bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC).
Authors: Apolo Andrea Borghese , Lee Young H. , Cecchi Fabiola , Agarwal Piyush K. , Parnes Howard L. , Khadar Kattie , Summerell Amelia , Gulley James L. , Compton Kathryn , Figg William Douglas , Dahut William L. , Bottaro Donald P. 
Published: March 2020

4543 Background: Mounting evidence supports Met as a therapeutic target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (P=0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (P=0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.
Association between pioglitazone (PZD) therapy and bladder cancer (BC): A meta-analysis of epidemiologic evidence.
Authors: Shimanovsky Alexei , Appiah Juliet , Njei Basile M. , Clement Jessica Mary 
Published: March 2020

4546 Background: There is evidence suggesting that PZD use may be a risk factor for BC, yet these reports are controversial. The aim of this meta-analysis is to review available data and evaluate the association between PZD and BC. Methods: Two independent reviewers conducted a systematic search of the Cochrane Library, OvidSP and PubMed for articles published January 1970 to April 2012. MeSH search terms included PZD, Actos, thiazolidinediones, diabetes mellitus (DM), and BC. Only studies reporting an effect measure for the association between PZD and BC were included. Subgroup analyses by study design and country were performed. Analysis was done using a random effect model after a preliminary review showed evidence of study heterogeneity. This was then assessed using the Cochrane’s Q and I2 statistics. Publication bias was evaluated using the Begg’s and Egger’s tests, and funnel plots. All analyses were performed using REVMAN 5.1. Results: A total of 6 studies (3 cohort and 3 case control) met the inclusion criteria. The overall pooled risk ratio (RR) for the association between PZD and BC was 1.12 (95% CI 1.09, 1.15; P <0.001). The summary RR for cohort and case control studies were 1.13(95% CI 1.07, 1.19; P <0.001) and 1.11(95% CI 1.07, 1.15; P <0.001), respectively. The subgroup analysis showed a significant association with BC in the USA and Europe, but not in Asia (RR 0.98, 95% CI 0.71, 1.34; P = 0.88). The association of PZD and BC was more sensitive for treatment duration (>12 month). Conclusions: Our study analyzed 1,214,071 patients, demonstrating a weak association between PZD and BC. The results were significant with increase in treatment duration, which corresponds to previous studies. This meta-analysis has limitations. Not all studies reported known variables associated with BC, such as smoking or occupational exposure. They did not address patient BMI, time from DM diagnosis or previous drug therapy. These parameters reflect severity of disease and level of insulin-resistance. Future studies should evaluate markers of insulin-resistance with PZD use and correlate with BC. Understanding the link between PZD and BC in the context of DM may allow physicians to determine a more accurate risk of PZD use.
Preliminary safety, product parameters, and immune response assessments from a phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy (ACI), in patients (pts) with surgically resected HER2+ urothelial cancer (UC) at high risk for recurrence.
Authors: Bajorin Dean F. , Sharma Padmanee , Lerner Seth P. , Sims Robert Brownell , Sanders Amanda , DeVries Todd , Sheikh Nadeem A. , Gomella Leonard G. 
Published: March 2020

4547^ Background: DN24-02 is a HER2-targeted ACI, consisting of antigen presenting cells (APC) cultured with BA7072, a recombinant HER2-derived antigen (HER500) linked to GM-CSF; DN24-02 is based on the same manufacturing platform as sipuleucel-T, approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. NeuACT (N10E1; NCT01353222) is an open-label, randomized phase 2 trial comparing adjuvant DN24E02 to surveillance in HER2+ UC pts at high risk of relapse following cystectomy or nephroureterectomy. The primary endpoint is overall survival. Here we report preliminary evaluation of adverse events (AE), product potency, and immune response. Methods: Pts randomized to DN24-02 underwent leukapheresis followed by infusion of DN24-02 (total of 3 infusions with 2 wk intervals). AEs were assessed at each visit. Product potency was assessed for each infusion by measuring CD54 upregulation on APCs, a marker of APC activation. Antigen-specific immune responses were evaluated by ELISA to HER500 and BA7072. Results: As of November 2012, 13 pts had received ≥1 DN24-02 infusion. The most commonly reported AEs within 1 day after DN24-02 infusion were mild–moderate chills (54%), nausea (31%) and fatigue (23%). Ten pts completed all DN24-02 infusions and were assessed for product potency. Increased median APC activation at infusions 2 and 3 compared with infusion 1 was indicative of an immunological prime-boost effect; this effect was also seen in the 7/10 pts with prior neoadjuvant chemotherapy. Median anti-BA7072 and anti-HER500 titers (IgM) were 128- and 256-fold higher at week 6 vs baseline, respectively. The emergence of IgG indicated a memory antibody phenotype. Conclusions: Preliminary data indicate that DN24-02 product potency (CD54 upregulation) is comparable to sipuleucel-T. DN24-02 appears to be well tolerated in UC. Favorable immune responses were observed, including in pts with prior neoadjuvant chemotherapy. Updated results, including preliminary T-cell immune response data, will be presented. Clinical trial information: NCT01353222.
Phase I/II study of biweekly pemetrexed plus cisplatin in patients with locally advanced, nonresectable or metastatic urothelial cancer: Safety and efficacy results from phase II.
Authors: Lopez Martin Ana , Bellmunt Joaquim , Maroto José Pablo , Gallardo Enrique , Lopez Brea Marta , Perez-Gracia Jose Luis , Castellano Daniel E. , Valverde Claudia María , Bezares Susana , Calvo Emiliano , Paz-Ares Luis 
Published: March 2020

