bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I dose escalation trial of vaccine replicon particles (VRP) expressing prostate-specific membrane antigen (PSMA) in patients (pts) with castration-resistant prostate cancer (CRPC): Preliminary results.
Authors: Slovin S. F. , Kargman M. , Durso R. , Curley T. , Israel R. J. , Olson W. C. , Morris S. , Murphy D. , Scher H. I.
Published: February 2017

140

Background: Prostate-specific membrane antigen (PSMA), a type II transmembrane protein overexpressed in prostate cells as they emerge into the androgen-independent state, remains a target to which vaccines with novel adjuvants or naked DNA has been directed. The PSMA-Viral Replicon Package (VRP) is a propagation-defective vector system from an attentuated strain of an alpha virus (VEE) encoding PSMA for use as a vaccine in prostate cancer. The PSMA gene is encoded by a subgenomic messenger RNA (mRNA), leading to high level expression of PSMA protein and presentation to the immune system.. We report preliminary results of a first in human trial using PSMA VRP to elicit immune responses targeting PSMA.

Methods: Up to 18 pts with chemotherapy naïve CRPC metastatic to bone or soft tissue were permitted with 12 pts enrolled with ECOG status of 0 or 1. PSMA VRP was administered SC doses of either 0.9×107 IU or 0.36×108 IU for a total of 5 doses given on weeks 1, 4, 7, 10 and 18. Adverse events, PSA, circulating tumor cells, and clinical disease progression were assessed. Immune assessment was performed on patients' sera by ELISA and flow cytometry of serum binding to PSMA expressing tumor cells (3T3) and cellular (IFN-g EliSpot) components. Patients underwent imaging with bone and CAT scans every 3 months.

Results: Three pts received 0.9×107 IU and 9 received 0.36×108 IU. Of these, 8 pts received all 5 vaccines. Four pts were taken off study for disease progression. One pt at the 0.36×108 continues on study and will be receiving his seventh vaccine. The demographic featuresof the 12 subjects enrolled were similar (mean age 69±11 yrs). No significant adverse events were noted; no aberrant laboratory abnormalities were associated with treatment. Weak humoral responses were observed in 1 patient in the 0.9×107 IU group and in 3 treated at 0.36×108.

Conclusions: In this first-in-man evaluation, vaccination with PSMA VRP appeared to be well-tolerated but does not appear to show impact on disease progression. Further studies are ongoing to assess immune responses and identify potential pathways for enhancement of the PSMA VRP approach.

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The efficacy and safety of degarelix, a GnRH receptor antagonist: A multicenter, randomized, maintenance dose-finding phase II study with Japanese prostate cancer patients.
Authors: Ozono S. , Ueda T. , Hoshi S. , Yamaguchi A. , Maeda H. , Fukuyama Y. , Ohashi Y. , Tsukamoto T. , Naito S. , Akaza H. ,   Degarelix Japan Study Group
Published: February 2017

154

Background: Degarelix, a GnRH receptor antagonist inducing rapid, profound and sustained suppression of serum testosterone levels, without testosterone surge, was evaluated in a phase II dose finding study in Japan.

Methods: A total of 278 patients with adenocarcinoma of the prostate were randomized and 273 patients (any stage; median age, approx. 76 years; median testosterone, 4.46 ng/mL; median prostate-specific antigen (PSA) level, 22.8 ng/mL) received study treatment. Degarelix was administered subcutaneously at an initial dose of 240 mg followed by monthly maintenance doses of either 80 mg or 160 mg. The treatment continued for 12 months in the study.

Results: The primary endpoint was the proportion of patients with testosterone suppression to castrate level of ≤0.5 ng/mL during 12 months treatment. Both dose regimens of 80 mg and 160 mg kept 94.5% and 95.2% of patients on castrate level respectively throughout the treatment period. At 3 days of treatment, approximately 99% of the patients reached the castrate level without testosterone surge. The percentage change in serum PSA reduction exceeded 76% at 4 weeks. The overall tumor response rates (proportion of patients with complete and partial responses) were from 77.4% to 90.8% across the groups. Eighteen patients (6.6%) withdrew from the study due to adverse events. The most common adverse events were injection site reactions; other adverse events included pyrexia, weight increased, hypertension and hot flush. Degarelix appeared well tolerated.

Conclusions: With an initial dose of 240 mg followed by monthly maintenance doses of 80 mg or 160 mg, Degarelix resulted in a rapid profound and sustained testosterone suppression to castrate level and PSA reduction without testosterone surge for 12 months. Degarelix was well tolerated. The maintenance doses of 80 mg and 160 mg had similar efficacy and safety profiles. The study shows results similar to those from the degarelix pivotal phase III study (CS21). Assessment of risk-benefit would support the recommendation of the maintenance dose of 80 mg as a safe and effective monthly dose for the treatment of prostate cancer.

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Identification of a small-molecule inhibitor of Stat5a/b through structure-based screen for therapy development for prostate cancer.
Authors: Liao Z. , Gu L. , Shen F. , Dagvadorj A. , Gupta S. , Pattabiraman N. , Nevalainen M. T. , Trabulsi E. J. , Gomella L. G. , McCue P.
Published: February 2017

17

Background: There are no effective treatments for metastatic or castration resistant prostate cancer. We have shown that transcription factor Stat5a/b is constitutively active in high-grade prostate cancer, but not in normal human prostate epithelium. Stat5a/b is active in 95% of clinical castration resistant prostate cancers, and the expression of active Stat5a/b in primary prostate cancer predicts early disease recurrence. Stat5a/b is critical for the viability of prostate cancer cells in vitro and for growth of prostate xenograft tumors in nude mice. Stat5a/b synergizes with androgen receptor (AR) and Stat5a/b promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Here, we hypothesize that Stat5a/b is a molecular target for rational drug design for prostate cancer.

