bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of anti-inflammatory therapy in patients with metastatic renal cell carcinoma on clinical response
Authors: Reichle A. , Grassinger J. , Bross K. , Wilke J. , Suedhoff T. , Berand A. , Wieland W. , Andreesen R. 
Published: March 2020

14500 Background: Interaction among signalling networks from tumor and neighbouring stroma cells in complex disease traits is poorly understood. Methods: Two consecutive multi-centre phase II trials were designed (case calculation according response rate, T. Chen two stage design) to prove the hypothesis, whether the activation of presumably complementary receptor-triggered transcriptional cascades (via pioglitazone, and interferon alpha, IFNa) could result in synergistic clinical effects. Therapy in both trials consisted of low-dose capecitabine 1 g/m2 twice daily po for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily, day 1+ (from 11/04 etoricoxib 60 mg daily instead) plus pioglitazone 60 mg daily, day 1+. In study II low-dose IFNa 4.5 MU sc three times a week, week 1+, was added until disease progression. Results: Eighteen, and 33 patients (pts, 31 eligible for analysis), respectively, with clear cell carcinoma, progressive disease, and ECOG 0–2 were enrolled between 2/02 to 2/03 and 4/03 to 4/05, respectively. Mean Bradley score in both trials was not significantly different, 4.1(I)/4.9(II), however, the rate of previous systemic treatments 33%/19%. Objective response (48%) was exclusively observed in study II (PR 35%, CR 13%), and paralleled by a strong CRP response (after 4 weeks on treatment) in all 29 pts with elevated CRP levels (93%) (study I: no significant CRP response): CRP values decreased from mean 41.3 mg/l, range 8.1 to 221, to 5.1 mg/l, range 2.1 to 15.6, p = 0.005. Stable disease > 2 months (mos) occurred in 50%/48%. Median progression-free survival could be more than doubled from a median of 4.7 mos (95% CI, 1.0 to 10.4) to 11.5 mos (6.8 to 16.2) in study II, p = 0.0000. Median overall survival of population II has not been reached, yet. Toxicities > WHO grade II were reported (study I/II): Hand-foot syndrome (3/3), diarrhoea (2/2), depression (0/1), pneumonia (0/1). Conclusions: (1) Clinical results of anti-inflammatory/angiostatic therapy compare with available immuno-therapies. (2) Improved outcome with additive IFNa argues for a synergistic drug interaction. (3) Control of tumor-associated inflammation is an important therapeutic principle in metastatic clear cell carcinoma. No significant financial relationships to disclose.
Combination therapy with docetaxel (D) and celecoxib (C) in patients (pts) with hormone resistant prostate cancer (HRPC)
Authors: Kasimis B. , Chang V. , Cogswell J. , Sambamoorthi N. , Gonzalez M. , Srinivas S. , Zhong F. , Morales E. , Duque L. , Blumenfrucht M. 
