bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of warfarin on the risk of prostate cancer
Authors: Tagalakis V. , Tamim H. , Collet J. , Kahn S. R. , Blostein M. , Hanley J. A. 
Published: March 2020

14524 Background: The anticancer activity of oral anticoagulants has been a matter of debate for several years. Recent evidence suggests that prolonged treatment with warfarin may be associated with a reduced incidence of newly diagnosed urogenital cancer during long-term follow-up of patients with venous thromboembolism. The aim of this study was to assess whether exposure to warfarin was associated with reduced risk of prostate cancer in a large population-based cohort. Methods: We conducted a matched case-control study nested within the population of beneficiaries of the Saskatchewan Prescription Drug Plan aged 50 years and older from 1981–2002 with no history of cancer since 1967. New cases of prostate cancer diagnosed between 1981 and 2002 were identified using the linked Saskatchewan Cancer Agency registry. Six controls per case matched on age, gender, and sampling time were randomly selected. The cumulative exposure to warfarin in the five years preceding the cancer diagnosis was assessed. Prescription counts were used to define warfarin exposure. Exposure in the year immediately preceding the cancer diagnosis was excluded to control for detection bias. Conditional logistic regression analysis was used to assess confounding by other drugs such as nonsteroidal anti-inflammatory medications. Results: Among 11502 cases and 69012 controls, 7.4% of cases and 7.1% of controls had a history of any warfarin use. Compared to men who had never used warfarin, adjusted odds ratio (OR) for prostate cancer among ever-users in the 5 year period was 0.94 (95% confidence interval (CI), 0.86–1.03). In those who accumulated 1, 2, 3 and 4 years of warfarin use, the adjusted ORs were 1.01 (95% CI, 0.89–1.16), 1.00 (95% CI, 0.82–1.23), 0.81 (95% CI, 0.60–1.09), and 0.80 (95% CI, 0.65–0.99), respectively (p-trend=0.03). Conclusion: Our results suggest that cumulative use of warfarin of at least 4 years may be associated with a reduced risk of prostate cancer. However, confounding by other determinants of prostate cancer associated with warfarin use is possible. Nonetheless, confirmation of these findings by prospective studies may provide the evidence necessary to consider the use of warfarin in prostate cancer prevention. No significant financial relationships to disclose.
A phase II study of biweekly docetaxel and vinorelbine for hormone-refractory prostate cancer (HRPC)
Authors: Vázquez Estévez S. , Mel Lorenzo J. , Álvarez Gómez E. , Quintero Aldana G. 
Published: March 2020

14529 Background: Docetaxel is active in HRPC alone, with prednisone, and with estramustine. We evaluated the efficacy and toxicity of its combination with vinorelbine, another active drug in HPRC. Methods: Patients with metastatic HRPC, no praevious chemotherapy, ECOG PS=0–2 and adequate organ function were included. Docetaxel was administered at 40 mg/m2 and vinorelbine at 20 mg/m2 days 1 and 14. Cycles were repeated every 28 days until disease progression, occurrence of unacceptable toxicity or voluntary withdrawal. A maximum of 6 cycles was allowed. Results: A total of 25 patients were included, with median age73 years (61–81) and ECOG PS 0–1 in 96% of patients. Median number of metastatic lesion was 1 (84% of patients), located in bone (96%), lymph nodes (12%), pleural effusion (4%) and liver (4%). A total of 128 cycles (median 5, range 2–9) and 243 infusions (median 10, range 4–17) were administered. Median relative dose intensity for both drugs was 91.68%. Toxicity: Grade III/IV hematologic toxicity per patient was neutropenia (48%) and anemia (4%). Febrile neutropenia was observed in 2 patients. Grade III/IV non-hematologic toxicity per patient was asthenia (8%), diarrhea (4%) and constipation (4%). There were no toxic deaths. Efficacy: Of 22 evaluable patients (3 have just begun chemotherapy), 1 achieved CR, 12 PR, 5 SD and 4 progressed (PSA response), resulting in an ORR of 59% (95% CI: 38.5–79.6%). Median TTP were 340 days (95% CI: 274.47–405.53). Median OS has not been achieved. Mean OS was 765.8 days (95% CI: 590.84–940.76). Conclusions: Biweekly docetaxel and vinorelbine is an active and feasible regimen in HRPC. No significant financial relationships to disclose.
