bluuebunny/crossref_metadata_2025_split huggingface dataset:
PFS to predict long-term OS after first-line treatment for advanced renal cell carcinoma (aRCC): Correlation and power analysis of randomized trials (RCT).
Authors: Milella Michele , Massari Francesco , La Russa Francesca , Maines Francesca , Felici Alessandra , Vaccaro Vanja , Porta Camillo , Bracarda Sergio , Cognetti Francesco , Giannarelli Diana , Tortora Giampaolo , Bria Emilio 
Published: March 2020

4541 Background: Targeted agents (TA) have become standard 1st line aRCC treatment based on evidence of PFS advantage. Retrospective series indicatePFS as a reliable intermediate end-point in this setting; however, correlation, surrogacy testing, and validation are required. Methods: RCT evaluating the efficacy of TA as 1st line treatment for aRCC were eligible. PFS/OS Response/Disease Control rates (ORR, DCR) and HR were extracted from papers/updated presentations. Correlations between 6-, 9-, and 12-mo PFS and OS rates according to parametric (Pearson’s r) and non-parametric (Spearman’s Rho and Kendall’s Tau) coefficients (with 95% CI) were analyzed to avoid lead-time biases. Regression analysis (parametric R2) and a power-analysis-model to determine patients’ sample necessary to detect 3%, 5% and 10% OS gain were developed. Results: Six RCT (4096 pts) were gathered. The best overall correlation between PFS and OS at concurrent timepoints was found at 9 mos. With regard to overall rates, 3- and 6-mo PFS significantly correlated with 9-mo OS, as shown in the table below. Pearson’s coefficients for the correlation between 3-mo PFS and 6- and 12-mo OS were 0.70 (p=0.01) and 0.67 (p=0.01); the correlation between 6-mo PFS and 12-mo OS was also significant (Pearson 0.74, p=0.005; Spearman 0.83, p=0.005; Tau 0.71, p=0.001). The regression equation was: Y=0.391861 + 0.4914X [R2 0.44, p(slope)=0.01]; based on this model, the demonstration of a 3-mo PFS absolute difference of 6%, 10% and 21% (corresponding to a 9-mo OS benefit of 3%, 5% and 10%) would require 2043, 696 and 155 patients, respectively. A significant correlation was also found between DCR and OS. Conclusions: Early PFS is an acceptable intermediate end-point for OS in the context of 1st line TA for aRCC. Individual patient data analysis to verify Prentice criteria would be required for definitive confirmation. [Table: see text]
A phase I study of the androgen signaling inhibitor ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rathkopf Dana E. , Morris Michael J. , Danila Daniel Costin , Slovin Susan F. , Steinbrecher Jill Elise , Arauz Gabrielle , Curley Tracy , Rix Peter J. , Chow Maneval Edna , Chen Isan , Fleisher Martin , Landa Jonathan , Fox Josef J. , Larson Steven M. , Scher Howard I. 
Published: March 2020

4548 Background: ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012) We conducted a phase I trial to assess safety, pharmacokinetics (PK), and determine the recommended phase II dose (RP2D). Methods: Eligible patients with mCRPC received ARN-509 orally on a continuous daily dosing schedule. Seven doses (30, 60, 90, 120, 180, 240, and 300 mg) were tested using standard 3x3 dose escalation criteria. Once drug concentrations were achieved that met or exceeded optimal levels predicted preclinically, an additional 2 dose levels were tested to further confirm the safety margin of ARN-509 (390 and 480 mg). Anti-tumor activity was assessed by PSA, radiographic responses, and FDHT-PET imaging. Results: Thirty patients were enrolled. The most common grades 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden. PK was shown to be linear and dose-dependent. At 12 weeks, 42% of patients have had ≥ 50% PSA declines. Eleven (37%) patients have discontinued the study due to progression, with the longest patient still on study for more than 16 months. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Conclusions: In this phase I study, ARN-509 was shown to be safe and well tolerated with linear PK. Based on promising activity across all dose levels and pharmacodynamic evidence of AR antagonism, an optimal biologic dose of 240 mg daily was selected for phase II investigation. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals.
Durable radiologic and clinical disease stability beyond PSA progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).
Authors: Bianchini Diletta , Sandhu Shahneen Kaur , Mulick Cassidy Amy , Zivi Andrea , Mezynski Janusz , Mukherji Deborah , Pezaro Carmel Jo , Reid Alison Helen , Oommen Nikhil Babu , Olmos David , Omlin Aurelius Gabriel , Sarvadikar Ajit , Thompson Emilda , Hunt Joanne , Sheridan Elizabeth , Attard Gerhardt , De Bono Johann Sebastian 
Published: March 2020

