bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of pre-existing diabetes mellitus on survival in stage I renal cell carcinoma.
Authors: Ryan Stephen , Bindayi Ahmet , Bloch Aaron , Nasseri Ryan , Hamilton Zachary , Yim Kendrick , Reddy Madhumitha , Wan Fang , Capitanio Umberto , Larcher Alessandro , Montorsi Francesco , Lane Brian R. , Noyes Sabrina L , Dey Sumi , Uzzo Robert , Joshi Shreyas , Derweesh Ithaar 
Published: February 2018

676 Background: AUA guidelines recommend consideration of nephron sparing surgery in patients with comorbidities that are likely to impact renal function, such as diabetes mellitus (DM). We compared the impact of partial nephrectomy (PN) and radical nephrectomy (RN) on overall survival (OS) in patients with pre-existing DM and Stage I Renal Cell Carcinoma (RCC). Methods: Multicenter retrospective analysis of surgically treated Stage I RCC from 2005-16 with or without DM. Primary outcome was OS analyzed by DM+ or DM- and surgical approach (PN or RN) for AJCC Stage I. Logistic (OR) and Cox (HR) regression were utilized for OS. Results: 2173 patients were analyzed (1223 RN, 1819 PN, 555 DM+, 2487 DM-) with mean follow-up of 49.1 months. Increasing Age (OR 1.028, p = .009), RN (OR 2.446, p = .001), and most recent eGFR < 45 (OR 2.306 p = .002) remained significant on multivariate analysis for OS (Table 1). In the PN subgroup, DM+ or DM- was not associated with decreased OS (HR 1.48 p = 0.19). DM+ was associated with decreased OS in the RN subgroup (HR 1.97 p = 0.005). Conclusions: In Stage I RCC, DM and RN negatively impacted OS, while only RN remained significant on MVA. Subgroup analysis of PN showed that OS was similar in DM- and DM+ patients, but diagnosis of DM had a profound impact on OS in the RN group. This supports the guideline statements and offers evidence that urologists should prioritize nephron sparing surgery in patients with DM and Stage I Renal Cell Carcinoma.[Table: see text]
Characterization of the benefit-risk profile of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced renal cell carcinoma (aRCC; CheckMate 214).
Authors: Tannir Nizar M. , Hammers Hans J. , Amin Asim , Grimm Marc-Oliver , Rini Brian I. , Mekan Sabeen , McHenry M. Brent , Kollmannsberger Christian K. 
Published: February 2018

686 Background: The phase 3 CheckMate 214 study demonstrated superior efficacy for N+I v S in intermediate/poor-risk aRCC patients (pts), with manageable safety (Escudier, ESMO 2017). Here we report additional data to define benefit-risk. Methods: Pts with clear-cell aRCC were randomized 1:1 to N 3 mg/kg + I 1 mg/kg every 3 wk for 4 doses followed by N 3 mg/kg every 2 wk, or S 50 mg daily orally for 4 wk (6-wk cycles). Primary endpoints were efficacy parameters in intermediate/poor-risk pts. Secondary endpoints included adverse event (AE) incidence in all treated pts. Select AEs were defined as AEs pooled by organ category that may differ from AEs caused by non-immunotherapies, may require immunosuppression, and whose early recognition may mitigate severe toxicity. Results: 1096 pts were randomized (pts treated: N+I: n = 547; S: n = 535). N+I showed statistically significant OS benefit, significantly higher ORR, numerically longer PFS, and better symptom control v S. 79% of N+I pts received all 4 I doses. Drug-related grade 3-5 AEs occurred in 46% with N+I v 63% with S; drug-related AEs leading to discontinuation occurred in 22% v 12%. Drug-related select AEs resolved in 72%-92% of N+I pts, except endocrinopathies (43%; Table). An analysis of the relationship between safety and efficacy will be presented. Conclusions: Drug-related select AEs with N+I were manageable, with the vast majority resolving except endocrinopathies. These additional data further support the favorable benefit-risk profile of N+I v S in CheckMate 214. Clinical trial information: NCT02231749. [Table: see text]
Identification and characterization of circulating tumor cells in post prostatectomy patients with localized high risk prostate cancer.
Authors: Friedlander Terence W. , Welty Christopher J. , Anantharaman Archana , Hough Jeffrey , Edwards Matthew , Stromlund Alise , Simko Jeff , Graf Ryon , Rodriquez Angel , Wang Yipeng , Carroll Peter , Cooperberg Matthew R. , Dittamore Ryan Vance , Paris Pamela 
Published: February 2018

