bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world experience with cabozantinib in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Lemke Emily , Shah Amishi Yogesh , Chandramohan Anuradha , Campbell Matthew T. , VanAlstine Michael , Jonasch Eric , Tannir Nizar M. 
Published: February 2018

684 Background: Cabozantinib (C) inhibits tyrosine kinase activity at MET, AXL, and VEGF receptors and is approved in mccRCC after progression on prior VEGFR-TKI. Little off-protocol data exists on tolerability and response. Methods: We retrospectively gathered baseline and treatment details on mccRCC patients treated with C at MD Anderson from 2015-present. Blinded radiologist determined best response by RECIST 1.1. Descriptive statistics were utilized. Results: We report on 38 patients with mccRCC treated with C in a “real-world” setting. Median age at mccRCC diagnosis was 58 years (range 37-71). 25 patients (66%) were male. 22 (58%) had de-novo metastatic disease. 4 patients had sarcomatoid dedifferentiation. 32 (84%) underwent nephrectomy. Cohort had a median of 3 sites of metastatic disease, including: bone 22 (57%), liver 9 (23%), and brain 6 (16%). 6 patients (16%) received C as 2nd line therapy, 10 (26%) as 3rd line, and 22 (58%) as 4th line or later. By IMDC risk score, 7 (18%) were favorable, 22 (58%) were intermediate, and 9 (24%) were poor risk. All patients had received at least 1 prior VEGFR-TKI and 24 (63%) had received prior immune checkpoint inhibitor. At C initiation, 20 (53%) patients had unfavorable neutrophil to lymphocyte ratio (NLR) of ≥ 3. 12 (32%) patients had favorable shift of NLR to < 3 on C. 22 patients (58%) required dose reduction and 24 (63%) required treatment break due to C-related toxicity. At time of analysis, 26 patients had discontinued treatment, with median time on treatment of 32.2 weeks (range 15.7-130.7 weeks). For the 12 patients remaining on C, median duration of therapy has been 54.3 weeks (range 26.6-68.9 weeks). 1 (3%) patient had CR, 11 patients (29%) had PR, 23 (60%) had SD, and 3 (8%) had PD as best response to C. Conclusions: C has a high disease control rate (92%) even as a late line of therapy in mccRCC. However, careful monitoring is warranted as many patients require treatment breaks and dose reductions for therapy-related toxicity. [Table: see text]
The probability of indolent versus aggressive histology based on renal tumor size: Implications for surveillance and treatment.
Authors: Bhindi Bimal , Thompson Robert Houston , Lohse Christine M. , Mason Ross , Frank Igor , Boorjian Stephen A. , Cheville John C. , Leibovich Bradley C. 
Published: February 2018

704 Background: While the probability of benign versus malignant histology based on renal tumor size has been described, this alone does not sufficiently inform decision-making in the modern era since indolent malignant tumors can be surveilled. Thus, we sought to characterize the probability of indolent versus aggressive histology based on radiographic tumor size. Methods: We evaluated patients who underwent radical or partial nephrectomy at Mayo Clinic for a pT1-2, pNx/0, M0 solid renal tumor between 1990-2010. Pathology was reviewed by one genitourinary pathologist. Benign tumors, low grade (1-2) clear cell and papillary renal cell carcinoma (RCC), and any chromophobe, clear cell papillary, mucinous tubular and spindle cell, SDH-B deficient, and tubulocystic RCC were considered indolent. All other histologies were considered aggressive, as were any malignancies with necrosis or sarcomatoid differentiation. Cancer-specific survival (CSS) was estimated using the Kaplan Meier method. Logistic regression models were used to estimate the probability of malignant and aggressive histology based on tumor size. Sex-stratified analyses were also performed. Results: Of the 2650 patients included, there were 1773 patients with indolent tumors (303 benign; 1470 malignant) and 877 with aggressive tumors. Ten-year CSS was 96% for indolent malignant tumors and 82% for aggressive tumors. The predicted probabilities of any malignant histology and aggressive malignant histology increased with tumor size (Table; 1-7cm point estimates shown). For example, a 3 cm tumor had an 87% probability of malignancy and a 27% probability of being aggressive. For any given tumor size, men had a greater probability of aggressive histology than women. Conclusions: We present tumor size-based estimates of the probability of aggressive histology for renal masses. This information should be useful for patient counseling and treatment decision-making. [Table: see text]
Laboratory eligibility criteria as potential barriers to participation by black men in prostate cancer clinical trials.
Authors: Vastola Marie , Yang David Dewei , Mahal Brandon Arvin Virgil , Muralidhar Vinayak , Lathan Christopher S. , McGregor Bradley Alexander , Nguyen Paul L. 
Published: February 2018