4553 Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment of mCRPC with a survival advantage of 4.9 months. In clinical practice, response evaluation remains challenging for pts with mCRPC. CTC conversion from CTC ≥ 5 to CTC < 5 with treatment predicts for improved overall survival in mCRPC. We hypothesized that pts continue to have durable disease stability beyond PSA progression on AA. Methods: Prostate Specific Antigen (PSA) responses, radiological responses and CTC conversion rates were retrospectively analysed in pts treated on AA at our institution. CTCs, PSA and imaging were obtained at predefined time points during these studies. Radiological and PSA progression were defined by standard Prostate Cancer Working Group Criteria II. Clinical progression consisted of worsening disease related pain, skeletal events or declining performance status.Pearson’s chi-squared test and the Kaplan-Meier method were used for this analysis. Results: 141 patients [ECOG Performance Status 0-2; Median Age: 69.7 (range 44.7-87.1); 85 post-docetaxel, 56 pre-docetaxel] received AA. The median duration of clinical and radiological stable disease (SD) was 16.8 months (n=55) and 5.6 months (n=75) in patients with a baseline CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. In the 105 patients with documented PSA progression on AA there was a median 5.7-month delay in detecting radiological and/or clinical progression (95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological and clinical SD of ≥ 1 year, ≥ 2 years and ≥ 3 years on AA was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusions: Radiological and clinical disease stabilization beyond PSA progression is maintained in a high proportion of mCRPC patients treated with AA. Future studies should evaluate whether continued AA treatment beyond PSA and radiological progression can impact outcome.
Abiraterone in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and MDV3100.
Authors: Ileana Ecaterina , Loriot Yohann , Albiges Laurence , Massard Christophe , Blesius Aurore , Di Palma Mario , Escudier Bernard J. , Blanchard Pierre , Bossi Alberto , Fizazi Karim 
Published: March 2020

4554 Background: Chemotherapy with docetaxel is the standard first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). In patients progressing after docetaxel, both abiraterone and MDV3100 have yielded improved survival for patients with mCRPC. The efficacy of abiraterone in patients pre-treated with MDV 3100 is unknown. Methods: We investigated abiraterone-prednisone in 24 patients with cancer progression after docetaxel followed by MDV3100. All patients received abiraterone 1000 mg/day plus prednisone 10mg/day. Prostate-specific antigen (PSA) response, symptom response, and time to progression were assessed. Results: Patient characteristics were as follows: median age: 74 years (53-84), median PSA: 108 ng/mL (2-2541), metastatic sites: bone: all 24 patients, liver/lung: 6 patients (25%), and lymph nodes : 9 patients (38%). Five patients (21%) had a PSA decrease on abiraterone-prednisone. Three patients (13%) achieved a PSA response, defined as a decrease of >50% in PSA, confirmed after≥ 4 weeks. The duration of PSA response was 2, 3 and 4.5 months. Six patients (29%) had a symptomatic response on the pain score and analgesic consumption was decreased. Treatment was well tolerated. Abiraterone-prednisone was discontinued in one patient due to edema and hypokaliemia. Conclusions: This study shows preliminary evidence that abiraterone-prednisone yields activity in patients with mCRPC pretreated with docetaxel and MDV3100.
Expression of MET and HGF in bladder cancer tumorigenesis and invasion.
Authors: Sweis Randy F. , Grivas Petros , Pearson Alexander T. , Day Kathleen C. , Day Mark L. , Hussain Maha 
Published: March 2020