MDX-070, a human anti-plasma antibody, administered as either a single dose or as multiple doses to patients with hormone-refractory prostate cancer
Authors: Mays T. A. , Sarantopoulos J. , Tolcher A. , Lowy I. , Preston G. , Levy E. , Oslund M. D. , Manchen E. , Kelly A. , Stadler W. M. 
Published: March 2020

14549 Background: Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is specifically expressed in prostatic epithelial cells and up-regulated in hormone refractory prostate cancer (HRPC). MDX-070 is a HuMAb that recognizes conformational epitopes on PSMA, mediates anti-body-dependent cellular cytotoxicity (ADCC), and is internalized. The primary objective of these studies was to establish the safety and tolerability and maximum tolerated dose (MTD) of MDX070 in patients (pts) with HRPC. Secondary objectives included characterization of the pharmacokinetic (PK) profile and a preliminary assessment of clinical antitumor activity measured by PSA levels and scans. Methods: MDX070 was administered intravenously over 90 minutes to pts with HRPC as either a single dose (Protocol MDX070–01) at dose levels of 0.1 (3 pts), 0.5 (3 pts), 1 (3 pts), 5 (3 pts), or 10 (6 pts) mg/kg/dose or every two weeks for up to 4 doses (Protocol MDX070–02) at dose levels of 1 (9 pts), 5 (6 pts), and 10 (15 pts) mg/kg/dose. Pts with stable disease or better at the end of the treatment period could receive additional treatment cycles until progression in a companion protocol (MDX070–03). Results: There were no Grade 4 toxicities judged to be related to MDX070 administration. One patient experienced Grade 3 anorexia that was possibly drug-related (5 mg/kg). Grade 1 or 2 toxicities (reported in 35 pts in the clinical database- 18 in 01, and 17 in 02) deemed to be related to MDX070 included anorexia (2), fatigue (3), fever (4), nausea (3) and vomiting (2). No significant differences in toxicity were seen between dose groups. No >50% decline in PSA or response according to RECIST criteria occurred in any of the dosing cohorts, but 6 patients had stable disease and received 1 or more additional cycles of treatment at the same dose. Conclusions: MDX-070 as monotherapy, at the dose levels administered, was safe and well tolerated. No objective antitumor activity was observed at the dose levels tested, however, 20% (6/30) had stable disease. Enrollment is continuing at the 10 mg/kg multi-dose cohort. PK analysis is ongoing. [Table: see text]
Phase I study of gemcitabine and cisplatin followed by pemetrexed and gemcitabine in patients with metastatic transitional cell carcinoma of the urothelium: Preliminary results
Authors: Hutson T. E. , Vukelja S. , Nicol S. , Hood K. E. , Delgado A. , Ilegbodu D. , Berry W. R. 
