bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II trial of irofulven (IROF)/prednisone (P), IROF/capecitabine (C)/P or mitoxantrone (M)/P in docetaxel-pretreated hormone refractory prostate cancer (HRPC) patients (pts)
Authors: Hart L. , Ciuleanu T. , Hainsworth J. , Oudard S. , Berger E. R. , Alexandre J. , Chi K. N. , Ruether D. , MacDonald J. R. , Cvitkovic E. 
Published: March 2020

14513 Background: IROF, a semisynthetic derivative of the natural product illudin S, is a novel DNA binding agent. IROF alone or in combination has shown activity in phase I-II trials in HRPC, notably with IROF/C (Cvitkovic et al, ASCO 2004). Methods: Pts with histologically-proven metastatic HRPC who progressed (RECIST or PSA) during prior docetaxel or within 3 months of discontinuing treatment, with adequate hematologic and organ functions and KPS ≥70% were stratified by pain and randomized to one of three treatments: Arm A: IROF (0.45 mg/kg, day 1 and 8 q3weeks [w]) and P (10 mg po daily); Arm B: IROF (0.4 mg/kg day 1 and 15), C(2000 mg/m2 day 1–15 q4w) and P; or Arm C: M (12 mg/m2 q3w) and P. Primary endpoint was TTP (RECIST, PSA or clinical progression); secondary endpoints included PSA response (≥50% decrease for ≥4 w), pain response, and toxicity; 135 pts are planned in a 2:2:1 ratio. The study was powered to detect a difference in TTP of 1.5 vs 3 months. Results: As of Dec 2005, 78 pts were randomized and treated with ≥ 5 months follow-up (A/B/C: 31/31/16). Median age (A/B/C) 69/70/61, KPS ≥80% 24/28/9, median baseline PSA ng/mL 90/147/235, disease related pain at baseline 61%/58%/63%; other characteristics, including metastatic site distribution, were similar between arms. Safety: 65 pts were evaluated for safety. Median cycles/Pt (A, B, C) 3/2/2; grade 3/4 toxicities (% pts A, B, C): asthenia (4%, 16%, 0%), vomiting (0%, 12%, 0%) and diarrhea (4%, 8%, 0%). The most common grade 3/4 laboratory abnormalities were neutropenia (10%, 6%, 31%) and thrombocytopenia (15%, 12%, 0%). Conclusion: IROF in combination with P and, in particular, C/P shows improved activity and acceptable tolerance compared to M/P in docetaxel-resistant HRPC. Patient accrual is complete as of Jan 2006, and final results will be presented. [Table: see text] [Table: see text]
Cellular localization of thrombin in prostate: Implications for thrombin targeted therapy in prostate cancer
Authors: Kohli M. , Huang J. , Palapattu G. , Dennis R. , Yao J. , Lester T. , Ricke W. 
Published: March 2020

14527 Background: Tumor and coagulation interaction is complex and heterogeneous. Expression of an intact repertoire of coagulation proteins is not detected in all tumor types. Thrombin, a key coagulation protein, which has been observed to promote tumorigenesis in experimental models, is not expressed on breast, colon and squamous lung cancer cells, but has been detected on small cell lung, melanoma and renal cancer epithelium. In prostate cancer, expression of its receptor, protease activated receptor-1 (PAR-1) has been previously reported but thrombin expression on epithelium not determined. Therefore, we evaluated thrombin and prothrombin expression in prostate specimens. Methods: Quantitative real-time PCR was performed for (pro)thrombin mRNA expression in fresh prostate cancer tissue lysates obtained from localized disease (n = 9 prostatectomy specimens) and advanced disease (n = 7 channel trans-urethral prostate resection specimens). Prothrombin and thrombin protein immunohistochemistry was performed on anonymized prostate tissue micro arrays which included benign (n = 117), prostate intra-epithelial neoplasia (PIN; n = 26) and prostate cancer (n = 112) cores. Results: (Pro)thrombin mRNA expression (normalized to 18s mRNA) was detected in all cancer tissue lysates. Mean intensity of expression in advanced cancer specimens was 20.3 compared to 14.0 for local stage specimens (p = 0.09; Wilcoxon rank sum test). Spatially, expression of thrombin was detected in stroma, benign and malignant epithelium (see Table) and on vascular endothelium. Prothrombin localization was similar to thrombin expression. Conclusions: Thrombin’s tumorigenic effects via PAR-1 activation provide novel therapeutic targets in tumors expressing thrombin-PAR1 axis. The current study confirms thrombin expression on prostate epithelium and taken with previous results of PAR1 epithelial expression, provides a rationale for exploring specific thrombin inhibitors and/or PAR inhibitors in prostate cancer. [Table: see text] No significant financial relationships to disclose.
Literacy and race predictors in localized prostate cancer treatment choice
Authors: Wolf M. S. , Zagory J. A. , Chang C. , Knight S. , Ray P. , Kozloff M. , Starr A. , Lyons E. A. , Costello S. , Bennett C. L. 
Published: March 2020

