bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is there a "trial effect" on outcome of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib?
Authors: Keizman Daniel , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Boursi Ben , Weitzen Rony , Hayat Henry , Peer Avivit , Neumann Avivit , Kovel Svetlana , Sella Avishay , Mermershtain Wilmosh , Roubinov Keren , Carducci Michael Anthony , Berger Raanan 
Published: February 2017

453 Background: Several studies have suggested the existence of a trial effect, in which for a given treatment, participation in a clinical trial is associated with a better outcome of cancer patients. The VEGFR inhibitor sunitinib is a standard treatment for mRCC. The effect of clinical trial participation on the outcome of sunitinib treatment in mRCC is poorly defined. We aimed to study the effect of clinical trial participation on outcome of mRCC patients treated with sunitinib. Methods: Records from 275 mRCC patients treated with sunitinib from 2004 to 2012 in 7 centers across 2 countries were reviewed. We compared the response rate, progression free survival, and overall survival, between clinical trial participants (n=49) and a matched cohort of non participants (n=49) who received standard therapy. Each patient participating in a clinical trial was individually matched with a non-participant by clinicopathologic factors. Progression free survival and overall survival were determined by Cox regression. Results: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 24%, intermediate 60%, poor 16%), ECOG performance status (0-1 92%), prior nephrectomy (92%), renal cell carcinoma histology (clear cell 80%), sunitinib induced hypertension (56%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants vs. non participants, objective response was partial response/stable disease 80% (n=39) vs. 73% (n=36), and progressive disease at first imaging evaluation within the first 3 months (mos) 20% (n=10) vs. 27% (n=13) (p = 0.63, OR 1.2). Median progression free survival was 10 vs. 11 mos (HR=0.96, p = 0.84), and median overall survival 23 vs. 24 mos (HR=0.97, p=0.89). Conclusions: In mRCC patient treated with sunitinib, the outcome of clinical trial participants was similar to matched non participants who received standard therapy.
VHL protein (pVHL) and Src expression in metastatic RCC.
Authors: Robinson Kyle William , Chen Yiyi , Podolak Jennifer , Forquer Kerri , Cook Megan , Thomas George , Ryan Christopher W. 
Published: February 2017

457 Background: Rational therapeutic strategies are lacking for RCC with intact pVHL expression. We recently demonstrated that Src signaling output was elevated in RCC cells expressing pVHL (Suwaki Sci Transl Med 2011). We sought to prospectively identify and clinically characterize RCC patients according to tumor expression of pVHL and Src using an immunohistochemical (IHC) assay, including the association of pVHL and Src expression with response to targeted therapies. Methods: Metastatic RCC patients with available archival tumor tissue provided written informed consent. Primary and metastatic tumors were evaluated by IHC staining using the following scale: 0: absent; 1: weak; 2: moderate-strong. We scored the percent of tumor cells staining at these intensities, giving a total possible score of 200. Association of pVHL and Src score was determined using Spearman correlation coefficient. Time to treatment failure (TTF) > 300 days was used to stratify patients as treatment success versus failure. Logistic regression was used to analyze whether there was an association between pVHL and Src staining and clinical outcome, and ROC curve analysis was used to find the predictive ability of pVHL and Src positivity. Results: 27 patients were consented, from which the nephrectomy specimens of 23 patients and 17 metastatic tumor samples were available. 22 patients had received systemic therapy (21 with VEGF TKI, 1 with mTOR-I). Expression of pVHL and Src were positively correlated (p<0.001). Expression of pVHL in primary tumor, but not Src, was associated with fewer treatment failure events (p=0.0384). Those who had TTF > 300 days had a mean pVHL score of 127.3, and Src of 134, while those with TTF < 300 days had mean pVHL of 57.5, and Src 89.5. Performing ROC analysis, the combination of pVHL and Src score displayed a higher area under the curve (c=0.8) in predicting treatment failure or success than pVHL or Src score alone. Conclusions: We have shown a correlation between pVHL and Src expression in tumors from a prospective population of RCC patients. Accrual continues to this study of a novel quantitative IHC profile that could identify patients for whom currently available therapies may not be effective or for whom a clinical trial of a Src inhibitor may be appropriate.
Correlation of pathologic findings after brief neoadjuvant sorafenib with results of dynamic-contrast enhanced (DCE) and diffusion-weighted magnetic resonance imaging (DW-MRI) in patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC).
Authors: MacVicar Gary R. , Miller Frank , Rustogi Rahul , Chen Zong-Ming , Martone Brenda K. , Kuzel Timothy 
Published: February 2017