Published: March 2020

14550 Background: Pemetrexed has activity as a single agent and combined with gemcitabine (G) in platinum refractory metastatic urothelial cancer. The tolerability and activity of this new multi-targeted antifolate combined with standard platinum-based therapy is unknown. This Phase I multicenter trial was conducted in patients (pts) with metastatic TCC to determine the maximum tolerated dose (MTD) of G and cisplatin (C) followed by pemetrexed (P) and G. Methods: Cohorts of 3 to 6 pts were treated with escalating doses of G+C followed by P+G: Dose Level 0 -G+C (800+60 mg/m2) Day 1 and P+G (400+800 mg/m2) on Day 15; Dose Level I -G+C (800+70 mg/m2)/P+G (400+800 mg/m2); Dose Level II -G+C (1000+70 mg/m2)/P+G (400+1000 mg/m2); Dose Level III -G+C (1000+70 mg/m2)/P+G (500+1000 mg/m2) in a 28-day cycle. Pts received a maximum of 6 cycles of therapy; and all pts received folic acid and vitamin B12 supplements. The 3+3 standard Phase I escalation rule was used to establish the MTD. Results: A total of 10 pts have registered, 1 pt received only 1 dose and was replaced, and 9 have been treated: 3 at Dose Level 0 and 6 at Dose Level I. Of these 10 pts, 40% had Karnofsky PS of 100, and the median age was 68 years (range 58–82). One pt had a confirmed CR after 2 cycles, 1 pt at Dose Level I had a PR and received all 6 cycles, 6 pts did not finish treatment (4 pts due to toxicity and 2 pts due to PD), 1 pt at Dose Level I is continuing on therapy. Dose-limiting toxicity occurred in 2 pts at Dose Level I and included Grade 3–4 febrile neutropenia, pulmonary embolism, and diarrhea. The MTD of this triplet is Dose Level I, and the recommended Phase II dose (RP2D) is Dose Level 0. Patient accrual is continuing to further define toxicity at the RP2D. Conclusion: The addition of pemetrexed to standard gemcitabine and cisplatin as initial therapy for metastatic urothelial cancer is feasible. Toxicity of this triplet has been moderate. A Phase II trial is planned to determine the response rate, duration of response, TTP, time to treatment failure, and survival. Supported by Eli Lilly and Company, Indianapolis, IN [Table: see text]
TGFBR3 is lost in prostate cancer, contributing to malignant transformation
Authors: Sharifi N. , Hurt E. , Farrar W. L. 
Published: March 2020

14552 Background: Resistance to transforming growth factor-beta (TGF-beta) is common in solid tumors. Alterations of TGF-beta biology in prostate cancer are complex, with a downregulation of this cytokine reported in early disease and upregulation of TGF-beta in advanced disease. Mechanisms of TGF-beta resistance in early disease are not well understood. We have investigated the function of TGF-beta receptor 3 (TGFBR3) to determine its role in prostate cancer. Methods: We undertook an analysis of the data in seven published DNA microarray studies of nonneoplastic prostate tissue versus prostate cancer specimens using oncomine. Of the genes we identified as known to be directly involved in the TGF-beta pathway, loss of TGFBR3 was most significantly associated with prostate cancer. We determined TGFBR3 expression in prostate cancer cell lines and the immortalized prostate epithelial cell line RWPE-1. To assess the consequences of loss of TGFBR3 expression, we created an shRNA construct and stably infected RWPE-1 cells. We analyzed gene expression changes by DNA microarray analysis and confirmed changes by Western Blot. We then searched TGFBR3 regulated genes based on our knockdown studies in the data set from the seven previously published studies. Furthermore, we evaluated the phenotypic consequences of TGFBR3 knockdown. Results: TGFBR3 expression was significantly lost in 6 of 7 microarray studies. TGFBR3 was downregulated in 3 of 4 of prostate cancer cell lines, compared with RWPE-1. DNA microarray analysis of TGFBR3 knockdown in RWPE-1 cells showed that expression of DPYSL3, Vimentin, COCH, SERPINF1, PMP22, LTBP1 and BMP4 were decreased both with TGFBR3 knockdown and in the transition to prostate cancer. Of these genes, vimentin expression was most dramatically downregulated in TGFBR3 knockdown cells and we showed that vimentin protein expression was completely lost. The phenotypic consequence of TGFBR3 knockdown in RWPE-1 cells was formation of colonies that appear to reflect loss of contact inhibition. Conclusions: TGFBR3 is lost in prostate cancer. TGFBR3 knockdown leads to colony formation by immortalized prostate epithelial cells. Our data suggests that loss of TGFBR3 contributes to malignant transformation of the prostate. No significant financial relationships to disclose.