Published: March 2020

14519 Background: Cox-2 expression is an independent predictor of survival and is over expressed in 89.3% of pts with HRPC. Cox-2 expression has angiogenic and cytoprotective effects. Its suppression could lead to angiogenesis inhibition and increase chemotherapy sensitivity. D in low doses and C are angiogenesis inhibitors. The main objectives were to study the effects on PSA, time to progression (TTP), toxicity and survival. Methods: In a two stage, phase II trial designed for 66 pts, 30 pts with HRPC and evidence of biochemical and radiographic progression were treated with D 30 mg/m2 IV/wk for 3 wks and C 400 mg po bid for 4 wks of each cycle. Response evaluation after every two cycles was made. RECIST criteria and PSA reduction by >50% for biochemical response were used. Independent safety monitoring for renal (R) and cardiovascular (CV) toxicity were made. Results: Thirty (30) evaluable pts received minimum of 2 cycles, median (M) 4.5 (range 2–8). The M age was 74 yr (55–94), ECOG PS 1 (0–2), Hb 11.8 g/dl (8.6–14.6), and PSA 92.5 ng/dl (15.3–4192). Metastases were present in 24 pts (80%) by bone scan and 25 pts (83.3%) by CT scan. Twelve (12) pts (40%) had PSA response of >50% and 4 pts (13.3%) had PSA normalization. By CAT scan, 3 pts (10%) had CR, 5 pts (16.7%) had PR, and 12 pts (40%) had SD. By bone scan 1 pt (4.8%) had a major response. The M TTP by PSA was 3.65 mos (0.87–12.0). With 27% pts still alive, the M survival was 10.9 mos (3.0– 30.7+), with 95% CI for the mean (9.3–15.2). One pt (3.3%) withdrew due to abdominal discomfort, 2 pts (6.6%) had grade III diarrhea and 1 pt (3.3%) had grade III nail toxicity. Conclusions: 66.7% pts had soft tissue response (CR+PR+SD), and 13.3% pts had PSA normalization. Safety analysis for R and CV toxicity demonstrated excellent safety of this regimen. Considering the unfavorable prognostic indicators of this population the MST of 10.9 mos indicates the activity of this combination. [Table: see text]
USP2a is an oncogenic isopeptidase and a potential target in prostate cancer
Authors: Priolo C. , Tang D. , Brahmandam M. , Benassi B. , Sicinska E. , Ogino S. , Farsetti A. , Porrello A. , Febbo P. G. , Zimmermann J. , Loda M. F. 
Published: March 2020

14522 Background: De-ubiquitinating enzymes (isopeptidases) remove ubiquitin side chains prior to degradation by the proteosome thus stabilizing their protein targets. We have identified a novel androgen regulated isopeptidase, USP2a, and demonstrated that it binds and prolongs the half-life of fatty acid synthase (FAS), a key enzyme in lipid metabolism of tumor cells. Methods: We determined whether USP2a has oncogenic properties in vitro and in vivo. Wild-type and catalytically inactive USP2a were introduced in immortalized normal prostate epithelial cells (AR-iPrECs). Clonogenicity assays and apoptosis induction by chemotherapeutic agents were performed on these cells. Anti-USP2a siRNA were transfected in normal and transformed (LNCaP, DU145 and PC-3) prostate cell lines. Oncogenicity in vivo was shown by s.c. injection of NIH3T3-USP2a cells in nude mice. Furthermore, USP2a mRNA expression and gene microarrays were tested in 52 human prostate adenocarcinomas. Results: Wild-type USP2a overexpression in AR-iPrEC cells resulted in a significant increase in number and size of colonies compared to those obtained in parental cells. Growth in soft agar was significantly enhanced as well. Silencing of USP2a in LNCAP and DU145 cells resulted in a strong apoptotic effect, evaluated by FACS analysis and cleaved-PARP expression. The role of this isopeptidase in apoptosis regulation was confirmed on AR-iPrEC-USP2a cells, that showed resistance to apoptosis induced by cisplatin and taxol. Importantly, USP2a overexpression was able to transform NIH3T3 cells, generating greater than or equal to 0.5 cm subcutaneous tumors in 12/12 nude mice within 3 weeks, while none of the negative controls grew. USP2a mRNA was overexpressed in 39% of human prostate cancers, showing 1.6–104 (median 5.48) fold induction relative to normal tissues by qRT-PCR. Gene expression profiling of the same tumors revealed specific signatures in USP2a-overexpressing tumors. Conclusions: Our results demonstrate that USP2a behaves as an oncogene in vitro and in vivo and is overexpressed in organ-confined prostate cancer. These data strongly suggest that this isopeptidase is a potential drug target in prostate cancer. [Table: see text]
Treatment outcomes of patients (pts) with primary mediastinal germ cell tumors (PMGCT): The M. D. Anderson Cancer Center (MDACC) experience
Authors: Rodney A. J. , Siefker-Radtke A. , Tannir N. M. , Swisher S. , Walsh G. , Millikan R. E. , Pagliaro L. C. 