Methods: We identified a small- molecule inhibitor of Stat5a/b dimerization by structure-based virtual screen from a database of 30 million chemical structures. The efficacy of the Stat5a/b inhibitor was determined by reporter gene assays, dimerization by co-immunoprecipitations, nuclear translocation by cytochemistry and binding to DNA by EMSA. Cell viability was analyzed by MTT assay.

Results: The novel Stat5a/b inhibitor IST5-002 inhibited transcriptional activity of Stat5a/b at IC50 of 1.5 μ M for Stat5a and 3.5 μ M for Stat5b, but not of Stat3 in prostate cancer cells. IST5-002 inhibited dimerization, nuclear translocation, and binding of Stat5a/b to the Stat5 DNA consensus sequence. Furthermore, IST5-002 inhibited expression of Stat5a/b target gene cyclin D1, and induced massive apoptosis of DU145, CWR22Rv1 and LNCaP human prostate cancer cells. IST5-002 blocked prostate cancer xenograft tumor growth in nude mice and induced death in clinical prostate cancers ex vivo in 3D organ cultures.

Conclusions: We have identified a small molecule Stat5a/b inhibitor IST5-002 for therapy development for prostate cancer. Future work will focus on chemical modifications of IST5-002 to achieve IC50 below 1 μ M and oral administration.

No significant financial relationships to disclose.
Comorbidity and treatment regret in men with recurrent prostate cancer.
Authors: Nguyen P. L. , Chen M. , Chen R. C. , Hoffman K. E. , Hu J. C. , Bennett C. L. , Kattan M. W. , Sartor A. O. , Stein K. , D'Amico A. V. ,   COMPARE Registry Steering Committee
Published: February 2017

187

Background: To determine whether concurrent comorbidity is associated with treatment regret among men with PSA recurrence following primary therapy for prostate cancer.

Methods: Among 795 men in the Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry (COMPARE) study who experienced PSA failure and were assessed a median of 5.5 (interquartile range 2.8-9.1) years after prostatectomy (n=410), external beam radiation (n=237), brachytherapy (n=124), or primary androgen deprivation (n=24), multivariable logistic regression was used to determine whether comorbidity level, sociodemographic factors, and other treatment factors were associated with treatment regret, as defined by a validated two-question screen. Significant comorbidity was defined as myocardial infarction, congestive heart failure, angina, diabetes, stroke, circulation problems, inflammatory bowel disease, or amputation.

Results: Of 795 men, 14.8% reportedregret. Men with significant comorbidity were more likely to experience post-therapy bowel toxicity (p=0.029) and urinary problems (p=0.051). On multivariable analysis, significant comorbidity [adjusted odds ratio (AOR)=1.57 (95% CI:1.04-2.37); p = 0.033] and younger age [AOR: 0.965 (0.937-0.994) per year increase in age; p = 0.019] were associated with increased regret even after adjusting for post-therapy bowel and urinary complications.

Conclusions: In a population of men with PSA recurrence, those with significant comorbidity were particularly prone to treatment regret, which highlights the growing importance of considering comorbidity when counseling patients about prostate cancer treatment options. To properly set expectations, such men should be informed about their potential for increased post-treatment toxicity, which may reduce their risk of regret if toxicity occurs, and serious consideration should be given to active surveillance.

[Table: see text]
Comorbidities predict overall survival (OS) in men with metastatic castrate-resistant prostate cancer (CRPC).
Authors: Halabi S. , Kelly W. K. , George D. J. , Morris M. J. , Kaplan E. B. , Small E. J.
Published: February 2017

189

Background: Management of prostate cancer in senior adults represents an important challenge as the median age at diagnosis is 68 and comorbidities in patients increase with advancing age. The objective of this analysis was to determine if baseline comorbidities number (CON) prior to initiating frontline chemotherapy impacts OS in men with CRPC.

Methods: Data from a randomized phase III trial of 1,050 men who received docetaxel, prednisone with or without bevacizumab were used in this analysis. Eligible patients had metastatic CRPC with evidence of progressive disease despite castration and anti-androgen withdrawal, ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function. Comorbidities on 14 conditions including cardiovascular, hypertension, diabetes, arthritis, thrombosis, AIDS, renal disease, liver disease and peptic ulcer were prospectively collected at baseline from men enrolled on this trial. The proportional hazards model was used to test if CON predicted OS adjusting for treatment arm, age, race, body mass index and predicted survival probability at 24 months using the CALGB nomogram.

Results: In 1,048 men with comorbidity data, the mean CON was 1.5 (s.d.= 1.47, range=0-9) and 73% of men had at least one comorbidity. There was a statistically significant association between CON and risk of death. In multivariable analysis, the hazard ratio (HR) for death for one unit increase in CON was 1.09 (95% CI= 1.04- 1.14, p-value=0.0008).

Conclusions: To our knowledge, this is the first analysis to show that CON is a statistically significant predictor of OS in men with CRPC. These results require prospective validation in phase III trials of men with CRPC.

[Table: see text]
Real-world clinical resource utilization of metastatic prostate cancer patients in the United States: Results from two large claims databases.
Authors: Lafeuille M. , Senbetta M. , McKenzie R. S. , Lefebvre P.
Published: February 2017

204

Background: In metastatic prostate cancer (MPC) patients, treatment options include hormonal therapies, chemotherapy, and radiotherapy. This study quantifies the real-world healthcare resource utilization of MPC patients.