69 Background: Over 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features that raise the recurrence risk. Better biomarkers could allow for even earlier detection of biochemical recurrence (BCR) and inform adjuvant treatment decisions. Circulating tumor cells (CTCs) may represent the earliest form of metastases, however their role as biomarkers in men with localized PCa is not well defined. Here, we aim to enumerate and molecularly and genomically analyze CTCs using an enrichment-free, unbiased CTC identification technology from men with high-risk, localized PCa after radical prostatectomy (RP) and correlate the analysis with clinical outcomes. Methods: Blood samples from 37 patients with high-risk, localized PCa were obtained 2-5 mos post RP and shipped to Epic. All nucleated cells were subjected to immunofluorescent staining for cytokeratin (CK), CD45, and AR. CTCs were identified using algorithmic analysis. CK+ CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number alterations (CNA). Patients were followed for BCR, defined as detectable PSA > 0.2ng/dL. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 81.1%(30/37) of patients with an average of 5.2 CTCs/ml (range: 0 – 22.9) detected per patient. AR expression was detected in 18.9% (7/37) of patients. Ninety nine CTCs from 14 patients were picked and sequenced. CNAs were identified in CTCs in commonly mutated genes in PCa, including MYC amplification and CHD1 deletions. Patients with higher traditional CTC (CK+) burdens exhibited a trend towards shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p = 0.13). Conclusions: There was a high incidence of CTC detection after RP in patients with high-risk, localized PCa. A trend toward shorter PFS was seen in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa. With further testing in appropriately powered cohorts early CTC detection after primary therapy could represent an informative biomarker to stratify patients with high risk PCa.
External beam radiotherapy (EBRT) and high dose rate (HDR) brachytherapy for intermediate and high-risk prostate cancer: Whole pelvis or prostate-only EBRT?
Authors: Tharmalingam Hannah , Tsang Yatman , Choudhury Ananya , Hoskin Peter ,   The UK National HDR Prostate Brachytherapy Database Group
Published: February 2018

86 Background: In high-risk prostate cancer, the risk of occult lymph node metastases in the pelvic lymph nodes can be as high as 40%. However, the use of whole pelvis radiotherapy (WPRT) in high-risk patients remains controversial with mixed retrospective evidence and two negative prospective trials. Data from a national UK database of patients treated with external-beam radiotherapy (EBRT) and high-dose rate (HDR) brachytherapy was reviewed to evaluate the benefit of pelvic treatment. Methods: From 2009 to 2013, 755 patients with intermediate- and high-risk prostate cancer (clinical stage ≥T2c, Gleason score ≥7 or presenting prostate-specific antigen (pPSA) ≥10) were treated with EBRT and HDR brachytherapy. The pelvic nodes to the level of the common iliac chain were treated in 370 patients with a dose of 46Gy in 23 fractions. The remaining 385 patients received radiotherapy to the prostate only (PORT) at a dose of 37.5Gy in 15 fractions. A single dose of 15Gy was delivered with HDR brachytherapy in each case. Corresponding biologic effective doses to the prostate were 107Gy and 100Gy respectively (α/β = 1.5). 96.5% of patients received ADT with a median duration of 24 months. Biochemical failure was defined as a PSA rise of ≥2ng/ml above nadir. Analysis used log-rank and Cox univariate and multivariate tests. Results: Median follow-up was 4.5 years; 5-year biochemical progression-free survival rates for the WPRT versus the PORT arms were 88% vs 80% (p < 0.05) for all patients and 89% vs 76% (p < 0.05) for high-risk patients. Differences in bPFS remained significant (p < 0.05) after accounting for Gleason score, pPSA, T stage and ADT duration as co-variates. There was no difference in overall survival. Conclusions: Whole pelvis EBRT with HDR brachytherapy appears to significantly improves 5-year biochemical progression-free survival in intermediate- and high-risk prostate cancer compared to prostate-only EBRT and HDR brachytherapy which persists after allowing for covariates including presenting tumour parameters and ADT use. The PIVOTAL boost trial in the UK will assess this further in a prospective randomised study.
Neoadjuvant enzalutamide and androgen deprivation therapy for high-risk prostate cancer: Early results from a feasibility trial.
Authors: VanderWeele David James , Turkbey Baris , Karzai Fatima , Harmon Stephanie , Sowalsky Adam G. , Ye Huihui , Wilkinson Scott , Chun Guinevere , Gold Samuel , Pinto Peter A. , Choyke Peter L. , Dahut William L. 
Published: February 2018