Published: March 2020

14538 Background: PMGCT are uncommon germ cell malignancies. Mediastinal nonseminomatous germ cell tumors (NSGCT) have a poor prognosis, whereas pure seminoma (Sem) has a good or intermediate prognosis irrespective of mediastinal presentation. Methods: We retrospectively identified 19 male pts with PMGCT seen at MDACC between October 1998 and September 2004 from a clinical database. Pts with resectable NSGCT were offered surgery upon plateau of their chemotherapy response. Prior to referral, 1 pt had primary surgical resection without preoperative (preop) chemotherapy. Results: There were 14 pts with NSGCT and 5 with good prognosis Sem. The median age was 29.5 (20–60). Seven pts with NSGCT had mixed or undifferentiated histology, and the remainder had pure yolk sac (5 pts) or choriocarcinoma (2 pts). The estimated median survival (Kaplan-Meier) for all patients (Sem + NSGCT) was 21 months. All pts with Sem were alive and disease-free at last follow-up (median 12 months, range 7–34). All pts with Sem received 4 courses of etoposide and cisplatin (EP); one also received bleomycin (BEP); one received radiotherapy consolidation; none received surgery. Of the pts with NSGCT, 9 (64%) have died, including 1 who refused surgery. Five pts with NSGCT were alive at last follow-up and 3 (21%) were disease-free (15+, 27+ and 35+ months). Four pts with NSGCT (29%) reached beyond 2 years survival (27+, 28, 35+, and 63+ months) including 3 with lung metastases and one with elevated preop alpha-fetoprotein (28,022 ng/ml). Each of these pts received 6–10 courses of multiple-regimen preop chemotherapy, and 2 received initially 4 courses of BEP without marker normalization. Conclusions: Mediastinal Sem treated with 4 courses EP had an excellent outcome without surgery. Pts with mediastinal NSGCT had a 64% mortality rate despite aggressive treatment. Several pts with mediastinal NSGCT did achieve long-term survival following aggressive chemotherapy and surgery, even with lung metastases and failure to normalize markers. A phase III trial of BEP versus dose-dense chemotherapy for poor-prognosis NSGCT is now in progress at MDACC. No significant financial relationships to disclose.
Pilot study of VHL mutation analysis to predict response to interleukin-2 in patients with metastatic renal cell carcinoma
Authors: Pantuck A. J. , Fergelot P. , Patard J. , Lam J. , Belldegrun A. S. , Figlin R. A. 
Published: March 2020

14539 Background: More than 300 different mutations have been described in von Hippel-Lindau (VHL) families and nearly 100 in sporadic RCC. In familial cases, there is an excess of mutations in exon 3 and exon 1, whereas mutations are evenly distributed in sporadic cases. Recent evidence suggests the importance of genotype/phenotype correlations with different VHL gene mutations contributing to a tumor’s unique biological behavior. We performed a pilot study to compare the incidence and type of VHL mutation in IL-2 complete responders (CR) and non-responders (NR). Methods: Genomic DNA was extracted from 20 frozen clear cell tumour samples (10 CR and 10 NR) using Qiamp DNA mini kits (Qiagen). Four amplimers covering the entire coding sequence and three exon/intron junctions of the VHL gene were synthesized by PCR. PCR products were subsequently purified and were sequenced using Big Dye Primer Cycle Sequencing kit (Perkin-Elmer Applied Biosystems) and an automated DNA sequencer (Perkin-Elmer Applied Biosystems). Point mutation detection was performed on DNA sequencing gels from colored peak chromatograms. Mutation bearing sequences were confirmed by a second round of PCR and sequencing. Results: In the CR patients, only 2 out of 10 samples (20%) had evidence of a VHL mutation. These VHL mutations included a false sense mutations in exon 2, comprised of a C to T transition at position 646 in the cDNA, creating a stop codon, and a frameshift mutation in exon 1 introducing in one allele an abnormal stop codon at the beginning of exon 3 potentially leading to a shorter protein product. In the 10 non-responder samples, there was also a 2 out of 10 (20%) incidence of VHL mutations. These mutations included a complex 12 nucleotide deletion in the third exon in the a domain of the protein, and a G deletion in the first exon introducing a premature stop codon. Conclusions: In this small pilot study of metastatic RCC patients, there were relatively few VHL gene mutations, and VHL mutations did not appear to correlate with response to IL-2 therapy. This study, however, does not assess inactivation of VHL genes due to hypermethylation. An expanded genetic profile to evaluate IL-2 responders versus non-responders using 500k SNP Chips is underway. No significant financial relationships to disclose.