14541 Background: Studies have shown that African American populations have low rates of surgery, while similar assessments based on literacy skills have not been reported. Methods: Newly diagnosed prostate cancer patients (n = 311) were approached at 3 hospitals: private, county, and VA. Patients completed demographic and quality of life questionnaires as well as a literacy assessment at baseline, 3 month, and 12 month intervals. Results: Majority (60%) of African American patients were at low functional literacy. In multinomial regression analysis controlling for patient age, clinical stage at presentation, comorbidity, and treatment site, both African American race (RRR 2.4, 95% CI 1.35–5.91) and low literacy (6th grade reading level or below) were significantly and independently associated with a greater likelihood to receive external beam radiation treatment only in relation to other treatment options (AOR 4.26, 95% CI 2.34–7.75). Conclusions: In our inner city population of prostate cancer patients, white patients with high literacy skills opted for radical prostatectomy and persons with low literacy and/or African American race opted for radiation therapy. No significant financial relationships to disclose.
Activity of the Src-kinase inhibitor AZD0530 in androgen-independent prostate cancer (AIPC): Pre-clinical rationale for a phase II trial
Authors: Evans C. P. , Lara P. N. , Kung H. , Yang J. C. 
Published: March 2020

14542 Background: Cells with neuroendocrine (NE) differentiation are found in prostate cancer and may facilitate the transition to AI by supplying alternate growth factors. Androgen deprivation further induces a subgroup of AI NE cells by transdifferentiation. We hypothesized that androgen receptor (AR)- and src kinase-mediated signaling participates in this NE progression, and tested inhibition using the src kinase inhibitor AZD0530. Methods: The neuropeptide gastrin-releasing peptide (GRP) was minimally expressed in androgen-sensitive LNCaP cells. LNCaP-GRP clones demonstrated androgen- and anchorage-independent growth, developed orthotopic tumors in castrated SCID mice & activated PSA with nuclear localization of AR. LNCap-GRP clones & xenografts showed activation of src kinase. Xenografts were recultured (LNCaP-Pro) & grown in androgen-free soft agar or tissue culture either alone, with synthetic androgen R1881 or with inhibitors including: GRP monoclonal antibody 2A11, 10 μM antiandrogen bicalutamide, Src kinase inhibitors AZM475271, AZD0530 (5 μM) and PP2 (10 μM). Mice bearing orthotopic LNCaP-GRP tumors were treated orally with 50 mg/kg AZD0530 daily for 6 weeks. Results: Androgen-depleted soft agar colony counts showed that LNCaP-Pro cell proliferation was not stimulated by R1881 but was partially inhibited by 2A11 antibody or bicalutamide, when compared to controls. A combination of 2A11 & bicalutamide resulted in significant growth reduction (p < 0.05). R1881 mostly reversed the 2A11 inhibition. The Src kinase inhibitors AZM475271 & PP2 showed greatest colony formation inhibition (p < 0.05). AZD0530 inhibited growth in culture (not tested in soft agar) at micromolar concentrations. Testing in vivo inhibited primary tumor growth in 5 of 7 dosed mice (71%), but completely inhibited metastasis in all AZD0530-treated mice (compared with metastasis in 100% of controls). Conclusions: Neuropeptide-mediated AIPC growth is dependent on both GRP and AR. There appears to be a beneficial role for Src kinase inhibition in this model. A CTEP-sponsored phase II trial of the dual Src/Abl kinase inhibitor AZD0530 in AIPC has been initiated. (KO8 DK60748–01, 2RO1 DK/AG52659–04, DOD PC10520, Astra-Zeneca, NO1 CM17101). [Table: see text]
Effect of zoledronic acid (Z) on pain in prostate cancer patients with bone metastases based on performance status
Authors: Barghout V. , Abetz L. , Arbuckle R. , Bosch V. , Hei Y. , Saad F. 
Published: March 2020