466 Background: Many pts receiving tyrosine kinase inhibitors for RCC manifest stable disease as their best response by RECIST criteria. We hypothesized that tumor necrosis by DCE and DW-MRI after brief treatment with neoS may correlate with pathologic findings. We investigated in a pilot study whether these MRI changes may serve as an imaging biomarker predictive of clinical outcome. Methods: Pts with locally advanced or metastatic clear cell RCC undergoing nephrectomy or metastastectomy were treated with neoS 400mg PO bid for 28 days prior to surgery. The feasibility and safety of neoS was determined. Tumor necrosis detected by DCE and DW MRI’s pre- and post-neoS were compared and correlated with survival and pathologic findings at surgery. RECIST/WHO criteria were also compared. Results: 9 pts were enrolled, and all underwent surgery after neoS, 4 weeks (n=7) or less for toxicity (n=2). Clear cell/sarcomatoid histology was noted in 8 pts, and papillary in 1. All pts had T3 or T4 disease. 7 had M1 disease. No surgical complications occurred. 7 pts (78%) experienced grade 3 toxicities, including hypertension (n=1), pancreatitis (n=1), hand-foot syndrome (n=1), hyponatremia (n=2), and rash (n=2). No grade 4 or 5 toxicities were observed. 4 of 8 clear cell/sarcomatoid pts (50%) have died, 3 because of progressive disease and 1 of unrelated causes. DCE and DW MRI’s with direct surgical pathological correlation were available in 7 of these pts. The mean ADC DW MRI changes in the renal lesion of 4 longer term survivors (median survival = 43 months) was +.22 vs. –0.07 in the 3 short term survivors (median survival = 13 months). RECIST/WHO criteria did not correlate with response. Evaluation of lack of enhancement on DCE MRI and increase in ADC on DW MRI were seen and correlated with necrosis on pathologic specimens. Conclusions: Four weeks of neoS is associated with significant necrosis that correlates with DCE-MRI and DW-MRI. There may be a trend in survival with greater necrosis, suggesting a role for these imaging biomarkers to assess early benefits of therapy. Clinical trial information: NCT00727532.
Prognostic factors and validation of prognostic nomograms in patients (pts) treated with three targeted therapies (TTs) for metastatic renal cell carcinoma (mRCC): Results from an Italian survey.
Authors: Iacovelli Roberto , Milella Michele , Santoni Matteo , Di Lorenzo Giuseppe , Ortega Cinzia , Sabbatini Roberto , Ricotta Riccardo , Lorusso Vito , Messina Caterina , Atzori Francesco , Zucali Paolo A. , Cinieri Saverio , Mosca Alessandra , Verzoni Elena , Primi Francesca , Baratelli Chiara , Cortesi Enrico , Carteni Giacomo , Sternberg Cora N. , Procopio Giuseppe 
Published: February 2017

470 Background: Outcomes of pts treated with three TTs for mRCC have not been well characterized. Survival data as well as existing prognostic criteria in this population were evaluated. Methods: Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was send to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type, and length of first-, second-, and third-lines were collected. Values of serum Hb, PLT, neutrophils, LDH and Ca, ECOG-PS, previous RT and number of metastatic sites >2 before the start of third-line were evaluated. Cleveland Clinic, French, Heng, and MSKCC scores and relative survival were calculated. Results: Following the screening of 1,905 pts, 252 (13%) with 3 TTs were identified. The median age was 60 yrs (range 52-68), 73% were male, 96% had nephrectomy and 38% were metastatic at diagnosis. At first-line, the Motzer class was good, intermediate, and poor in 48%, 47%, and 5% of pts, respectively. The median OS from the start of third-line was 14.3 mos (95%CI, 10.1–18.6). Rate and survival by prognostic group according to each classification are reported in table below. When prognostic factors were considered separately, at the univariate analysis ECOG-PS≥2, Hb<LLN, LDH>1.5ULN, Ca>ULN; PLT>ULN; Neu>ULN, and sites of disease >2 had negative prognostic role. Multivariate analysis shows an independent prognostic role only for ECOG-PS≥2 (HR: 1.8; 95%CI: 1.1–2.8), Hb<LLN (HR: 1.8; 95%CI: 1.2–2.6) and neu>ULN (HR: 2.1; 95%CI: 1.2–3.8). Pts were stratified in 3 groups according to the presence of none, 1 or ≥2 prognostic factors. The median OS was 20.3, 13.6 and 7.8 months, respectively (p<0.001). Conclusions: Current nomograms are able to predict survival in patients with mRCC before the third-line with TT. Neutrophils, hemoglobin and ECOG-PS were the most important prognostic factors. [Table: see text]
Severe lack of comprehension of common prostate health terminology in underserved populations: External validation.
Authors: Master Viraj A. , Wang Daniel Shin-Ping , Tai Caroline Gar-Ling , Sesay Musu , Kilbridge Kerry L. , Goodman Michael , Jani Ashesh B. 
Published: February 2017

