bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment of patient-derived renal cell carcinoma (RCC) models based on orthotopic xenografts (PDX) and cancer stem cell (CSC) isolation to provide prognostic and predictive information.
Authors: di Martino Simona , de Luca Gabriele , Grassi Ludovica , Federici Giulia , De Salvo Laura , Di Pace Anna Laura , Addario Antonio , Muto Giovanni , Costantini Manuela , Biffoni Mauro , Signore Michele , Sperduti Isabella , Sentinelli Steno , Milella Michele , Cognetti Francesco , Gallucci Michele , De Maria Ruggero , Bonci Desiree 
Published: September 2018

e16055 Background: The introduction of VEGF/VEGFR- and mTOR, and immune checkpoint-targeted agents has radically changed metastatic RCC treatment; however, predictive biomarkers are still lacking and the potential for curative impact of such treatments in earlier disease stages is hotly debated. To identify potential diagnostic, prognostic, and predictive biomarkers, we developed patient-derived preclinical RCC models based on PDX obtained from freshly dissociated cancer tissues and combining isolation of cell populations endowed with self renewal and multi-lineage differentiation abilities (CSC). Methods: 182 surgical RCC specimens (clear cell, n = 110; papillary type I/II, n = 23, chromophobe/oncocytoma, n = 26, other, n = 23; stage I-III, n = 124, stage IV, n = 28, n/a n = 30) were collected; tumor spheroids were obtained and characterized in 57 cases, using a stem-cell isolating medium supplemented with EGF/b-FGF; 30 cancer samples were orthotopically injected in immunocompromised mice and were able to engraft in 67% of cases (G3-G4 cases more frequently than G1-G2 cases, p = 0.04). Results: PDX tumors recapitulated histological appearance, sarcomatoid features when they were present, and tumor heterogeneity of their human counterpart; interestingly, PDX engraftment was significantly correlated with shorter DFS in the corresponding patient population (p = 0.12). We conducted proteomic analysis by Reverse Phase Protein Array (RPPA) in 21 patient-derived CSC models in vitro: a panel of established (HIF, VEGFR, mTOR) and novel (EGFR(Y1148)), AKT, PI3K) oncogenic signals were deregulated in our isolated cell populations; molecular endpoints were correlated with grading and with angiogenesis and mTOR pathways (p < 0.05). Data analysis is ongoing to ascertain whether specific RPPA-signatures can potentially complement clinical prognostic information and suggest candidate biomarkers and potential targets for therapy. Conclusions: In the era of personalized therapy, the combined use of PDX and RPPA from tumor specimens may be very useful for drug testing and patient stratification in RCC.
Renal cell carcinoma with perirenal fat invasion: Is partial nephrectomy as good as radical surgery?
Authors: Cordeiro Mauricio , Bastos Diogo Assed , Gallucci Fabio Pescarmona , Barbosa Joao Arthur Brunhara , Ilario Eder Nisi , de Carvalho Paulo Afonso , Nonemacher Henrique T. S. , Albuquerque George Lins , Mattedi Romulo Loss , Carvalho Arnaldo Fazoli , Nahas William Carlos 
Published: September 2018

e16056 Background: Partial nephrectomy (PN) is the standard of care in the management of cT1a tumors, while radical nephrectomy (RN) is indicated in more advanced tumors. Recent studies provided evidence that PN could be performed in patients with tumors greater that 7 cm with complication rates and oncological outcomes comparable with those undergoing RN. This study compares the recurrence-free survival (RFS), overall (OS) and cancer-specific survival (CSS) of PN and RN in patients with non-metastatic pathological T3a renal cell carcinoma (RCC) with perirenal fat invasion only. Methods: We reviewed 1202 patients undergoing RN (n = 653) and PN (n = 549), at a oncological referral center, from January 2003 to June 2016. Of all patients, we identified 25 RN and 41 PN pT3a tumors with exclusively perirenal fat invasion. None had nodal or distant metastasis at pretreatment clinical staging. Patients characteristics were compared with Mann-Whitney U test and Student t-test for categorical and numeric variables with normal distribution, respectively. Both groups were compared for RFS, OS and CSS with a Kaplan-Meier survival analysis. Results: All patients included had pT3a stage with isolated perirenal fat invasion. Groups undergoing RN and PN were not significantly different regarding Charlson Comorbidity Index (Median 3 for RN vs 4 for PN, p = 0.24) or Age (Mean 65.3 for RN vs 62.0 for PN, p = 0.99). Patients undergoing RN had bigger tumors (7.9 cm vs 4.6, p < 0.001) and higher Fuhrman grade (p = 0.01). Median follow-up was 36 months for RN and 34 months for PN. At the end of follow-up, recurrence was seen in 3 patients undergoing RN (12%) and 2 undergoing PN (5%), p = 0.36. Mortality was similar across groups (16% for RN vs 15% for PN, p = 0.99) as well as Cancer-specific mortality (4% for RN vs. 5% for PN, p = 0.99). At the end of follow-up, RFS was 80% (20/25) for RN and 82% (34/41) for PN. Conclusions: In our data, renal cell carcinoma with T3 stage due to perirenal fat invasion exclusively had similar outcomes when treated with Radical or Partial Nephrectomy. OS as well as RFS were comparable for both surgical modalities, suggesting that, although RN is currently the gold standard for this staging, PN may provide similar oncologic results.
The impact of kidney function on the efficacy and safety of pazopanib in metastatic renal cell carcinoma (mRCC) patients: CORE-URO-01 study.
Authors: Vitale Maria Giuseppa , Masini Cristina , Procopio Giuseppe , De Giorgi Ugo , Buti Sebastiano , Rossetti Sabrina , Iacovelli Roberto , Mucciarini Claudia , Cosmai Laura , Vignani Francesca , Prati Giuseppe , Scagliarini Sarah , Berselli Annalisa , Pinto Carmine 
Published: September 2018