14544 Background: Z has demonstrated efficacy in reducing, preventing, delaying the occurrence of an SRE (Skeletal Related Event) including pathologic fractures, severe bone pain requiring radiation therapy, spinal cord compression, surgery to bone and hypercalcemia of malignancy which could lead to a loss of independence. Effects of Z on pain were analyzed in a subgroup of patients based on performance status. Methods: Subjects were randomised to Z 4mg (n = 201) or placebo (n = 201). The short form of the Brief Pain Inventory (BPI) was administered at baseline (visit 2), and visits 3 (weeks 3–4), 4 (weeks 6–8), and then every second visit (every 6 weeks) until study end. Changes in BPI individual item scores and the Pain severity and Pain Interference scale scores were compared between Z and placebo groups. Post baseline missing data were replaced by Last Observation carried forward (LOCF). Changes in scores were examined in the subgroup of patients with ECOG performance status scores of ≥ 1. Results: For patients ECOG score of ≥ 1 at baseline (n = 227), Z was superior to placebo in the BPI items ‘pain at its worst’, ‘pain at its least’, ‘pain on average’, and the Pain Severity scale at visit 4 (weeks 6–8) and visit 6 (week 12) (p < 0.05). At visit 8 (weeks 18–20) Z was superior to placebo on the ‘pain on average’ item and Pain Severity scale (p < 0.05). For visit 12 (weeks 30–32) and for LOCF Z was superior to placebo for ‘pain at its worst’, ‘pain on average’ and Pain Severity (p < 0.05 for all). For the ‘pain right now’ item there were statistically significant differences at visits 4, 6, 12 and LOCF (p < 0.05). In addition, at visit 6 (week 12), Z was superior to placebo for changes in items assessing interference with: sleep, general activities, mood, walking and enjoyment of life (p < 0.05). Z was also superior to placebo for ‘interference with general activities’ at visits 12 (weeks 30–32), 16 (weeks 42–44) and LOCF (p < 0.05). Conclusion: Results suggest Z provides significant benefit in pain reduction and Z may have an impact on patients’ daily activities which may lead to a preservation of patients’ functionality. [Table: see text]
Clinical experience with extended lymph node dissection during radical prostatectomy
Authors: Sonpavde G. , Slawin K. , Levitt J. M. , Guariguata L. 
Published: March 2020

14545 Background: The value of the extent of lymph node dissection at radical prostatectomy remains controversial. We report our experience with extended lymph node dissection in patients undergoing open radical prostatectomy. Methods: 201 consecutive patients with cT1c-cT3a prostate cancer who underwent open radical prostatectomy with an extended regional lymph node (LN) dissection of up to six packets (iliac, hypogastric, and obturator; right and left) by a single surgeon at The Methodist Hospital between July 2002 and April 2004 were studied. No patient was treated with adjuvant radiation or hormonal therapy before elevated PSA levels were observed. Ultrasensitive PSA (uPSA) using the 3rd generation Immulite assay (DPC) was performed periodically beginning at 6 weeks post operatively. A uPSA level ≥ 0.03 ng/mL and rising on at least one subsequent uPSA obtained at least six weeks later was classified as a biochemical recurrence (BCR). Results: The mean patient age was 59 years at the time of surgery (median, 59; range, 39 to 73 years). Median follow-up after surgery was 21 months (range 1–37 months). Gleason Score was ≤ 6, 7, and 8–10 in 37%, 53% and 10% of patients, respectively. Sixty-two patients had extra prostatic extension and 16 patients had seminal vesicle involvement. A total of 3125 pelvic lymph nodes were removed (per patient: mean, 15.64; median, 15; range 4–42). Of these 22 LN (0.71%) were positive in 11 (5.5%) patients. By specified region, 2/1775 (0.23%) of iliac nodes, 6/642 (0.93%) of hypogastric nodes and 9/708 (1.27%) of obturator nodes were positive. Of the 11 patients with positive LN, 3/11 (27.27%) had positive iliac nodes, 6/11 (54.54%) had positive hypogastric nodes, and 6/11 (54.54%) had positive obturator nodes. Using a very stringent definition of BCR in order to compensate for the relatively short follow-up period, the 2 year progression-free survival (PFS) for patients with at least one positive LN was 37.5%. Conclusions: Extended LN dissection may alter the biology of early nodal metastatic prostate cancer and lead to longterm PFS without additional therapy. A higher percentage of patients and nodes are positive in the hypogastric and obturator regions, supporting the rationale to include these with the iliac nodes when performing LN dissection. No significant financial relationships to disclose.
A ligand-independent androgen receptor function protects from inositol hexakisphosphate-induced cell death
Authors: Diallo J. , Péant B. , Lessard L. , Delvoye N. , Le Page C. , Mes-Masson A. , Saad F. 
Published: March 2020

