bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of race on adverse pathologic features at the time of radical prostatectomy in men with prostate cancer and implications for adjuvant radiotherapy.
Authors: Jordan Gregory Arthur , Bhasin Richa , Block Alec , Gorbonos Alex , Quek Marcus Lee , Gupta Gopal Nand , Flanigan Robert Charles , Harkenrider Matthew M. , Solanki Abhishek A
Published: February 2018

75

Background: Patients with adverse pathologic features (≥pT3 disease or positive margins) at the time of radical prostatectomy (RP) have higher biochemical recurrence (BR). Adjuvant radiotherapy (ART) reduces BR, but has potential toxicities. Also, studies suggest Black men are more likely to have aggressive prostate cancer. Our objective was to identify whether black men undergoing RP are more likely to have adverse pathologic features (APF) that lead to an indication for ART. Methods: We conducted a retrospective cohort study of men with cT1-4 Nx/0 Mx/0 prostate adenocarcinoma in the National Cancer Database who underwent RP. Race was divided into 3 groups (Caucasian, Black, Other). Chi-square tests and analysis of variance (ANOVA) tests were used to compare clinical and socioeconomic covariates between race groups. Univariate (UVA) and multivariable analysis (MVA) were performed using logistic regression (LR) to identify covariates predicting for APF. LR was performed to identify the impact of race on pT3 disease and positive margins. Results: A total of 313,013 patients diagnosed between 2004-2014 and undergoing RP were included. 256,315 (85%) were Caucasian, 33,725 (11%) were Black, and 12,973 (4%) were Other race. Fewer Black men had Gleason group 1 (33% vs. 41%) but more had Gleason group 2 disease (46% vs. 38%, p < 0.001). Black men more frequently had PSA ≥10 ng/ml (18% vs. 16%, p < 0.001) and ≥cT2b disease (18% vs. 14%, p < 0.001). On UVA, Black men were more likely to have APF (Odds Ratio [OR] 1.18; 95% Confidence Interval [CI] 1.15-1.21; [p < 0.001]). On MVA, black race was independently associated with having APF (OR 1.21; 95% CI 1.18-1.24; p < 0.001). Black men were more likely to have positive margins (OR 1.26; 95% CI 1.22-1.29; p < 0.001) but less likely to have ≥pT3 disease (OR 0.77; 95% CI 0.74-0.79; p < 0.001). Conclusions: Independent of socioeconomic and clinical factors, Black men undergoing RP are more likely to have APF, increasing the risk of BR in this group, and more frequently creating an indication for ART. This appears to be more due to positive margins than locally advanced tumor. The underlying cause of this disparity warrants further exploration.
Perspectives of health care professionals on active surveillance for the management of prostate cancer.
Authors: Saad Fred , Pang Kittie , Fitch Margaret , Ouellet Veronique , Chevalier Simone , Drachenberg Darrel , Finelli Antonio , Lattouf Jean-Baptiste , So Alan , Sutcliffe Simon , Tanguay Simon , Mes-Masson Anne-Marie
Published: February 2018

81

Background: Active surveillance has gained widespread acceptance as a safe approach for patients with low risk prostate cancer. Despite presenting several advantages for both patients and the health care system, active surveillance is not adopted by all eligible patients. In this study, we evaluated the factors that influence physicians to recommend active surveillance and the barriers that impact adherence to this approach. Methods: We conducted five focus groups with a total of 48 health care providers (HCP) including family physicians, urologists, surgeons, radiation oncologists, fellows, and residents/medical students. These participants were all providing care for men with low risk prostate cancer and had engaged in conversations with men and their families about active surveillance. The experience of these HCP from academic hospitals in four Canadian provinces was captured. A content and theme analysis was performed on the verbatim transcripts to understand HCP decisions in proposing active surveillance and reveal the facilitators that affect the adherence to this approach. Results: Participants agreed that active surveillance is a suitable approach for low risk prostate cancer patients, but expressed concerns on the rapidly evolving and non-standardized guidelines for patient follow-up. They raised the need for additional tools to appropriately identify the patients best suited for active surveillance. Collaborations between urologists, radiation-oncologists, and medical oncologists were favoured, however, the role of general practitioners remained controversial once patients were referred to a specialist. Conclusions: Integration of more reliable tools and/or markers, and more specific guidelines for patient follow-up would help both patients and physicians in the decision-making for active surveillance.
The prospective assessment of the prostatic cancer mortality with PSA progression in the groups treated or not treated by salvage local brachytherapy.
Authors: Nietupski Karol Edward , Kulik Anna , Wiechno Pawel , Demkow Tomasz , Peczkowski Piotr , Pilichowska Małgorzata , Poniatowska Grazyna Maria , Michalski Wojciech , Rzymkowska Joanna , Sadowska Malgorzata , Ligaj Marcin , Kucharz Jakub , Jonska-Gmyrek Joanna , Wieczorek Ewa , Stencel Katarzyna
Published: February 2018