4550 Background: Pemetrexed (P) plus cisplatin (C) combination is effective against several malignant tumors. Single-agent P has shown antitumor activity in advanced urothelial cancer; we performed a phase I/II study to define the maximum tolerated dose of biweekly P plus C combination. Here, we report the final results of the phase II study. Methods: Eligible patients (pts) had locally advanced or metastatic transitional cell carcinoma of the urothelium not suitable for curative therapy, performance status (PS) 0-2, estimated life expectancy of at least 12 weeks, and adequate organ function. P and C were administered on days 1 and 15 of each 28-day cycle, up to a maximum of 6 cycles. Pts received the recommended dose from phase I, with P at 400 mg/m2 plus C at 50 mg/m2 (folic acid and vitamin B12 supplementation were also administered). Primary objective was overall response rate (ORR) according to RECIST 1.0. Results: Thirty-eight pts were recruited, 32 (84.2%) pts had bladder cancer with a mean diagnosis time of 1 (range 0-7) year and 30 (78.9%) had metastatic disease; 19 (50%) pts had visceral metastasis and 2 (5.3%) pts had a PS 2. Only 2 pts did receive adjuvant systemic therapy. Median number of cycles was 3 (range 0-7). Twelve (31.6%) pts discontinued the study treatment due to toxicity. The most common treatment-related AEs (> 20%) were asthenia (n=27 pts), nausea and vomiting (n=21, respectively), diarrhea (n=18), anorexia (n=17), mucosal inflammation (n=14), and constipation (n=8). Most treatment-related AEs were of mild or moderate severity. Neutropenia (n=5) and asthenia (n=3) were the most frequent Grade 3 or 4 treatment-related AEs. Serious related AEs were observed in 8 (21.1%) pts. ORR was 39.5% (95% CI 24.0-56.6): 2 (5.3%) pts achieved complete response and 13 (34.2%) pts, partial response. Median progression free survival was 6.7 months, and median overall survival was 10.5 months. Conclusions: In this study, biweekly P (400 mg/m2) plus C (50 mg/m2) combination showed anti-tumor activity in pts with advanced urothelial cancer, with an acceptable safety profile. Clinical trial information: NCT00374868.
Patterns of chemotherapy and survival in elderly patients with advanced bladder cancer: A large Medicare database study.
Authors: Chen Guoqing J. , Galsky Matt D. , Latini David M. , Sonpavde Guru 
Published: March 2020

4551 Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients (≥66 years) presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use of and overall survival (OS) with chemotherapy regimens employed in elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4bN0M0; Any TN1–N3M0; Any T, Any N, M1 between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between chemotherapy regimen, clinical characteristics and OS. Results: A total of 1,031 patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 4.6% (n=47) were T4bN0M0, 55.3% (n=570) were anyT,N1-3M0 and 40.1% (n=414) were any T, any N, M1. Overall, 20.5% (n=211) received cisplatin, 26.1% (n=269) received carboplatin, 5% (n=52) received no platinum and 48.4% (n=499) received no chemotherapy. There were no differences in regimen according to gender, race, stage and age. The median OS for cisplatin, carboplatin, no platinum and no chemotherapy groups were 1.67, 1.41, 1.5 and 1.41 years, respectively (F=5.36, p<0.001). Patients with Any TN1–N3M0; Any T, Any N, M1 receiving cisplatin had better OS compared to carboplatin. T4bN0M0 patients receiving carboplatin exhibited better OS relative to those receiving cisplatin, but this finding is limited by the small number of patients. Conclusions: Among patients presenting with ABC in the Medicare database aged ≥66 years, only 20.5% received cisplatin and 48.4% received no chemotherapy. Those with distant and nodal metastasis displayed better OS with cisplatin. Further analysis will control for baseline prognostic factors and comorbidities. Drug development in the ABC population, especially the elderly, should focus on chemotherapy-ineligible and cisplatin-ineligible patients.
Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in patients with non-seminomatous testicular germ cell tumors.
Authors: Mendoza Julia , Martinez-Cedillo Jorge , Hernández Carlos Alberto , Pérez-Montiel Delia , Castro Clementina , Fabián-Morales Eunice , Santibañez Miguel , González-Barrios Rodrigo , Díaz-Chávez José , Andonegui Marco Alonso , Onate-Ocana Luis F. , Jimenez Miguel , Reynoso Nancy , Núñez Marlene , Dyer Richard , Herrera Luis A. 
Published: March 2020

