bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequential use of new agents (NAs) after docetaxel (DOC) first line in metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A pooled-analysis of the published studies.
Authors: Maines Francesca , Caffo Orazio , Veccia Antonello , Bria Emilio 
Published: February 2017

258 Background: NAs have recently demonstrated a survival advantage in mCRPC pts progressing after DOC: two hormonal NAs (HNA), abiraterone and enzalutamide, and one chemotherapeutic agent, cabazitaxel (CAB). Recent evidences of possible cross-resistance has opened a debate about the best strategy when these drugs are used sequentially. We performed a pooled analysis of the published studies in order to assess if one of the following sequence strategy was potentially better than the others: a) HNA→ HNA, b) HNA → CAB or c) CAB → HNA. Methods: We evaluated the studies reporting clinical outcomes of a single NA administered after sequential treatment with docetaxel followed by another NA in mCRPC pts. All studies reporting monthly overall survival (OS) rates were considered eligible for the analysis; data were extracted, cumulated and weighted by taking into account each trial sample. We also evaluated possible differences in terms of factors able to produce potential patient-selection biases (age, Performance Status, visceral metastases and Gleason score). Results: Ten retrospective studies met the selection criteria of our analysis. They reported the outcomes of 735 pts who have received HNA → HNA (320 pts), HNA→ CAB (249 pts), and CAB → HNA (166 pts). No statistically significant differences were observed in terms of selection factors. Cumulative OS rates (with CIs), according to treatment sequence, are summarized in the Table. Conclusions: Our data seems to confirm a potential cumulative survival benefit of sequential use of NAs without a clear superiority of a single strategy over the others after DOC first-line in mCRPC patients. This conclusion is tempered by the retrospective nature and the potential selection biases. Nevertheless, a possible OS advantage could be observed when a CAB-based sequence is adopted. [Table: see text]
Phase I trial of weekly cabazitaxel with concurrent intensity-modulated radiation therapy (IMRT) and androgen deprivation therapy (ADT) for the treatment of high-risk prostate cancer (PCa).
Authors: Lin Jianqing , Den Robert Benjamin , Showalter Timothy Norman , Hoffman-Censits Jean H. , McGuire Monica , Kennedy Brooke , Hurwitz Mark , Trabulsi Edouard John , Lallas Costas D. , Yang Hushan , Birbe Ruth C. , Chervoneva Inna , Dicker Adam , Kelly William Kevin 
Published: February 2017

26 Background: Cabazitaxel (C) improves overall survival and has been approved in second line chemotherapy for patients (pts) with metastatic castrate resistant PCa. We hypothesized that C is a radiosensitizer and performed a phase I trial of weekly C with standard IMRT and ADT for pts with high risk localized PCa. Methods: Conventional “3 + 3” design. Pts with newly diagnosed high risk PCa defined as either Gleason score (GS) 8 – 10, or T3/T4 with GS 7, or PSA > 20 with GS 7 are eligible. Dose escalation occurred only after all the cohort pts completed weekly C ( 4 cohorts at the dose of 4, 6, 8 and 10 mg/m2) and the total planned dose IMRT. ADT was started two months prior to C and IMRT then continued on for a total of 24 months. Daily bicalutamide started within 1 day to 2 weeks prior to LHRH agonist therapy and stopped on the last day of IMRT for approximately 4 month duration. IMRT is delivered to a total dose of 75.6 Gy at 1.8 Gy daily fraction for 8.5 – 9 wks. The primary objective of this study was to determine the safe dose of the combination of weekly C with IMRT and ADT . Results: At present, 14 pts of mean age 62 yrs (range 53 – 82), T2 - T4; mean PSA 89 (range 4 – 253); and median GS 9 (GS 7 – 10) were enrolled and 10 pts completed the chemo-radiation therapy. Grade 3 dose-limiting toxicites in the first two pts at the 8 mg/m2 C dose level were diarrhea and elevated transaminase, thus the maximum tolerable dose (MTD) of C with IMRT was determined to be 6 mg/m2. An expansion cohort is ongoing. In this dose level, there were ≤ grade 2 toxicities only (diarrhea, hypophosphatemia and leukopenia). No long term toxicities are observed. Standardized measurement of health status and quality of life will be presented. Conclusions: Concurrent weekly C with current standard IMRT is feasible with no unexpected toxicity. In combination with IMRT and ADT, the MTD of weekly C is 6 mg/m2 in pts with newly diagnosed high risk PCa. Clinical trial information: NCT01420250.
In vivo assessment of the therapeutic effects of lyophilized leech saliva extract from (Huridinaria manillensis) on LNCaP tumor xenograft model in nude mice.
Authors: Ammar Amr , Hessein Mohamed , Guns Emma , Chin Mei , Helaluddin Abul Bashar , Abdualkader Abdulrahman , Alaama Mohamed , Merzouk Ahmed , Ghawi Abbas , Kucuk Omer 
Published: February 2017