85

Background: The effectiveness of diagnostics of local recurrence of prostatic adenocarcinoma after radical radiotherapy and local retreatment high definition brachytherapy and its influence on the prostatic cancer survival. Methods: 55 patients with locally advanced prostatic adenocarcinoma with rising PSA level after radical radiotherapy and exclusion of distant metastases underwent prostatic biopsy. ECOG performance status 0-1 were eligible. The histopathological confirmation was obtained in 22 cases, and 33 patients had negative biopsy. In the case of positive biopsy radical salvage brachytherapy was performed in all patients. In the case of negative biopsy definitive anti-androgen therapy was administered in patients with PSA progression. Anti – androgen therapy was performed as adjuvant and neoadjuvant treatment after brachytherapy. In the course of the long (median 108months) observation we assessed prostatic specific mortality in both groups. In addition we assessed time to PSA progression during the antiandrogen therapy Results: From Mar 2002 we observed 55 patients with rising PSA after radical radiotherapy for the prostatic adenocarcinoma. We confirmed local recurrence of prostatic adenocarcinoma in 22 cases. The median time to biopsy after radiotherapy was 41months. The median observation time after post-radiotherapy biopsy was 108 months. All of the 22 patients were treated with salvage brachytherapy. There were 8 prostatic cancer specific deaths, 1 in the group treated by brachytherapy and 7 in the non-treated group. Median prostatic cancer survival (PCSOS) was 120 months in the treated group vs 75,6 months non-treated, but this difference was not statistically significant (P value 0,49). Median time to progression PSA was 108 months in the treated group vs 48 months non-treated and was not statistically significant. Significant toxicity were not reported. Conclusions: In long time observation we revealed, including the time of antiandrogen treatment depletion therapy, that in the patients with rising PSA and local recurrence treated with high-dose brachytherapy have no worse prognosis than patients with no local progression.
Adjuvant enzalutamide (Enza) for men with non-metastatic high-risk prostate cancer (HRPCa) after radical prostatectomy (RP).
Authors: Ornstein Moshe Chaim , Stephenson Andrew J. , Elson Paul , Tyler Allison Janine , Profusek Pam , Allman Kimberly D , Barata Pedro C. , Magi-Galluzzi Cristina , Fergany Amr Farouk , Stein Robert , Fareed Khaled , Haber Georges-Pascal , Campbell Steven C. , Kaouk Jihad , Grivas Petros , Rini Brian I. , Klein Eric A. , Garcia Jorge A.
Published: February 2018

88

Background: Management of HRPCa is a clinical challenge. Novel AR inhibitors could potentially impact outcome in HRPCa men following RP. We conducted a phase II study evaluating the efficacy/safety of Enza in men with HRPCa following RP. Methods: HRPCa pts (≥pT3a, GS≥8, iPSA ≥20 ng/mL, +ve lymph nodes (LN), or ≥35% chance of biochemical recurrence (BCR) at 5 yrs based on MSKCC’s nomogram) with undetectable PSA within 3 months from RP were eligible. Enza 160mg PO daily was given in 28-day cycles until disease progression, intolerability, consent withdrawal, or study completion at 24 months. Accrual goal was N=40 to provide 80% power to detect a 75% decrease in the risk of BCR from historical 55% rate. BCR was defined as PSA ≥0.2ng/mL on 2 consecutive lab results or any PSA rise that resulted in subsequent therapy. Results: 42 men enrolled. Median age 59 (range 43-70), based on biopsy 45% were GS7; 36% GS8, 19% GS9. 76% men had cT1, 24% cT2, median iPSA was 8.2 (range 2-77). On prostatectomy pathology: 50% had pT3b; 52% +ve margins; 50% SVI; 24% had +LN. 37 (88%) pts completed 24 planned cycles. Of the 5 pts who did not complete all cycles, 3 withdrew consent for toxicity (2 had G3 fatigue, 1 had G3 fatigue and arthralgias/myalgias), 1 had rising PSA requiring subsequent therapy, and 1 had financial concerns. With median follow-up of 31 months (range 2.5-44.5), 37 (88%) pts remain free of BCR. Of the 5 pts who developed BCR, 4 completed all 24 months on therapy. Median time to BCR was 31 months (range 13-40). Most common adverse events (AE) are listed (Table). Conclusions: Adjuvant Enza in men with HRPCa following RP is safe and relatively well-tolerated. Long-term safety, efficacy, and genomic correlations (including tumor RNA expression) are ongoing. Clinical trial information: NCT01927627. [Table: see text]
Evaluation of the MiCheck MIA test performance in differentiating aggressive from non-aggressive prostate cancer: The MiCheck-01 prospective trial.
Authors: Shore Neal D. , Pieczonka Christopher Michael , Henderson Ralph Jonathan , Bailen James L. , Beebe-Dimmer Jennifer Lynn , Ruterbusch Julie J. , Saltzstein Daniel R. , Concepcion Raoul S. , Borotkanics Robert , Levin Rachel , Wissmueller Sandra , Campbell Douglas , Walsh Brad ,   Minomic CUSP Authors
Published: February 2018