e16063 Background: Pazopanibhas been approved for treatment of patients (pts) with mRCC based on the prospective randomized trial that enrolled only pts with adequate renal parameters. There are no data on the toxicity profile and efficacy of pazopanib in pts with renal insufficiency (RI).The aim of this study is to investigate the effect of renal function on treatment outcomes in pts treated with pazopanib for mRCC. Methods: We retrospectively analyzed the data of the mRCC pts treated with pazopanib with respect to renal function in eleven Italian institutions from January 2010 to June 2016. Baseline glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula at the time of therapy initiation. Pts with MDRD < 60 mL/min/1.73 m2 (group 1) were compared with pts with MDRD ≥60 mL/min/1.73 m2(group 2) in terms of response rates, progression free survival (PFS), overall survival (OS) and side effects. Results: One hundred and twenty-ninepts with mRCC were included in this study: 70 pts in group 1 and 59 pts in group 2. 67% of pts were male, median age was 66 years (34-83) and median CrCl was 49 ml/min (6.3-59.5) in group 1. In group 2, 64% of pts were male, median age was 65 years (38-80), and median CrCl was 64 ml/min (58.1-137.1) Pts with MDRD < 60 were more likely to have had a previous nephrectomy (84.3% vs 79.7%). No difference between the 2 groups was observed in terms of outcomes: PFS was 9.6 months (0.6–56.9) and 9.0 months (0.4–60.1), OS was 16.1 months (1.3–56.9) and 17.0 months (1.2–60.1), for MDRD < 60 group and MDRD ≥60 respectively. The disease control rate was 85.8% in group 1, and 72.9% in group 2. About grade 1-2 toxicity, no difference between the 2 groups was reported (67.1% vs 67.8%) while a higher incidence of grade 3-4 toxicity was evident in the group 1 (25.7% vs 18.6%). Conclusions: RI was commonly observed in pts with mRCC. Renal function at therapy initiation does not adversely affect the efficacy and safety of pazopanib. More frequent monitoring of side-effects in patients with RI is recommended.
Patients with advanced renal cell carcinoma: Immediate or delayed treatment? Study of a cohort of patients followed at Instituto Oncológico Henry Moore (IOHM).
Authors: Morgenfeld Eduardo L. , Gil Deza Ernesto , Martin Reinas Gaston , Acuna Claudia Lorena , Niewiadomski Dario , Rivarola Edgardo G. J. , Ares Sandra L. , Gercovich Felipe G. 
Published: September 2018