71 Background: Patients diagnosed with prostate cancer are often counseled about treatment options by healthcare providers who commonly use terms that are part of the ‘core’ vocabulary of prostate cancer. We hypothesized that a predominantly lower-literacy patient population would demonstrate a severe lack of comprehension of prostate cancer terms, which would validate the findings of Kilbridge et al. (JCO, 2009) who found a profound lack of comprehension in a single institution series. Methods: A previously developed survey was used to evaluate understanding of terms related to urinary, bowel, and sexual function. The survey was conducted by trained evaluators, recruiting patients, age ≥ 40, from two low-income safety-net clinics with primarily African-American populations. Comprehension was assessed using semi-qualitative methods coded by two independent investigators. Literacy and numeracy were also evaluated. Results: 109 patients completed the study. Overall prostate cancer knowledge was poor, with only 5% of patients understanding the function of the prostate, 15% understanding the term ‘incontinence’, 29% understanding ‘urinary function’ and 32% understanding ‘bowel habits’ (see Table). Comprehension decreased with the use of compound words, such as ‘intercourse’ (95%) vs. ‘vaginal intercourse’ (58%), validating previous work. Median school level completed was the 12th grade; yet median literacy level was only 9th grade, and reading level was significantly correlated with comprehension. Only 30% of patients correctly calculated both a fraction and a percent. Conclusions: Lack of comprehension of terms related to prostate health is pronounced in this patient population and may be widespread. This lack of comprehension potentially limits the ability of patients to participate in shared and informed decision-making. These results validate the findings of previous studies and support a continued need for refined methods of prostate cancer education. [Table: see text]
Feasibility of RNA sequencing to detect TMPRSS2:ERG fusions following laser capture microdissection of prostate cancer.
Authors: Kim Won , Foye Adam , Bengtsson Henrik , Kim Hyunsung John , Taylor Barry S. , Pourmand Nader , Febbo Phillip G. 
Published: February 2017

76 Background: Recent sequencing efforts continue to fuel our growing insight into the genetic basis of prostate cancer (PCa). One of the key challenges remaining is to identify genetic events that drive PCa biology. RNA sequencing (RNA-seq) is commonly used to determine unbiased gene expression as a proxy for tumor biology. However, tumors often contain a mixture of cancer and normal cells that can confound data analysis. Cancer cells can be isolated by laser capture microdissection (LCM), but the feasibility of RNA-seq on small amounts of RNA following LCM of PCa tissue needs to be assessed. Methods: A set of 5 localized PCa specimens, frozen at the time of prostatectomy, was analyzed. RNA was isolated following LCM from these 5 specimens and assessed for quality with an Agilent Bioanalyzer and for quantity with RiboGreen. Paired-end, 300-bp insert sequencing libraries were prepared from the 5 specimens in duplicate; one specimen was also prepared for sequencing without LCM. The 12 samples were then sequenced on a single lane of an Illumina HiSeq. Sequencing reads were aligned with Tophat to build hg19 of human genome. Initial quality control was performed with Picard using refFlat and ribosomal RNA (rRNA) annotations provided by UCSC. PCR using previously published primer pairs was used to confirm the presence of TMPRSS2:ERG fusions. Results: 4-5mm2 of tumor was targeted by LCM from each PCa specimen. At least 100ng of total dsDNA was generated for library construction. For the first run, an average of 8,743,722 reads per paired-end was obtained (range: 1,335,939 to 16,134,097); the second run was comparable (mean: 8,612,188 reads; range: 1,312,823 to 15,842,480). Mapping of the sequences revealed no 5’ or 3’ read coverage bias, but the percentage of mappable reads per sample was less than 30%; sequencing was inefficient due to a high percentage of rRNA (mean: 38% per sample; range 28 to 44%). However, TMPRSS2:ERG fusions were confirmed in the samples with known fusion-positive status. Conclusions: RNA-seq is feasible and can detect fusions that are known and highly expressed. The inclusion of rRNA reduces the depth of coverage of the transcriptome and additional optimization is required to maximize efficiency.
Maximum tumor diameter as a predictor for outcome following salvage radiation for prostate cancer.
Authors: Johnson Skyler B. , Jackson William C. , Song Yeohan , Foster Benjamin , Li Darren , Foster Corey , Palapattu Ganesh S. , Mehra Rohit , Kunju Priya , Feng Felix Yi-Chung , Hamstra Daniel A. 
Published: February 2017