Methods: Health insurance claims from 40 self-insured companies across the US (Employer [E]; 01/1999-02/2009), and from the Medicare 5% ([M]; 1999-2008) databases were analyzed. Patients with a metastasis diagnosis (ICD-9: 196-199) following 2 prostate cancer diagnoses (ICD-9: 185, V10.46) within 365 days were identified. Patients with other malignant diagnoses at baseline, defined as 365 days prior to metastasis diagnosis (index date), were excluded. Patients were evaluated for baseline medical history and for chemotherapy, hormonal agents, radiation, and corticosteroids utilization during both baseline and observation periods. Hospitalization rates and prostate cancer-related procedures post index date were also reported.

Results: The study population comprised 11,725 patients (E: 3,227; M: 8,498). Mean age (SD) was 72.8 (10.2) in Employer and 78.1 (7.7) in Medicare. Mean observation period (SD) was 803 (753) days in Employer and 9.2 (8.2) quarters in Medicare. During the baseline period, chemotherapy, hormonal agents, radiation therapy, and corticosteroids were administered to 5%, 52%, 9%, and 21% of Employer, and 2%, 45%, 8%, and 12% of Medicare patients respectively, whereas these interventions increased to 22%, 55%, 39%, and 46% for Employer, and to 21%, 50%, 33%, and 29% for Medicare during the observation period. A total of 66% Employer and 79% Medicare patients were hospitalized post index date. Most patients (E: 92%; M: 98%) had prostate cancer-related procedures, including prostate specific-antigen testing (E: 39%; M: 80%), computerized axial tomography scan (E: 72%; M: 81%), prostate biopsy (E: 47%; M: 54%), X-ray (E: 11%; M: 64%), bone scan (E: 56%; M: 60%), and magnetic resonance imaging scan (E: 35%; M: 37%).

Conclusions: This observational study describes real-world utilization patterns in patients with advanced prostate cancer.

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Correlation of elevated alkaline phosphatase (ALP) and survival in metastatic castration-resistant prostate cancer (CRPC) treated with docetaxel chemotherapy: Results of SWSW Uro-oncology Group study from three U.K. centers.
Authors: Bahl A. K. , Bertelli G. , Lewis P. D. , Jenkins P. , Aziz A. , Davies P. J. , Persad R. , Smith C. G. , Hurley K. , Mason M. D.
Published: February 2017

206

Background: Treatment with docetaxel in CRPC based on the results of the TAX 327 study has been recommended by NICE guidance in UK. Paucity of UK data on any significant difference in median survival of CRPC patients receiving chemotherapy with normal or elevated ALP is a possible contributory factor to the delayed consideration of chemotherapy in CRPC. We therefore analysed differences in survival in metastatic CRPC patients with normal or elevated ALP treated with docetaxel chemotherapy in 3 cancer centres in UK with a contemporary referral population.

Methods: Survival data were collected on consecutive cases of metastatic CRPC treated with at least 1 cycle of docetaxel chemotherapy in these 3 centres. Variables analysed included: presence or absence of pain, PSADT, Gleason score, Haemoglobin, Alkaline phosphatase and number of previous lines of hormone therapy.

Results: Median overall survival in 170 eligible patients was 18.1 months (15.3-20.7) with median follow-up of 30.1 months. 84 cases had normal ALP and 86 cases had elevated ALP at time of commencing docetaxel chemotherapy. Median survival was 14.1 months (95% CI= 11.1-17.1) in the elevated ALP group and 22.2 months (95% CI= 17.5- 26.9) in the normal ALP group. The difference between group medians was significant (p<0.001). In multivariate analysis, elevated ALP was a significant prognostic factor for outcome after docetaxel chemotherapy in metastatic CRPC.

Conclusions: Regular monitoring of ALP along with PSA monitoring can be a relatively simple way of ensuring that patients with metastatic CRPC are referred for chemotherapy appropriately. To our knowledge this is the first UK data on the impact of ALP level on survival in this group of patients after docetaxel chemotherapy. It is important that decision regarding chemotherapy is based on the parameters of disease progression and regular ALP monitoring may be a relatively simple and practical way of ensuring the right timescales for referral for chemotherapy in metastatic CRPC.

[Table: see text]
Effect of dual inhibition of the Src and insulin-like growth factor-1 receptor (IGF-1R) pathways on antitumor effects in prostate cancer (PCa).
Authors: Dayyani F. , Parikh N. , Song J. H. , Araujo J. C. , Carboni J. M. , Gottardis M. M. , Trudel G. C. , Logothetis C. , Gallick G. E.
Published: February 2017

21

Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases and IGF-1R, respectively. The aim of this study was to establish antitumor co-operativity by combining IGF-1R and Src blockade in a preclinical PCa model.

Methods: LNCaP and PC3 cells were used as models for androgen-dependent and independent PCa, respectively. Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IGF-1R) as well as by shRNA. Serum IGF-1 levels were measured in patients (pts) with castration-resistant PCa (CRPC) treated with dasatinib and docetaxel in a phase II trial.

Results: Src inhibition decreased proliferation of PCa cells, and migration in modified Boyden Chamber and wound assays. In contrast, IGF-1R blockade induced apoptosis (increased Sub-G1 fraction cells, Annexin-V(+) cells and PARP cleavage). Phosphorylation of Akt was partially inhibited by either drug alone and almost completely abrogated by the combination. Intraprostatic injection of shIGF-1R or shSrc PC3 cells in nude mice led to an 83% and 60% decrease in tumor size compared to control shRNA, respectively. In both cell lines, all observed antitumor effects were enhanced when dual blockade was used, relative to blocking the Src or IGF-1R pathway alone. In 9/19 (47%) pts with CRPC, treatment with dasatinib resulted in a compensatory increase of serum IGF-1 levels.