The role of androgen ablation with low dose rate brachytherapy in the treatment of prostate cancer
Authors: Jani A. B. , Shoushtari A. , Feinstein J. 
Published: March 2020

14546 Background: We report a single-institution analysis of the role of androgen ablation (AA) with low-dose rate brachytherapy. Methods: A cohort of 189 consecutive patients (AA: n = 68, no-AA: n = 121) receiving brachytherapy (iodine-125: n = 125; palladium-109: n = 64) at our institution who had demographic (age), disease (T-stage [T1–70%, T2–28%, T3–2%], Gleason Score [median score 6], PSA [median-7.7 ng/mL]), and treatment (isotope, dosimetric endpoints, use of supplemental external beam radiotherapy [EBRT, administered as 45 Gy/1.8 Gy to the pelvis using 4-field technique with isocentric prescription]) information available, and a minimum of 2 years of follow-up available, constitute the analysis study group (median follow-up - 4.0 years). This cohort was divided into 2 major groups based on the use of AA (leuprolide 22.5 mg IM injection(s) 3–6 months [mean 4.0 months] prior to brachytherapy). Using 2 successive PSA rises > 1 ng/mL as the failure definition, biochemical failure-free survival (BFFS) curves were constructed and compared using the logrank test; additionally, multivariate analysis of all major patient and treatment factors was performed using the Cox proportional hazards model. These analyses were done for the whole cohort as well as for subgroups defined by the use of EBRT and for subgroups of patients with low-, intermediate-, and high-risk prognostic factors (defined as the basis of 0, 1, or ≥ 2 prognostic factors [PSA > 10 ng/mL, Gleason score > 6, T-stage > T2a], repectively). Results: The 4-year BFFS in the AA vs no-AA groups was 76 vs 70% (p = 0.230) for the whole cohort, 75 vs 62% (p = 0.182) for EBRT patients, and 75 vs 82% (p = 0.764) for no-EBRT patients. For the whole cohort, the use of EBRT was the only factor reaching significance on multivariate analysis (p = 0.040). When analyzing the EBRT and no-EBRT subgroups separately, no factor, including AA, reached significance on multivariate analysis. 4Y-BFFS of the AA vs no-AA subgroups were 82 vs 76% (p = 0.236) for the low-risk, 76 vs 70% (p = 0.437) for the intermediate-risk, and 75 vs 70% (p = 0.185) for the high-risk subgroup. Conclusions: In our study, short-course AA conferred no significant biochemical control advantage when added to low-dose rate brachytherapy overall or for any subgroup based on prognostic risk. No significant financial relationships to disclose.
Testicular ultrasound (TU) screening in men from familial testicular cancer (FTC) kindreds
Authors: Korde L. A. , Premkumar A. , Kramer J. L. , Linehan W. , Pfeiffer S. , Bratslavsky G. , Greene M. H. 