78 Background: While maximum tumor diameter (MTD), as identified on radical prostatectomy (RP) specimens, has been associated with prostate cancer recurrence, the prognostic significance of this variable is unknown in the context of salvage external beam radiation therapy (EBRT) following a rising PSA after RP. Here, we investigate associations between MTD and outcomes in this setting. Methods: From an IRB approved retrospective single-institutional cohort, 575 patients treated with salvage radiation therapy (SRT) were identified, with MTD data available on 173. ANOVA and chi-square were utilized to compare prognostic variables with MTD. The impact of MTD on biochemical failure (BF), metastasis (Mets), prostate cancer-specific mortality (PCSM) and overall survival (OS) was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox-proportional hazards regression. Results: Median follow up was 76.5 months (IQR, 46.5-104.0) and median MTD was 18 mm (IQR, 13-22). Median RT dose was 68.4 Gy (IQR, 64.8-68.4). MTD size correlated with pT-stage, Gleason score, and presence of seminal vesicle invasion or lymph node invasion. Receiver operator characteristic (ROC) curve analysis was used to correlate MTD with clinical end-points and identified 14 mm as the most prognostic cut-point. A MTD >14 mm was associated with a 1.8, 4.0 and 8-fold increase in the risk of BF (p<0.02), Mets (p<0.002), and PCSM (p<0.02), respectively. As a continuous variable, on multivariate analysis, MTD was shown to be a marginally significant predictor of OS (p=0.056, HR [95%] 1.6 [1.0-2.5]), and a significant predictor of PCSM (p<0.03, HR [95%] 2.0 [1.1-3.8]) and Mets (p=0.01, HR [95%] 1.7 [1.1-2.6) but not BF. In this model, for every 10 mm increase in MTD, there is a 1.7, 2.0, and 1.6 fold risk of metastasis, prostate cancer death and overall death, respectively. Conclusions: As a categorical and continuous variable, MTD is a significant predictor of prostate cancer outcomes following SRT and should be used in clinical decision making in this population and in future clinical risk assessment tools.
Genomic analysis of prostate cancer.
Authors: Barnett Christine M. , Heinrich Michael C. , Nelson Dylan A. , Lim Jeong Youn , Beadling Carol , Warrick Andrea , Neff Tanaya , Thomas George , Garzotto Mark , Higano Celestia S. , Beer Tomasz M. , Qian David Z. 
Published: February 2017

80 Background: The characterization of actionable mutations is a prerequisite for the development of individualized, targeted therapy. We sought to characterize the prevalence of potentially therapeutically actionable mutations in patients with high risk prostate cancer. Methods: 48 samples of formalin fixed paraffin embedded prostatectomy tissue from a neoadjuvant chemotherapy trial (Garzotto M, Cancer 2010 Apr 1;116(7):1699-708) were analyzed. DNA was extracted from microdissected tumor. Tumor DNA was analyzed for 643 common solid tumor point mutations in 53 genes using mass spectroscopy based sequencing (Sequenom MassArray). Low level mutations were validated using ion chip pH based sequencing (Ion Torrent). In addition, PTEN loss and ERG translocations were examined using immunohistochemistry in associated tissue microarrays. Correlation with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations examined. Results: Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 45 tumors evaluable for IHC, 36% had PTEN loss (6% with a heterogenous pattern) and 40% had ERG rearrangement (2% with heterogeneous pattern). Individual mutations were not frequent enough to determine associations with progression. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median progression free survival, 19 vs. 106 months (p = .01). Conclusions: This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. While point mutations alone did not have a statistically significant effect on relapse, PTEN loss was associated with an increased relapse in high risk prostate cancer treated with chemotherapy followed by surgery. It is yet unclear if the 16 weeks of chemotherapy played a role in selecting for tumors with these biologic features, and this will therefore be the subject of future investigations. [Table: see text]
Impact of intermittent (I) first-line docetaxel (D)-based chemotherapy on quality of life (QL) of patients (pts) with castration-resistant prostate cancer (CRPC): Results of a phase II randomized trial.
Authors: Caffo Orazio , Sava Teodoro , Basso Umberto , Buti Sebastiano , Lo Re Giovanni , Sacco Cosimo , Lodde Michele , Facchini Gaetano , Zustovich Fable , Perin Alessandra , Russo Lucianna , Veccia Antonello , Galligioni Enzo 
Published: February 2017