73 Background: Eligibility criteria may disproportionately affect black patients and contribute to their underrepresentation in clinical trials. We studied this potential barrier by examining clinical trials in prostate cancer, a disease in which black men face higher incidence and mortality. Specifically, we investigated the use of serum creatinine (sCr) alone instead of race-adjusted measurements for renal function, and the use of an absolute neutrophil count (ANC) threshold that could exclude men with benign ethnic neutropenia, which afflicts 6.7-8% of black patients and could lead to the exclusion of patients despite having healthy immune systems. Methods: We identified 401 interventional prostate cancer clinical trials with an overall survival endpoint. The list of trials was collected on January 16, 2017 from clinicaltrials.gov using the following criteria – study type: interventional studies; conditions: prostate cancer; interventions: drug; outcome measures: overall survival. Characteristics gathered from each trial included sponsor type, phase, accrual goal, start year, and toxicity. Results: Overall, 47.9% (192) of these trials used either sCr alone and/or required participants to have ANC ≥1.5×109 cells/L. Specifically, 25.2% (101) of the trials used sCr alone to determine eligibility, and 41.4% (166) of the trials required patients to have an ANC ≥1.5×109 cells/L. Conclusions: Of clinical trials in prostate cancer, 47.9% used criteria that disproportionately excluded black patients. The reevaluation of these two eligibility criteria could improve minority trial enrollment. First, lowering the ANC cutoff for patients with benign ethnic neutropenia would increase the number of eligible black participants, as 89% of these patients have an ANC ≥1.0×109 cells/L. Second, using race-adjusted equations for renal function would take into account racial differences in creatinine. While adopting race-based differences in trial criteria may add slight logistical challenges when ensuring patients meet trial eligibility, these adjustments would prevent healthy patients from being excluded solely because of benign laboratory differences caused by their race.
Nuclear factor-kappa B p65 evaluation on the Canadian Prostate Cancer Biomarker Network (CPCBN) TMA-series for biomarker validation.
Authors: Saad Fred , Ouellet Veronique , Grosset Andree-Anne , Caron Christine , Barres Veronique , Latour Mathieu , Trudel Dominique , Aprikian Armen G. , Bergeron Alain , Brimo Fadi , Chevalier Simone , Drachenberg Darrel , Fazli Ladan , Fleshner Neil Eric , Gleave Martin , Karakiewicz Pierre I. , Lacombe Louis , Lattouf Jean-Baptiste , van der Kwast Theodorus , Mes-Masson Anne-Marie 
Published: February 2018

80 Background: The CPCBN has assembled a TMA-based resource comprising the specimens of 1512 prostate cancer patients treated by radical prostatectomy. This richly annotated and multi-institutional resource is available to researchers who wish to access a large cohort to validate prognostic biomarkers (http://www.tfri.ca/en/research/translational-research/cpcbn.aspx). Over the last decade, our laboratory demonstrated with an independent cohort (Gannon PO, et al. Eur J Cancer. 2013 Jul;49(10):2441-8, Labouba I, et al. PLoS One. 2015 Jul 17;10(7):e0131024), the reproducible association of nuclear factor-kappa B (NF-kB) p65 with patient’s risk of biochemical recurrence. Here, we evaluated the CPCBN TMA-series for p65 expression. Methods: Two independent observers scored the frequency of p65 nuclear localisation on digital images obtained after automated immunohistochemistry analysis of p65. Over the available minimum 3 cores of tumour tissue per patient, an average percentage of positive nucleus frequency was used. Statistical analyses were performed using SPSS software. Results: High nuclear frequency of NF-kB p65 (cut-off at 3%) was associated with an increased risk for patients to experience a biochemical relapse (p < 0.001; Exp(B) = 1.599; 95%CI = 1.321-1.937), develop bone metastasis (p = 0.007; Exp(B) = 2.126; 95%CI = 1.234-3.663)and die from their disease (p = 0.001; Exp(B) = 3.117; 95%CI = 1.55-6.266). In multivariate analyses, p65 also remained independent from clinical parameters (PSA, Gleason score and pTNM): biochemical relapse (p = 0.005; Exp(B) = 1.331; 95%CI = 1.092-1.623), bone metastasis (p = 0.033; Exp(B) = 1.82; 95%CI = 1.04- 3.158), mortality (p = 0.007; Exp(B) = 2.626; 95%CI = 1.298-5.312) Conclusions: Using a large cohort of Canadian men, our study reiterates the previous study linking NF-kB p65 with prostate cancer progression and highlights the suitability of CPCBN TMAs for biomarker validation. Our results also reveal the role of p65 as a predictor of bone metastasis development and prostate cancer-specific mortality.
Identification of occult prostate malignancy in a large patient cohort using a stereotactic transperineal prostate biopsy technique.
Authors: Moran Brian Joseph , Braccioforte Michelle H. 
Published: February 2018

