bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dacomitinib (PF-0299804) in untreated patients (pts) with advanced or metastatic penile squamous cell carcinoma (PSCC): Early findings of an open-label, single-group, phase II trial (HER-Uro01).
Authors: Necchi Andrea , Giannatempo Patrizia , Raggi Daniele , Nicolai Nicola , Torelli Tullio , Catanzaro Mario , Piva Luigi , Biasoni Davide , Stagni Silvia , Colecchia Maurizio , Calareso Giuseppina , Togliardi Elena , Marchiano' Alfonso , Crippa Flavio , Salvioni Roberto 
Published: February 2017

384 Background: Prognosis of pts with advanced/metastatic PSCC is poor and chemotherapy exerts a low efficacy. PSCC is consistently depending on the epidermal growth-factor receptor (EGFR) pathway and early signals of activity of anti-EGFR targeting have been reported. Dacomitinib is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. The primary objective of the trial will be to investigate the activity of PF-0299804 until surgical removal of nodal disease (locally-advanced setting) or until disease progression/onset of unacceptable toxicity (metastatic setting) (ClinicalTrials.gov NCT01728233). Methods: 37 pts with clinical N2-3or metastatic disease will receive oral dacomitinib 45 mg daily. Further eligibility requirements are ECOG-PS≤1, locoregional relapse after prior surgery, and no prior systemic therapy. Computed tomography (CT) and PET scans are scheduled at baseline and every 2 months. Simon’s Optimal 2-stage design is applied. The primary endpoint is the response-rate (CR/PR according to RECIST v1.1, H1:20%, H0: 5%). In stage 1, 12 evaluable patients will be accrued. Results: From 06/13 to 07/14, 9 pts were enrolled. Median age was 55 yrs (IQR: 54-72). 4 had received inguinal/pelvic lymphadenectomy, 4 had inguinal+pelvic nodes, 7 bilateral disease, and 2 distant mets. One patient achieved a PR, 6 a SD, 2 PD. 5 pts had a metabolic PR. After a median follow-up of 5 months, 4 pts (44.4%) are still progression-free (2-month PFS was 77.8%, 95%CI: 36.5-93.9). Skin toxicity was observed in 5 cases (4 G1, 1 G3), G2 diarrhea in two, and bleeding of cutaneous mets in one case. Conclusions: The minimum requirements to move to the second stage and full accrual have been met. Dacomitinib is showing activity in patients with PSCC. Further understanding of drug activity will come from the body of translational imaging and molecular characterization of tumors from enrolled patients. Clinical trial information: NCT01728233.
Prognostic significance of perirenal fat invasion and tumor size in pT1 to pT3a renal cell carcinoma: Results of a comprehensive multicenter study of the CORONA project—Can we improve prognostic discrimination of patients with stage pT3a tumors?