4555 Background: Cisplatin-based chemotherapy cures over 80% of testicular germ cell tumors (TGCTs); nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. In this work we explored the association between NER-proteins and their polymorphisms (SNPs) with cisplatin-sensitivity (CPS) and overall survival (OS) of patients with advanced non-seminomatous (ns)-TGCTs treated with bleomycin-etoposide-cisplatin (BEP). Methods: ERCC1, XPA-expression and gammaH2AX-presence, were tested in cisplatin-treated cancer cell lines. ERCC1 and XPA-expression were also analyzed in ns-TGCTs by qPCR. Immunohistochemistry was performed to detect ERCC1 protein in ns-TGCTs specimens. The SNPs were genotyped by PCR-RFLPs technique. Results: High basal ERCC1-expression was observed in non-CPS cancer cell lines; ERCC1-expression augmented further, as well as gammaH2AX, after cisplatin-treatment. Basal ERCC1 expression increases in the non-CPS patients in Mexican and Peruvian populations compared to CPS patients (p<0.001; p=0.002). XPAexpression levels weren’t different. These polymorphisms weren’t associated with CPS or OS. ERCC1-positive immunostaining was observed in 30/108 patients (27.8%). From 76 patients that were CPS, 59 (77.6%) were ERCC1-negative, compared with 17 (22.4%) that were ERCC1-positive (p=0.05). 5-year OS probability was smaller for those patients ERCC1-positive and non-CPS (15.38%) than tumor ERCC1-negative and CPS (89.3%) (p<0.001). Using the Cox Model, adjusted on the prognosis groups, the hazard ratio (HR) of death in patients with ERCC1-negative and non-CPS was >14.43 and in patients ERCC1-positive and non-CPS the HR was >11.86 (p<0.001). Conclusions: High-levels of ERCC1-expression and ERCC1-protein are associated with non-CPS, suggesting the use of ERCC1 as a potential indicator of response to cisplatin-based chemotherapy and the prognosis in patients with ns-TGCTs. Moreover, it’s important to identify patients potentially non-CPS in order to diminish the toxicity of cisplatin and improved quality of life avoiding adverse effects due to this agent. Work supported by CONACYT 83959 and PAPIIT IN213311-3.
Expression profiling of peripheral blood (PB) enriched for circulating tumor cells (CTCs) in testicular germ cell tumors (TGCTs).
Authors: Mego Michal , Gronesova Paulina , Miskovska Vera , Obertova Jana , Palacka Patrik , Rajec Jan , Sycova-Mila Zuzana , Vertakova-Krakovska Bibiana , Chovanec Michal , Janega Pavol , Svetlovska Daniela , Usakova Vanda , Bujdak Peter , Spanik Stanislav , Ondrus Dalibor , Mardiak Jozef 
Published: March 2020