TPS152

Background: A diagnostic test which can better inform both clinicians and patients regarding a decision to proceed with a prostate biopsy, while still utilizing traditional parameters of Prostate Specific Antigen (PSA) kinetics and/or the digital rectal examination (DRE) is still an unmet need. The MiCheck® test is designed as a triage test to assist clinicians in the decision to proceed to prostate biopsy. The MiCheck®test is a simple blood test that measures the levels of the Glypican-1 protein and related signalling molecules. The MiCheck®-01 prospective trial builds on a previous pilot trial that examined the ability of the MiCheck® test to distinguish between normal subjects, patients with benign disease or Gleason 7 and above prostate cancer. The MiCheck® test showed sensitivity of 60% and specificity of 96% in distinguishing between subjects with Gleason ≥7 and normal or BPH patients. In a separate study, the MiCheck® test could differentiate aggressive (GS ≥3+4) from non-aggressive (GS 3+3) prostate cancer with a sensitivity of 85% and specificity of 90%. Methods: The trial consists of two arms: Arm 1 (normal patients, n = 50) and Arm 2 (prostate biopsy patients, n = 300). Inclusion criteria: Arm 1: Age ≥50, Low PSA (performed at most 12 months prior, defined as PSA < 1.5 ng/mL between ages 50 and 60 and PSA < 3 ng/mL above age 60). Arm2: Age ≥40, all subjects who are referred for or have undergone either a de novo or a repeat prostate biopsy for high PSA (defined as PSA ≥ 1 ng/ml between ages 40 and 49, PSA ≥2 ng/mL between ages 50 and 60 and PSA ≥ 3 ng/mL for age 60 and above age 60). Key exclusion criteria: prior history of cancer, patients taking ADT, DRE or other prostate manipulation within 72 hrs, subjects taking 5 ARIs. Results: The trial has recruited 30 Arm 2 patients to date. Interim analyses will be performed following accrual of 100 and 200 Arm 2 patients. Full accrual is expected by mid Q4 2017. Conclusions: Interim analysis data will be presented showing test performance. COI and Funding: The trial is funded by Minomic International Ltd. Neal Shore is a member of Minomic’s Clinical Advisory Panel.
Phase II study of olaparib (without ADT) in men with high-risk biochemically-recurrent prostate cancer following prostatectomy, with integrated biomarker analysis.
Authors: Teply Benjamin A. , Wang Hao , Sullivan Rana , King Serina , Handy Catherine , Lotan Tamara L. , Antonarakis Emmanuel S.
Published: February 2018

TPS386

Background: Patients with a high-risk biochemical recurrence (BCR) of prostate cancer after local therapy, defined by a rapid PSA doubling time (≤6 mo), are likely to experience metastases and subsequently death from their disease. Early use of androgen deprivation therapy (ADT) in these patients is controversial and is associated with side effects. Non-hormonal therapies that alter the natural history of BCR disease are needed. Olaparib is a PARP inhibitor that produces responses in some men with advanced prostate cancer, particularly those with dysregulation of DNA repair genes (i.e. synthetic lethality). Preclinical data support the activity of olaparib in prostate cancer beyond the DNA repair-deficient subset, yet the optimal biomarker for treatment selection is unknown. We hypothesized that olaparib monotherapy would show activity in men with high risk BCR and sought to further define the optimal patient population for olaparib in this setting. Methods: In this investigator-initiated multi-center open-label study, eligible patients will have non-metastatic BCR after prostatectomy, with a PSA doubling time of ≤6 mo. Prior limited ADT is allowed, but testosterone must have recovered (≥150 ng/dL). Patients will receive 300mg olaparib twice daily, with disease evaluation by PSA monthly and radiographic studies every 6 mo. Patients continue olaparib until evidence of metastasis or until PSA doubles from baseline, with a minimum exposure of 3 months. The primary endpoint is the rate of decline in PSA to ≥50% from baseline (PSA50 response). Secondary endpoints include safety, progression-free survival, and the rate of durable responses. Exploratory analysis will involve biomarker discovery including somatic DNA mutation analysis, RNA expression analysis, and immunohistochemistry for DNA damage markers, done on prostatectomy specimens. The study will initially enroll an all-comer (unselected) population and will then proceed via a staged-adaptive design; if futility is observed in the all-comer population at interim analyses, enrichment with biomarker-selected patients will occur. Clinical trial information: NCT03047135.
TRITON3: An international, randomized, open-label, phase III study of the PARP inhibitor rucaparib vs. physician’s choice of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).
Authors: Ryan Charles J. , Abida Wassim , Bryce Alan Haruo , Balar Arjun Vasant , Dumbadze Igor , Given Robert W. , Morris David , Petrylak Daniel Peter , Redfern Charles H. , Scher Howard I. , Watkins Simon Paul , Simmons Andrew , Passler Luke , Golsorkhi Tony , Chowdhury Simon
Published: February 2018

