATOR that the sequence of bevacizumab followed by everolimus displays interesting efficacy with not unexpected toxicity from everolimus and compares favourably with RECORD-1.
Single-fraction radiosurgery for the treatment of renal cell carcinoma.
Authors: Staehler Michael D. , Schlenker Boris , Karl Alexander , Spek Annabel , Muacevic Alexander 
Published: February 2017

590 Background: We report on patients with renal cell carcinoma (RCC) who were treated with single fraction high-dose local stereotactic radiosurgery (SRS) using the robotic Cyberknife system to avoid nephrectomy and consecutive hemodialysis. Methods: Fifty-two patients with histologically confirmed RCC and median age of 63.6 years (43.6-86.5) with the indication for renal surgery and highest risk for consecutive hemodialysis were entered into a prospective case control study of single fraction SRS with 25Gy. Tumor response, renal function, survival, and adverse events were estimated every three months with a follow-up of at least six months. Results: R.E.N.A.L. score was low in 1, moderate in 30 and high in 21 patients. 28 patients had singular renal units. Median follow-up was 26.9 months (1.8 - 52.6). Local tumor control nine months after SRS was 98% (95% CI: 89-99%). 43 lesions showed a measurable tumor size reduction including six complete remissions and 33 partial remissions. Renal function remained stable with a median serum creatinine at baseline of 1.10 mg/dl (0.4 -2.0) and 1.11 mg/dl (0.8-2.2) at follow-up. In one patient grade I erythrodermia, in three patients grade I fatigue and in two patients grade I nausea occurred. In all patients nephrectomy was avoided. Conclusions: Single-fraction SRS as an outpatient procedure is a treatment modality with short-term safety and efficacy to avoid treatment-related loss of renal function and hemodialysis in selected patients with RCC. Short term follow up of oncological and functional results so far is excellent. Further studies are needed to determine the limits of SRS in this setting and long term results.
Sunitinib's effect on tumor infiltration of CD8 T cells in renal cell carcinoma (RCC) and modulation of their function by altering VEGF-induced upregulation of PD1 expression.
Authors: Haywood Samuel , Chen Roy , Pavicic Paul , Lin Lin , Diaz-Montero C. Marcela , Rayman Pat A. , Przybycin Christopher , Finke James , Rini Brian I. 
Published: February 2017

591 Background: The effect of VEGF inhibitors such as sunitinib to modulate RCC tumor microenvironment and the effect on immunotherapy using checkpoint inhibitors is unknown and of clinical interest. Methods: Immune infiltrate in tissue sections from clear cell renal cell carcinomas (ccRCC) (n = 13) treated with sunitinib in the neoadjuvant setting were compared to that of untreated RCC patients with localized disease (n = 15). Immune infiltrate was scored in H&E stained tissue sections. Infiltrates were further characterized by IHC using antibodies against CD4 (Novocastra NCL-CD4-1F6 clone 1F6), CD8 (BiogeneX MU422-UC clone 1A5) or PD1 (Abcam ab52587 clone EPR4877). Intensity of staining was quantified using a Leica microscope equipped with a Retiga SRV camera. Scanned images of multiple tumor fields were analyzed using ImagePro Plus software. For pre-clinical studies, Balb/c mice bearing Renca tumors (RCC) were treated with sunitinib (40mg/kg) daily for 14 days, and tumors were dissociated and analyzed for CD8 and CD4 infiltrate by FACS analysis. Results: Qualitative analysis showed a more prominent accumulation of lymphocytes in tumor sections of patients receiving sunitinib. Quantitative analysis of these infiltrates revealed higher levels of CD8+ T cells in sunitinib treated patients (p = 0.04). By contrast, sunitinib treatment was associated with a reduction of intratumoral expression of PD1. Preclinical studies in the Renca model also showed an increase in the frequency of tumor infiltrating CD8+ T cells following sunitinib treatment. Remarkably, a higher fraction of these tumor infiltrating CD8 T cells were found to co-express the activation marker of cytotoxic effector cells (CD107a) when compared to untreated mice. Conclusions: These findings suggest that sunitinib not only promotes the accumulation of CD8+ T cells within the tumors, but also affects their activity by modulating PD1 expression and enhancing cytotoxic function.
A personalized sunitinib (S) first-line approach in elderly patients with metastatic renal cell carcinoma (mRCC).
Authors: Cossu Rocca Maria , Iacovelli Roberto , Verri Elena , Crescio Claudia , Aurilio Gaetano , Detti Serena , Cullura Daniela , Nole Franco 
Published: February 2017