94 Background: Intensive androgen-targeted therapy improves survival for patients with androgen naive metastatic prostate cancer. Neoadjuvant androgen deprivation therapy (nADT) with abiraterone for localized disease leads to complete responses (pCR) rates of up to 10%. In this study we tested the efficacy of nADT with enzalutamide for patients with high risk, localized disease and the ability of post-treatment multiparametric MRI (mpMRI) to evaluate response. Methods: A single institution trial (NCT02430480) evaluated nADT and enzalutamide 160 mg daily in patients with high risk non-metastatic prostate cancer. Patients underwent MRI-TRUS-guided fusion biopsy at screening and repeat mpMRI followed by radical prostatectomy (RP) after completing six months of therapy. Results: Twenty patients have completed therapy and undergone radical prostatectomy. Clinical characteristics were typical of those with high risk disease: median PSA 8.96 ng/ml (range 2.07-985.9) and clinical stage by mpMRI cT2 (one patient), cT3 (17 patients), or cT4 (2 patients); 7 patients had enlarged pelvic lymph nodes. Following 6 months of therapy, median pre-RP PSA was < 0.02 ng/ml (range < 0.02 – 0.35). On final pathology, 0 patients were upstaged, 5 (25%) were unchanged, and 15 (75%) were downstaged, including 3 (16%) pCR. Four patients were downstaged from N1 to N0. There was little correlation between post-treatment mpMRI tumor volume and pathologic tumor volume. Two patients had radiographic complete responses, one of whom had extensive residual disease. Conclusions: Six months of nADT with enzalutamide has activity in high risk, localized prostate cancer, with a small number of patients having exceptional responses. Standard analysis of mpMRI does not reliably characterize depth of response. Evaluation of molecular characteristics that predict exceptional response or intrinsic resistance is on-going. Patients are being followed for recurrence. Clinical trial information: NCT02430480.
The PACE trial: International randomised study of laparoscopic prostatectomy vs. stereotactic body radiotherapy (SBRT) and standard radiotherapy vs. SBRT for early stage organ-confined prostate cancer.
Authors: Morrison Kirsty , Tree Alison , Khoo Vincent , Van As Nicholas John ,   On Behalf of the PACE TMG
Published: February 2018

TPS153 Background: The development of Stereotactic Body Radiotherapy (SBRT) has provided a further treatment option for early stage prostate cancer. In addition to the benefits of an overall treatment time reduction, profound hypofractionation could result in therapeutic gain given the radiobiology of prostate cancer. Evidence suggests SBRT to be safe and effective; however randomised data is lacking comparing outcomes with standard treatment options. Aim: To assess whether SBRT offers therapeutic benefit in comparison to prostatectomy or standard radiotherapy. Methods: The PACE trial is an international multicentre phase III trial, comprising two parallel randomisation processes. Within PACE A, potential surgical candidates are randomised between radical prostatectomy and SBRT (36.25 Gy in 5 fractions). In PACE B, randomisation is between standard radiotherapy (78Gy in 39 fractions or 62Gy in 20 fractions) and SBRT (36.35Gy in 5 fractions). SBRT can be delivered using Cyberknife or gantry based techniques. Patients with low or intermediate risk prostate cancer are eligible for the trial, and are treated without the use androgen deprivation therapy. Follow up is for a period of 10 years. The aim is to recruit 234 patients to PACE A (117 in each arm) and 858 patients to PACE B (429 patients in each arm). Primary Objectives: PACE A: To determine whether there is improved quality of life after SBRT compared with surgery at 2 years post treatment, using EPIC score to measure urinary incontinence and bowel bother. PACE B: to determine whether SBRT is non-inferior to surgery in terms of freedom from biochemical/clinical failure at 5 years from randomisation. Progress: PACE A has been slower to recruit than anticipated due to the difficulties of a surgery versus radiotherapy randomisation. However, it is expected to reach target accrual, having recruited 57 patients from 3 centres. In contrast, PACE B is recruiting exceptionally well, open in 40 centres, and as of October 2017 recruited 762 patients. Accrual target is expected to be reached by the end of 2017. Clinical trial information: NCT01584258.
A phase 1b/2 study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Taplin Mary-Ellen , Hussain Arif , Shore Neal D. , Bradley Bill , Trojer Patrick , Lebedinsky Claudia , Senderowicz Adrian Mario , Antonarakis Emmanuel S. 
Published: February 2018