271 Background: Ancient traditional physicians from many countries used leeching to treat a wide range of diseases for thousands of years. A large number of peptides and proteins have been identified and characterized in leech saliva extract (LSE), including anti-thrombotic agents, cancer metastasis inhibitors and anti-microbials Currently, leech therapy is established as an important tool in microsurgery and reconstructive operations having demonstrated superior clinical outcomes for the optimal salvage of grafted tissues. Methods: In the current study, we have determined the in vivo efficacy of LSE from (Huridinaria manillensis) on castration resistant LNCaP xenograft mouse model. Mice were divided into three groups of six, mice were subcutaneously injected with either LSE (5 mg/kg), docetaxel (10 mg/kg), or vehicle once a week. PSA and tumor volume were measured weekly. After four weeks of treatment, mice were euthanized, tumors and organs were collected for transcriptome and immunohistochemical (IHC) analysis. Results: There was a significant decrease in the tumor volume and PSA with either docetaxel (10mg/kg) or LSE (5 mg/kg) treated groups compared to the control. While there was no significant difference between the anti-tumor activity of docetaxel (10mg/kg) and LSE (5 mg/kg). IHC showed significant increase in caspase-3 and significant decrease in Ki-67 and PCNA expression in the LSE treated mice compared to the control group. Interestingly, transcriptome analysis of tumor samples showed that LSE modulated cytokine production, monocyte adhesion, steroidogenesis, and P38 MAPK signaling pathways. Conclusions: LSE has significant anti-tumor activity in LNCaP tumor xenograft models with no apparent side effects. This can be attributed, at least partly, to its inhibition of cellular proliferation, induction of apoptosis, modulation of immunity and steroidogenesis.
Quantitative imaging by automated bone scan index (BSI) as a response biomarker in standard clinical care of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide.
Authors: Anand Aseem , Lindgren Belal Sarah , Reza Mariana , Edenbrandt Lars , Bjartell Anders 
Published: February 2017

288 Background: Enzalutamide (ENZ), an androgen receptor antagonist therapy, was approved for patients (pts) with mCRPC. However, in standard of care for mCRPC pts, change in prostate specific antigen (PSA) is not accepted as an efficacy response measurement and the radiological change is inadequately measured in an interpreter-dependent subjective analysis of bone scan. Therefore, an objective efficacy response biomarker is warranted. In this registry study, we evaluated BSI as a quantitative analysis of bone scintigraphy, to access response in mCRPC pts being treated with ENZ. Methods: Pts with mCRPC, at Skåne University Hospital (SUH), Sweden, who initiated treatment with ENZ after failing chemotherapy were eligible for the study. Primary objective was to associate the change in BSI and PSA, after 12 weeks (wks) of treatment with EZN, with overall survival (OS). Automated BSI generated by EXINI boneBSI platform is quantitative representation of tumor burden as a percent of total skeletal mass. Bivariate cox regression analysis was used to evaluate the association of BSI and PSA with OS. Results: Thirty-five pts, who initiated ENZ treatment at (SUH), were eligible for the BSI analysis. Follow-up scans for the BSI analysis were available from 24 pts. Median baseline BSI value was 2.92 (range: 0.0 - 11.72) and at follow-up the median BSI value was 2.83 (range: 0.0 - 12.65). OS was associated with BSI at both baseline and at follow-up as opposed to that of PSA (table 1). The change in BSI between baseline and follow-up was also significantly associated with OS, whereas the change in PSA was not. Conclusions: Automated BSI and its relative change were observed to be associated with OS in mCRPC pts receiving ENZ as standard of care treatment. The result deserves further validation, in controlled investigational studies, of BSI as a quantitative imaging biomarker indicative of efficacy response to second-line treatment in mCRPC pts. [Table: see text]
Effect of AXIN2 expression on prostate cancer recurrence and an invasive, tumorigenic phenotype.
Authors: Hu Brian Robin , Fairey Adrian S , Madhav Anisha , Yang Dongyun , Li Meng , Groshen Susan G. , Stephens Craig , Kim Philip , Virk Navneet , Wang Lina , Martin Sue Ellen , Erho Nicholas , Davicioni Elai , Jenkins Robert B. , Den Robert Benjamin , Xu Tong , Xu Yucheng , Gill Inderbir S , Quinn David I. , Goldkorn Amir 
Published: February 2017