A dose and schedule optimizing evaluation of MG98 given as either a 2 hour IV infusion twice weekly or as a 7 day continuous infusion in combination with interferon alpha (INF) in nephrectomized patients (pts) with advanced renal cell carcinoma (RCC)
Authors: Stephenson J. , Amato R. J. , Hotte S. , Nemunaitis J. , Berman B. , Bélanger K. , Patterson T. A. , Macleod A. R. , Reid G. K. , Martell R. E. 
Published: March 2020

14557 Background: RCC is often associated with hypermethylated and silenced tumour suppressor genes. The enzyme DNMT1 is responsible for the majority of cellular DNA methylating capacity. MG98 is a second generation antisense inhibitor of DNMT1 which has been shown to reduce DNMT1 mRNA and protein. Methods: A trial of MG98 given as a 2 hour IV infusion twice weekly (Intermittent Schedule, IS) or as a 7 day continuous infusion (CI) in combination with INF has been conducted with nephrectomized pts with advanced RCC. Main endpoints: identification of the optimum regimen, safety, tolerability, pharmacokinetics (PK) and the degree of PBL DNMT1 mRNA suppression. Results: CI schedule: dose levels of 125mg of MG98 combined with 12 MIU of INF (125/12) and 125/9 have been evaluated (9 pts). The MTD has been reached; thrombocytopenia is dose limiting at 125/12. Pt demographics: M:F= 6:3, mean age of 63.2y (52–71). Most common Adverse Events (AEs): fever and chills (gr.1), fatigue (gr.1–2; 100% of pts), nausea and anorexia (gr.1–2), vomiting (gr.2; 66%). Best response: Stable Disease (SD) =3; Partial Response (PR) =1. Currently within the IS schedule, 3 dose levels (9 pts) have been evaluated: 160/12, 200/12 and 200/9, totaling 26 cycles. The MTD has been reached, with GI/constitutional symptoms being dose limiting at 200/12. Demographics: M:F= 7:2 median age 59.8y (40–76). Most common AEs in the first 3 pts are nausea and chills (100% of patients); fatigue (gr.1–2) and fever (66%; gr. 1–3). Best responses: 3 SD, 1 PR. PK evaluation on both schedules revealed no interaction between INF and MG98. DNMT1 inhibition data will be presented. Conclusions: Combination of INF and MG98 exhibits clinical activity and acceptable safety. [Table: see text]
A phase II study of paclitaxel and vinorelbine (Pacl-Vin) in hormone-refractory metastatic prostate cancer (HRPC): Double tubulin targeting
Authors: Sewak S. , Kosmider S. , Ganju V. , Woollett A. , Le B. , Yeow E. , Henry M. , Bell R. 
Published: March 2020

14559 Background: Phase 2 trials of Paclitaxel+corticosteroid or Vinorelbine+corticosteroid have shown 20–40% PSA responses. Preclinical models have shown synergy between Paclitaxel and Vinorelbine. A phase I trial showed this to be a tolerable combination. Methods: The aim of this study was to determine the efficacy and safety of Paclitaxel and Vinorelbine. 30 castrate pts with progressive, metastatic prostate cancer were enrolled. Previous radiotherapy, strontium therapy, 1 line of chemotherapy, and concurrent bisphosphonate therapy were allowed. Pts were treated with Paclitaxel 40 mg/m2 (1 hr), and Vinorelbine 20 mg/m2 iv on day-1 & day-8 of a 21-day cycle. All pts received standard premedication for Paclitaxel including dexamethasone. Results: Baseline pt characteristics were: median ECOG PS of 1 (range 0–2), median age 71, mean PSA 413ng/mL, mean Hb 11.9 g/dL. For 10 pts with measurable disease the partial response rate was 20%, with 70% of pts achieving stable disease (SD). Of 23 assessable pts, 9% had 50% decline in PSA, and 78% had SD, maintained for at least 4 weeks. Median overall survival was 7.3 months. Median progression free survival was 3.3 months. All pts completed quality of life (QOL) questionnaires. There was an improvement over baseline after 3 cycles of therapy in pts pain, appetite, constipation, voiding and overall wellbeing (p = non-significant). Grade 3/4 toxicities were: anemia 3%, neutropenia 8%, infection 2%, febrile neutropenia 4%, lethargy 1%, and somnolescence 1%. 1 pt died as a result of sepsis and neutropenia. Conclusions: In this poor prognostic cohort of pts the combination of Paclitaxel and Vinorelbine is a tolerable regimen, which has demonstrated minor PSA response, with the majority of pts achieving PSA stability. There was some objective response to this regimen and importantly it stabilized disease in a majority of pts. Important QOL parameters such as pain were improved.This is a useful regimen to test in poor prognosis HRPC pts. No significant financial relationships to disclose.