Conclusions: Dual inhibition of Src and IGF-1R is effective and complementary in PCa, mediated, in part, through inhibition of the downstream target Akt. In about half of pts treated with dasatinib, an increase in soluble IGF-1 levels was observed, indicating there is a compensatory upregulation of survival pathways that might be abrogated by dual inhibition of Src and IGF-1R. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression.

[Table: see text]
Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer.
Authors: Morgans A. K. , Hancock M. L. , Barnette G. , Steiner M. S. , Morton R. A. , Smith M. R.
Published: February 2017

212

Background: In the general population, black men have higher bone mineral density (BMD) and lower fracture rates than white men. Whether race influences bone loss and fracture risk during androgen deprivation therapy (ADT) for prostate cancer is unknown. Using data from a recently completed prospective, randomized, clinical trial we compared BMD and fracture rates of black and white men receiving ADT for prostate cancer.

Methods: Subjects in these analyses (n=516) were members of the placebo group of a two-year randomized controlled trial of toremifene to prevent fractures in men receiving ADT for prostate cancer. All subjects resided in United States and reported their race as either black (n=68) or white (n=448). We compared baseline characteristics, including BMD and prevalent vertebral fractures, between black (n=68) and white men (n=448). We also compared changes in BMD and rates of new vertebral fractures over the two year study period.

Results: Black men had higher baseline hip BMD than white men (0.98 ± 0.15 g/m2 and 0.91 ± 0.15 g/m2, respectively; p=0.001). Black men had similar BMD of the spine (1.09 ± 0.22 g/m2 and 1.11 ± 0.22 g/m2 in black and white men, respectively; p=0.51), but fewer prevalent vertebral fractures (7.4% versus 15.0%; p=0.13). Changes in BMD from baseline to 24 months were similar between black and white men (total hip percentage change −2.54 ± 0.26 in white men and −2.09 ± 0.60 in black men; p=0.55; lumbar spine percentage change −1.30 ± 0.33 in white men and −1.67 ± 0.71 in black men; p<0.71). Rates of new vertebral fractures trended towards being lower in black men (1.15% of black men versus 4.83% of white men; relative risk 0.24; p<0.12).

Conclusions: Among men receiving ADT for prostate cancer, black men had higher baseline BMD at the hip and fewer prevalent vertebral fractures. Changes in BMD during ongoing ADT were similar for black and white men. Consistent with lower baseline risk for fracture, however, black men had fewer new vertebral fractures than white men.

[Table: see text]
Comparison of health care resource use before and after docetaxel treatment among prostate cancer patients.
Authors: Mehra M. , Wu Y. , Dhawan R.
Published: February 2017

215

Background: Docetaxel is standard of care among late-stage prostate cancer patients. We analyzed patterns of health care resource utilization (RU) among patients before and after exposure to docetaxel using a large commercial claims database.

Methods: A random sample of patients (N = 336) with a diagnosis of prostate cancer (ICD 9 code: 185.X) and a claim for docetaxel (2003–2009) was identified from the PharMetrics database, a nationally representative, non-payer-owned integrated commercial U.S. claims database. All patients had ≥ 12 months of enrollment prior to initiation of docetaxel. Patients were followed from their first docetaxel claim until lost to follow-up or June 30, 2009 (censored). RU was defined as all-cause hospitalization, ER, physician, and ambulatory visits. Incidence rates were derived.

Results: Mean age of patients was 67.9 years (SD 10.6); mean number of docetaxel prescriptions was 9.9 (SD 10.3). Mean time to study end/lost to follow-up was 15.41 (SD 12.49) months from the index date. The table shows health care RU for the 12 months before, and over the follow-up period after docetaxel initiation. Hospitalizations, ER, physician, and ambulatory visits were significantly higher in the follow-up period. The average length of hospital stay was significantly longer after docetaxel treatment (8.2 vs 5.5 days). Prior to docetaxel, two-thirds of the patients were on hormonal therapy; 51% on analgesics, and 31% on bisphosphonates. After docetaxel, the proportions were 62%, 58%, and 54%, respectively.

Conclusions: The significantly higher RU with disease progression in prostate cancer patients suggests a need for new treatment options that can effectively manage and improve patient outcomes.

[Table: see text]

[Table: see text]
BRAF and KRAS mutations in penile cancer and their correlation with clinical features.
Authors: Valverde C. M. , Hernandez-Losa J. , Ferrandiz-Pulido C. , Morales R. , Suarez C. , de Torres I. , Serrano C. , Carles J.
Published: February 2017

221

Background: Penile cancer is a rare disease in developed countries. While surgery may be curative for patients with localized disease, for metastatic patients systemic chemotherapy may offer palliation with usually short-lived responses. Thus, new options in this setting are needed. Retrospective series have reported EGFR overexpression in more than 90% of the cases and also interesting results of EGFR directed therapies in these patients have been comunicated. The role of KRAS status or other molecular markers as prognostic or predictive factors remains unclear. The aim of this study was to determine the prevalence of BRAF and KRAS somatic mutations in penile cancer and their correlation with clinicopathologic features.

Methods: We analyzed 28 samples collected from de archives of the Pathology Department at our institution from 1996 to 2009. The DNAs were extracted from FFPE blocks by Biorobot EZ1 following the manufacturer protocol of the EZ1-DNA Tissue kit (Qiagen). KRAS and BRAF mutations were amplified with specific primers, and sequenced by Sanger with Bigdye terminator v3.1 Cycle Sequencing Kit. Medical records were reviewed for clinical data.