29 Background: Better biomarkers are needed in prostate cancer (PCa) to predict disease recurrence and guide optimal therapy. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor cancer phenotype impact PCa biology and clinical outcomes in localized disease. Methods: Genes associated with self-renewal, drug resistance, and tumorigenicity were analyzed by qRT-PCR on PCa mRNA from radical prostatectomy (RP) specimens (+/- disease recurrence). Wilcoxon rank sum two-sample test, multivariable recursive partitioning, and bootstrap internal validation measured and confirmed associations with recurrence. Further validation was conducted in external cohorts and in-silico, as well as in vitro and in vivo using siRNA knockdown and lentiviral overexpression to determined the effect of gene expression on PCa proliferation, invasion and tumor growth. Results: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. Validation in external cohorts demonstrated low AXIN2 expression was associated with more aggressive prostate cancer and was independently associated with biochemical recurrence (BCR) and metastasis-free survival (MFS) after RP. In vitro, low AXIN2 expression was associated with a cancer stem-like cell-surface signature, and siRNA knockdown of AXIN2 resulted in significantly greater invasiveness. Conversely, ectopic overexpression of AXIN2 significantly reduced cell proliferation and tumor growth in mice. Conclusions: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts. AXIN2 expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. AXIN2 represents a putative biomarker and potential therapeutic target in early prostate cancer.
Genomic landscape of high-grade T1 micropapillary bladder tumors.
Authors: Bellmunt Joaquim , Guo Guangwu , Mullane Stephanie A. , Orsola Anna , Werner Lillian , Van Hummelen Paul , Thorner Aaron , Loda Massimo , Choueiri Toni K. , Barletta Justine A. , Kwiatkowski David J. , Meyerson Matthew , Van Allen Eliezer Mendel 
Published: February 2017

299 Background: The genomic landscape of high-grade T1 micropapillary bladder tumors (HGT1micropap) is unknown. Clinically, micropapillary bladder cancer is an aggressive and possibly lethal disease. Our main objective was to assess the genomic landscape of HGT1micropap through identifying mutations, insertions/deletions (indels), translocations, and copy number variations (CNVs). Methods: We prospectively identified nine HGT1micropap with 45.4 months of median follow up. Patients were treated in a uniform manner using TUR, BCG, and appropriate follow up. We performed whole exome sequencing using Ilumina Exome _v5 plus translocation. Mutations and indels were called using the Firehose pipeline. CNVs were called using ExomeCNV. We examined the mutational landscape and compared the genomic alterations to TCGA (>T2, n=131)2 and publicly available data on non-muscle invasive bladder tumors (Ta/T1, n=37)1. Results: Within the HGT1micropap, mutations on TP53, KMT2D, TSC1, and ATM were suggested to occur more frequently compared to the NMIBC control group1. FGFR3 was seen at the expected frequency for NMIBC. The mutations of interest are presented in Table 1 with the percentage seen in the other cohorts. Of interest, TSC1 was seen in higher frequency in micropapillary than in the NMIBC or the TCGA cohort2. We did not see any patterns between CNVs and mutations. We also saw two patients with severe chromothripsis. 3 patients had loss of chromosome 9 or 9q without any other severe chromosome alterations. CNV alterations will be presented and compared to MIBC. Conclusions: In this preliminary analysis, our HGT1micropap, showed a mutational landscape more similar to MIBC compared to NMIBC bladder landscape. We did not find any clear driver of the micropapillary histology at the exome level in this limited sample of patient, which may indicate that tumor heterogeneity or epigentic changes may be driving this aggressive phenotype. [Table: see text]
Clonality of bladder tumors following radical nephroureterectomy: Against the field defect hypothesis.
Authors: Cha Eugene K. , Sfakianos John , Scott Sasinya N. , Murugan Paari , Iyer Gopa , Bagrodia Aditya , Shah Ronak , Bajorin Dean F. , Rosenberg Jonathan E. , Berger Michael F. , Al-Ahmadie Hikmat , Bochner Bernard H. , Coleman Jonathan A. , Solit David B. 
Published: February 2017