Thoracic surgery of residual masses after first-line chemotherapy in patients with testicular (T) or primary retroperitoneal (PR) non seminomatous germ cell tumors (NSGCT)
Authors: Flechon A. , Noel N. , Rivoire M. , Mithieux F. , Droz J. 
Published: March 2020

14563 Background: Exeresis of all post-chemotherapy residual masses is the standard initial treatment of T and PR NSGCT patients. The aim of the study was to analyse the surgical procedure of thoracic exeresis of residual masses in patients receiving chemotherapy in a single cancer center. Methods: We reviewed the clinical, surgical and histological charts of 143 T or RP NSGCT patients operated on between 01/01/93 and 31/12/2003. All patients had initially at least one thoracic site (lung metastases and/or mediastinal lymph node involvement). We reviewed the indications for surgery according to the size, number of lung metastases and localization of mediastinal lymph nodes. Outcome criteria were relative risk (RR) of relapse and death. Median time of follow-up was 41 months (range 4–140). Results: After first-line chemotherapy, 43 patients (30%) obtained a thoracic complete response, and 100 had thoracic residual masses (70 PR markers -, 24 PR markers +, 2 SD, 4 PD).Thoracic surgery was performed in 32 patients (25 RP-, 4 RP+, 2 SD, 1 PD) by 14 different surgeons. Among these 32 patients, 26 had less than 10 pulmonary lesions, and 14 had only one. Wedge resections were performed in the majority of cases. The histological pattern was necrosis and/or fibrosis in 13 patients, teratoma in 11, growing teratoma in 4, active disease in 3 and nodular sarcoidosis in 1 patient. Six of the 32 operated patients relapsed (one of them in the thorax): 4 died of disease, 2 are alive with evolutive disease (AWD); all others are alive with no evidence of disease (NED). Sixteen of the 68 not operated patients died of disease and 2 of other cancers, 4 are AWD; all others (46) have NED. Five of the 43 patients with thoracic CR died of disease; all others (38) have NED. Patients not operated on for residual thoracic disease had respectively 1.6 and 2 RR of relapse and death when compared to patients with surgical exeresis of residual thoracic disease. Conclusions: Thoracic surgery is an important part of the management of patients with post-chemotherapy residual NSGCT masses in the thorax. No significant financial relationships to disclose.
22 year phase 1/2 study of single agent carboplatin in metastatic seminoma: Potential for acceleration by a new surrogate end point, 72 hr PET scan response?
Authors: Oliver R. , Powles T. , Ell P. , Somasundram U. , Shamash J. 