TPS389

Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.
A phase Ib open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer.
Authors: Vaishampayan Ulka N. , Narayan Vivek , Wise David , Lang Joshua Michael , Lowentritt Benjamin H , Mellado Begona , Carles Joan , Sáez M Isabel , Abida Wassim , Taplin Mary-Ellen , Azad Arun , Wang Karrie , Barbash Olena , Ferron-Brady Geraldine , Fecteau Doug , Khaled Ahmed Hussein , Dhar Arindam , De Bono Johann S.
Published: February 2018

TPS391

Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent. Methods: This is a Phase Ib open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level. Funding: GSK Clinical trial information: NCT03150056.
A phase 2 trial of ODM-201 maintenance therapy in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a AR targeting agent and non-progressive on a second line taxane (SAKK 08/16).
Authors: Gillessen Silke , Hayoz Stefanie , Fuhrer Andrea Corinne , Biaggi Christine , Pedrazzini Augusto , Procopio Giuseppe , Cathomas Richard
Published: February 2018

TPS393

Background: Treatment with the AR targeting agents abiraterone or enzalutamide followed by a taxane is currently the most used treatment for men with mCRPC. Further treatment after response to chemotherapy is only indicated in case of disease progression, with limited treatment options available. ODM-201 (Darolutamide) is a second-generation oral androgen receptor antagonist which has demonstrated a good safety profile and antitumor activity in mCRPC. This trial evaluates whether the immediate use of darolutamide after successful chemotherapy can prolong radiographic progression-free survival (rPFS) compared with watchful waiting in patients with mCRPC. Methods: This is a multicenter, randomized, double-blind, placebo-controlled phase 2 trial (NCT02933801) conducted in approximately 19 sites in Switzerland and Italy. Patients with mCRPC are required to have been previously treated with abiraterone or enzalutamide and have no evidence of disease progression on docetaxel or cabazitaxel. Patients (N = 88) will be randomized 1:1 to receive 600 mg darolutamide BID or placebo BID, both with best supportive care, until disease progression. Patients will be stratified by country, WHO performance status (0, 1 vs 2), presence/absence of visceral metastases, enzalutamide vs abiraterone prior to chemotherapy, and planned start of trial treatment after last taxane dose ( < 35 days vs ≥35 days). The primary endpoint is rPFS at 12 weeks after treatment initiation. The secondary endpoints are rPFS, time to PSA progression, time to symptomatic/clinical progression, event-free survival, overall survival, PSA response (30%, 50%, 90%, and best), duration of PSA response (50%), adverse events, and fatigue. The rPFS rate at 12 weeks after treatment initiation will be compared between the two treatment arms using a one-sided test statistic using the Kaplan–Meier method. Recruitment is ongoing, with the first patient randomized on 20.04.2017. Clinical trial information: NCT02933801.
A multicenter, randomized, controlled trial comparing the occurrence of major adverse cardiovascular events (MACEs) in patients (pts) with prostate cancer (pc) and cardiovascular disease (CVD) receiving degarelix (GnRH receptor antagonist) or leuprolide (GnRH receptor agonist).
Authors: Slovin Susan F. , Melloni Chiara , Mansor-Lefebvre Samreen , Neijber Anders , Roe Matthew
Published: February 2018

TPS395

Background: Epidemiological studies showed an association between GnRH agonists and a long-term increased risk of CVD, early after treatment initiation and with a higher risk seen in pts with pre-existing CVD. Retrospective pooled safety analyses of 6 randomized trials showed that significantly fewer pts treated with the GnRH receptor antagonists, degarelix, had a CV event or death compared with pts receiving a GnRH receptor agonist. In those studies showing an increased CV risk, Androgen-Deprivation Therapy (ADT) was primarily with GnRH receptor agonists. The mechanistic differences between GnRH antagonists and agonists, including testosterone surge and time to suppression at initiation, effect on follicle-stimulating hormone and on GnRH receptors e.g. T-lymphocytes in atherosclerotic plaque, raises the possibility of different CV risk profiles. The PRONOUNCE trial is the first to prospectively assess whether a GnRH agonist/antagonist can worsen pre-existing CVD; assess the impact of GnRH agonist/antagonist on CV risk biomarkers; and effects of hormonal therapy on immune system. Methods: PRONOUNCE is a multi-center, randomized, controlled trial of 900 men with pc and concomitant CVD, assessing adjudicated MACEs, i.e. myocardial infarction (fatal, non-fatal), stroke (fatal, non-fatal), or death in pts randomized 1:1 to either degarelix or leuprolide according to label recommendations for up to one year. Eligibility include pre-defined CVD, metastatic or locally advanced pc; high-risk disease with plan for definitive radiation therapy (RT); recurrence after local therapy with PSA doubling time <12 months; or salvage RT with neoadjuvant/adjuvant ADT for at least 12 months. Serum samples are collected for the analysis of various CV, inflammatory, and immune biomarkers. The primary endpoint will be based on Kaplan-Meier estimator of survival function and stratified for age group and region. Interim analysis is scheduled when 50% of MACE events have occurred allowing the DSMB to recommend for sample size correction. Clinical trial information: NCT02663908.
AR-V7 in Asian patients with metastatic CRPC: A multinational, multicentre study.
Authors: Tan Hui Shan , Wong Alvin Seng Cheong , Chong Kian Tai , Wong Siew Wei , Saad Marniza Bte , Ng Chi-Fai , Horie Shigeo , Chansriwong Phichai , Tan Min-Han , Toh Chee-Keong , Ng Quan Sing , Lim Kiat Hon , Tay Liang Seah , Ong Whee Sze , Kanesvaran Ravindran
Published: February 2018