Authors: Brookman-May Sabine Doris , May Matthias , Zigeuner Richard , Cindolo Luca , Shariat Shahrokh F. , Wirth Manfred , Gunia Sven ,   CORONA Group
Published: February 2017

416 Background: The renal cell carcinoma (RCC) TNM system merges perirenal fat invasion (PFI) and renal vein invasion (RVI) as stage pT3a despite limited evidence concerning their prognostic equivalence. Additionally, the prognostic value of PFI compared to pT1-pT2 tumors remains controversial. Methods: Data of 7,595 pT1a-pT3a RCC patients undergoing radical nephrectomy or nephron-sparin surgery were pooled from 12 European and U.S. centers (1999-2010). Patients were grouped according to stages and presence of PFI/RVI, i.e., pT1-2N0M0 (n=6,137; 80.8%), pT3aN0M0+PFI (n=1,036; 13.6%), and pT3aN0M0 (RVI±PFI; n=422; 5.6%). Cancer-specific survival (CSS) was estimated by Kaplan-Meier method. Univariate and multivariable Cox proportional-hazards regression models, sensitivity and discrimination analyses were conducted to evaluate the impact of clinico-pathological parameters on cancer-specific mortality (CSM). Results: Compared to stage pT1-2, patients staged pT3a were significantly more frequently male (58.9 vs. 53.1%), older (65 vs. 62.1 yrs), more often had clear cell RCC (86.1 vs. 77.7%), Fuhrman grade 3-4 (30.5 vs. 13.4%), tumor size >7 cm (39.6% vs. 13%), and less often underwent NSS (7.1 vs. 36.6%; each p<0.001). On multivariable analysis, CSM of both patients with PFI and RVI±PFI was significantly enhanced compared to pT1-2 patients (HR 1.96 and 2.14, resp.; p<0.001), whereas patients featuring PFI only and RVI±PFI did not differ (HR 0.92; p=0.48). Tumor size instead significantly influenced CSM in stage pT3a (HR 1.07; p<0.001) with a 7 cm cut-off yielding the highest c-index. Conclusions: Since the prognostic impact of PFI and RVI on CSM seems to be comparable, merging both as stage pT3a might be justified. Enhanced prognostic discrimination of stage pT3a RCC patients appears to be possible by employing a 7 cm tumor size cut-off within an alternative staging system.
Patients with metastatic chromophobe renal cell carcinoma treated with sunitinib therapy: Analysis of an international database regarding outcome and comparison to clear cell histology (mccRCC).
Authors: Keizman Daniel , Sarid David , Lee Jae-Lyun , Gottfried Maya , Maimon Natalie , Hammers Hans J. , Eisenberger Mario A. , Carducci Michael Anthony , Sinibaldi Victoria J. , Neiman Victoria , Rosenbaum Eli , Gez Eli , Peer Avivit , Mermershtain Wilmosh , Rouvinov Keren , Berger Raanan , Yildiz Ibrahim 
Published: February 2017

429 Background: Sunitinib (Su) is a standard therapy (tx) for mccRCC. Data on its activity in the rare variant of metastatic chromophobe renal cell carcinoma (mchRCC) are limited by very small or heterogeneous (mixed histology with papillary type, or mixed targeted therapies) studies. We analyzed the activity of Su in a relatively large and homogenous international cohort of mchRCC pts, in terms of outcome and comparison to mccRCC. Methods: Records from mchRCC pts treated with first-line Su in 9 centers across 4 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and outcome were performed. Subsequently, mchRCC pts were individually matched to mccRCC pts. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS) between the groups. Results: Between 2004-2014, 33 pts (median age 64, 45% male) with mchRCC were treated with Su as first-line tx. 76% had a prior nephrectomy. HENG risk was good 27%, intermediate 55%, and poor 18%. 33% were active smokers, and 30% users of angiotensin system inhibitors (ASIs). 55%, 27%, and 33% had lung, liver, and bone metastases, respectively. 48% had a pre-tx neutrophil to lymphocyte ratio (NLR) >3. 42% had dose reduction/tx interruption (DR/TI). Su-induced hypertension (HTN) occurred in 48%. 75% achieved a clinical benefit (partial response + stable disease), while 25% had disease progression within the first 3 months of tx. Median PFS and OS were 10 and 26 months, respectively. Factors associated with PFS were the HENG risk (HR 3.8, p=0.025) and pre-tx NLR >3 (HR 0.6, p=0.012). Factors associated with OS were the HENG risk (HR 4.27, p=0.027), liver metastases (HR 4.6, p=0.029), and pre-treatment NLR <3 (HR 0.5, p=0.04). Tx outcome was not significantly different between mchRCC pts and mccRCC pts, who were individually matched by HENG risk, nephrectomy/smoking status, pre-tx NLR, use of ASIs, DR/TI, and Su induced HTN. In mccRCC pts (p value versus mchRCC), 70% achieved a clinical benefit (p=0.58), and median PFS and OS were 9 (p=0.7) and 24 (p=0.6) months, respectively. Conclusions: In mchRCC pts, Su tx may have similar outcome to mccRCC pts.