Results: No BRAF mutations were found, but we identified somatic missense mutations in the KRAS gene (all activating G12D mutations) in 6/27 samples (22%, one not evaluable). Median age at diagnosis (73 vs. 71), grade and histologic subtype did not differ between wt and mutated (mt) patients. There was a trend toward a more advanced stage at diagnosis in mt versus wt : 33 versus 47% stage I, 16 versus 9% stage II and 50 versus 38% stage III respectively. 2/6 mt patients died (due to other causes) as did 5/21 wt patients (3 of them because of disease progression).

Conclusions: BRAF mutations seem not involved in the EGFR pathway in penile carcinomas. The prevalence of KRAS mutations was unexpectedly high in our series and mt patients tended to be diagnosed at a more advanced stage. Unfortunately, no correlation was found with other clinicopathologic features, including overall survival in our small series. These results suggest a role of KRAS mutation in the development of these carcinomas and support the importance to determine KRAS status in patients to be treated with anti-EGFR based therapies.

No significant financial relationships to disclose.
Late CT surveillance in nonseminoma germ cell tumors (NSGCT).
Authors: Singhera M. , Johnson B. , Harris V. , Horwich A. , Dearnaley D. P. , Huddart R. A.
Published: February 2017

223

Background: Testicular cancer is the commonest solid malignancy in 18-35 year old men. With the introduction of cisplatin, most patients with metastatic disease are cured.Over recent years a risk of late relapse (>2 years after first line therapy) has been recognised in 2- 6% of NSGCTs. Appropriate follow-up strategies have not been determined. To investigate, the utility of long term CT surveillance we initiated a study to see if late CT could detect late relapses at an early stage.

Methods: Eligible patients had been treated for Stage IM – Stage IV NSGCT diagnosed 5 years prior to entry. CT scans were at study entry and 5 years. Patients are reviewed annually with tumour markers and clinical examination. We plan to recruit 300 patients. This reports details the outcome of a planned interim analysis of the first round of screening after recruiting 100 patients

Results: 108 patients have been enrolled into the study since 2006. Full clinical data was available for 88 patients. Median age was 31 years at diagnosis. 52 patients had evidence of teratoma differentiated (TD) in the primary.Stage at treatment was IM (1), II (45), III (6) and IV (36). Treatment was BEP [bleomycin, cisplatin and etopside (3 cycles: 30), (4 cycles: 20)], CBOP/BEP (16) and other platinum schedule (8) at diagnosis. 27 patients relapsed.Overall 38 had retroperitoneal lymph node.TD noted in 28. 10 had a metastatectomy [brain (2), pelvic mass (1:TD), pulmonary (6;TD:2), neck (2), iliac node (1:TD)]. Study scan was reported normal in 71 patients. None of these have relapsed however 1 patient died of interval lung cancer. Radiological abnormalities were identified in14 patients. 4 underwent surgery (3 RPLND and 1 lung nodule excision). 2 were benign and 2 had TD.1 patient had liver lesions proven to be cysts on ultrasound. 8 had small volume nodal abnormalities which are stable on repeat imaging. 1 is on annual CT surveillance for indeterminate lung nodules.4 patients are awaiting the initial study scan

Conclusions: Late CT scan detected significant abnormalities in patients treated for NSGCT leading to surgery. Abnormalities not deemed appropriate for surgical intervention are being followed up surveillance scans.

No significant financial relationships to disclose.
Comparing the perioperative management of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in patients with pure seminomatous and nonseminomatous germ cell tumors (NSGCT).
Authors: Pfister D. J. , Busch J. , Winter C. , Schrader M. , Dieckmann K. , Schmelz H. U. , Albers P. , Heidenreich A.
Published: February 2017

230

Background: PC-RPLND is a potentially complicated intervention. By the time the rate of complications and adjunctive surgery increased. Only few data are available concerning PC-RPLND in patients with advanced seminomas and residual retroperitoneal tumour lesions. We examined the intra and postoperative complications as well as the frequency of adjunctive surgeries in patients with seminoma and compared the data to a cohort of patients with NSGCT who underwent PC-RPLND.

Methods: In our multicenter retrospective analyses 408 patients underwent PC-RPLND between 1989 and 2010. 47 patients with advanced seminomas and 327 patients with NSGCT. The surgical approach was preferred via a midline incision or a thoracoabdominal approach due to the location of the residual tumour. In one center a laparoscopic approach was preferred.

Results: Of the 47 patients with seminoma a total number of 18 adjunctive surgeries were performed in 11 patients (8 nephrectomies, 3 inferior v.cava resections, 3 resections of the abdominal aorta, 2 resections of the colon, one nerv and 2 hepatic resections/biopsies). There was only one major intraoperative complication, injury of the v. cava and two postoperative complications, (prolonged intestinal paralyses). There were no significant differences adjunctive surgeries and postoperative complications (p=0.48 and p=0.133). There were significantly less intraoperative complications in favour of seminomas (p=0.006).

Conclusions: PCRLND in seminomas and NSGCT is a demanding surgical intervention. In contrast to other series we did not find significant differences in the two patient groups concerning adjunctive surgeries and postoperative complications. The indication for PCLND in patients with seminoma is limited, but if necessary it can be performed safely in experienced centers.

No significant financial relationships to disclose.
Anthropomorphic and hormone abnormalities in testicular cancer patients.
Authors: Singhera M. , Coffey J. , McDonald F. , Horwich A. , Dearnaley D. P. , Rapley E. , Huddart R. A.
Published: February 2017

233

Background: Studies show a range of environmental and genetic associations with testicular cancer, specifically testicular dysgenesis, increased height, and multiple dysplastic naevi. To confirm these findings, we studied a cohort of testicular cancer patients and healthy controls. We also studied a cohort of unaffected relatives of patients to identify if any noted differences might be due to shared genetic/environmental background.