4573 Background: The human MET gene encodes the hepatocyte growth factor (HGF) tyrosine kinase receptor. Limited studies in human bladder cancer have demonstrated that expression of MET protein is linked with disease progression and survival. We hypothesized that the expression of both MET and its ligand HGF are altered in bladder cancer. Methods: Expression of MET and HGF in human bladder tissues was explored using Oncomine, an online compendium of cancer transcriptome profiles. The largest relevant dataset was identified and contained 157 samples (Sanchez-Carbayo, et al. 2006). Normalized and log2 transformed mRNA expression values for Affymetrix U133 microarray probe sets corresponding to the genes of interest were compiled and averaged for each gene. Mann-Whitney U testing was used to compare means. Nominal and standard least squares logistic regression was used to evaluate the predictive significance of, and relevance of clinicopathologic variables on, gene expression. Statistical analyses were carried out using JMP 9.0.2. Results: Expression of MET and HGF was compared across subsets of normal bladder tissue (n=48), superficial tumors (n=28), and invasive tumors (n = 81). Relative to normal tissue, MET expression was greater in superficial (p = 0.0008) and invasive tumors (p<0.0001). HGF expression was reduced in both invasive and superficial tumors vs. normal tissue (both p< 0.0001), but was higher in invasive vs. superficial tumors (p= 0.0007). In a logistic regression model of tumor samples, both MET and HGF correlated with tumor invasion (model p=0.0003). Interaction between MET and HGF was not significant (p=0.55). Neither MET nor HGF expression was predicted by regression using age, gender, grade, or nodal stage (p=0.16 and 0.27, respectively). Conclusions: Decreased HGF expression and MET over-expression are strongly associated with tumorigenesis and invasion in bladder cancer. The reduction in HGF expression is blunted in invasive vs. superficial tumors, suggesting a potential loss of negative feedback in more aggressive tumors. Expression of both genes could not be predicted by modeling clinicopathologic variables. MET signaling represents a potential therapeutic target in bladder cancer.
Quality of life and late toxicities in germ-cell cancer patients after high-dose chemotherapy.
Authors: Wuendisch Thomas , Naermann Regina , Beyer Joerg , Lorch Anja ,   for the German Testicular Cancer Study Group
Published: March 2020

4600 Background: The number of long term survivors after treatment for relapsed/refractory germ cell cancer (GCC) is increasing but little is known about quality of life (QOL) and late toxicities (LT). Methods: We assessed LT and QOL in GCC patients (pts), treated in a prospective, randomized, multicenter, phase III trial comparing single versus sequential high-dose chemotherapy (HDCT) (Lorch 2007). All 216 pts were asked to complete the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) prior to HDCT, 6 weeks after and yearly thereafter. Results were analyzed according to standard methods (Fayers 2001). In addition pts were contacted at a median of 76 months (range 45-109) after HDCT to obtain information about current social and professional activities as well as LT. Results: Among 216 pts, 92/216 (42%) were alive and without evidence of disease one year after randomization. Median age of pts was 34 years (range 15-56). A median of 4 conventional-dose cisplatin-based treatment cycles had been given prior to HDCT. Questionnaires and response to the survey were evaluable in 86/92 (93%) pts overall and in 59/86 (69%) pts more than 3 years after HDCT. Values for global health status, role functioning and emotional functioning declined during the first year after HDCT, increased in the following years, but did not reach the reference values from large samples of the general population in Norway (Hjermstad 1998). Pts after sequential HDCT scored better in a number of items (e.g. emotional-, cognitive-, social-functioning, fatigue and dyspnoea) in comparison to single HDCT including high-dose cyclophosphamide. Persisting polyneuropathy was reported in 59%, ototoxicity or tinnitus in 56%, erectile dysfunction in 24%, hypertension in 23%, hypercholesterinemia in 17%, diabetes mellitus in 6%, nephrotoxicity in 6%, myocardial infraction in 2% and second cancers in 1% of pts. Overall 82 % of pts were employed, 30% exercised regularly. Conclusions: HDCT has a negative impact on QOL, including social and professional life. Most common late toxicities were ototoxicity and polyneuropathy. Sequential HDCT without cyclophosphamide seems to result in a better outcome in respect to QOL.
Can abdominal ultrasound replace CT scanning in long-term follow-up of male patients with germ cell tumor?
Authors: Gerl Arthur , Hauck Adina , Hentrich Marcus 
Published: March 2020