602 Background: About 24% of mRCC are older than 74 yo. S is a well-established first-line therapy for mRCC with a specific toxicity profile requiring a dose reduction in 30% of pts. Actually few data are available in the Literature about its use in patients > 75 yo especially as regards efficacy and cost effectiveness of tailored approaches. Methods: The primary end-point of this prospective single arm study, is to assess if a personalized approach is able to decrease the rate of dose reduction to 8% after the first cycle of S.. 19 pts have been estimated to be necessary to explore this hypothesis. Secondary objectives were the safety, treatment duration (TD) and overall survival (OS). Personalized approach was defined as the starting dose of S choose by the medical oncologist based on performance status (PS ECOG) and number of comorbidities. Results: From 2007 to 201421 pts were enrolled. The median age was 77.9 yrs (IQR 74.1-82.1). Seventy-five % had a clear cell carcinoma, 20% had a metastatic disease at diagnosis and 60% had > 2 sites of metastasis. All pts had PS ECOG ≥ 1 and 50% suffered from > 2 comorbidities. 43% were good, 52% intermediate and 5% poor prognosis by IMDC criteria. 3 pts (14%) started S at 50 mg/d, 9 pts (42%) at 37.5 mg/d and 9 pts (42%) started with 25 mg/d. All pts received S with the 4/2 schedule. The dose reduction after the first cycle was 28%. The reason was always toxicity, but no treatment interruption occurred. No pts starting at 25 mg had dose modification. The main toxicity requiring dose reduction was G3 anemia in 1pt, G3-4 thrombocytopenia in 3 pts and G3 leuconeutropenia in 3 pts . The median TD was 11.9 mos (95%CI, 6.5-17.3). The median OS was 33.3 mos (95%CI, 26.1-40.6). Conclusions: This study shows that a personalized starting dose is not able to decrease the rate of dose reduction at first cycle. Nonetheless a personalized strategy does not affect negatively the OS of elderly pts. Actually in elderly pts a disease stabilization without acute adverse events, could be considered an adequate goal. A well tolerated therapy could also be cost effective because part of health cost, especially for elderly pts, derives from their hospitalization for adverse events. Further data are required.
Time to targeted therapy after cytoreductive nephrectomy (CN) and surveillance in patients with synchronous unresectable metastases of renal cell carcinoma (RCC).
Authors: Bex Axel , de Bruijn Roderick , Noe Allard , Blank Christian U. , Horenblas Simon , Haanen John B. A. G. 
Published: February 2017

604 Background: VEGF-targeted therapy does not cure metastatic RCC. Guidelines recommend cytoreductive nephrectomy and complete resection of solitary-/oligometastases when feasible to potentially cure patients. However, in patients with low-volume but unresectable multiple metastases at single or more sites surveillance with or without local therapy after debulking CN may be an option to delay non-curative systemic therapy and associated toxicity. Methods: From an IRB approved institutional database of patients with primary metastatic RCC we identified patients with low-volume but unresectable oligometastatic disease in whom surveillance after debulking CN was a local multidisciplinary tumour board recommendation. Patient data, IMDC risk, site and number of sites, time-to-progression (TTP), time-to-targeted therapy (TTT) and overall survival (OS) were retrospectively analyzed. Results: From 203 primary mRCC patients treated since 2006, 28 (13.8 %) were identified who had low-volume multiple metastasis at a single site (13 with 7 lung, 5 bone) or multiple sites (15 with ≥ 2 sites). IMDC risk was favorable in 1, intermediate in 18 and poor in 6. Median TTP was 12 (range 3-36) months and TTT was 14 (range 3-43) months. Of 8 (28.7 %) progressing within 6 months, 2 had sarcomatoid tumours, 4 grade 4, 3 IMDC poor risk and 7 had ≥ 2 sites . In 15 patients TTT was further delayed by surveillance beyond RECIST progression (median time 5 (range 1-15) months) or additional local therapy of the most rapidly progressing lesion (5 radiation, 1 ablation). Median OS was 21.5 (range 4-75) months. Conclusions: Debulking CN followed by surveillance may substantially delay VEGF-targeted therapy and associated adverse events in a subset of patients with primary mRCC and unresectable low-volume metastasis. Local therapy to control the most rapidly progressing lesion or surveillance beyond progression were additional means to delay systemic therapy.
An optimized microRNA signature algorithm to predict clear cell renal cell carcinoma metastasis: A 265-case validation study using paraffin specimens.
Authors: Wu Huiqing , Wu Xiwei , Jin Jennifer M , Li Arthur X , Tong Tommy , Ma Dongling , Nelson Rebecca A. , Li Yuping , Pal Sumanta K. , Kim Young S , Haberman Ken , Zhai Jing , Lau Clayton S. , Guo Chao , Wu Jeffrey J , Chen Wengang , Yuh Bertram E. , D'Apuzzo Massimo , Li Wenzhe , Wilczynski Sharon 
Published: February 2017