14566 Background: The androgen receptor (AR) is often aberrantly expressed or activated in hormone-refractory (HR) prostate cancer (PCa). Though it is not clear whether this is directly linked to AR expression, various cell survival pathways are over-activated in HR-PCa, which is characterized by its poor clinical outcome and resistance to available therapies. Inositol hexakisphosphate (IP6) is a phytochemical anti-cancer agent, which we have found to be more effective in PCa cell lines that do not express the AR. Our goal was to address the mechanism of IP6-induced cell death and to evaluate if and how the AR may interfere with its activity. Methods: We used LNCaP, DU145, 22Rv1 as well as wild-type PC3 and AR-expressing PC3 (PC3AR) cell lines to assess the metabolic toxicity of IP6 by WST-1 assay in normal, androgen-supplemented, and androgen-depleted cell culture conditions. A siRNA targeting the androgen receptor (AR) was used to control for genuine AR-mediated effects in the PC3/PC3AR cell lines. Apoptosis was quantified using fluorogenic caspase-3 assays as well as quantitative DNA fragmentation assays. Expression of a variety of genes involved in apoptosis and cell survival pathways was evaluated by real time PCR. Results: While the activity of IP6 was not modulated by the presence of androgens for any cell line, PC3AR cells were significantly more resistant to IP6 than wild-type PC3 cells according to WST-1, caspase-3 and DNA fragmentation assays (p < 0.05). Down-regulation of the AR in the PC3AR cell line resulted in increased metabolic toxicity of IP6 on these cells (p < 10−5). Although treatment with IP6 resulted in the up-regulation of the pro-apoptotic genes Puma, Noxa, as well as of IRF-2 and IkB-αλπηα in PC3 cells, this did not occur in PC3AR cells (p < 0.05). Conclusion: We conclude that, at least in PC3/PC3AR, cells IP6 sensitivity is linked to a ligand-independent function of the AR. To our knowledge, this is the first report of a ligand-independent AR function involved in resistance to a cytotoxic compound. Establishing the molecular details of this novel function is a major part of our ongoing research. No significant financial relationships to disclose.
Serum pharmacoproteomics of erlotinib-treated advanced prostate cancer patients: A SELDI-TOF mass spectrometry analysis
Authors: Gonçalves A. , Taylor B. , Toiron Y. , Esterni B. , Salem N. , Bladou F. , Viens P. , Gravis G. 
Published: March 2020

14603 Background: EGFR (Epidermal Growth Factor Receptor) is a promising target in various epithelial cancers. Erlotinib is an orally active small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, under evaluation in prostate cancer. To identify protein biomarkers associated with EGFR TKI treatment we performed serum protein profiling in advanced prostate cancer patients receiving erlotinib, using Surface Enhanced Laser Desorption/Ionization-Time of Flight Mass Spectrometry (SELDI-TOF MS). Method: Serums from 23 advanced or metastatic prostate cancer patients enrolled in a phase II study of erlotinib as single agent were collected before treatment, on D28 and D56 and kept frozen in liquid nitrogen until analysis. Serum samples from each patients and each time points were first urea treated and then incubated with 3 different ProteinChip arrays (Ciphergen Biosystems): IMAC-Cu, CM10 and H50 using a fully automated platform (Tecan). After adding SPA matrix, arrays were analysed using a PBSIIc ProteinChip reader (Ciphergen Biosystems). After noise reduction, baseline substraction, and data normalisation, protein peaks were detected using the Biomarker Wizard tool integrated to the ProteinChip Software 3.1. Numeric data were then exported to excel files that were used for further biostatistic processing. Results: Combining protein profiles resolved from each experimental condition, several hundreds of protein peaks were obtained. Protein profiles from untreated and D28 and D56-treated patients were compared using non-parametric statistical methods and several protein peaks appeared differentially expressed between pre and post-treatment samples. Supervised methods identified protein peaks correlating with specific erlotinib toxicity on day 28. Since only minimal activity was noted in this trial, no protein profile correlating with anti-tumor effect was identified. Purification and identification of proteins modulated by treatment and associated with toxicity are ongoing. Conclusion: Serum protein profiling using SELDI-TOF MS is a promising method to characterize pharmacoproteomics of innovative compounds under development and to identify protein biomarkers potentially associated with drug effects. No significant financial relationships to disclose.
ErbB1–4 expression in prostate cancer patients and its correlation to patients’ ethnicity and outcome
Authors: Ben-Yosef R. , Barnea I. , Sarid D. , Vexler A. , Marmor S. , Starr A. , Greif Y. , Inbar M. , Barak N. 
Published: March 2020