TPS401

Background: The detection of androgen-receptor splice variant 7 (AR-V7) mRNA transcript in circulating tumor cells (CTCs) of progressive metastatic castration-resistant prostate cancer (mCRPC) patients is associated with resistance to abiraterone and enzalutamide. This finding was validated by other studies that found no association between the presence of AR-V7 transcripts and response to both docetaxel and cabazitaxel. The results suggest that AR-V7 could represent a biomarker to guide treatment selection in mCRPC. However, data in Asian population is limited. This multinational study aims to prospectively investigate the incidence and prevalence of ARV7 in Asian mCRPC patients. This is also the first study to evaluate 3 different detection platforms and help provide guidance on which will be the best platform to carry forward in terms of clinical utility. Methods: 101 Asian subjects with histologically confirmed mCRPC whom are going to be treated with AR-directed therapies (abiraterone, enzalutamide) or taxane chemotherapy (docetaxel) will be enrolled from Singapore, Malaysia, Thailand, Hong Kong and Japan. Subjects will be excluded if they plan to receive additional concurrent anticancer therapies. Peripheral-blood samples will be obtained at baseline and at the time of progression. We will use 3 methods to analyse the samples: (i) CTC enrichment platform followed by automated immunofluorescent staining for DNA, cytokeratins, CD45 (lymphocyte common antigen), and AR-V7; (ii) CTC enrichment platform followed by reverse-transcription polymerase chain reaction analysis; and (iii) the AdnaTest platform for molecular characterization of CTCs. Subjects will be followed up to 2 years. The clinical outcomes of AR-V7-positive and AR-V7-negative patients will be compared. PSA response rates will be compared using the Fisher exact test. Time-to-event outcomes (PFS, OS) will be evaluated using Kaplan-Meier analysis, and survival time differences will be compared using log-rank test. Cox regression analyses will be used to assess the effect of AR-V7 status in predicting clinical outcomes. The study is in progress; 32 of 101 planned patients have been enrolled at the end of September 2017.
Radium-223 and atezolizumab in platinum refractory urothelial carcinoma with bone metastases: NCT03208712.
Authors: Yentz Sarah Elizabeth , Reimers Melissa Andrea , Daignault Stephanie , Piert Morand , Alva Ajjai Shivaram
Published: February 2018

TPS543

Background: Immunologically, radiation increases tumor antigen release, cytotoxic CD8+ T cell infiltration while reducing myeloid derived suppressor cells (MDSCs), with distant abscopal responses occasionally reported. Radium-223 is a systemically administered bone-targeted alpha emitter that causes double-stranded DNA breaks and may induce similar immune effects. Anti-PD(L1) immune checkpoint inhibitor monotherapy with Atezolizumab demonstrates objective responses in metastatic urothelial cancer. In mouse models, radiotherapy and checkpoint immune inhibitor in combination synergistically reduce tumor growth. We hypothesized that the combination of Atezolizumab and Radium-223 in metastatic urothelial cancer pts with bone metastases would target bone metastases more effectively and yield higher response rates. Methods: Eligibility criteria for this single-site, phase 2 trial of Radium-223 in combination with Atezolizumab include diagnosis of advanced urothelial carcinoma with ≥1 bone metastasis, RECIST 1.1 measurable disease, progression of disease after/on platinum-containing chemotherapy in the metastatic or perioperative setting, ECOG PS of 0-2 and adequate organ function. Twenty-two pts will be treated with Radium-223 at a dose of 55 kBq/kg IV and Atezolizumab 1200mg IV both on day 1 of 21 day cycles. Up to 6 doses of Radium-223 will be administered. Atezolizumab will be continued until lack of clinical benefit or intolerable toxicity for up to 17 cycles. Routine response assessment will be performed every 12 weeks. Primary endpoint is best overall response per RECIST 1.1. Secondary objectives are to determine the safety and tolerability; determine the overall survival, progression free survival, clinical benefit rate, complete response rate and duration of response; and changes in quality of life as assessed by the EORTC QLQ-C30 score. Exploratory objectives are PD-L1 status by IHC, changes in bone scan per EXINI bone scan index and efficacy measures by irRC. If ≥6 pts respond, corresponding to an ORR of 27% with 80% confidence limits of 15%-43%, further study of the combination would be warranted. Blood and archival tissue will be collected for correlative studies. Clinical trial information: NCT03208712.
A multicenter clinical trial of intravesical BCG in combination with ALT-803 in patients with BCG-unresponsive non-muscle invasive bladder cancer.
Authors: Chamie Karim , Salmasi Amirali , Rosser Charles Joel , Rock Amy , Ferguson Lydia , Wong Hing C.
Published: February 2018

