bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of mammalian target of rapamycin (mTOR) inhibitor RAD001 plus imatinib mesylate (IM) in patients with previously treated advanced renal carcinoma (RCC)
Authors: Chan J. S. , Vuky J. , Besaw L. A. , Beer T. M. , Ryan C. W. 
Published: March 2020

15600 Background: The serine-threonine kinase mTOR is a valid target for RCC therapy with temsirolimus treatment resulting in improved overall survival in poor-risk patients (Hudes G et al., ASCO 2006). RAD001 is an oral inhibitor of mTOR which has demonstrated activity in RCC at 10mg/day (Amato R et al., ASCO 2006). IM is a tyrosine kinase inhibitor (TKI) of platelet-derived growth factor receptor (PDGFR), a target that may promote angiogenesis and growth of RCC. Combined mTOR and PDGFR inhibition with RAD001 and IM may achieve vertical blockade through the PI3K/AKT pathway. Methods: Eligibility: metastatic clear cell RCC, performance status (PS) 0–2, adequate organ function, and prior treatment with = 1 systemic therapy. Doses were based on a phase I study of the combination in GIST (Van Oosterom AT et al., ASCO 2005): RAD001 2.5 mg p.o. daily and IM 600 mg p.o. daily. Patients were reimaged every 6 weeks. This is a 2-stage phase II study to determine the 3-month progression-free rate. Results: 14 pts have been enrolled. Median age 66 years (51–79). 6 pts PS 0 and 8 pts PS 1. Median number of prior therapies 1.5 (1–4). 12 of 14 patients had prior TKI therapy. Prior therapies included sorafenib (11 pts), interferon (7), sunitinib (3), bevacizumab (2), erlotinib (1), panitumumab (1), high-dose IL-2 (1). Of 10 pts evaluable for the primary endpoint, 3 are progression-free = 3 months. Best response for 9 pts evaluable by RECIST: PR/CR 0, SD 7, PD 2. Most common adverse events in 11 evaluable patients include nausea (8), edema (7), increased creatinine (7), fatigue (7), transaminase elevation (6), thrombocytopenia (5), leukopenia (5), cough (5), diarrhea (5). Grade 3 adverse events include fatigue (3), LE edema, rash, pleural effusion, increased creatinine, abdominal pain, and thrombocytopenia (1 each). There were no grade 4 toxicities. Unique suspected RAD001 toxicities include grade 3 pneumonitis (1) and angioedema (1). Conclusions: The combination of RAD001 and IM has moderate toxicity. This is one of the first studies in RCC patients predominantly pretreated with a TKI. 3 month progression-free rate appears to be a clinically relevant endpoint in this population. [Table: see text]
Erlotinib has activity in androgen-independent prostate cancer (AIPC) patients who are chemotherapy-naive: A phase II trial
Authors: Nabhan C. , Tolzien K. , Newman S. , Kelby S. , Lestingi T. , Galvez A. , Bitran J. D. 
Published: March 2020

15606 Background: Mechanisms of hormone resistance for AIPC are variable. One proposed mechanism is the over expression of the epidermal growth factor receptor (EGFR) which in turn stimulates proliferation through its pathway. We aimed to determine the efficacy of an oral anti-EGFR inhibitor (erlotinib) in this patient population that was chemotherapy-naive. The primary end point was to evaluate the overall clinical benefit defined as the sum of complete response (CR), partial response (PR), and stable disease (SD). Methods: Between January and December 2006, sixteen patients were enrolled onto this phase II study. Median age was 78 years (66–85). Median PSA was 61.9 (9.2–800.2). Median time from initial diagnosis until starting Erlotinib was 7.8 years. Erlotinib was given daily at 150 mg until disease progression. Patients were evaluated every 2 weeks for toxicity. Response assessment took place every 2 cycles (each cycle was 4 weeks). Evaluations included computed tomography of measurable disease areas, bone scans, and serum PSAs. Patients who progressed radiographically but maintained a PSA response or those who progressed biochemically but maintained a radiographic response were considered stable and were allowed to continue on study. Results: Sixteen patients were enrolled with 14 being evaluable at this time (2 patients are early in their course). Median cycles received is 2 (range 1.5–12). One patient achieved a PR and continues on Erlotinib after one year of enrollment. Three patients demonstrated stable disease but two of them later progressed. One patient withdrew after 9 days of starting therapy due to fatigue and poor taste. All other patients developed disease progression after two cycles of therapy. The calculated overall clinical benefit was 28% (4 responses out of 14 patients). One patient died from pneumonia and seizures unrelated to Erlotinib as confirmed by an autopsy that showed progression in the central nervous system. Erlotinib was well-tolerated with skin rash and diarrhea being the most common toxicities. Conclusions: Erlotinib has clinical activity as a single agent in AIPC. Updated results of this ongoing study will be presented at the meeting. Further studies with this agent alone or in combination are warranted. No significant financial relationships to disclose.
Sorafenib treatment of clear-cell renal cell carcinoma (CCRCC) and colorectal carcinoma (CRC) cells: Differential effects on gene expression and cell death pathways
Authors: Vaziri S. A. , Al-Hazzouri A. , Grabowski D. R. , Ganapathi M. K. , Bukowski R. M. , Ganapathi R. 
Published: March 2020