Published: March 2020

14547 Background: A family history of testicular cancer (TC) is associated with a 2- to 10-fold increase in TC risk. Specific abnormalities of the urogenital tract (e.g., cryptorchidism, inguinal hernia) also increase risk. The association between testicular microlithiasis (TM) and testicular intraepithelial neoplasia (TIN) has suggested that the former may be a TC risk factor. The finding of inhomogenous echotexture on ultrasound has also been associated with an increased risk of TIN. In this study, we evaluate ultrasongraphic abnormalities in men with a history of TC and their kindreds. Methods: We analyzed testicular ultrasounds (TU) from 45 FTC cases and 35 unaffected male relatives, drawn from 31 multiple-case FTC families. TU were performed between January 2003 and November 2005 as part of an NCI multidisciplinary etiologic study of FTC. All studies were reviewed by a single radiologist. Results: We found no incident TC. Five focal lesions were seen. Three were thought to be cysts and 2 required further follow-up. The frequency of varicocele and epididymal cyst was similar in both groups. Hydrocele was seen in 7 (16%) cases and 3 (9%) unaffecteds (OR = 2.0; 95% CI = 0.5–8.3). Inhomogenous testicular parenchyma was noted in 12 (27%) cases and 3 (9%) unaffected family members (OR = 3.9; 95% CI = 1.0–15.0). TM was seen in 20 subjects [15 (34%) cases and 5 (14%) unaffecteds, OR = 3.1; 95% CI = 1.0–9.6]. An additional 10 subjects (7 cases, 3 unaffecteds) had calcifications that did not meet diagnostic criteria for TM. The finding of TM was confined to 13 of the 31 families. In 6 of these 13 families, 2 or more subjects had TM. Conclusion: A number of genitourinary conditions were more common in FTC cases than in unaffected blood relatives, providing support for the testicular dysgenesis hypothesis related to TC etiology. TM was found in a high proportion of cases and in a smaller proportion of unaffecteds. In this small series, TM appeared to cluster in families. If validated, these findings could have important implications for both screening and follow-up of FTC families. No significant financial relationships to disclose.
Predicting the pathology of post-BCG lesions
Authors: Blitstein J. , Macchia R. 
Published: March 2020

14573 Background: This study evaluated the accuracy of office cystoscopy and urinary cytology in predicting the histopathology of post-BCG bladder lesions. Methods: A retrospective chart review was performed of all patients who had received intravesical BCG at two Veteran Affairs Hospitals from July 1995 to July 2005. The initial pathology, the post-treatment cystoscopy findings, urinary cytology and post-BCG biopsy were correlated. Results: A total of 136 biopsies from 64 patients who had received 79 courses of BCG were reviewed. The mean time to the first repeat bladder biopsy and to the first recurrence was 8.8 months and 11.7 months, respectively. During the study, 83% of patients developed recurrence. Malignancy was confirmed in 61% of all biopsies. For all lesions, cytology alone had a sensitivity of 53.7%, specificity of 90.5%, PPV 85%, NPV 47%. The biopsy was positive in 84% of patients with visible papillary lesions and a negative cytology. Improved accuracy was seen in papillary lesions with a positive cytology; 94% positive biopsy. The bladder biopsy was positive in 91% of patients with erythema and a positive cytology in comparison to 9.5% of patients with erythema and a negative cytology. Conclusions: There is controversy regarding the necessity of obtaining transurethral biopsies of erythematous lesions in patients who have undergone intravesical BCG therapy. Combining the cystoscopic findings and the urine cytology increases the ability to delineate BCG effect from recurrence. This study suggests that patients with post-BCG erythematous patches and a negative cytology can avoid an unnecessary transurethral bladder biopsy. This study also demonstrates that most BCG failures occur after the traditionally believed 3-month evaluation. No significant financial relationships to disclose.
Looking for new targets for prostate cancer therapy: Nuclear factor kappa B and CXCR4 co-expression in prostate specimens from RTOG-8610
Authors: Bernstein E. D. , Bae K. , Baldridge L. A. , Zhang S. , Cheng L. , Wolkov H. , Pilepich M. , Dicker A. P. , Sweeney C. J. 