90 Background: Eight consecutive courses of D are usually considered a standard first line treatment for CRPC pts. The pts quality of life (QL) may be worsened and an I administration could mitigate this effect. We verified if an I therapy may reduce the impact on pts’ QL compared to continuous (C) treatment. Methods: The treatment was D 70 mg/m2IV q 3 wks ± estramustine (E) 280 mg/TID PO for 5 days. Pts were randomized to receive 8 courses D±E continuously (C) or intermittently, with a 3-month rest period after the first 4 courses. QL was evaluated by EORTC QLQ C30 at baseline and every 6 weeks. For the study aim, we considered evaluable for QL pts who received at least 5 D±E courses and filled the QL instruments. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 94 pts evaluable for QL (53 and 41 treated with I with C therapy, respectively). No statistically differences were observed between C and I treatments for QL outcomes: the table shows the median value of single EORTC QLQ C30 scales scores at each assessment time-point. Conclusions: The present study failed to demonstrate that I treatment may produce a QL advantage compared to C treatment which remains the reference therapy for first-line of CRPC pts. Clinical trial information: 2006-005728-17. [Table: see text]
Effect of generation 2.5 antisense inhibitor of androgen receptor on MDV3100-resistant prostate cancer cell growth in vitro and in vivo.
Authors: Yamamoto Yoshiaki , Beraldi Eliana , Loriot Yohann , Zhou Tianyuan , Kim Youngsoo , Monia Brett P. , MacLeod A. Robert , Fazli Ladan , Zoubeidi Amina , Gleave Martin Edwin 
Published: February 2017

94 Background: MDV3100 is a potent androgen receptor (AR) antagonist with activity in castration resistant prostate cancer (CRPC); however, progression to MDV3100-resistant (MDV-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length or variants in disease progression. We studied the activity of Generation 2.5 antisense oligonucleotide (ASO) targeting the AR full length (ARfl) and splice variants in MDV-R CRPC models. Methods: and Results: ThreeASOs targeting exon 1, intron 1, or exon 8 were designed to suppress ARfl and known AR splice variants. We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both ARfl and AR-V7 compared to CRPC LNCaP cell lines. MDV-3100 induced time- and dose-dependent increases in ARfl and AR-V7 protein levels; ARfl levels were ~20-fold higher than AR-V7. All 3 AR-ASO decreased ARfl and PSA expression. Exon 1 ASO decreased expression of both ARfl and AR-V7 in MDV-R-LNCaP cells; in contrast, exon 8 ASO decreased ARfl without reducing AR-V7 levels. Exon 1 ASO also most potently suppressed ARfl and splice variants in M12 cells stably overexpressing AR splice variants AR-V7 and AR-V567es. Despite these differential effects on ARfl and splice variant knockdown, the AR ASO similarly inhibited cell growth and induced apoptosis and G1 cell cycle arrest in LNCaP-derived CRPC and MDV-R cell lines. In 22RV-1 cells (which express endogenous ARfl and AR-V7), exon 1 ASO more potently suppressed ARfl and AR-V7 levels, AR transcriptional activity and AR-regulated gene expression compared to exon 8 ASO, but inhibition of cell growth did not differ significantly. Exon 1 ASO was evaluated in vivo in MDV-R49F CRPC LNCaP xenografts; mean tumor volume and serum PSA levels decreased significantly by 40% and 50%, respectively, compared to controls. Conclusions: While MDV-3100 induces both ARfl and AR-V7 levels, the biologic consequences appear cell line dependent and mainly driven by ARfl. AR-ASO knockdown of ARfl and its splice variants suppresses MDV-R LNCaP tumor growth, providing pre-clinical proof of principle to support clinical evaluation in post-AR pathway inhibitor CRPC.