TPS544

Background: BCG unresponsive NMIBC includes patients with persistent high-grade disease or recurrence within 6 months of receiving at least two courses of BCG; or T1 high-grade disease at the first evaluation following BCG induction alone. The recommendation after failing BCG in patients suitable for surgery is cystectomy or for unwilling/unfit patients, salvage chemotherapy or immunotherapy (administered with limited success). This highlights a critical need for novel preservation therapies to facilitate a better quality of life and reduce health-care costs for patients who are unresponsive to BCG (Correa 2015, Dalbagni 2006, Dinney 2013, Kamat 2017). Altor BioScience has initiated a phase II clinical study in BCG unresponsive patients to expand on promising data collected from a compassionate use patient who remains disease free more than 2.5 years after ALT-803 plus BCG treatment for refractory NMIBC (Huang 2017). Methods: This is a Phase II, open-label, single-arm, multicenter study of intravesical BCG plus ALT-803 in patients with BCG unresponsive high grade NMIBC. Group A will enroll patients who have histologically confirmed presence of CIS [with or without Ta or T1 disease]. Group B will enroll patients who have histologically confirmed high-grade Ta or T1 disease (in the absence of CIS). All patients will receive BCG plus ALT-803 weekly for 6 consecutive weeks. A cystoscopy will be performed at Week 12. Patients with no disease or low-grade Ta will receive a maintenance course of therapy (3 weekly instillations of BCG plus ALT-803). Patients with residual CIS and/or high-grade Ta will receive a re-induction course of therapy. Presence of Ta will require a TURBT. Patients with greater than or equal to T1 disease or new CIS will be deemed treatment failures. Patients with a Complete Response (CR) or low-risk disease at Months 6, 9 and 12 are eligible for continued BCG plus ALT-803 maintenance. Patients will be followed for recurrence, progression, and survival. The primary endpoint is to assess complete response (CR; absence of lesions on cystoscopy or negative, for cause, biopsies along with negative urine cytology) of CIS at six months. Enrollment is underway. Clinical trial information: NCT03022825.
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for adult and paediatric male and female patients with intermediate and poor-risk metastatic germ cell tumors (GCTs).
Authors: Nayar Namrata , Lawrence Nicola Jane , Stockler Martin R. , Martin Andrew James , Yip Sonia , Wong Nicole , Yeung Annie , Friedlander Michael , Mazhar Danish , Pashankar Farzana , Quinn David I. , McDermott Ray , Walker Rick , Winstanley Mark , Hanning Fritha J. , Weickhardt Andrew James , Stevanovic Amanda Gwendolyn , Davis Ian D. , Toner Guy C. , Grimison Peter S. ,   Australia and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2018

TPS574

Background: Bleomycin, etoposide, cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for metastatic GCTs. Acceleration of standard regimen with shorter cycle lengths has improved cure rates in other cancers. This is the first international randomised clinical trial for intermediate and poor-risk metastatic extracranial GCTs involving both adult and paediatric age group males and females. We aim to determine if accelerated BEP is superior to standard BEP. Methods: DESIGN: Open label, randomised, stratified multicentre, 2 stage, phase 3 trial. Primary endpoint for stage I (n = 150) is complete response rate (RR), and for entire trial (n = 500) is progression free survival (PFS). SAMPLE SIZE: 150 and 500 patients gives > 80% power to detect a 20% improvement in RR and 7% absolute improvement in 2yr PFS, respectively. POPULATION: Males and females aged 11-45 years with intermediate or poor-risk metastatic GCTs of the testis, ovary, retroperitoneum or mediastinum for 1st line chemotherapy. TREATMENT: Randomisation 1:1 to 4 cycles of “standard BEP” or “accelerated BEP”: cisplatin 20mg/m2 IV days (D) 1-5; etoposide 100mg/m2 IV D1-5; bleomycin 30000 IU IV (D 1, 8, 15 or D 2, 9, 16 of a 21 day cycle; D 1, 8 or D 2, 9 of a 14 day cycle); and peg G-CSF or Filgrastim; given every 3 weeks or every 2 weeks respectively. Accelerated BEP arm receives 4 additional weekly doses of bleomycin. ASSESSMENTS: Response assessments at 30 day safety assessment, and 6 months from randomisation or after all post-chemotherapy intervention is completed. Regular follow-up up to 5 years, then annually. Archival tumour tissue and baseline blood collected for translational substudies. STATUS: 25 sites open in ANZ, 1/19 sites open in UK (led by Cambridge Clinical Trials Unit), 41 patients recruited by September 2017. International collaborations with USA (led by Children’s Oncology Group) and Ireland (led by Cancer Trials Ireland) confirmed with sites expected to open by late 2017 and more sites sought for stage 2. Clinical trial information: NCT02582697.
A phase 2 study of cabozantinib as first-line treatment in collecting ducts renal cell carcinoma: The BONSAI trial.
Authors: Procopio Giuseppe , Ratta Raffaele , Fucà Giovanni , Grassi Paolo , Porcu Luca , Prisciandaro Michele , Calareso Giuseppina , Montone Rosanna , Sorrentino Margherita , Verzoni Elena
Published: February 2018