Methods: We identified index cases from the hospital database. They nominated an unaffected relative and an unrelated friend. Controls were supplemented by recruitment of institutional staff.

Results: 183 index cases (IC), 57 unaffected relatives (UR) and 103 unrelated controls (UC) were identified. Mean age was 47 years (25-78) IC, 44 years (18-74) in UR and 42 years (20-74) in UC. IC treated by chemotherapy (ch) had higher mean FSH than non chemotherapy patients (s)[18.98 v 13.22 (p=0.01)] and lower mean testosterone [ch:12.21, s:13.52 (p=0.04)] though mean LH [ch:7.94, s:6.05 (p=0.10)] and BMI (ch:27.38 s:26.81 (p=0.33) were not significantly different.

Conclusions: In contrast to other studies, we found both testicular cancer patients and their relatives were shorter and with reduced arm length compared with controls; a sign of a possible shared genetic or environmental effect. There was no significant difference in weight, BMI, body fat %, lean body mass, and leg length. FSH and LH were significantly elevated and testosterone reduced in index cases (but not relatives) particularly in those who had chemotherapy. The lack of difference between relatives and controls suggests these are most in keeping with direct treatment effects.

[Table: see text]

No significant financial relationships to disclose.
Germline single-nucleotide polymorphisms (SNPs) associated with response of urothelial carcinoma (UC) to platinum-based therapy: The role of the host.
Authors: Gallagher D. , Joseph V. , Garcia-Grossman I. R. , Przybylo J. A. , Riches J. C. , Ostrovnaya I. , Hamilton R. , Milowsky M. I. , Offit K. , Bajorin D. F.
Published: February 2017

236

Background: Platinum-based therapy improves outcome in neoadjuvant and metastatic UC. Since cell-line and human subject studies in other cancers show germline associations with platinum response, we hypothesized that germline variation also identifies genes that determine UC response to platinum-based therapy.

Methods: Saliva or blood was prospectively collected from 651 UC patients (pts) diagnosed between 1984 and 2010. SNPs (n=80) were selected based on previously reported associations with UC and/or platinum response and genotyped using Sequenom MassArray iPLEX system. Samples and SNPs were filtered for genotyping rate (<0.8), minor allele frequency (<0.05) and departures from Hardy-Weinberg equilibrium (<1E-03). Clinical data were ascertained and linked with the genomic data in an anonymized manner. This analysis focused on 199 pts who received cisplatin or carboplatin and were eligible for response assessment (RES=partial response or complete response, n=90). Associations between SNPs and RES were tested using one and two degree of freedom tests.

Results: Sixty-nine pts received neoadjuvant therapy (RES=54%), 126 chemo-naive pts received first-line metastatic treatment (RES=37%) and 4 received systemic treatment after prior chemoradiotherapy (RES=25%). We expected 4 associations due to chance alone at p < 0.05. However, on univariate analysis using a 2 degree of freedom test, 9 SNPs were associated (p < 0.05) with RES. Individual odds ratios (ORs) ranged from 0.32 to 3.29 with p-values ranging from 0.006 to 0.05. In analysis of rs9344 (CCND1) in all treated pts, 75/148 (51%) responded with AG/GG compared to 12/44 (27%) with AA [p=0.005312, OR 2.74 (CI 1.34, 5.92)]. In neoadjuvant pts treated with cisplatin, rs9344 analysis showed 29/48 (60%) responses in AG/GG pts compared to 5/17 (29%) with AA [p=0.026, OR 3.66 (CI 1.16, 13.1)].

Conclusions: We identified associations between 9 SNPs and response of UC to platinum-based therapy that are biologically and clinically relevant. A larger study will be required to independently validate these findings. Additional investigation of associations with time to metastasis and overall survival is ongoing.

[Table: see text]
Effect of a therapeutic sphingosine 1-phosphate antibody on intratumoral hypoxia and sensitivity to standard chemotherapy in prostate cancer animal model.
Authors: Cuvillier O. , Ader I. , Bouquerel P. , Malavaud B. , Sabbadini R. A.
Published: February 2017

24

Background: Hypoxia promotes neovascularization, metastasis, growth and resistance to treatments. The activation of HIF-1α has been identified as the master mechanism of adaptation to hypoxia. We recently identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α activity under hypoxia in multiple cancer cell models (Ader et al, Cancer Res, 2008). S1P elicits proliferation, survival, or angiogenesis, and is believed to exert most of its actions as a ligand for a family of specific GPCRs to elicit paracrine or autocrine signaling. We have suggested that inhibiting SphK1/S1P signaling, which is up-regulated under hypoxia, may help normalizing the tumor microenvironment and increase sensitivity to chemotherapy, in the broader concept of normalization of tumor vessels as tumor oxygenation is known to enhance response to chemotherapy (Ader et al., Cancer Res, 2009).

Methods: Quantitation of hypoxia and angiogenesis, and treatment efficacy using an orthotopic (o.t) xenograft model of fluorescent HRPC cells.

Results: We provide in vitro evidence that inhibiting the S1P exogenous signaling, through pharmacological inhibition of its receptors or by taking advantage of a monoclonal antibody neutralizing S1P, blocks HIF-1α accumulation and its activity in prostate cancer cells under hypoxia. Second, using an o.t model of prostate cancer, we show that an anti-S1P antibody inhibits intratumoral hypoxia and modifies vessel architecture within 5 days of treatment. Third, we demonstrate that an anti-S1P strategy sensitizes to docetaxel, the “gold standard” treatment for HRPC. A 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/GFP model established in nude mice. The combination anti-S1P antibodytogether withdocetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel alone, but also significantly reduced the occurrence and number of metastases.