301 Background: Urothelial carcinoma is characterized by multifocal and metachronous tumors. To explain this phenomenon, two hypotheses have been proposed: the ‘field defect’ hypothesis - urothelial cells are primed to undergo transformation by exposure to carcinogens, and the clonal, or ‘single progenitor cell,’ hypothesis - tumors arise from intraluminal seeding of transformed cells. Methods: To examine their clonal relationships, we compared the genomic profiles of primary upper tract urothelial carcinoma (UTUC) tumors and metachronous bladder tumors (intravesical recurrences) in patients treated with radical nephroureterectomy (RNU) and subsequent transurethral resection. Specimens were analyzed using a next-generation, targeted sequencing assay designed to identify point mutations, indels, and copy number alterations in 341 cancer-associated genes. Results: We analyzed 16 primary UTUC tumors and 41 intravesical recurrences in patients treated with RNU. The median number of intravesical recurrences per patient was 2 (range 1-7) and the interval from RNU to intravesical recurrence ranged from 3.5 months to 129 months. With an average sequencing coverage of 516x, we found strong evidence delineating the clonal relationship between primary UTUC tumors and subsequent bladder tumors. The majority of somatic mutations present in the primary UTUC tumors (median=7, range 4-39) were detected in all subsequent bladder tumors (128/146, 88%). In an illustrative case, one patient followed with periodic cystoscopy/cytology who had been NED for 5.5 years then developed 7 bladder tumors over the next 44 months, each with the identical mutation profile (8 mutations) as the primary tumor. Conclusions: We demonstrate that bladder tumors following RNU represent true intravesical recurrences, with almost all tumors sharing the same somatic mutation profile as the primary UTUC tumor. This has important implications for surgical techniques to minimize the risk of intraluminal seeding, the delivery of intravesical therapy following RNU, and the development of strategies employing systemic chemotherapy or targeted agents.
Urinary EGFR as a marker of urinary bladder cancer.
Authors: Regan Hannah Louise , Ward Douglas G , Bryan Richard T 
Published: February 2017

327 Background: Better biomarkers must be found to develop clinically useful urine tests for urothelial bladder cancer (UBC). Our objective was to identify proteins released by bladder cancer cells in vitro and assess their potential as urinary biomarkers. EGFR was identified as a promising biomarker and is overexpressed in numerous cancers including UBC. EGFR is a member of the ErbB family of transmembrane tyrosine kinase receptors. It is a 170kDa protein that facilitates cell growth and differentiation by acting upon downstream signaling pathways. Methods: We used shotgun proteomics to identify the proteins released into culture media by 8 UBC cell lines. These data were compared with protein expression data from the Human Protein Atlas. EGFR was measured by ELISA in the urine of 436 patients with primary bladder cancer (prior to commencing treatment) and 60 non-UBC control subjects (all samples were obtained from the Bladder Cancer Prognosis Programme). Outcomes were, presence of bladder cancer (yes/no) and bladder cancer-specific survival. Data were analysed with Mann-Whitney tests and Cox multivariable modelling. Results: EGFR was selected as a candidate biomarker because it was released by 5 out of 8 bladder cancer cell lines, but not by a ‘normal urothelium’ cell line, and is documented as highly overexpressed in UBC in the Human Protein Atlas. A soluble form of EGFR is detectable in urine and is increased in some patients with high-grade bladder cancer. With a cut-off defined as mean + 2 SD (630pg EGFR/mg creatinine), elevated urinary EGFR was an independent indicator of poor bladder cancer-specific survival with a hazard ratio of 2.89 (95% CI 1.81-4.62, p<0.001). In multivariable models urinary EGFR and EpCAM (previously reported) are strong independent predictors of bladder cancer-specific survival. Urinary EGFR is not useful as a diagnostic marker. Conclusions: Aggressive bladder cancers shed the ectodomain of EGFR into urine. Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of those patients with the most aggressive bladder cancers, expediting their care to improve outcomes.
Who should be performed perioperative chemotherapy in upper-tract urothelial cancer? Risk classification for selecting candidate using preoperative factors.
Authors: Nagao Kazuhiro , Inoue Ryo , Inamoto Teruo , Takahara Kiyoshi , Matsumoto Hiroaki , Yamamoto Yoshiaki , Kobayashi Keita , Sakano Shigeru , Azuma Haruhito , Matsuyama Hideyasu ,   Yamaguchi Uro-Oncology Group
Published: February 2017