TPS709

Background: Collecting ducts carcinoma (CDC) is a rare and aggressive form of renal cell carcinoma, characterized by extremely poor prognosis and resistance to agents effective in other forms of RCC. We hypothesized that cabozantinib, an inhibitor of multiple kinases including VEGFR 2, MET and AXL, may be superior in terms of efficacy to other angiogenesis inhibitors in the treatment of CDC due to its high-spectrum of activity against multiple and non-redundant oncogenic pathways. Methods: The BONSAI study is a prospective, single-centre, single-arm phase II trial evaluating cabozantinib in patients with untreated locally advanced or metastatic CDC. Cabozantinib will be administered at the dose of 60 mg orally once daily until the evidence of disease progression (PD) evaluated by RECIST 1.1 or unacceptable toxicity. Primary objective is the evaluation of objective response rate (ORR). Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety profile of cabozantinib. Exploratory objectives include the evaluation of genetic and immunological landscape of CDC and its correlation with response to treatment. Overall, 23 patients will be enrolled into the study based on a Simon’s two-stage optimal design. In order to reject an ORR equal to 15% with a one-sided alpha error of 10% and to detect an ORR equal to 35% with a power of 80%, 9 patients will be enrolled in the first stage. If at least 2 responses will be observed in the first stage, 14 additional patients will be included in the second stage. If at least 6 responses will be observed at the second stage the activity of cabozantinib will be proved. First patient enrollment is scheduled in November 2017.
Medication Safety in Oncology Care: Mapping Checking Procedures From Prescription to Administration of Chemotherapy
Authors: Pfeiffer Yvonne , Gut Stephan S. , Schwappach David L.B.
Published: February 2018

Purpose:

To increase medication safety in oncology, checking procedures are increasingly applied by nurses, physicians, and pharmacists. However, little is known about the number, types, and consistency of implemented checks. The aim of the study was to assess the number and types of different checking procedures that are performed along the lifecycle of a chemotherapy prescription across three hospitals, different care settings, administration routes, and professional groups.

Methods:

A scheme to evaluate checking procedures and a mapping approach to illustrate the checks along the phases of the medication process were developed. Checking procedures were assessed on the basis of analysis of internal guidelines and interviews with nurses and physicians who work on wards and in ambulatory infusion units of three hospitals.

Results:

There were considerable differences in number and type of checking procedures among administration routes, professional groups, wards and ambulatory infusion units, and hospitals. During the prescribing phase, the lowest number of checks was performed. In internal guidelines, checking procedures were documented poorly, though the pharmacy process was an exception.

Conclusion:

In contrast to the pharmacists, nurse and physician clinician checking procedures are less standardized within and across hospitals. The results point to different checking habits for the professional groups; for example, physicians would rather perform plausibility reviews than checks. Our evaluation scheme to categorize checks and the visualized mapping approach was feasible and understandable for practitioners.
Participation Costs and Inefficiency in Takeover Contests
Authors: Hounwanou Didier Dègnidé
Published: February 2018

We consider a takeover in which risk neutral bidders incur private costs when they participate in the auction. Supposing that valuations for a target firm are common knowledge, we study the optimal strategy of bidders and analyze the takeover result when they get or do not get toeholds in the target firm. We find that bidders’ decision of participation is endogenous. By analyzing bidders’ condition of participation, we find that there is a probability that the potential bidder with the highest valuation does not participate in the control. We show that this probability increases with the size of toeholds possessed by the bidder with a low valuation. Nevertheless, a larger size of toeholds possessed by the bidder with the highest valuation increases the probability of his participation in the auction. Asymmetric toeholds between potential bidders can accentuate inefficient allocation when participation costs are private information. However, if the bidder with toeholds deters completely bidders without toeholds in private valuation setting (Ettinger [Ettinger D (2009) Takeover contests, toeholds and deterrence. Scandinavian J. Econom. 111(1):103–124.]), the results of the current papers show that the phenomenon of fully deterring is destroyed when valuations are common knowledge.
Long-term bone remodelling around ‘legendary’ cementless femoral stems
Authors: Rivière Charles , Grappiolo Guido , Engh Charles A. , Vidalain Jean-Pierre , Chen Antonia-F. , Boehler Nicolas , Matta Jihad , Vendittoli Pascal-André
Published: February 2018

Bone remodelling around a stem is an unavoidable long-term physiological process highly related to implant design. For some predisposed patients, it can lead to periprosthetic bone loss secondary to severe stress-shielding, which is thought to be detrimental by contributing to late loosening, late periprosthetic fracture, and thus rendering revision surgery more complicated. However, these concerns remain theoretical, since late loosening has yet to be documented among bone ingrowth cementless stems demonstrating periprosthetic bone loss associated with stress-shielding. Because none of the stems replicate the physiological load pattern on the proximal femur, each stem design is associated with a specific load pattern leading to specific adaptive periprosthetic bone remodelling. In their daily practice, orthopaedic surgeons need to differentiate physiological long-term bone remodelling patterns from pathological conditions such as loosening, sepsis or osteolysis. To aid in that process, we decided to clarify the behaviour of the five most used femoral stems. In order to provide translational knowledge, we decided to gather the designers’ and experts’ knowledge and experience related to the design rationale and the long-term bone remodelling of the following femoral stems we deemed ‘legendary’ and still commonly used: Corail (Depuy); Taperloc (Biomet); AML (Depuy); Alloclassic (Zimmer); and CLS-Spotorno (Zimmer).