Performance of MRI-TRUS-guided fusion biopsy to detect progression on active surveillance for low- and intermediate-risk prostate cancer.
Authors: Frye Thomas P. , Shakir Nabeel Ahmad , Abboud Steven , George Arvin Koruthu , Merino Maria J , Choyke Peter L. , Turkbey Baris , Wood Bradford J. , Pinto Peter A. 
Published: February 2017

43 Background: Active surveillance (AS) is an established treatment option for men with low risk prostate cancer. Its role in intermediate prostate cancer is still being investigated. Recent studies have shown that multiparametric-MRI (mp-MRI) along with MRI-TRUS fusion-guided biopsy may better assess risk in patients eligible for AS, compared to 12-core biopsy, due to improved detection of clinically significant cancers. The objective is to determine the performance of MRI-TRUS guided biopsy for men on AS with both low and intermediate risk disease. Methods: Between 2007-2014 men on AS were included if they had complete mp-MRI and pathology data for 2 or more MRI-TRUS biopsy sessions. Fusion guided biopsy procedures consisted of MRI identified targeted biopsies as well as random 12 core biopsies. Men were allowed to participate in AS with low and intermediate risk prostate cancer, Gleason score ≤ 3+4=7. Progression was defined by patients with initial Gleason 3+3=6 to any Gleason 4, and Gleason 3+4=7 disease progressing to a primary Gleason 4 or higher. Results: 89 men met our study criteria with an average age of 62 years old (range 45-79). 75 men had low risk Gleason 3+3=6 at the outset of AS by 1st biopsy session with a median PSA 5.1 ng/ml. The other 14 men had intermediate risk prostate cancer Gleason 3+4=7 at the outset of AS and a median PSA 4.6 ng/ml. During follow-up, 25 (33%) low risk men progressed to 3+4 or above at a median of 20.6 months. Of these, 19 were found by targeted biopsy. 6 (43%) of the intermediate risk men progressed to Gleason 4+3=7 at a median of 36.8 months. 4 of these progressed on targeted fusion biopsy. In the intermediate risk men, 84 random biopsy cores were require to detect 1 progression versus 15 targeted biopsy cores to detect 1 progression. Conclusions: The majority of patients on AS who progressed were identified by MRI-TRUS targeted biopsy. Less biopsy cores are required to detect progression with targeted biopsy. These results are preliminary and a larger cohort with longer follow-up would be beneficial.
Comprehensive genomic profiling of 443 cases of renal cell carcinoma to reveal frequent clinically relevant genomic alterations.
Authors: Pal Sumanta Kumar , Ali Siraj M. , Chalmers Zachary , Karam Jose A. , Elvin Julia Andrea , Chmielecki Juliann , Yelensky Roman , Van Allen Eliezer Mendel , Lipson Doron , Wang Kai , Fay Andre Poisl , Choueiri Toni K. , Miller Vincent A. , Stephens Phil , Ross Jeffrey S. 