Conclusions: These data establish the proof-of-concept that blocking the exogenous action of S1P reduces intratumoral hypoxia and sensitizes to chemotherapy in prostate cancer animal model.

[Table: see text]
Effect of EGFR inhibition with cetuximab on the efficacy of paclitaxel in previously treated metastatic urothelial cancer.
Authors: Wong Y. , Litwin S. , Plimack E. R. , Vaughn D. J. , Song W. , Cohen S. M. , Lee J. W. , Dabrow M. B. , Tuttle H. , Hudes G. R.
Published: February 2017

243

Background: The benefit of salvage chemotherapy such as weekly paclitaxel (TAX) is modest in metastatic (met) urothelial ca, with median TTP of ≤3 months and ORR of 10% (95% CI 4-18% [combined results, Vaughn 2002; Joly, 2009]). Cetuximab (CET) is a monoclonal antibody against the epidermal growth factor receptor (EGFR). High-grade urothelial cancer overexpress EGFR. We conducted a multicenter randomized, noncomparative phase II study to measure the efficacy of CET ± TAX in patients (pts) with previously treated met urothelial cancer.

Methods: Pts with met urothelial cancer who received one line of chemotherapy in the adjuvant, neoadjvuant, or met setting were enrolled. Pts were randomized to CET 250mg/m2 (after 400 mg/m2 load) ± TAX 80 mg/m2 weekly. A cycle was 4 weeks (wks). Response (RECIST) was assessed by imaging every 8 wks. We used early progression to assess futility (Litwin Stats Med 2007). Either arm would close if 7 of the initial 15 pts in that arm progressed at the first disease evaluation. Either arm would be considered promising if ≥9/28 patients had PFS>16 wks (90.4% power to detect an improvement in Median [Med] PFS from 8 to 16 wks with a 7.1% type 1 error).

Results: We enrolled 39 evaluable pts (30 male). Median age was 69 years (range 49-79). All pts received prior platinum-based chemotherapy. CET arm closed after 9 of the first 11 pts progressed by 8 wks (ASCO GU 2009). CET-TAX arm completed full accrual (28 pts), of which 11 had visceral disease and 13 received chemo for met disease. 10/28 pts had PFS>16 wks. Overall RR was 28.5%, (8/28 pts, 95% CI 13-49%) (2 CR, 6PR). 4 additional pts had unconfirmed PR. 2 pts have maintained PR 3 and 4 months after discontinuing CET-TAX. Med PFS for the CET-TAX was 115 days (16 weeks)(95% CI 58-174 days). Med PFS for pts with visceral disease was 84 days (95%CI 50-NR). Med PFS for pts who received prior chemo for met disease was 142 days (95% 58-NR). Med number of cycles for the CET-TAX was 3 (range 0-25). Grade 3 AEs occurring in more than 2 pts were rash (5), fatigue (4), anemia (4), low magnesium (3).

Conclusions: EGFR inhibition with CET appears to augment the antitumor activity of TAX in pts with previously treated urothelial cancers. The CET-TAX combination merits further study to establish its role in treatment of urothelial cancers.

[Table: see text]
Prognostic factors of cancer recurrence and progression in non-muscle-invasive urothelial carcinoma: A multicenter study of over 4,300 patients.
Authors: Chromecki T. F. , Svatek R. S. , Holmäng S. , Karakiewicz P. I. , Mazumdar M. , Dunning A. , Kamat A. M. , Tagawa S. T. , Scherr D. , Shariat S. F.
Published: February 2017

249

Background: The outcomes of patients with non-muscle-invasive urothelial carcinoma of the bladder (NMIUCB) remain poorly understood. The aim of our study was to identify prognostic factors of cancer recurrence and progression in patients with primary UCB.

Methods: We performed a combined analysis on individual data from 4,325 patients with primary NMIUCB.

Results: Within a median follow-up of 64 months, 1,960 patients (45.4%) experienced disease recurrence, 498 (11.5%) experienced progression to muscle-invasive stage, 1,155 (26.7%) died of any cause, and 310 (7.2%) died of their cancer. In multivariable Cox regression analysis, advanced age, higher grade, larger tumor size, higher number of tumors, number of prior recurrences, and type of intravesical therapy were independent predictors of disease recurrence and progression. While treatment intravesical chemotherapy was only associated with decreased/delayed cancer recurrence, intravesical BCG therapy was associated with decreased/delayed cancer recurrence and progression. The predictive accuracies of the models for recurrence and progression were 63.5% and 71.3%, respectively.

Conclusions: Even in a heterogenous patient population, BCG therapy appears to decrease frequency and delay time to cancer recurrence and progression in patients with NMIUCB. Predictive tools based on combination of multiple clinical variables which capture the biological and clinical potential of nonmuscle-invasive disease could help with patient counseling and individualized risk assessment for adjuvant intravesical therapy and clinical trial design.

[Table: see text]

No significant financial relationships to disclose.
Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: A randomized phase II trial.
Authors: Khaled H. , Abu-Taleb F. , Haggag R. , Zekri A.
Published: February 2017

266

Background: Bladder carcinoma is the foremost oncologic problem in Egypt. Prolonged infusion of gemcitabine and cisplatin is an effective treatment for advanced bilharzial-related bladder cancer based on a previously published phase II trial.

Methods: To compare efficacy and safety of both prolonged infusion and standard gemcitabine-cisplatin combination, this phase II randomized study of 60 untreated patients with stage III/IV bladder cancer was conducted. Patients were randomized to receive either gemcitabine (250 mg/m2) 6-hour infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (Arm1) or gemcitabine (1,250 mg/m2) 30-min infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (Arm 2).