9 Background: Continued rising PSA, despite prior transrectal prostate biopsy (TRPB), can cause significant anxiety for patients and physicians. This study investigates the detection rate of non-palpable, isoechoic occult malignancy using a stereotactic transperineal prostate biopsy (STPB) technique in patients with previous negative TRPB. Methods: 2,565 men with continued rising prostate specific antigen (PSA) with a minimum of 1 prior benign TRPB, underwent STPB at a single out-patient institution between 04/04 - 02/17 (See table). Specimens were obtained according to x, y, and z coordinates from 8 equal octants with pathology reported accordingly. A greater number of specimens were obtained from the apical half than the basilar half of the prostate; this was attributed to smaller glands in which the apical specimens sufficiently sampled the anterior curvature of the gland. Results: STPB yielded adenocarcinoma in 965/2,565 (37.6%) patients. The number of biopsy cores obtained per patient approximated the prostate gland volume in cm3. Statistical analysis demonstrated there was a significant difference in detection rates with the apex having a higher incidence of malignancy than the base of the prostate gland (p=.000). Furthermore, the anterior apex harbored significantly more adenocarcinoma when compared to the posterior apex (p=.026). Conclusions: STPB is efficacious for diagnosis of non-palpable, isoechoic occult prostate malignancy. Repeated sequential analysis of malignancy identification has consistently resulted in approximately 40% positive yield. Furthermore, a possible explanation for the significant finding in this study that occult malignancies occupy a higher percentage of apical biopsies using STPB may be related to difficulty and limitations of apical sampling using a standard transrectal biopsy approach. [Table: see text]
Urinary toxicity in men treated with stereotactic body radiation therapy (SBRT) for localized prostate cancer following procedures for benign prostatic hyperplasia (BPH).
Authors: Kataria Shaan , Tsou Harry , Datta Subhradeep , Gurka Marie Kate , Lei Siyuan , Ayoob Marilyn , Danner Malika , Yung Thomas M. , Collins Brian Timothy , Krishnan Pranay , Suy Simeng , Lynch John J. , Collins Sean P. 
Published: February 2018