Published: February 2017

433 Background: Despite the availability of targeted therapy, effective management of advanced RCC is an unmet medical need as treatment is not personalized and is not guided by patient-specific genomic alterations (GAs). To assess the spectrum of clinically relevant GAs (CRGAs) in advanced RCC, comprehensive genomic profiling (CGP) of clinical RCC samples was performed with the goal of informing use of existing and novel targeted therapies. Methods: DNA was extracted from 40 microns of FFPE sections from 443 consecutive patients with relapsed/metastatic RCC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: There were 73% male and 27% female patients with a mean age of 56 years, and the majority of cases were advanced stage with 198/443 specimens (44.6%) from metastatic sites. 400/443 patients (89%) had at least 1 GA on CGP with a mean 3.1 GA/case. 396/400 RCC harboring GA had at least 1 CRGA involving 111 individual genes with a mean of 1.32 CRGA/UC. The most common novel CRGA in order of frequency were: CDKN2A (21%), BAP1 (12%), ATM (11%), PTEN(8.5%), TSC1(8.3%), mTOR (7%), MET (6.5%), AR (5.3%), DNMT3A (5%) and TSC2 (5%). Moreover, VHL harbored a diversity of GA’s in in 49% of cases. Collecting duct carcinomas harbored an enrichment of NF2 truncating alterations (>40%), distinct from renal medullary carcinoma which did not harbor such GA. Multiple clinical antitumor responses to targeted therapies will be presented. Conclusions: Using a CGP assay capable of detecting all classes of GA simultaneously, a high frequency of CRGA was identified in a large series of patients with advanced RCC. The diversity of CRGA suggests opportunities for the rational application of existing and investigational targeted therapies, and for possible deeper characterization of histological types of RCC.
The risk of second primary cancers in clear cell and papillary renal cancer.
Authors: Hamid Muhammad Saad , Shameem Raji , Jain Rishi , Sullivan Kevin M. 
Published: February 2017

446 Background: Renal cell carcinoma (RCC) survivors have an increased risk of developing second primary cancers. We sought to determine the role of RCC tumor histology for the risk of developing second primary solid tumors. Methods: The Surveillance Epidemiology and End Results (SEER) database was used to detect RCC cases diagnosed up to 12/31/2011. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cases of second primary malignancy based on incidence data in the general United States population. The two most common RCC histological subtypes were included; clear cell and papillary. The latency exclusion period from the date of diagnosis was 60 months. We investigated for the effect of latency period after initial diagnosis (5-10 years and >10 years) that may increase the risk for a second primary cancer. Results: A total of 2,669 patients with an initial diagnosis of RCC (clear cell: 2,368, papillary: 301) that developed second primary cancers were included in our analysis. There was a significantly increased risk of thyroid cancer (SIR: 2.30, p<0.05), prostate cancer (SIR: 1.12, p<0.05) and “all solid tumors” (SIR: 1.14, p<0.05) in clear cell RCC cases. Regarding latency period, thyroid cancer (SIR: 2.87, p<0.05) risk was increased in the 5-10 years latency period, but not in the >10 years latency period. Overall, in patients diagnosed with papillary RCC, tumors of the prostate (SIR: 1.30, p<0.05), lung (SIR: 1.78, p<0.05) and pancreas (SIR: 2.70, p<0.05) were increased. Exclusively in the 5-10 years latency period, the risk for developing lung cancer (SIR: 1.90, p<0.05) was significant. Conclusions: RCC histology may impact the risk for developing specific second primary solid tumors.
Angiogenic profile and pathological features in the prediction of clinical outcome of advanced renal cell carcinoma patients receiving sunitinib.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Zizzi Antonio , D'Anzeo Marco , Giampieri Riccardo , Del Prete Michela , Bittoni Alessandro , Montironi Rodolfo , Cascinu Stefano 
Published: February 2017

458 Background: Metastatic renal cell carcinoma (mRCC) ever represented a challenge in patients’ treatment, there is a wide variability in the amount and duration of response among patients. It has been previously reported how VEGF and VEGFRs SNPs could predict response to treatment with sunitinib. Tumour heterogeinity is a matter of debate in mRCC. The aim of our study is to assess if pathological features and the expression of VEGF and VEGFRs polymorphisms in tumour, metastatic, and normal renal tissues could have a role in patients’ treatment and prognosis. Methods: We enrolled 123 patients treated at our institution. We collected histologic samples of tumour, metastatic, and normal renal tissue of 92 patients with mRCC treated with first-line sunitinib. For 21 patients, all three tissues were available. A pathological revision was conducted evaluating: granular cells percentage, grading, necrosis, regressive and sarcomatoid areas, and vascularization pattern. Histologic samples were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Polymorphisms were correlated with pathological features and PFS and OS. We then analysed concordance in SPNs expression among tissues. Results: VEGF A rs833061, VEGF A rs699947, VEGF A rs2010963, and VEGR3 rs6877011 were confirmed as significant SNPs in PFS. 19 out of 21 patients presented concordance among tissues polymorphisms expression (97%). The presence of a G allele in the rs6877011 seems to correlate with a higher percentage of granular cells. The presence of C allele in rs2010963 correlates with an alterated vascularazation. Conclusions: A preliminary analysis of our data shows the predictive and prognostic value of angiogenic polymorphisms and their concordance in tumoral, metastatic, and normal tissue. Furthermore, they are correlated with the percentage of granular cells and the vascular architecture, with possible predictive and prognostic significance. Further data will be presented at the meeting.