Results: The 47 males and 13 females had a median age of 60 years (range 40-73 years). A total of 44 patients had transitional cell, 12 had squamous cell, and 4 had undifferentiated cell carcinoma. Among the 53 evaluable patients (26 patients in arm1 and 27 patients in arm 2), complete response rate was achieved in 19.3% (5/26 patients of arm 1) and 7.4% (2/27 patients of arm 2). Eight patients in arm 1 (30.7%) and 7 patients (25.9%) in arm 2 had partial response on therapy. Thus the overall response rate of patients in arm1 and arm 2 was 50% (13/26 patients) and 33.3% (9/27patients), respectively (p = 0.21). No significant difference in median time to disease progression (6.7 months versus 7.9 months, p = 0.42), median survival (9.7 months versus 8.8 months, p = 0.3), and 1-year survival (27% versus 6%, p = 0.3) was detected between arms 1 and 2, respectively. No treatment- related deaths occurred. Main hematologic and nonhematologic toxicities were similar in both arms with no statistically significant differences.

Conclusions: In the treatment of advanced bilharzial bladder cancer, gemcitabine in low dose and prolonged infusion in combination with cisplatin is not inferior to high-dose short infusion gemcitabine and cisplatin in terms of overall survival, time to disease progression, and response rates with favorable toxicity profile and less financial costs.

No significant financial relationships to disclose.
Use of cytokeratin 18 and EAU score to predict tumor recurrence in patients with non-muscle-invasive bladder cancer following single postoperative immediate intravesical chemotherapy instillation.
Authors: Horinaga M. , Murata S. , Matsushima M. , Nakahira Y. , Yanaihara H. , Ueno M. , Asakura H.
Published: February 2017

269

Background: We examined the prognostic factors for recurrence after TURBT using molecular markers as well as the scoring system of the EAU.

Methods: Eighty-eight patients with primary or recurrent bladder tumors who underwent TURBT followed by the single postoperative immediate instillation of pirarubicin and no further instillations were enrolled between 2003 and 2006; the median follow-up period was 46 months. The time to first recurrence was the primary end point of this study. Patients were divided into EAU recurrence risk groups as follows: low-risk group (total score, 0), intermediate-risk group (total score, 1-9) and high-risk group (total score, 9-17). The intermediate-risk group patients were subdivided into a total score of 1-4 and a total score of 5-9. Immunostaining using Ki-67, pHH3, CK18 and Survivin were performed on the TURBT specimens.

Results: According to the risk stratification, 5, 82, and 1 were assigned to the low-, intermediate-, and high-risk recurrence groups, respectively. During the follow-up, recurrences were observed in 0% of the low-risk group, 45% (37 out of 82) in the intermediate-risk group and 100% in the high-risk group. We evaluated various predictors of a recurrence-free outcome among the 82 intermediate-risk patients. In univariate analyses, EAU score (1-4, 32.1% vs 5-9, 62.1%; p = 0.0011), high CK18 expression (negative, 31.4% vs positive 88.8%; p < 0.0001), high Ki-67 index (< 5%, 35.4% vs > 5%, 52.5%; p = 0.017) and high Survivin nuclear staining (< 5%, 35.9% vs > 5%, 62.5%; p = 0.004) were associated with recurrence. In a multivariate analysis, EAU score (HR 2.95, p = 0.003) and a high CK18 immunostaining (HR 6.70, p < 0.0001) were independent predictors of disease recurrence.

Conclusions: A single immediate chemotherapy instillation is, by itself, insufficient for the treatment of patients in the intermediate- or high-risk recurrence groups defined by the EAU guidelines. Strong immunohistochemical expression of CK18 and the EAU scoring system appeared to be independent predictors of clinical outcome among patients with urothelial carcinoma of the bladder.

No significant financial relationships to disclose.
Role of heat shock protein 90 inhibition with 17-(allylamino)-17 (demethoxygeldenamycin) in muscle-invasive bladder cancer cells.
Authors: Williams H.
Published: February 2017

273

Background: Muscle invasive bladder cancer portends a poor long term prognosis. Platinum based therapy is the mainstay of treatment but more effective agents are needed for management of this disease. Heat shock protein 90 (Hsp90) is a ubiquitous protein that has been shown to be overexpressed in tumor cells. It functions as a molecular chaperone responsible for the stability and function of a number of proteins critical to the oncogenic process. 17-(allylamino)-17 demethoxygeldanamycin (17 AAG) is a Hsp90 inhibitor that is currently in phase III trials in several tumor models. The purpose of this study was to evaluate the role of 17 AAG treatment for bladder cancer in vitro.

Methods: Seven bladder cancer cell lines representing muscle invasive bladder cancer were treated in the presence and absence of 17 AAG. Both short term and long term treatments were evaluated for their effects on growth, motility and invasion of the cancer cells. Expression of proteins involved in cell growth, survival and metastasis were evaluated with Western blotting.

Results: Our data demonstrated that 17 AAG treatment resulted in induction of apoptosis, inhibition of cell cycle progression through inhibition of MAP kinase pathway and cyclin D1 expression. Decreased tumor cell motility and invasion was observed with 17 AAG treatment. Several intracellular signaling pathways involved in cell proliferation, invasion and metastasis were inhibited.

Conclusions: Hsp90 inhibition in muscle invasive bladder cancer cells impacts growth, motility and invasiveness by inhibiting numerous intracellular signaling pathways. Taken together, these findings suggest a possible role for Hsp90 inhibitors in bladder cancer tumorigenesis.

No significant financial relationships to disclose.