4602 Background: To date, there is no international consensus on how best to follow patients (pts) with GCT after their initial management. In the absence of a generally accepted follow-up schedule the possible benefits of regular CT scanning must be weighed against their cost, potential contrast media reactions and the long term risk of cumulative X-ray exposure. The present study focuses on the role of abdominal ultrasound in the follow-up of males with GCT and raises the question whether CT-scanning may be replaced by abdominal ultrasound. Methods: This retrospective single-center cohort study included 887 GCT pts followed between January 2001 and November 2011. The follow-up schedule was predominately based on abdominal ultrasound performed by the same physician (A.G.). Patterns of recurrence and the long-term outcome were analyzed. Results: 462 of 887 pts (52.1%) had stage I, 258 (29.1%) stage II and 130 (14.7%) stage III disease (not evaluable in 37 pts). The median time between baseline and the most recent follow-up examination was 5.0 years. A total of 14.604 abdominal ultrasound examinations (16.5/pt.), 1170 CT scans (1.32/pt.), and 956 chest X-rays (1.08/pt) were performed. A relapse occurred in 58 pts (6.5%) with 11 of 58 pts experiencing multiple relapses. 34 of 58 relapses (58.6%) were detected in pts with stage I GCT. The sites of relapse included the abdomen (n=42), other sites (n=10), and marker elevation only (n=10). 33 of 42 abdominal relapses (78.6%) were detected by abdominal ultrasound. The median size of abdominal lymph nodes was 25 mm (range, 6 - 67 mm). After a median follow-up of 5 years the GCT specific survival of the entire cohort was 98.4%. Regarding the subgroup of pts with relapse the GCT specific survival was 94.7%. Conclusions: Ultrasound appears to be an appropriate method to detect abdominal recurrences in pts with GCT. However, training and cumulative experience is necessary to detect retroperitoneal recurrences at an early stage. The number of expensive and potentially harmful CT scans may be markedly decreased by abdominal ultrasound.
Evaluation of selective inhibitors of nuclear export (SINE) CRM1 inhibitors for the treatment of renal cell carcinoma (RCC).
Authors: Inoue Hiromi , Kauffman Michael , Shacham Sharon , Landesman Yosef , Weiss Robert H 
Published: March 2020

4634 Background: For the ~30% of patients who present with RCC at the metastatic stage, multi-kinase inhibitors have been used with moderate success: progression-free survival remains at only one to two years, and thus it is imperative to discover novel therapeutic approaches for metastatic disease. We asked whether (1) SINE inhibitors of chromosome region maintenance protein 1 (CRM1) attenuate key cell cycle regulatory and apoptotic molecules and whether these compounds exert salutary effects in a human RCC xenograft mouse model. Methods: Four RCC cell lines (ACHN, Caki-1, 786-O, and A498) with distinct genotypes, and primary normal human kidney (NHK) cell lines, were used in this study. The cells were treated with the chemically related SINE CRM1 inhibitors KPT-185 or 251 and MTT assays were performed. In addition, cell cycle analyses, immunofluorescence for p53 and p21, and immunoblotting for CRM1, p53, p21, p27, and p-MDM2 were performed for all cell lines. RCC mice with Caki-1 xenografts were treated with vehicle, the orally-available CRM1 inhibitor KPT-251, or sorafenib for 26 days. Tumor volume was measured over several days. Results: Both KPT185 and 251 specifically reduced CRM1 protein levels in RCC cells. KPT-185 caused dose-dependent cytotoxicity in RCC cells, which was greater than sorafenib in RCC cell lines but less in NHK cells, suggesting a possible clinical advantage of KPT-185 over sorafenib. By FACS analysis, we showed that KPT-185 arrests the cell cycle in both G2/M and G1, and increased the sub-G0 cell population. KPT-185 and 251 both increased p53 and p21 in RCC cells, and KPT-185 confined these proteins to the nucleus. In vivo, KPT-251 inhibited Caki-1 xenografts in mice compared to both vehicle and sorafenib without obvious systemic adverse effects. Conclusions: We introduce a completely novel therapeutic approach to the treatment of RCC based on inhibition of the nuclear export of key cell cycle regulatory proteins. Inhibition of CRM1 leads to forced nuclear retention, and thereby activation, of several key p53-pathway proteins, leading to cell cycle arrest and apoptosis in RCC cell lines in vitro and tumor growth inhibition in vivo.
Genetic polymorphisms’ influence in outcome of metastatic renal cell cancer patients treated with VEGF-targeted agents.
Authors: Schutz Fabio Augusto Barros , Gray Kathryn P. , Pomerantz Mark M , Atkins Michael B. , Hirsch Michelle S. , McDermott David F. , Lampron Megan , Percy Andrew , Lee Gwo-Shu Mary , Rosenberg Jonathan E. , Signoretti Sabina , Kantoff Philip W. , Freedman Matthew , Choueiri Toni K. 
Published: March 2020