91 Background: Patients with a history of procedures for BPH experience worse urinary toxicity following interstitial brachytherapy for localized prostate cancer. This retrospective study sought to evaluate the rates of urinary toxicity following SBRT in men with a history of procedures for BPH. Methods: Localized prostate cancer patients, treated with SBRT from August 2009 to February 2015 and a minimum follow up of 2 years, with a history of at least 1 procedure for BPH associated with a prostatic defect identified on the treatment planning MRI were evaluated. Radiotherapy was delivered in 5 fractions to a dose of 35 or 36.25 Gy using the CyberKnife system with fiducial tracking. Urinary QOL was assessed pre- and post-treatment using the International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite (EPIC-26). Cystoscopy findings were retrospectively reviewed. Toxicities were scored using the CTCAE v4. Results: Thirty nine men with a median age of 72 years, 7 with a history of more than 1 procedure for BPH, were treated with a median follow up of 49 months. Grade 1, grade 2, and grade 3 urinary toxicity occurred in 11, 24, and 3 men, respectively; there were no grade 4 or 5 toxicities. Overall, 22 men experienced hematuria; the median time to the onset hematuria from the start of SBRT was 13 months (range 1-70). Cystoscopy was performed on 12 of these patients and bladder neck/prostatic urethra hyperemia were found in a majority of cases. Active bleeding from the bladder neck or prostatic urethra was found in 4 men. A mean baseline IPSS score of 9 did not significantly change at any point during follow up. A mean baseline EPIC-26 obstructive/irritative score of 84 significantly decreased to 76 at 1 month (p = 0.023). There was no significant change from the mean baseline EPIC-26 urinary incontinence score at any point during follow up. Conclusions: A history of procedures for BPH may lead to worse urinary quality of life and high rates of hematuria following SBRT for localized prostate cancer. Stricter urethra/bladder neck dose constraints or an alternative fractionation schedule may be required to decrease the risk of urinary toxicity.
Integrative molecular profiling challenges robustness of prognostic signature scores in multifocal prostate cancer.
Authors: Hovelson Daniel , Salami Simpa Samuel , Kaplan Jeremy B , Mathieu Romain , Udager Aaron , Curci Nicole , Lee Matthew , Lazo De La Vega Lorena , Susani Martin , Rioux-Leclercq Nathalie , Spratt Daniel Eidelberg , Morgan Todd Matthew , Davenport Matthew , Rubin Mark A. , Shariat Shahrokh F. , Tomlins Scott A. , Palapattu Ganesh S. 
Published: February 2018

96 Background: Tissue based biomarkers are increasingly utilized in men diagnosed with low grade prostate cancer (PCa) to guide definitive management vs. active surveillance. PCa is uniquely multifocal, suggesting ideal prognostic biomarkers should be robust to both undersampling of a high grade component of a mixed-grade tumor focus, as well as unsampled multifocal high grade tumor foci. Methods: To assess the robustness of prognostic biomarkers to multifocality, we designed a comprehensive multiplexed targeted RNA sequencing assay (mxRNAseq) capable of assessing multiple classes of transcriptional alterations and deriving available prognostic signature scores (e.g. Prolaris CCP and OncotypeDX GPS). We applied this assay to a retrospective cohort of 176 FFPE tissue samples representing the range of PCa progression. Single candidate biomarkers and derived prognostic signatures were analyzed in multifocal cases with only low-grade disease as well as those with extreme grade differences across tumor foci. Results: Our mxRNAseq assay robustly detected known coding gene/lncRNA expression, gene fusions, splice variants, and expressed somatic and germline mutations. Supervised clustering of target gene expression confirmed expected transcriptional module deregulation and derived prognostic signatures across PCa progression. Prognostic biomarkers (including derived signatures) showed no significant expression differences between low grade foci from prostates with and without high grade disease foci and were uniformly higher in high vs. low grade foci from the same case. In four cases of extreme multifocality (Gleason score 6 vs. ≥ 8 foci), prognostic signatures were significantly lower in low vs. high grade foci. In a clinical prostatectomy cohort of 1,418 men with diagnostic biopsy Gleason score 3+3 = 6 or 3+4 = 7, 21 (1.5%) had Gleason score ≥ 4+4 = 8, suggesting the initial biopsy missed or undersampled the most clinically relevant focus. Conclusions: Using a novel comprehensive mxRNAseq assay, our results challenge the robustness of prognostic biomarkers between multifocal low and high grade PCa foci, critically important in the context of un/under-sampled aggressive tumor foci.
Three-month post-treatment PSA as a biomarker of treatment response in intermediate or high-risk prostate cancer treated with androgen deprivation therapy and radiotherapy.
Authors: Alex Bryant , D'Amico Anthony Victor , Nguyen Paul , Einck John Paul , Kane Christopher J. , McKay Rana R. , Simpson Daniel Robert , Mundt Arno James , Murphy James Don , Rose Brent Shane 
Published: February 2018