15612 Background: The von Hippel Lindau gene (VHL) is often mutated in CCRCC and leads to loss of VHL protein (pVHL) expression. Sorafenib is a TKI with clinical activity in metastatic CCRCC. Studies to define mechanisms governing anti-tumor activity of this agent in CCRCC or CRC cell lines that express wild-type pVHL were conducted. Methods: We evaluated CAKI-1 (CCRCC) and HCT- 116/p53 +/+ (CRC) cell lines as model systems expressing wild-type pVHL. Cells were treated at 37°C in an atmosphere of normoxia (21% O2) or hypoxia (1% O2), 5% CO2 and the remainder N2 in the absence (control) or presence of sorafenib (2.5–20 μM) for 24–96 hours. Expression of target angiogenesis, apoptotic and anti-apoptotic genes was determined by real-time RT- PCR. Fluorescence microscopy following staining with Hoechst 33342 plus propidium iodide was used to analyze cell death by apoptosis and/or necrosis. Caspase-3 activity was measured using the target substrate DEVD-AFC. Results: In CAKI-1 and HCT-116 cells, exposure to 1% O2 relative to 21% O2, led to increased expression (2 to 6-fold) of angiogenesis (VEGF) and anti-apoptosis (TNFAIP3 & MCF2) genes. However, in an atmosphere of 1% O2 relative to 21% O2, a decreased (>2-fold) and increased (>3-fold) expression of the apoptotic (TNFRSF25) gene was observed in CAKI-1 cells and HCT-116 cells. Sorafenib treatment (7.5 μM) of CAKI-1 cells in 1% O2 led to a >3–4-fold decrease in expression of the VEGF and TNFAIP3 and a 3-fold increase TNFRSF25 genes. Following treatment with 10 μM sorafenib for 48h, cell death was >80% by necrosis in CAKI-1 cells and >95% by apoptosis in HCT-116 cells. Apoptotic cell death in the HCT-116 was also confirmed by increased caspase-3 activity in cell extracts following sorafenib treatment. Apoptotic cell death or necrotic cell death induced by sorafenib was unaffected by normoxia or hypoxia. Conclusions: In contrast to CCRCC cells, hypoxia led to upregulation of the apoptotic gene TNFRSF25 in the CRC cells. Anti- proliferative effects of sorafenib were primarily by necrosis in CCRCC cells and by apoptosis in CRC cells. No significant financial relationships to disclose.
The effect of surgical volume on the rate of secondary therapy after radical prostatectomy
Authors: Jeldres C. , Gallina A. , Walz J. , Fred S. , Perrotte P. , Valiquette L. , McCormack M. , Huland H. , Montorsi F. , Karakiewicz P. 
Published: March 2020

15620 Introduction and Objective: Some argue that prostate cancer (PCa) detection and treatment at a younger age may translate into higher rate of clinically insignificant PCa. We assessed the effect of patients age at diagnosis on the pathological stage at radical prostatectomy (RP). Methods: Clinical and pathological data were available for 11975 patients from 3 European and 3 North American tertiary care centers. All RPs were performed between 1987 and 2006. Univariable and multivariable logistic regression analyses addressed the effect of age at RP on the rate of extracapsular extension (ECE), seminal vesicle invasion (SVI) and lymph node invasion (LNI), after controlling for PSA, clinical stage, biopsy Gleason sum and year of surgery. Age at RP was coded as cubic spline to allow non-linear effects. Results: Mean age was 61.6 years (range 32–85) and mean PSA was 8.7 ng/mL (range 0.1–50.0). Biopsy Gleason sum was 2–6, 7 or 8–10 in 7510 (62.7%), 3656 (30.5%) and 809 (6.8%) patients, respectively. At RP, ECE, SVI and LNI were identified in 3383 (28.3%), 1309 (10.9%) and 469 (3.9%), respectively. In multivariable analyses, age was only an independent predictor of SVI (p<0.001). Older men had a higher rate of SVI. Conclusions: Pathological age only affects the rate of SVI. However, only one in ten men harbored SVI and this percentage may decrease even further with ongoing stage migration. Nonetheless, these data suggest that the removal of seminal vesicles should not be omitted in older men. No significant financial relationships to disclose.
Surveillance for stage I testicular seminoma: Retrospective analysis of prognostic factors for relapse at a single institution in Japan
Authors: Kakimoto K. , Ono Y. , Meguro N. , Kawashima A. , Kinouchi T. , Usami M. 
Published: March 2020