Evaluation of major histocompatibility complex class I expression in clear cell renal cell carcinoma as a prognostic tool.
Authors: de la Calle Claire M. , Holzman Sarah A. , Sheikh Umer , Huang Jonathan H. , Kissick Haydn T. , Osunkoya Adeboya O. , Pollack Brian P. , Patil Dattatraya , Ogan Kenneth , Master Viraj A. 
Published: February 2017

469 Background: After nephrectomy for clear cell renal cell carcinoma (ccRCC) approximately one-third of patients develop metastases. Yet, with currently used prognostic tools such as the TNM staging and the Fuhrman nuclear grade (FNG) system, it is difficult to accurately assess prognosis for each patient. Here, we evaluated Major Histocompatibility Complex Class I (MHCI) expression as a potential prognostic immune marker in ccRCC. Methods: Fifty-five post-nephrectomy patients that presented with localized ccRCC were included. All patients had four or more years of follow up. MHCI was stained in the tumor sections via immunohistochemistry. Then, via an automated image analysis algorithm MHCI expression was quantitated with the Positivity score, the ratio of positively stained pixels over the total number of pixels. Results: Mean MHCI positivity score of the cohort was 0.75 (SE= ±0.20). At the end of the follow-up period, the patients who were alive had higher MHCI expression (0.80 positivity score; SE ±0.14) than those who died of disease (0.62 positivity score; SE= ±0.16; t test, p<0.0001). MHCI positivity scores above the mean were associated with increased cancer specific survival (Mantel-Cox, p=0.0021). MHCI expression was higher among patients with no recurrence (0.80; SE= ±0.16) compared to those that recurred during the study period (0.70; SE= ±0.22; t test, p=0.017); and time-to-recurrence was longer in patients with above mean MHCI positivity scores (Mantel-Cox, p=0.017). Patients who were alive with recurrence had increased MHCI expression (0.81; SE= ±0.10) compared to those who succumbed to disease recurrence (0.62; SE= ±0.25; t-test, p=0.0009). No correlation was detected between FNG and tumor expression of MHCI (ANOVA, p=0.655, F=0.423) or between stage at presentation and MHCI tumor expression (ANOVA, p=0.734, F=0.311). Conclusions: With an automated high-throughput image analysis, this cohort shows that increased MHCI expression in ccRCC is associated with improved prognosis after curative nephrectomy.
Kinase gene expression profiling of metastatic tumor tissue to prioritize therapeutic targets in clear cell renal cell carcinoma.