Published: March 2020

14578 Background: The transcription factor Nuclear Factor-kappa B (NFκB) promotes the production of angiogenic, anti-apoptotic and prometastatic factors that are involved in carcinogenesis. The chemokine receptor CXCR4, which is under the control of NFκB, has been implicated in regulating metastasis of breast, pancreatic, and prostate cancer. This retrospective cohort study evaluated the frequency and co-expression of NFκB and CXCR4 in human prostate cancer specimens. Methods: Paraffin embedded samples from a subset of patients in the RTOG 8610 trial underwent immunohistochemical staining for NFκB and CXCR4. This study compared radiotherapy plus hormonal therapy to radiation therapy alone. The amount of NFκB and CXCR4 was scored by a blinded pathologist for the percentage of cells stained (0 to 100%) and staining intensity (0 to 3+). Results: NFκB and CXCR4 status was determined for 55 and 63 patients, respectively. Both NFκB and CXCR4 status were available for 51 of these patients. Of these, 51% were 2/3+ for NFκB and 61% were 2/3+ for CXCR4. There was a trend towards correlation between CXCR4 and NFκB staining as 18 of the 36 patients who were 2/3+ positive for NFκB were 2/3+ for CXCR4. 10 of the 11 pts with 3+ NFκB had 2/3+ CXCR4. This was consistent with the understanding that CXCR4 is regulated by NFκB, but did not reach statistical significance (p = 0.1298). Neither NFκB or CXCR4 were statistically significantly prognostic factors in this small subset of patients. Conclusion: NFκB and CXCR4 are expressed in a significant number of patients with organ confined prostate cancer. Neither predicted outcomes in this analysis, which may be due to the small sample size. This data supports the notion that NFκB regulates CXCR4 expression in prostate cancer and that one or both may be potential new targets for therapeutic intervention. Studies in larger prospective studies to determine the utility of NFκB and CXCR4 as predictive biomarkers and/or therapeutic targets is warranted. [Table: see text] No significant financial relationships to disclose.
A phase II study utilizing oxaliplatin and docetaxel in androgen independent prostate cancer in men treated with up to two prior chemotherapy regimens
Authors: Feinstein T. M. , Friedland D. M. , McIntire K. E. , Jacobs S. A. , Ferri W. A. , Earle M. F. , Hyoung K. D. , Brown L. M. , Chatta G. S. 
Published: March 2020

14580 Background: Second line treatment of androgen independent prostate cancer (AIPC) is unsatisfactory. Single agent docetaxel has demonstrated survival benefit in AIPC. In a phase-I study utilizing oxaliplatin at the University of Pittsburgh (UP), two patients with AIPC experienced a substantial and durable reduction in PSA. Thus, we hypothesised that a combination of docetaxel and oxaliplatin may be synergistic in AIPC. Methods: This single arm phase II trial commenced in June 2005, with the objectives of evaluating PSA response rates, progression free survival, and the toxicity (tolerance/safety) of the regimen. Using Simon stage II design, a total of 37 patients (pts) with AIPC will be accrued. To date, 20 men have been enrolled: median age 67 yrs (56–84); 9 patients being chemo-naïve and 11 having received prior chemotherapy. Treatment consisted of docetaxel (60 mg/m2) and oxaliplatin (110 mg/m2), infused every 21 days. Follow-up assessments (every two cycles) include serum PSA and imaging studies. Results: 14 of 20 men have completed at least two cycles and are evaluable. In the chemo-naïve subset (n = 8), the average pre-treatment PSA was 312.8 ± 275.8 ng/ml, with 3 of 8 pts experiencing > 50% reduction in PSA and 2 of 8 pts with > 25% reduction. In pts with prior chemotherapy (n = 6), the average pre-treatment PSA was 1194.4 ± 1777.8 ng/ml, with 3 of 6 pts experiencing > 50% reduction in PSA and 1 of 6 pts with > 25% reduction. 4 of 8 men with measurable soft tissue disease had a partial response. There were < 7% grade 3/4 adverse events (AEs). Treatment-related AEs include: neutropenia (41%), thrombocytopenia (11.8%) and anemia (5.9%). Non-hematologic toxicity included neuropathy (53%) diarrhea (47%), nausea (41%) fatigue (76%) and anorexia (29.4%). Conclusions: The combination of oxaliplatin and doxetaxel is well tolerated in patients with AIPC, and has significant activity even in patients with prior exposure to chemotherapy. The study continues to accrue pts, and the results will be updated at presentation. [Table: see text]