612 Background: Clear cell renal cell carcinoma (ccRCC) metastasis is associated with a dismal prognosis. Early identification of patients at high or low risk of metastasis may help to guide appropriate treatment. There are currently no reliable clinico-pathologic and laboratory modalities for this purpose in a routine clinical setting. We previously performed a microarray study using frozen ccRCC specimens and identified dysregulation of 4 microRNAs (miRNAs), miR-10b, miR-139-5p, miR-130b and miR-199b-5p, to be highly associated ccRCC metastasis and prognosis. Methods: We established a training cohort including formalin-fixed paraffin-embedded (FFPE) specimens of localized (n = 13; pT1) and metastatic (n = 15; M1) ccRCCs. We measured the expression of the 4 miRNAs of the training cohort samples by quantitative RT-PCR, normalized with miR-24, one of the most stably expressed miRNAs in human renal tissue as we previously reported. Using the risk score method, we rebuilt a mathematical formula with cutoff points to predict a patient to be at high, low or equivocal risk of metastasis. We validated the signature in an FFPE test cohort of 265-case primary ccRCCs. We examined the signature performance and its correlation with the cancer-specific survival. Results: Multivariate logistic regression analysis showed the signature to be highly associated with ccRCC metastasis (OR 7.67, 95%Cl 2.80-21.09, p < 0.0001), with the overall sensitivity and specificity of 80% and 76%. The sensitivities and specificities were 72% and 78%, 70% and 67%, and 78% and 75% for stage I, II or III patients, respectively. The signature predicted metastasis of small ccRCCs ( ≤ 4.0 cm), with the sensitivity of 60% and specificity of 77%. The overall positive and negative predictive values (PPV and NPV) were 61% and 89%. The area under the curve of ROC was 0.8. The signature was also found to be well correlated with worse cancer-specific survival (HR 3.06, 95%Cl 1.49-6.93, p < 0.01). Conclusions: This optimized miRNA signature can reliably predict ccRCC metastasis and prognosis and may help to stratify patients for more appropriate therapies and suitable clinical trials.
Utilization and sequencing of targeted therapy and cytoreductive nephrectomy in non–clear cell metastatic kidney cancer.
Authors: Macleod Liam Connor , Tykodi Scott S. , Holt Sarah , Gore John L. 
Published: February 2017

615 Background: Many patients with metastatic kidney cancer (mRCC) are ineligible for trials due to non-clear cell histology. Efficacy of targeted therapy agents in non-clear cell mRCC is still being investigated. We hypothesized that sequencing CN upfront is associated with improved overall survival. We analyze a population-based cohort of non-clear cell mRCC patients in the targeted therapy era. Methods: Patients from the SEER-Medicare files (2005-2011) with non-clear cell mRCC were categorized as having received upfront targeted therapy or upfront CN. Additional exclusions were age < 66 to avoid confounding by uncaptured non-Medicare coverage, and competing stage IV cancer. Targeted therapy was identified through Medicare Part D files. Cox proportional hazards regression determined association between treatment groups, clinical and cancer-related characteristics, and the main outcome, median overall survival (OS). Propensity matching controlled for measurable confounding in treatment selection. Results: Of 1,326 mRCC cases, 528 met inclusion criteria of whom 433 (82%) received targeted agents and 172 (33%) underwent CN. Of those not having CN, 74% were diagnosed by biopsy, 10% by cytology, and 16% radiographically (confirmed at autopsy). Thirteen percent received CN then targeted therapy (OS 14 mos, IQR 9-25), 2.5% received targeted therapy then CN (OS 14 mos, IQR 9-26), 18% received CN only (OS 14 mos, IQR5-40), 67% received targeted therapy only (OS 9 mos, IQR 4-19). On multivariable Cox proportional hazards regression upfront CN (regardless of post-CN therapy) was associated with improved OS (HR 0.54,95% CI 0.41,0.72). Using propensity scores, upfront CN patients (N = 161) were matched to upfront targeted therapy patient (N = 111) and the average treatment effect of CN was 8.3 months survival improvement (95% CI 4.0, 13.2). Conclusions: Although utilization of targeted agents in non-clear cell mRCC exceeds 80%, those with greatest OS received CN either upfront or after targeted therapy, though the latter was rare (2.5%). The variety of sequencing strategies observed is evidence of uncertainty regarding the best care for non-clear cell mRCC patients given limited options.