e16073 Background: Most of the treatment guidelines for advanced renal cancer (RCC) agree about what drugs must be used, but don’t indicate when the treatment should be started. This decision is left to the desire of the patient (pt) and/or the common sense of the doctor. The aim of this paper is to study which could be the best time of initiation of systemic treatment (Tx) in advanced RCC. Methods: Between 1/1/2001 and 11/30/2016, 828 patients diagnosed with RCC were followed at IOHM. We selected all pt with clear cell or papillary stage IV RCC who received systemic Tx; 80 pt met this inclusion criteria. We reviewed all the clinical records of this population and separated two groups according to the time of initiation of systemic treatment: Group A (Immediate = within three months of diagnosis) or Group B (Delayed = beyond three months of diagnosis). We compared the population’s characteristics and outcome of each group. Results: The results are shown in the table. Conclusions: 1) In this cohort of 80 patients with advanced clear cell or papillary RCC, 47 pt (59%) received systemic treatment immediately after diagnosis and 33 pt (41%) postponed it at least three months. 2) Both groups were similar in age, surgical treatment, metastatic sites and systemic treatments. 3) There was no difference in survival rates with immediate or delayed treatments. [Table: see text]
Predicting outcomes in renal cell cancer: The role of single nucleotide polymorphisms (SNPs).
Authors: Garrigos Carmen , Espinosa Marta , Osman Ignacio , Ávila Rainiero , Medina Rafael , Melendez Ricardo , Salinas Ana , Pérez-Valderrama Begoña , Duran Ignacio 
Published: September 2018

e16074 Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined mostly using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of RCC patients (pts) [localized and advanced] RCC treated at our institution. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). Sixty-four SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). Statistically significant SNPs were validated in an external cohort by individual assays. The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS) and response to treatment (RR). SPSS v20 was utilized for statistical analyses. Results: In pts with localized RCC, 2 SNPs in 2 genes involved in angiogenesis showed a protective effect (VEGFR2: rs2071559, PDGFRA: rs4358459) and others SNPs predicted for worse DFS (VEGFR2: rs10013228, rs1870377, PDGFRA: rs2228230) and shorter OS (VEGFR2: rs2305948, rs10013228; VEGFR3: rs6877011, rs307826) (p < 0.05). In the advanced setting, 6 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics were statistically implicated in OS (IL8: rs2227543, PDGFA: rs9800958, PDGFRB: rs2302273 (p≤0.05)) and RR (VEGFA: rs699947, rs3025010, VEGFB: rs594942 (p < 0.03)). These 14 SNPs are currently being validated in an external cohort of 80 patients with RCC and this data will be presented. Conclusions: These SNPs in genes critical to angiogenesis and metabolism of antiangiogenics might be used as potential prognostic/predictive biomarkers. Prospective validation is ongoing.
Oncological outcomes of positive surgical margins in partial nephrectomy for renal cell carcinoma.
Authors: Nonemacher Henrique T. S. , Cordeiro Mauricio , de Albuquerque George Lins , Galucci Fabio , de Carvalho Paulo Afonso , Borges Leonardo , Guglielmetti Giuliano Betuni , Bastos Diogo Assed , Coelho Rafael , Sarkis Alvaro , Dzik Carlos , Nahas William Carlos 
Published: September 2018

e16079 Background: The prognostic significance and optimal management of positive surgical margins following partial nephrectomy remain controversial. The association between positive margin and risk of disease recurrence in patients with clinically localized renal neoplasm undergoing partial nephrectomy was evaluated. Methods: We analyzed the records of 429 patients cases of non-metastatic renal cell carcinoma who underwent partial nephrectomy (PN) at our institution, from 2001 to 2016. Recurrence free-survival was evaluated using Kaplan–Meier method and the log rank test and Cox models adjusting for tumor size, grade, histology, pathological stage, focality and laterality. The relationship between positive margin and risk of relapse was evaluated independently for pathological high risk (Fuhrman grades III-IV) and low risk (Fuhrman grades I-II) groups Results: A positive surgical margin was found in 55 (12.8%) patients. Recurrence developed in 26 (6%) patients during a median follow up of 39 months. A positive margin was associated with an increased risk of relapse on multivariable analysis (HR 3.19, CI 95% 1.21 – 7.61 p=0.02) (Table). In a stratified analysis based on pathological features, a positive surgical margin was significantly associated with a higher risk of recurrence in cases of high risk (HR 13.8, CI 95% 4.19–45.9, p = 0.0005). Conclusions: Positive surgical margins after partial nephrectomy increase the risk of disease recurrence, primarily in patients with high-risk pathological features. [Table: see text]
Metastatic clear cell renal cell carcinoma: Proangiogenic gene expression and outcome on sunitinib.
Authors: Verbiest Annelies , Beuselinck Benoit , Couchy Gabrielle , Job Sylvie , De Reynies Aurelien , Meiller Clément , Albersen Maarten , Verkarre Virginie , Lerut Evelyne , Mejean Arnaud , Patard Jean-Jacques , Laguerre Brigitte , Rioux-Leclercq Nathalie , Schöffski Patrick , Oudard Stephane , Zucman-Rossi Jessica 
Published: September 2018