15630 Background: Treatment options for clinical stage I seminoma include adjuvant radiotherapy (RT) as well as surveillance and adjuvant chemotherapy. Although adjuvant RT remains the treatment of choice in most centers, the success of surveillance of patients with stage I nonseminomatous germ cell tumors and the establishment of curative chemotherapy for advanced disease have led to re-examination of the standard treatment approach. Data available from the surveillance and adjuvant RT series suggest that nearly 100% of patients with stage I testicular seminoma are cured, whichever approach is chosen. We report here results of a retrospective analysis of prognostic factors for stage I testicular seminoma. Methods: Between January 1980 and December 2004, surveillance was performed for 61 patients. Tumor characteristics (age at diagnosis, size, elevation of beta hCG level, invasion of the rete testis, vascular invasion, and lymphatic invasion) were examined as factors possibly predictive of relapse. Cause-specific survival rate was calculated using the Kaplan-Meier method. Results: With a median follow-up of 10.5 years (range, 2.35–20.8 years), 7 relapses were observed, with an actuarial 5- year relapse-free rate (RFR) of 89.2%. On univariate analysis, only tumor size (RFR: <8cm, 96%; =8cm, 76%; p=0.029) was predictive of relapse. Age at diagnosis (RFR: <36, 89%; =36, 91%), elevation of beta hCG level (RFR: 93% [normal] v 91% [elevated]), invasion of the rete testis (RFR:92% [absent] v 90% [present]), vascular invasion (RFR:89% [absent] v 86% [present]), and lymphatic invasion (RFR: 89% [absent] v 78% [present]) were not predictive of relapse. The overall relapse rate was 11.5%. Overall 5-year survival rate was 97%. Conclusions: Size of primary tumor was found to be predictive of relapse in patients with stage I seminoma managed with surveillance, on analysis at a single institution in Japan. No significant financial relationships to disclose.
Sunitinib malate is active and synergistic with cisplatin against human urothelial carcinoma in a preclinical model
Authors: Sonpavde G. , Jian W. , Lerner S. P. 
Published: March 2020

15632 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. Angiogenesis and plasma VEGF correlate with poor outcomes in human urothelial carcinoma. We designed a preclinical study to examine the efficacy of sunitinib malate alone and in combination with cisplatin against human urothelial carcinoma in vitro and in a murine xenograft model. Methods: The IC50 for sunitinib malate and cisplatin was determined separately against two human urothelial carcinoma cell lines (TCC-SUP and 5637). Sunitinib malate and cisplatin were also applied concurrently to determine activity of the combination. Immunohistochemical staining was performed to detect expression of VEGFR2 on the cell lines, and to measure modulation of this pathway by sunitinib by measuring phosphorylated (p)VEGFR2. Anti-tumor activity of sunitinib malate alone and in combination with cisplatin was determined in a murine xenograft model bearing 5,637 cells. Results: Both human urothelial carcinoma cell lines were found to express VEGFR2. Sunitinib malate displayed significant activity against both urothelial carcinoma cell lines in vitro at low nanomolar concentrations. Furthermore, sunitinib malate in combination with cisplatin was synergistic in vitro. We observed primarily cytostatic activity for sunitinib malate at both 20 mg/kg and 40 mg/kg orally once daily against a murine xenograft model bearing subcutaneous 5,637 cell tumors during 4 weeks of treatment. Anti-tumor activity of sunitinib malate in combination with cisplatin and correlative studies are being evaluated in the murine xenograft model. Conclusion: Sunitinib malate has anti-tumor activity against human urothelial carcinoma as a single agent and is synergistic in combination with cisplatin in vitro. Sunitinib also has significant efficacy in a murine xenograft model of human urothelial carcinoma. These results warrant further exploration of sunitinib malate as a single agent and in combination with cisplatin chemotherapy in human urothelial carcinoma. No significant financial relationships to disclose.
An analysis quantifies prostate brachytherapy swelling using peripheral seeds as fiducial reference points
Authors: Minehan K. J. , Groshek D. , McNamara K. , Mitchell E. , Emme M. , Price M. , Davis B. 
Published: March 2020