Authors: Ghatalia Pooja , Yang Eddy Shih-Hsin , Chen Dongquan , Wei Shi , Cooper Tiffiny , Sudarshan Sunil , Naik Gurudatta , Sonpavde Guru 
Published: February 2017

476 Background: Kinase inhibitors are the mainstay of therapy for patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC). Since kinases are actionable and lethal metastatic tumor tissue has not been comprehensively studied, we hypothesized that paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may help identify drivers of metastasis and potential therapeutic targets. Methods: Total mRNA isolated from macrodissected formalin fixed paraffin embedded tissue from T, N, and M from 35 pts (total 105 samples) with ccRCC underwent expression profiling for 519 kinase genes using the nCounter System by Nanostring Technologies. Digital raw counts of mRNA abundance were normalized using internal positive and negative controls as well as 7 housekeeping genes. The mean signals from N, T, and M sites were used to calculate change in gene expression, and a p value by t test <0.05 was considered significant. To identify genes unique to metastasis, kinases with significant expression in the M compared to N or T were selected. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Results: The median age of pts was 56 years and 30 were male. Fifteen pts had metastatic disease at presentation and the remaining developed subsequent metastasis. Clustering analysis for all 105 samples separated normal tissues from tumor or metastasis. The top pathways involved in the kinases overexpressed in M compared to N or T involved Pyridoxal 5'-phosphate Salvage, Salvage Pathways of Pyrimidine Ribonucleotides, NF-kB Signaling, NGF Signaling and Cell Cycle Control of Chromosomal Replication. The top kinases over-expressed in M compared to T include: EPHB2, AURKA, GUCY2C, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7, and MAP3K8. Conclusions: Multiple pathways and kinase genes wereover-expressed in metastatic ccRCC, which suggests a major role for agents targeting metabolic pathways and inhibitors of kinases not currently recognized as therapeutic targets. These data warrant validation and suggest potential drivers of metastasis and actionable therapeutic targets in metastatic ccRCC.
Percentage of sarcomatoid component as a prognostic indicator for survival in sarcomatoid renal cell carcinoma.
Authors: Adibi Mehrad , Thomas Arun Z. , Borregales Leonardo , Merrill Megan M. , Sircar Kanishka , Tamboli Pheroze , Slack Rebecca , Chen Hsiang-Chun , Tannir Nizar M. , Jonasch Eric , Matin Surena F. , Wood Christopher G. , Karam Jose A. 
Published: February 2017

499 Background: Renal cell carcinoma with sarcomatoid component (sRCC) is characterized by the microscopic spectrum of spindle cells within a background of RCC. The presence of sarcomatoid elements is associated with higher stage of presentation and decreased patient survival. The objective of this study is to examine the clinicopathological characteristics associated with overall survival (OS), specifically examining the percentage of sarcomatoid component (PSC) to stratify risk. Methods: We retrospectively reviewed data for all radical nephrectomy patients with pathologically confirmed sarcomatoid component from 1987−2011. All slides were re−reviewed by a GU pathologist to ascertain PSC. Patient characteristics were tabulated overall and by disease status (metastatic vs. localized). Cutpoints in the percent sarcomatoid providing a meaningful difference in OS were identified by recursive partitioning analysis (RPA) as univariate and combined with patient characteristics. Factors selected included age, gender, race, clinical stage, tumor histology, and treatment. The Kaplan−Meier method and two−sided log−rank test was used to assess differences in OS. Results: Among 186 patients with sRCC, 64 (34%) had localized and 122 (66%) metastatic disease. Patients were primarily white (76%) males (63%) with clear cell histology (73%), and did not receive neoadjuvant or adjuvant therapy (87%). The median follow−up time was 12.1 months (range, 0.1 to 242.2 months). The median OS was 12.6 months (95% confidence interval (CI) 10.7−14.9 months). Two subgroups were identified with a cut−point of 12.5% for PSC after univariate RPA. Patients with PSC ≥ %12.5 were at higher risk of death compared to patients with <%12.5 (45% vs. 61% 1 year OS; p value=0.04). Mutlivariate RPA revealed clinical stage and percent sarcomatoid were significantly associated with OS. Patients with localized disease were most likely to be alive at 1 year (74%). Among patients with metastatic disease with PSC<%42.5 had 1−year OS of 44% vs. 27% for patients with ≥%42.5 cutoff (p<0.001). Conclusions: The PSC appears to be a prognostic factor in the OS of patients with RCC, with larger percentage of involvement portending a worse survival.