4556 Background: CTCs are prognostic in several types of tumors and are easily accessible for repeat examination. TGCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. We investigated expression profiling of PB enriched for CTCs in TGCTs aimed to identify expression signature associated with treatment resistance. Methods: This prospective study included 30 patients (pt) treated with first line (27 pt) or salvage (3 pt) chemotherapy. CD45- peripheral mononuclear cells (PBMCs) were isolated from 10mL of PB on day 1 and on day 22 of first cycle of chemotherapy. Isolated PBMC were depleted of cells of hematopoietic origin (CD45+) using RossetteSep kit negative selection with anti-CD45 antibody. CD45-depleted PBMC represent compartment enriched for CTCs, as showed previously. RNA was extracted from CD45-PBMCs and the expression profiles were obtained using Roche NimbleGen microarrays. Data analysis was processed in R using a limma package followed by GO analysis and MetaCore pathway analysis. Results: Six patients achieved unfavorable response to chemotherapy (other than CR or PR with negative serum markers). We identified 1,506 and 211 genes that were expressed at significantly different levels (FDR<0.05) on day 1 and day 22 of chemotherapy, respectively, with 108 overlapping genes. Cluster analysis using principal component analysis showed, that 5 of 6 samples from patients with unfavourable response to chemotherapy form clearly defined cluster opposed to samples from patients with favourable response. Based on pretreatment expression profiling using MetaCore pathway analysis software, we further identified 758 genes, belonging to several critical functional groups such as immune response, signal transduction, cell proliferation, cell cycle progression, or apoptosis, to be significantly differentially expressed in patients with favourable vs. unfavourable response. Conclusions: Our data suggests that expression profiling of PB enriched for CTCs in TGCTs is feasible, and show great promise in identifying new therapeutic targets and gene expression signature associated with treatment resistance.
Smoking history and disease outcomes in patients with malignant germ cell tumors.
Authors: O'Donnell Elizabeth , Gray Kathryn P. , Hirsch Michelle S. , Kantoff Philip W. , Beard Clair , Sweeney Christopher 
Published: March 2020

4561 Background: In 2011, of 8260 cases of Germ Cell Tumor (GCT) in the US, about 350 (4%) died of disease. The impact of smoking on disease outcomes of relapse and death is unknown. Methods: Retrospective review of 891 GCT pts treated at Dana-Farber Cancer Institute (DFCI) between 1997 and 2010 was conducted. Inclusion criteria were men age>18 yrs treated for GCT with a quantified smoking history in an electronic medical record. The outcomes of interest were relapse after first-line chemotherapy and death from the disease. A Chi-square or Fisher’s exact test assessed the association of the disease outcomes and the smoking history (heavy smoker vs. less), and a Wilcoxon test for ordered categories assessed the association of the outcomes with the IGCCCG risk groups (good, intermediate, and poor), stratified by histology (seminoma vs non-seminoma (NS)). Results: 327 men with metastatic disease were identified. Median age was 31.5 years. 47(14%) had a history of smoking >10 pack-years (pyrs). Of the 256 NSGCT pts with metastases at time of chemotherapy, pts who smoked >10 pyrs constituted 27% of the 64 relapses vs. 11% of the 192 non-relapses (Odds Ratio (OR) 2.9, p=0.003). Of the 71 metastatic seminoma pts, 40% of the 10 relapses had smoked >10 pyrs compared with 8% of the 61 pts who did not relapse (OR 7.5, p=0.01). Smoking >10 pyrs was associated with (i) higher IGCCCG risk at time of metastatic disease [24% of poor-risk pts had a >10 pyr history compared with 12% who had good-risk or 19% who had intermediate-risk (p=0.01)] and (ii) higher staging at initial diagnosis, 23% of poor-risk pts were heavy smokers compared with 9% who were CS1 and 12% good-risk (p=0.002). Of the 50 pts who died of metastatic disease, 36% had smoked >10 pyrs compared to 9% who were cured, Pts who smoked >10 pyrs had significantly increased odds of death compared to those who smoked 0-10 pyrs (OR=5.5, p <0.0001). 3 out of 30 pts who smoked >10 pyrs received suboptimal bleomycin, and only 1 relapsed. Conclusions: Greater than 10 pack-year smoking history is a modifiable risk factor associated with a higher IGCCCG risk at diagnosis of metastatic disease, higher risk of relapse after 1st-line chemotherapy and higher risk of death from germ cell tumor.
A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients: Updated phase I results of the Disruptor-1 trial.
Authors: Sarantopoulos John , Dang Long H. , Lauer Richard C. , Starodub Alexander , Hauke Ralph J. , Galsky Matt D. , Bylow Kathryn A. , Cowey Charles Lance , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Lavranos Tina C. , Iglesias Jose Luis , Sonpavde Guru , Logan Theodore , Hahn Noah M. , Sweeney Christopher , Hutson Thomas E. ,   Hoosier Oncology Group
Published: March 2020

4563 Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Biomarker samples (pre- and post-dose during Cycle 1) were analyzed for 70 plasma analytes including VEGF, PDGF and other markers associated with angiogenesis and vascular responses. Results: Updated results from the completed phase I component confirm the BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single Grade 3 events of anemia and pericardial effusion. Grade 2 events of fatigue, anemia and oral mucositis were also observed. Eight of the 12 phase I subjects achieved disease stabilization. Across all subjects a median of 6 cycles (range: 1-24) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: Full dose BNC105P (16 mg/m2) can be combined with full dose everolimus (10 mg) and is being further evaluated in a randomized phase II study. Clinical trial information: NCT01034631.