TPS398 Background: EZH2 is frequently mutated and overexpressed in human cancer. High levels of expression are correlated with disease stage, aggressiveness, and poor outcome in patients with prostate cancer (Varambally, 2002). EZH2 inhibition restores androgen receptor expression and sensitivity to antiandrogen therapy in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as an approach to overcome resistance to antiandrogen therapy (Ku, 2017). CPI-1205 is a potent, selective and cofactor-competitive EZH2 inhibitor, that inhibits both wild-type and mutant EZH2 catalytic activity in a reversible manner. Preclinical studies have shown profound anti-proliferative effects of CPI-1205 in treating both lymphoma and prostate cancer cell models. Antitumor activity of EZH2 methyltransferase inhibitors has been observed in patients with non-Hodgkin’s lymphoma. These observations support the clinical evaluation of CPI-1205 with standard doses of A/P or E in mCRPC. Methods: We present a Phase 1b/2 study to explore the safety and efficacy of two regimens of CPI-1205 in combination with either E or A/P. Key eligibility criteria include progressive mCRPC in patients previously treated with a second generation androgen inhibitor, ECOG 0-1 and measurable or non- measurable disease. Key exclusion criteria include > 1 second generation androgen inhibitor. During the phase 1b, sequentially enrolled cohorts will receive CPI-1205 at continuous – 28-day cycles combined with either standard dose of E (160mg PO once daily) or A/P (1000mg PO once daily/ 5 mg BID). The primary objective is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of each regimen. Secondary objectives include safety, pharmacokinetic, pharmacodynamics profiles and activity (PSA, circulating tumor cells, imaging) in mCRPC. Once RP2D is established, we will start a Phase 2 trial of a 2nd generation androgen inhibitor combined with CPI-1205.
Phase I dose-escalation study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).
Authors: Tagawa Scott T. , Vallabhajosula Shankar , Jhanwar Yuliya , Ballman Karla V. , Hackett Amy , Emmerich Lauren , Babich John , Sartor A. Oliver , Harshman Lauren Christine , Beltran Himisha , Molina Ana M. , Nanus David M. , Bander Neil Harrison 
Published: February 2018

TPS399 Background: PC is a radiosensitive disease. PSMA is overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of beta-emitting radiolabeled anti-PSMA monoclonal antibody (mAb) J591 have demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable, reversible dose-limiting myelosuppression. Alpha emitters are significantly more potent with a shorter range than beta emitters. Though there is no direct tumor-targeting, the bone-targeting alpha emitter Ra223 is approved. Anecdotal reports of PSMA small molecule targeted alpha emitters have hinted at efficacy but are limited by xerostomia and in mouse models may lead to long-term renal damage. Intact mAb J591 has comparatively no to minimal distribution in salivary glands and kidneys. Preclinical studies demonstrated purity, immunoreactivity, and stability with efficacy in a xenograft model [AACR 2017]. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies (excluding beta-emitting bone-targeted radioisotopes) provided adequate organ function will undergo imaging with 68Ga-PSMA-11 PET/CT followed by a single dose of 225Ac-J591. Single-subject cohorts will be enrolled until grade > 1 attributable toxicity, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to 93.3 KBq/kg of 225Ac with fixed 20 mg J591. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS, and patient reported outcomes (FACT-P and BPI-SF). Correlatives include baseline/follow up PSMA imaging, CTC count (CellSearch) changes, tissue and circulating genomic assessment, and immune studies. Enrollment began in October, 2017. Clinical trial information: NCT03276572.
An open-label phase 1/2a study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rathkopf Dana E. , Saleh Mansoor N. , Tsai Frank Yung-Chin , Rosen Lee S. , Adams Bonne J. , Liu Lilian , Theuer Charles P. , Freddo James L. , Agarwal Neeraj 
Published: February 2018