e16085 Background: Clear cell renal cell carcinomas (ccRCC) are hypervascular tumors that respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. They can be divided into 4 mRNA-expression based subgroups (ccrcc 1-4) with different outcomes on sunitinib. We hypothesized that the expression of proangiogenic genes is predictive for response to sunitinib. Methods: Retrospective series of metastatic ccRCC-patients treated with sunitinib as first line targeted therapy (n = 104). We studied expression of genes involved in angiogenesis and the immune-suppressive microenvironment (qRT-PCR) and mutational status of Von Hippel Lindau and Polybromo (PBRM) 1 (sequencing) on primary tumor samples. Outcome parameters were response rate (Response Evaluation Criteria in Solid Tumors), progression free survival (PFS) and overall survival (OS). Gene expression levels were tested in multivariate analysis (MV) against the IMDC risk criteria, presence of bone metastases and sarcomatoid dedifferentiation ≥25%. Results: Expression of Hypoxia Inducible Factor (HIF) 2A, Platelet Derived Growth Factor Receptor B, VEGFC, VEGFR1 and VEGFR2 was significantly correlated with PFS on MV and expression of HIF1A, HIF2A and VEGFR2 with OS. VEGFR2-expression was also correlated with partial response (p = 0.03) and anti-correlated with early progressive disease (p = 0.008). HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3-expression was higher in ccrcc2-tumors compared to others. Expression of genes involved in angiogenesis and in the immune-suppressive microenvironment was not directly correlated nor anti-correlated. In tumors with a bi-allelic PBRM1-inactivation, HIF2A, VEGFA, VEGFR1 and VEGFR2-expression were higher compared to tumors with 1 or 2 functional PBRM1-alleles. This did not translate in different outcome on sunitinib. Conclusions: Tumoral expression of genes involved in the HIF-VEGF-VEGFR proangiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in metastatic ccRCC. Expression of these genes was high in the molecular ccrcc2-subgroup, known to be sensitive to sunitinib. These findings could be used for patient selection in future clinical trials.
Prognostication of outcome in men with bone metastatic castration-resistant-prostate-cancer with early rising PSA after initiation of abiraterone acetate.
Authors: Boegemann Martin , Grossmann Phillip , Steinestel Julie , Schlack Katrin , Krabbe Laura Maria , Brücher Benedikt 
Published: September 2018

e16514 Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC in the pre- and post chemotherapy setting and is mainly used in asymptomatic men. In the first 12 weeks an early rise of prostate specific antigen (PSA) may occur followed by either delayed decline (PSA-flare) or true progression. Bouncing of alkaline phosphatase (ALP-Bouncing) was shown to be a promising marker for outcome and response during very early AA therapy. This retrospective study was conducted to analyze the capability of ALP-Bouncing to predict overall survival (OS) in men with bone mCRPC (bmCRPC) with rising PSA after initiation of AA therapy. Methods: Men with bmCRPC and rising PSA during early AA therapy were includeded and analyzed. PSA response rate (RR) was monitored according to PCWG2 criteria and assessed 12 weeks after start of AA treatment. PSA-flare vs. no flare and ALP-Bouncing vs. no Bouncing were analyzed using Kaplan-Meyer estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bouncing was defined as increase of ALP after the beginning of AA with a subsequent significant decline below baseline during the first 8 weeks of therapy. Results: Forty men were evaluable for analysis: 20 men were chemotherapy naïve, 20 pretreated with docetaxel. The PSA RR was 30%. The median survival for ALP-Bouncing was 20 months (95% confidence interval (95%CI): 4.7-13.3) vs. 9 months (95%CI not distinguishable) for no ALP-bouncing (p = 0.04) and 13 months (95%CI: 8.8-17.2) for PSA-flare vs. 9 months (95%CI 4.4-13-6) for no PSA-flare (p = 0.62). In UV no ALP-bouncing was significantly associated with worse OS (Hazard Ratio (HR): 2.65 (95%CI: 1.0-7.0); p = 0.05). After adjustment for PSA-flare no AP-bouncing remained an independent prognosticator of worse OS (HR: 2.78 (95%CI: 1.0-7.71); p = 0.05). Conclusions: ALP-Bouncing, occurring earlier than delayed PSA-decline, may be a helpful marker to identify patients with subsequent favorable outcome in men with bmCRPC and rising PSA after initiation of AA therapy. These results have to be validated in a prospective trial.
Outcomes of prechemotherapy (pCHT) abiraterone (AA) or enzalutamide (E) for metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) + docetaxel (D) or ADT alone for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based registry.
Authors: Francini Edoardo , Gray Kathryn P. , Evan Carolyn , Kaymakcalan Marina D. , Shaw Grace Katherine , Kantoff Philip W. , Taplin Mary-Ellen , Sweeney Christopher 
Published: September 2018