Cite this article: EFORT Open Rev 2018;3:45-57. DOI: 10.1302/2058-5241.3.170024
The Emergence of Effortful Control in Young Boys With Fragile X Syndrome
Authors: Robinson Marissa , Klusek Jessica , Poe Michele D. , Hatton Deborah D. , Roberts Jane E.
Published: February 2018

Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This study compared the development of effortful control in preschool boys with FXS (n = 97) and typical development (n = 32). Unlike their typical peers, the boys with FXS did not exhibit growth in effortful control over time, which could not be accounted for by adaptive impairments, FMR1 molecular measures, or autism symptoms. These results contribute to our understanding of the childhood phenotype of FXS that may be linked to the poor social-emotional outcomes seen in this group.
The Impact of Spray Adjuvants on Solution Physical Properties and Spray Droplet Size
Authors: Fritz Bradley K. , Hoffmann W. Clint , Gizotti-de-Moraes Jesaelen , Guerrerio Marcella , Golus Jeff , Kruger Greg R.
Published: February 2018

Over the past several years, numerous anecdotes from aerial applicators have surfaced concerning observations of increased numbers of fine droplets seen in the applied spray clouds, often associated with tank mixtures that contain crop-oil concentrates (COCs) and foliar fertilizers (FFs). Efforts were made herein to correlate surface tension and viscosity to spray droplet size under a variety of aerial application conditions, but these efforts were unsuccessful. In addition, spray mixtures were examined to compare relative evaporation rates. Researchers are encouraged to actively pursue this line of work. The addition of several adjuvants and FFs were found to significantly affect spray droplet size, so applicators should pay careful attention to spray tank composition when making aerial spray applications.
New Organosilicon- and Lecithin-Based Adjuvant: Effect of Lecithin HLB on Adjuvant Properties
Authors: Naue Jeferson A. , Policello George A. , Brown William L.
Published: February 2018

A series of novel organosilicon- and lecithin-based adjuvants that contain different sources and types of lecithin was prepared. We investigated how lecithins influence the properties of the organosilicon surfactant such as spreading and dynamic surface tension. We also investigated how variations in the hydrophilic-lipophilic balance (HLB) of the lecithin component affected the stability of the adjuvant spray solution, as well as the impact on spray drift reduction, droplet adhesion, and herbicide uptake. The lecithins antagonized the spreading and increased the surface tension of the organosilicon surfactant, and this response was not altered by variations in the HLB of the lecithin component. On the other hand, 2,4-D dimethylamine uptake and spray drift reduction with glyphosate-isopropylamine was affected by the HLB of the lecithin source. Overall, these results indicate that this new adjuvant works as a penetrant that can enhance droplet adhesion, drift control, and herbicide uptake.
Railroad Ballast Testing and Properties
Authors: Stark Timothy D. , Swan Robert H. , Szecsy Richard
Published: February 2018

Description

Get 14 peer-reviewed papers from the first-ever D18 symposium dedicated to the study of the properties and behavior of railroad ballast.

Industry experts present their research on various best practices for field and laboratory ballast testing. Topics include
Sampling, Reconstituting, and Gradation Testing of Railroad Ballast
Authors: Stark Timothy D. , Wilk Stephen T. , Swan Robert H.
Published: February 2018

Ballast characterization is important for predicting ballast performance and serviceability in track. This paper investigates ballast sampling methods and sizes, reconstitution, splitting, and gradation testing for appropriate characterization of in-track ballast. This paper will review various ASTM test methods and determine how these procedures should be applied to railroad ballast sampling and testing. For example, ASTM D75/75M, Standard Practice for Sampling Aggregates, and ASTM C136/136M, Standard Test Method for Sieve Analysis of Fine and Coarse Aggregates, require sampling ballast with a maximum particle diameter of 75 mm (3 in.) and about 16 to 17 three-quarters full 5-gal buckets to meet the requirements. These methods are important because of the difficulty of obtaining representative in-field ballast samples. Undisturbed ballast samples are not feasible because of the nature of unbonded granular particles, so sampling emphasis must be placed on best methods to collect and reconstitute field ballast conditions in the laboratory. Another aspect that will be discussed is how to deal with local variations in ballast fouling and degradation that can result in significant differences in ballast characteristics. For example, the ballast underneath the tie (i.e., the ballast of interest) will likely be more degraded and fouled than shoulder or crib ballast, but this is also the most difficult location to obtain without track disturbance.