99 Background: Prostate-specific antigen (PSA) measurement after definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for localized prostate cancer (PC) has been proposed as an early prognostic biomarker. We investigate the association between 3-month post-RT PSA and biochemical progression-free survival (bPFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Methods: We identified 5,783 patients with intermediate- or high-risk localized PC diagnosed between 2000-2015 and treated with RT and ADT from Veterans Affairs data. Patients were divided into groups based on 3-month post-RT PSA values: < 0.10 ng/mL, 0.10-0.49 ng/mL, and ≥0.50 ng/mL. The effect of 3-month PSA group on bPFS, PCSS, and OS were evaluated in multivariable Cox models adjusting for potential confounders. Results: There were 2,651 intermediate risk and 3,132 high risk patients; 11% had a 3-month PSA of ≥0.50 ng/mL. Higher 3-month PSA was strongly associated with each outcome; compared to the < 0.10 ng/mL group, we noted greater hazards for the 0.10-0.49 ng/mL group (HR for bPFS: 2.41, p < 0.001; PCSS: 2.29, p < 0.001; OS: 1.21, p = 0.003) and the ≥ 0.50 ng/mL group (HR for bPFS: 5.23; PCSS: 3.97; OS: 1.50; p < 0.001 for all). When analyzed separately, 3-month PSA group was predictive of OS in the high-risk group (p < 0.001) but not the intermediate-risk group (p = 0.21). Conclusions: 3-month post-RT PSA is a strong prognostic biomarker for bPFS and PCSS in patients with intermediate and high-risk PC, and OS in patients with high-risk PC. 3-month PSA measurement may augment clinical decision-making and holds promise as a potential surrogate endpoint in clinical trials.
Randomised phase 3 trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for high risk, clinically localized prostate cancer: ENZARAD (ANZUP 1303).
Authors: Williams Scott , Davis Ian D. , Sweeney Christopher , Stockler Martin R. , Martin Andrew James , Hague Wendy , Coskinas Xanthi , Yip Sonia , Tu Emily , Lawrence Nicola Jane , Nayar Namrata , McDermott Ray , Kelly Paul , Deignan Olwyn , Hughes Simon , Fonteyne Valerie , Tombal Bertrand F. , Nguyen Paul L. 
Published: February 2018

TPS156 Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide improves overall survival (OS) in castration-resistant, metastatic prostate cancer. We hypothesized that the addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the effects of enzalutamide versus a conventional non-steroidal anti-androgen (NSAA) as part of neoadjuvant and adjuvant ADT in men undergoing RT for high risk, localized PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA progression free survival (PFS), clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival (MFS), adverse events and health-related quality of life (HRQOL). CORRELATIVE OBJECTIVES: identification of prognostic/predictive biomarkers from archival tumour tissue and serial blood samples. SAMPLE SIZE: 800 participants with a minimum follow-up of 5.5 yrs is designed to give 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months, and RT starting about week 16 delivered as 78Gy in 39#, or 46Gy in 23# plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. Imaging with CT/MRI and bone scan at baseline, PSA progression, then 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. 623 participants recruited from 61 sites as of 16 October 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. Clinical trial information: NCT02446444.
ARASENS: A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Smith Matthew Raymond , Saad Fred , Hussain Maha , Sternberg Cora N. , Fizazi Karim , Yamada Karin Sayuri , Kappeler Christian , Kuss Iris , Tombal Bertrand F. 
Published: February 2018

TPS383 Background: The addition of either docetaxel or abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improves overall survival (OS) compared with ADT alone in men with mHSPC. It is hypothesized that other androgen receptor (AR)-targeted therapies could be combined with docetaxel for mHSPC. Darolutamide (ODM-201) is an investigational oral AR antagonist with a unique chemical structure and negligible blood-brain barrier penetration that inhibits tumor growth by binding to AR and AR mutants (eg, W742L and F877L) with high affinity and specificity. In phase 1/2 ARADES and phase 1 ARAFOR trials, darolutamide demonstrated antitumor activity and was well tolerated in men with metastatic castration-resistant prostate cancer (mCRPC). ARASENS will evaluate the addition of darolutamide to standard ADT and docetaxel in men with mHSPC. Methods: This international, randomized, double-blind, placebo-controlled phase 3 trial (NCT02799602) is being conducted at > 300 sites in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to darolutamide (600 mg orally twice daily) or matching placebo. All patients will receive standard ADT + docetaxel (6 cycles). Patients will be stratified by disease extent and alkaline phosphatase level. Key inclusion criteria: histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation antiandrogen therapy ≤12 weeks before randomization, and ECOG performance status 0-1. The primary end point is OS. Secondary end points include time to mCRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event (SSE)-free survival, time to first SSE, first opioid use, pain progression, and worsening of physical symptoms. Safety will be assessed. ARASENS is actively enrolling at > 280 sites across 23 countries. Clinical trial information: NCT02799602.