TPS403 Background: Resistance to AR-targeted therapy is a challenge in the treatment of mCRPC. Single amino acid mutations of the AR ligand binding domain may mediate resistance to second generation AR inhibitors, including enzalutamide (Rathkopf, Annals of Oncology 2017). Development of potent antagonists of wild-type (WT) AR as well as mutated AR is a priority. TRC253 is an orally available, high-affinity, small molecule antagonist of AR with inhibitory activity against WT AR as well as mutated variants. TRC253 blocks AR nuclear translocation and AR binding to DNA and antagonizes transcription. TRC253 does not have agonist activity toward WT or mutated ARs. Methods: This phase 1/2a study of TRC253 in patients with mCRPC will be conducted in two parts: dose-escalation (part 1) and dose-expansion (part 2). Objectives include assessment of safety, selection of a phase 2 dose, and to evaluate PSA response at week 12. Secondary objectives include the evaluation of the extent of receptor occupancy (FDHT PET) and anti-tumor effects of TRC253. Toxicity and efficacy assessments will be determined using NCI-CTCAE and PCWG3 criteria. Dose escalation will begin with single-patient cohorts. Cohorts will be expanded to 3 patients when pre-defined grades of drug-related toxicity occur. TRC253 doses in part 1 are 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, and 400 mg. The DLT evaluation period will be the first 28 days of continuous daily dosing. Six patients have been enrolled to Part 1 to date. Part 2 will consist of two cohorts of up to 30 patients each. Cohort 1 (AR F876L mutation positive) and cohort 2 (AR F876L mutation negative) will receive TRC253 at the RP2D. Circulating tumor DNA will be analyzed in plasma samples to test for AR mutations. In Part 1 patients must have received ≥ 2 prior therapies. Part 2 patients must have demonstrated acquired resistance to enzalutamide or apalutamide. Descriptive statistics will be used to summarize patient characteristics, safety, efficacy, PK, and immunologic biomarkers. Clinical trial information: NCT02987829.
EV-103 study: A phase 1b dose-escalation and dose-expansion study of enfortumab vedotin in combination with immune checkpoint inhibitor (CPI) therapy for treatment of patients with locally advanced or metastatic urothelial cancer.
Authors: Hoimes Christopher J. , Petrylak Daniel Peter , Flaig Thomas W. , Carret Anne-Sophie , Melhem-Bertrandt Amal , Rosenberg Jonathan E. 
Published: February 2018

TPS532 Background: Immune checkpoint inhibitors (CPIs) are approved for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) who progress on prior platinum or are ineligible for first line cisplatin. However, only a minority of pts respond to CPI monotherapy and a combination approach may be beneficial. Enfortumab vedotin (EV), an antibody-drug conjugate (ADC), delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumors expressing Nectin-4, which is overexpressed in mUC. Preliminary results from an ongoing phase 1 study of EV monotherapy in pts with mUC (Petrylak ASCO 2017) showed that EV was well tolerated in pts with mUC. EV showed a 41% (29 out of 71 pts) objective response rate (ORR) across all doses (24 wks median response duration). In pts with liver metastasis the ORR was 47% (9 out 19 pts) across all doses. Preclinical data show that an MMAE ADC, but not the unconjugated antibody, increases tumor immunogenicity by inducing immunogenic cell death, antigen presentation and tumor immune infiltration (Gardai 2015). Based on encouraging phase 1 study results and potential enhanced immune response, combining EV with a CPI may result in improved response rates with longer durability. Methods: This phase 1b study (NCT03288545) evaluates the safety/activity of EV + CPI in pts with la/mUC who have not previously received a CPI. The study has 2 parts: dose escalation (EV + pembrolizumab) and dose expansion (EV + CPI [pembrolizumab or atezolizumab]). Pts must have la/m transitional cell carcinoma of the urothelium, be eligible for treatment with a CPI, and be either ineligible for first-line cisplatin-based chemotherapy or have disease progression during or following treatment with ≥1 platinum-containing regimen. The primary objective is to assess the safety/tolerability of EV + CPI. Secondary objectives include determining a recommended dose of EV + CPI in pts with la/mUC, antitumor activity as measured by ORR, disease control rate, duration of response, PFS, and OS. Response is assessed per RECIST v1.1 and iRECIST. Study enrollment began in Oct 2017. Clinical trial information: NCT03288545.