328 Background: The patients with advanced upper tract urothelial carcinoma (UTUC) have poor prognosis. Previous reports have not shown that neoadjuvant chemotherapy for UTUC improves patient survival and it is difficult to select appropriate candidates for neoadjuvant chemotherapy. We aimed to predict appropriate candidates for neoadjuvant chemotherapy. Methods: We reviewed the data of 536 patients with UTUC undergone total nephroureterctomy in the cohort of Yamaguchi Uro-Oncology Group (Group 1) and 150 cases in the cohort of Osaka Medical College (Group 2). We performed a multivariate analysis to the Group 1 to decide independent predictive factors and validated them in another cohort (Group 2). We evaluated the clinical significance of the predictive factors in cancer-specific survival (CSS) and overall survival (OS) between the cohort with and without perioperataive chemotherapy. Results: Multivariate analysis showed ≥cT3, cN+ and elevated CRP (≥0.31mg/dl) could become independent prognostic factors in Group 1, which showed 0.70 of AUC in predicting cancer death. We validated these factors in Group 2 and confirmed that they also showed 0.78 of AUC in predicting cancer death. Then, we divided the patients into 4 risk groups based on the number of the predictive factors: score 0 (202 cases), score 1 (152 cases), scores 2 (51 cases) and scores 3 (30 cases). Kaplan-Meier Curve showed that 5 year CSS in score 0, 1, 2, and 3 were 84.7%, 67.7%, 32.2% and 22.0%, respectively. Finally, we analyzed the difference in CSS and OS between the 138 cases with and 296 cases without perioperative chemotherapy. A significant difference in CSS and OS between the cases with and without perioperative chemotherapy was shown only in the cases with all the predictive factors: score 3. Additionally, fraction of patients with lymphovascular invasion of the surgical specimen were significantly increased with score advance. Conclusions: Survival in the patients with UTUC was predictable by preoperative factors. The patients with all the predictive factors, ≥cT3, cN+ and elevated CRP, were supposed to be the best candidates for neoadjuvant chemotherapy against UTUC.
Weekly paclitaxel versus ADT alone in localized high-risk prostate cancer: Results of a single-institution phase II trial.
Authors: Saldana Carolina , Salomon Laurent , Rousseau Benoit , Chaubet-Houdu Marie , Joly Charlotte , Ploussard Guillaume , Allory Yves , Tournigand Christophe , de la Taille Alexandre 
Published: February 2017

37 Background: Adjuvant chemotherapy’s role after radical prostatectomy (RP) remains controversial in localized high-risk prostate cancer (HRPC). This phase II trial assessed the combination of weekly paclitaxel (WP) with androgen deprivation therapy (ADT) in this population. Methods: All eligible patients (pts) had undergone a laparoscopic RP with pelvic lymph node dissection for a localized HRPC defined with ≥1 of the following criteria: T3b-T4 post-operated Gleason score (GS) ≥8, PSA≥ 20 ng/mL, pN+, in Henri Mondor Hospital. Pts were randomly assigned to either triptoreline 11.25mg every 3 months during 3 years and 8 cycles of WP 100 mg/ m2 (WP arm, n=21) or triptoreline alone (ADT arm, n=26). The primary endpoint is disease free survival (DFS); events=PSA relapse, clinical and radiographic relapse, death. The planned number of pts was 152. Toxicity results indicated a good tolerability with neutropenic fever in 4.3% (n=1), and no negative impact on QoL in the WP arm (Ploussard, Prostate Cancer Prostatic Dis. 2010). Here we report 8-year DFS and overall survival (OS) results. Results: Between February 2005 and October 2007, 47 pts were enrolled. This trial was terminated prematurely because of slow accrual. After a mean follow-up of 8.4 y, we identified a PSA relapse in 25 pts (53%) and castrate-resistant prostate cancer occurred in 6 pts. No statistically difference was found in terms of either biochemical or clinical DFS (bDFS, cDFS) and OS: 8-year bDFS rate: 50% [n=11/22] in the WP arm vs 46% [n=12/26] in the ADT arm (p=0.79); 8-year cDFS rate: 95.4% [n=21/22] in the WP arm vs 88.5% [n=23/26] in the ADT arm (p=0.38). The 8-year OS rate is 90.9% (n=20/22) and 84.6% (n=22/26) respectively with no difference between treatment arms (p=0.51). No clinical, histological or biological variable demonstrated a difference in either 8-year bDFS, cDFS or OS rate. Conclusions: Provided that this trial is probably underpowered to detect a DFS benefit, adjuvant weekly paclitaxel after RP was not associated with any significant reduction in the risk of biological relapse or death compared to ADT alone in patients with localized HRPC. Chemotherapy should be only proposed in dedicated clinical trial for localized HRPC.