Published: March 2020

14565 Background: That metastatic seminoma may be more chemo-curable than non-seminoma was first suggested by Samuels (1980 Proc ASCO 21 abst 415) 4 of 5 patients durable CR to single agent cisplatin and by Oliver (1984 Proc ASCO 3. Abst 636) 9 of 10 durable responses. Carboplatin proved less effective and in randomised trials involving 361 patients relapse free survival was 72% with Carbo and 92% with cisplatin-based combination. Prompted by successful dose escalation of carboplatin in ovarian cancer, the initial phase 1 study that preceded the UK randomised trial was reopened and dosage escalated to AUC 8 and then 10. This abstract updates this study and provides more prolonged follow up of the previous reported cases. Methods: Initially patients received Carboplatin 450 mg/m2 (1983–7) and then AUC 7 (88–94), 8 (95–6) and 10 (97–06). The treatment was repeated q21 when possible and if delayed because of toxicity blood counts were repeated every 24 hours. Results: 60 metastatic seminoma patients have been treated between 1983 and 2006. 79%/95% of 19 receiving 450 mg/m2, 88%/94% of 17 receiving AUC 7 or 8 and 92%/100% of 24 receiving AUC 10 are progression free/alive. Overall 58 (97%) are alive and with 28 patients followed more than 10 years there have been no relapses after 26 months. Mild and rapidly recovering (med 14 d) transaminitis in 64% of AUC × 10 (med 93 range 51–541) suggests this may be the upper limit for safe use. As a pilot study 5 seminomas receiving AUC × 10 and 6 non-seminomas receiving BEP had PET scan before and at 72 hours after treatment. The only patient failing to respond substantially was a seminoma who showed increased PET activity on AUC × 10 but achieved complete remission of PET activity after one course of BEP. Conclusion: This data confirms the need for more studies of single agent platinum analogues in seminomas and reinforces the view that it may be preferable to radiotherapy for patients electing adjuvant treatment. With increasing attention being paid to late events, minimizing treatment toxicity and finding a fast track approach to proving safety is an increasing need. The data presented demonstrates the potential of early PET scan as a surrogate for response and could have accelerated the phase 1/2 study reported. No significant financial relationships to disclose.
A phase II trial of epirubicin (E), estramustine phosphate (EP), and celecoxib (C) as second line treatment of patients (pts) with hormone resistant prostate cancer (HRPC)
Authors: Zhong F. , Kasimis B. , Chang V. , Sambamoorthi N. , Srinivas S. , Cogswell J. , Morales E. , Gonzalez M. , Duque L. , Blumenfrucht M. 
Published: March 2020

14567 Background: Celecoxib, epirubicin, and estramustine phosphate affect prostate cancer cells through different mechanisms. All three could be synergistic. We studied the effects of this combination on PSA, response, toxicity and survival in pts with HRPC. Methods: Pts after progression from first line taxane-based chemotherapy with rising PSA and radiographic progression were eligible. Treatment was E30 mg/m2 iv on day 1 and 8 of each 4 week cycle; EP 280 mg po bid daily × 3 days every wk × 2 followed by 2 wks rest; C 400 mg po bid daily for 28 days. All pts were assessed for response every 2 cycles. Dose modifications for hematologic and hepatorenal toxicity were made. RECIST criteria and PSA decline>50% were used to define response. Results: Sixteen pts enrolled, and 13 are evaluable for toxicity and response. Two withdrew before treatment and one for toxicity. The Median (M) age was 71.5 yrs (59–87), ECOG PS 1 (0–1), Gleason score 7 (4–9), LDH 172 (131–244), Hgb 11.1 (8.8–11.9), PSA 75 (6–814). Pts received M 4 cycles (2–10). Nine (69%) pts had soft tissue and 12 (92%) pts had bone metastases. For radiographic response, 11 pts were evaluable; 6 had stable disease and 2 had complete response by CT. Two pts had response by bone scan. Nine (69%) pts had PSA response. The M survival was 441 days (10–995). There were 5 SAE - DVT, diarrhea, bowel obstruction, cord compression and myocardial infarction. There was good renal and cardiac tolerance. Conclusions: This combination was safe and showed good and durable response as a second line regimen. [Table: see text]