e16515 Background: The E3805: CHAARTED trial noted use of D at time of commencing ADT for mHSPC was associated with an improvement in time to CRPC (PSA rise or clinical progression [CP]) or time to CP and resulted in a prolongation of overall survival (OS). Therefore, we postulated that pCHT AA or E maintained activity after ADT+D. Methods: A cohort of CRPC patients (pts) treated with pCHT AA or E for CRPC between 2010 and 2016 was selected from the Dana-Farber Cancer Institute IRB approved database. Patients were grouped by use of D and whether they had prior localized therapy (PLT) or de novo (DN) metastatic disease, at time of ADT start for mHSPC. The analysis endpoints included OS (time to death from all causes) from ADT start, time to AA/E start from ADT start, OS from AA/E start. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Results: Of the 147 pts selected, 134 (91.2%) had previously received ADT alone, while 13 (8.8%) had ADT+D. Once stratified by PLT or DN, the distributions of the 4 groups are 33.3% (ADT/PLT), 57.8% (ADT/DN), 0.7% (ADT+D/PLT), and 8.2% (ADT+D/DN). In the ADT alone group, the median OS with pCHT AA or E for CRPC was approximately 3 years from the AA/E start, regardless of PLT or DN. In the smaller cohort of pts selected for treatment with ADT+D, both the OS from ADT start and from AA/E start were shorter than the ADT alone cohort. However, even in this group with shorter time to AA/E start, the median OS from AA/E start was still 1.5 years despite prior chemotherapy. Conclusions: Within limitations of a hospital-based registry, small sample size for ADT+D and lack of volume of metastases data, pts selected for ADT+D show poorer outcomes but still have an OS of 1.5 yrs from AA/E start. [Table: see text]
Rate of occult metastases in patients (pts) with biochemically-recurrent prostate cancer (BRPC) from a phase 2 trial of sipuleucel-T and androgen deprivation therapy (STAND).
Authors: Kibel Adam S. , Drake Charles G. , Yu Evan Y. , Vogelzang Nicholas J. , Corman John M. , Karsh Lawrence Ivan , Elfiky Aymen , Shore Neal D. , Millard Frederick E. , Chang Nancy N. , Antonarakis Emmanuel S. 
Published: September 2018

e16516 Background: Identifying occult metastases in men with BRPC is critical, as treatment depends on disease state (biochemical recurrence vs oligometastatic disease). It is prudent to investigate pts for metastases, even men with low prostate-specific antigen (PSA) levels, to select appropriate salvage, local or systemic treatments. We evaluated baseline parameters of BRPC pts with occult metastases identified during screening for STAND (phase 2, NCT01431391). Methods: STAND eligibility criteria included prostate cancer primary therapy and PSA doubling time (PSADT) ≤12 months. Pts with metastases were excluded. We compared pts with and without metastases. Results: Of 99 screened pts, 68 entered STAND with non-metastatic BRPC, 11 (11%) failed screening due to metastases and 20 (20%) due to other reasons. In this small sample, no baseline parameters were identified that clearly distinguished between pts with or without metastases. For pts with metastases vs STAND pts, median age was similar (66 vs 65 y); all were Caucasian. Baseline median (range) PSA levels were numerically higher (4.3 [1.7–141.7] vs 2.4 [0.3–47.8] ng/mL) and PSADT values were numerically shorter (3.5 [1.1–7.6] vs 5.1 [1.0–16.4] months) for pts with metastases vs STAND pts, respectively. The proportion of pts with PSA > 10 ng/dL was 29% vs 19%, or PSADT < 6 months was 80% vs 59% for pts with metastases vs STAND pts, respectively. Baseline lactate dehydrogenase, alkaline phosphatase and hemoglobin levels were similar between groups. Conclusions: A substantial proportion (11%) of BRPC pts with presumed non-metastatic disease had undiagnosed occult metastases at low PSA levels. Such pts may benefit from closer monitoring with improved imaging technology, continuous androgen deprivation therapy or potentially docetaxel. While more rigorous screening (even at low PSA levels) may be advantageous, identifying such pts is challenging as their baseline parameters may not differ significantly vs BRPC pts with no metastases. In the future, detection of oligometastatic disease is likely to increase due to more sensitive imaging modalities, thus, the BRPC state will be reduced. Clinical trial information: NCT01431391.