15639 Background: Permanent prostate brachytherapy (PPB) assesses implant quality but may suffer significant variability due to: 1) Prostate edema may occur during the procedure which usually subsides within several months, and 2) interobserver variability of CT- derived prostate volumes. An analysis is described, which uses the seeds as prostate fiducials to produce an implant reference volume (IRV). The ratio of the IRV volumes at day 0 and day 33 provides a unique way to quantify prostate edema; thus reducing this factor as a source of variability. Methods: Thirteen low risk prostate cancer patients, (Stage ≤ T2, PSA<13.9, Gleason Score ≤7) were implanted with 125Iodine seeds (77% stranded; prescription dose of 145 Gy). PPB was completed for each patient on day 0 and 33 ±3 days following the implant. The IRV was defined as the volume obtained by contouring the outer most peripheral seeds, circumferentially, on each axial image, resulting in a 3D volume. Contouring was performed by three separate investigators (KJM, DCG, EKM), who were blinded with respect to patient identification. The IRV's were compared both by investigator and by time of PPB (day 0 vs. day 33). The radiation dose encompassing 90% (D90) of the IRV and Prostate (PST) was calculated and compared . Results: The IRVs contoured were reproducible between the investigators with a maximum mean difference of .56 (SD .33) cc. There was no statistical difference between any of the investigators contoured volume (minimum Spearman correlation was 0.978). The average IRV was significantly larger on day 0 (Avg. 52.7;SD 19.7 cc) compared to day 33 (Avg. 44.6; SD 19.1 cc) (p<0.001). The day 0 IRV was an average of 1.18 times larger than the Day 33 PRV. There was no difference between either the day 0 D90PST (Avg.149.1; SD18.7 cGy) vs the day 0 D90IRV (Avg.149.8, SD 27.5 cGy) (p=.442) nor between the day 33 D90PST (Avg.163.7; SD22.7 cGy) vs the day 33 D90IRV (Avg.166.6, SD 30.3 cGy) (p=.257). Both the D90IRV and D90PST were significantly different at day 0 vs 33 (p=.0003, p=<.0001 respectively). Conclusions: The IRV analysis demonstrates no significant interobserver variability, provides accurate quantification of prostate swelling after PPB, and is an accurate objective surrogate analysis for PSI quality. No significant financial relationships to disclose.
First-line phase II trial of sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma unsuitable for cytokine treatment
Authors: Maroto-Rey P. , Bellmunt J. , Trigo J. M. , Guillem V. , López-Martín J. A. , Carles J. , Antón-Torres A. , Urruticoechea L. 
Published: March 2020

15640 Background: Sorafenib (BAY 43–9006) is a serine/threonine and receptor tyrosine kinase inhibitor that prevents tumor cell proliferation and angiogenesis. The objective of this open-label, phase II trial was to determine median progression-free survival (PFS) following sorafenib therapy in patients with renal cell carcinoma (RCC) unsuitable for cytokine treatment. Methods: Eligible patients had cytologically or histologically confirmed clear cell RCC; Eastern Cooperative Oncology Group (ECOG) Performance Status 0–1; adequate renal, liver and medullar function; no active central nervous system metastases; had received no previous treatment with antiangiogenic agents; and had at least one evaluable lesion. Sorafenib was given as first-line treatment in patients unsuitable for cytokine therapy, defined as being intolerant to or ineligible for immunotherapy. Treatment consisted of oral sorafenib 400mg twice daily continuously until disease progression or unacceptable toxicity. The primary endpoint was PFS; secondary endpoints were response rate according to Response Evaluation Criteria in Solid Tumors, tolerability and overall survival. Results: Twenty-six patients were enrolled between March and July 2006 (median age: 68.5 years [48–82]; male/female: 17/9, ECOG Performance Status 0: 11 patients; prior nephrectomy: 19 patients). The main metastatic locations were lung and bone, 14 patients had = 2 metastatic lesions, and 2 patients had abnormal lactate dehydrogenase levels. As of 31 December 2006, with a median follow-up of 6.4 months, the median PFS had not been reached. In 19 patients evaluable for response, the overall clinical benefit rate was 68.4% (1 complete response; 1 partial response; 11 stable disease). Six patients experienced serious adverse events, only one of which was related to treatment. Conclusions: Sorafenib first-line therapy is a tolerable alternative for patients unsuitable for cytokine treatment. Final PFS data will be available in June 2007. No significant financial relationships to disclose.
Comparison of combination treatment with endostatin, soluble neuropilin-1 and thrombospondin-2 to single inhibitors in antiangiogenic therapy of renal cell carcinoma
Authors: Bartsch G. , Eggert K. , Loges S. , Fiedler W. , Laack E. , Hautmann R. , Gschwend J. , Bokemeyer C. , Schuch G. 
Published: March 2020