4635 Background: Single nucleotide polymorphisms (SNP) in critical signaling pathways may impact the outcome of metastatic renal cell cancer (mRCC) patients (pts) treated with VEGF targeted agents. Methods: Germline DNA was extracted from 263 pts of European-American ancestry enrolled in a prospective protocol with full baseline and follow up clinical data. A total of 113 common SNPs within select genes involved in RCC pathogenesis, angiogenesis and drugs metabolism were genotyped and associations sought with clinical outcome. The primary endpoint was progression free survival (PFS), defined as time from VEGF targeted therapy to progression or death. Cox model tested for the association between SNPs with PFS in univariate and multivariate model that adjusted for age, gender, type of VEGF inhibitor and MSKCC risk score. The false discovery rate (pFDR) was used to control for the number of tests performed. Results: The median follow-up time was 51.6 months (mo), 81% of pts had progression or death events. All patients were treated with an approved VEGF targeted agent (bevacizumab, sunitinib, sorafenib or pazopanib). Fifty three percent (140/263) of pts were treated with sunitinib. Two SNPs, one in HIF2α and one in VEGFR2, showed a significant association with the risk of progression. Compared to the dominant genotype (frequency 83%, median PFS 10.1mo), the VEGFR2 rs2305948 variant genotype (frequency 17%) showed a superior PFS (median 19.2mo) corresponded to an adjusted hazard ratio (HR) of 0.56 (95%CI: 0.37-0.84; p=0.005). Similarly and compared to the dominant genotype (frequency 94%, median PFS 10.6mo), the HIF2α rs11687512 variant genotype (frequency 6%) had a superior PFS (median 26.5mo) with an adjusted HR of 0.33 (95%CI 0.16-0.68; p=0.002). The analysis adjusted for age, gender, type of VEGF targeted therapy (Sunitinib vs. others) and MSKCC risk score. False discovery rate was <20% with both SNPs. Conclusions: Inherited variants may influence the PFS of pts with mRCC treated with VEGF targeted agents. Validation of these findings in an independent cohort is required. If validated, these results could help identifying subset of pts that are more likely to remain progression free on treatment.
Epidermal growth factor receptor (EGFR) expression and KRAS mutations in penile squamous cell carcinoma: Analysis of potential application of anti-EGFR monoclonal antibodies.
Authors: Gou Hongfeng , Liu Jiyan , Li Xiang , Qiu Meng , Cheng Ke , Bi Feng , Xu Feng 
Published: March 2020

4638 Background: Penile squamous cell carcinoma (SCC) is a rare cancer with poor prognosis and limited response to conventional chemotherapy. Anti-EGFR monoclonal antibodies (mAbs) have exhibited significant anti-tumor activities in several cancers such as colorectal carcinoma, head and neck cancer. KRAS mutations are linked to a poor response to mAbs and may thereby result in resistance to anti-EGFR agents. This study was aimed to examine EGFR expression and KRAS, BRAF mutations in penile SCC and to analyze the potential application of anti-EGFR monoclonal antibodies (mAbs) for this disease. Methods: Totally 150 penile SCC specimens from patients undergone surgical resection were included. EGFR expression was evaluated by immunohistochemistry. KRAS mutations at codons 12 and 13, and the BRAF mutation at codon 600 were analyzed on DNA isolated from formalin fixed paraffin embedded tissues by direct genomic sequencing. Results: EGFR expression was positive in all specimens, and its overexpression rate was 92%. We failed to observe a significant correlation between EGFR expression and tumor grade or lymph node metastases. The detection of KRAS and BRAF mutations analysis were performed in 94 and 83 tumor tissues, respectively. KRAS mutation was detected in only one sample and no patient was found to harbor BRAF V600E point mutation. Conclusions: We found the overexpression of EGFR and the absence of KRAS and BRAF mutations in penile SCC. This suggests that anti-EGFR mAbs may be potentially considerable therapeutic agents in penile SCC.