14615 Background: ErbB family is involved in both cancer progression and treatment response in solid tumors. Few inconclusive studies reported on ErbB over-expression in prostate cancer. We investigated ErbB1–4 expression in prostate cancer patients and its correlation to patients ethnicity and outcome. Methods: ErbB expression was evaluated by immunohistochemistry of prostate cancer specimen using polyclonal antibody (Santa Cruz, CA). The staining was recorded as negative (0/+1), moderately positive (+2) and highly positive (+3). Kattan nomogram was used to predict 5-yr progression-free probability, assuming that all patients received external beam radiation therapy (a total dose of 78 Gy) and hormonal manipulation. Origin was counted in all 43 patients: Ashkenazic patients were defined as those who immigrated from East/West Europe or North America and Sephardic patients - from Middle East and North Africa. Results: ErbB1 (+2/+3) was over-expressed in 12 and 7 patients for a total of 19/43 (44%). ErbB2 over-expression (+2/+3) was not found in all patients. ErbB3 over-expression of +2 was seen in 2 patients and none had +3 (2/43, 5%). ErbB4 over-expression (+2/+3) was seen in 5 and 11 patients for a total of 16/43 (37%). 22 patients were Ashkenazic and 21 - Sephardic. ErbB1 over-expression in Ashkenazic and Sephardic groups was 9/22 (41%) and 10/21 (48%). ErbB4 over-expression in the two groups was 7/22 (32%) and 9/21 (43%). Kattan score of <80 was seen in 20/43 and <60 in 7/43 patients. ErbB1 over-expression was noted in 11/20 and in 4/7 patients. ErbB4 over-expression was seen in 7/20 and in 4/7 patients. In both ErbB1 and ErbB4 over-expression and Kattan nomogram of <80 and <60 the Sephardic ethnicity dominated-7/11 (64%), 3/4 (75%), 5/7 (71%) and 3/4 (75%). Conclusions: ErbB1 and ErbB4 over-expression is presented in 43% and 37% patients while ErbB3 was over-expressed in 5%; no over-expression of ErbB2 was observed. Ashkenazic and Sephardic ethnicity were evenly distributed in the over-expressed ErbB1 and ErbB4 patients. However, a tendency to a worse prognosis, based on Kattan nomogram, was seen in over-expressed ErbB1 and ErbB4 patients from Sephardic ethnicity. Further studies on ethnicity and ErbB prevalence and prognosis are warranted. No significant financial relationships to disclose.
Retrospective comparison of treatment outcome and cost effective analysis of BEP and VIP for poor-prognosis metastatic germ cell tumors in India
Authors: Dadhich H. K. , Attili S. V. , Saini K. S. , Batra U. , Jacob L. A. , Anupama G. , Singhal N. , Pp B. 
Published: March 2020

14638 Purpose: Retrospective comparison of treatment out come and cost effective analysis in two chemotherapeutic regimens (BEP vs. VIP) for poor-prognosis metastatic germ cell tumors in India, a resource poor nation. Methods: All male patients with poor risk germ cell tumors were included in the study between 2001–2003. The patients were stratified into two categories depending on the type of the regimens they received. Results: Finally 36 patients were analyzed with median follow up of 21.8 months. Medical 7.5 for windows was used for the analysis. The baseline characters (age, stage, PS, histology and serum markers) were not different in two treatment arms (P > 0.05). The different treatments (BEP vs. VIP) had no statistically significant influence on the outcome. VIP is less cost effective and more toxic compared to BEP. Conclusion: In view of absence of survival advantage and more toxicities as well as cost of therapy it would be appropriate to still treat the patients of high risk germ cell tumors with the conventional BEP rather than VIP in the Indian setting and keeping the later reserved for the relapse. [Table: see text] No significant financial relationships to disclose.