15648 Background: Combinations of cytotoxic drugs lead to increased activity and minimize resistance compared to single agents in tumor therapy. Similarly, antiangiogenic treatment could be improved by combinations targeting different pathways. We investigated a combination of endogenous inhibitors using endostatin (ES), soluble Neuropilin-1 (sNP-1), and thrombospondin-2 (TSP-2) in a model of renal cell carcinoma. Methods: Porcine aortic endothelial cells have been engineered for stable production of angiogenic inhibitors by lipofection and were encapsulated in sodium alginate microbeads. Proliferation of human umbilical vein endothelial cells or Renca renal carcinoma cells was examined after incubation with different microbeads. Similarly, effects of inhibitors on endothelial cell function were tested in tube formation and in vitro wound assays. Microbeads were implanted into SCID mice with subcutaneously growing tumors derived from Renca cells or in mice developing lung metastases after intravenous injection of tumor cells. Results: Factors released from microbeads inhibited endothelial cell function but had no effect on tumor cell proliferation in vitro. In vivo, subcutaneous tumor growth was inhibited similarly by each angiogenic inhibitor alone. After 30 days mean tumor weight was 1.3 g in controls and 0.17, 0.18, 0.18g in ES, sNP-1, and TSP-2 treated mice, respectively. Tumor weight in mice treated with all three inhibitors was further reduced to 0.03g. Histological analyses confirmed antiangiogenic activity by inhibition of microvessel density in treated tumors. In a metastastic model treatment with angiogenic inhibitors induced a significant reduction in size and number of lung metastases with additive effects when factors were used in combination. Conclusions: We conclude that combination therapy targeting multiple angiogenic pathways has synergistic activity and could help to avoid resistance to single inhibitors in tumor treatment. No significant financial relationships to disclose.
Metronomic chemotherapy for hormone refractory prostate cancer (HRPC)
Authors: Hoshi S. , Numahata K. , Hoshi K. , Suzuki K. , Ono K. , Sugano O. , Ihidoya S. , Saito S. , Arai Y. 
Published: March 2020

15649 Background: Low dose continuous chemotherapy (metronomic chemotherapy) is trying to many advanced cancers. Metronomic chemotherapy has important anti-angiogenic activity to tumor vessels. For patients who progressed after docetaxel, no standard options exist. We have experienced complete regression of bone metastases on super scan by low does cisplatin, UFT, diethylstilbestrol, and dexamethasone (CUDD) in a patient with HRPC (Int JCO, 8,118, 2003). Methods: CUDD consisting of weekly 5 mg/body of cisplatin plus 125 mg/body of diethylstilbestrol and daily 300–450 mg of UFT/day plus 0.5–1 mg of dexamethasone were given to 47 HRPC patients, (median and range of age: 66 and 52–72, respectively). The ECOG performance status was 0 to 1. Gleason score was 7 in 10 patients and 8 in 17 patients and 9 in 20 patients, respectively. Metastatic site was bone in 45 (EOD grade 1:10, 2:18, 3: 15, 4:2), lymph node in 8. Six cases became refractory to docetaxel were treated with CUDD plus CPM (50 mg/day). Results: Among the 45 patients assessable for bone metastasis, 12 (27 %) obtained marked improvement on bone scan. One was EOD grade 4 (super bone scan) and 9 were EOD grade 1–3. Eighteen (40 %) were stable and 15 (33%) progressed on bone scan. Among 8 patients of lymph node metastasis, 3 (38%) showed partial response, 2 (25%) no change and 3 (38%) progression. Twenty-five (53 %) out of 47 patients showed a PSA decline of 50% or greater. Among the 25 patients assessable for bone pain, 7 (28%) improved, 12 (48%) remained stable and 6 (24%) progressed. Their median response duration and median survival time were 8 months (range; 2 to 44 months) and 20 months (range, 4 to 48 months), respectively. Their median response duration was 3 months. Three of 6 refractory to docetaxel were responded to CUDD plus CPM. Their median response duration was 10 months. Conclusions: CUDD is effective in almost half of hormone refractory prostate cancer patients and has advantage of minimal side effect. Three of 6 docetaxel refractory cases also responded to CUDD plus CPM. No significant financial relationships to disclose.