bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathologic response and surgical outcomes in patients undergoing nephrectomy after receipt of immune checkpoint inhibitors for renal cell carcinoma.
Authors: Margulis Vitaly , Singla Nirmish , Elias Roy , Ghandour Rashed , Freifeld Yuval N , Bowman I. Alex , Woldu Solomon L. , Gahan Jeffrey , Bagrodia Aditya , Brugarolas James , Hammers Hans J. 
Published: May 2019

e16102 Background: With the approval of immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (RCC), the role, timing, and safety of surgically excising the primary tumor remain unclear. We sought to evaluate the safety and feasibility of nephrectomy following receipt of ICI for RCC. Methods: We reviewed our experience of RCC patients who underwent nephrectomy from 2016-2018 following exposure to nivolumab or combination ipilimumab/nivolumab. Demographics, IMDC risk score, and pathology were collected. Surgical outcomes including operative time (OT), estimated blood loss (EBL), hospital length of stay (LOS), readmission rates, and 30- and 90-day complication rates were analyzed using descriptive statistics. Results: 11 nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. 6 patients received 1-4 cycles of ipilimumab/nivolumab, while 5 received 2-12 infusions of nivolumab preoperatively. One patient with non-metastatic, synchronous bilateral renal masses underwent staged left radical nephrectomy and right partial nephrectomy. 5 surgeries were performed laparoscopically, and 4 patients underwent thrombectomy. IMDC score for metastatic patients was intermediate (7/9) or poor (2/9). One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 mL, and 4 days, respectively. Four patients experienced any complication, including 3 that were addressed with a single interventional radiology procedure. One patient died of progressive disease > 3 months after surgery, and one patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients. Conclusions: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. As multimodal management in the era of ICI continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants attention.
Overall survival with or without brain metastases from diagnosis of metastatic renal cell carcinoma.
Authors: Bowman I. Alex , Christie Alana , Le Tri Cao , Bent Alisha , Brugarolas James 
Published: May 2019

e16112 Background: Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have historically been associated with a poor prognosis. We have previously reported improved outcomes for RCC patients diagnosed with brain metastases prior to or during 1st line systemic therapy among patients treated with modern systemic and local therapies. Here we report outcomes in all mRCC patients regardless of the timing of BM diagnosis. Methods: A retrospective database of mRCC patients treated at our institution between 2006 and 2015 was compiled and patients with BM identified. Overall survival (OS) was analyzed by the Kaplan-Meier method from the diagnosis of metastatic RCC, according to BM status and by IMDC risk group. Results: 271 patients with mRCC were identified, including 79 (29.2 %) diagnosed with BM. Clear-cell histology was more common among BM (94.2 v 81.0%, p = 0.01), otherwise patient characteristics were similar. BM were diagnosed prior to systemic therapy (44.3%), or after one or more lines of therapy (one 26.6%, two 13.9%, three 5.1%, four 6.3%, five 3.8%). Among BM patients, 54 (68.4%) received local therapy with stereotactic radiosurgery (SRS) and/or surgical resection, 14 (17.7%) received WBRT alone, and 11 (13.9%) had no CNS-directed treatment. Local therapy consisted of SRS in 43 (54.4%) and surgical resection in 18 (22.8%), with some patients receiving both. Medial OS from metastatic diagnosis for those with BM was not significantly different from those without BM (26.4 v 28.7 mo, p = 0.305). This remained true when analyzed according to IMDC risk factors (see table). Conclusions: OS from the diagnosis of metastatic RCC did not significantly differ with or without BM in a cohort treated with modern systemic and CNS-directed therapies regardless of the timing of BM diagnosis or presence of IMDC risk factors. [Table: see text]
Efficacy of bone resorption inhibitors (BRI) + abiraterone acetate + prednisone (AA) vs. AA alone as first-line therapy for men with castration-resistant prostate cancer (CRPC) and bone metastases (BM) in an international multicenter hospital-based registry.
Authors: Francini Edoardo , Montagnani Francesco , Pier Vitale Nuzzo , Alimohamed Nimira S. , Moreno Candilejo Irene , Rosellini Pietro , Gonzalez-Velez Miguel , Rubio Jaime , Zhang Li , Shaw Grace , Crivelli Francesca , Petrioli Roberto , Bengala Carmelo , Francini Guido , Foncillas Jesus Garcia , Bryce Alan Haruo , Sweeney Christopher , Harshman Lauren Christine , Lee-Ying Richard , Heng Daniel Yick Chin 
Published: May 2019

e16508 Background: BM in patients (pts) with CRPC correlate with higher mortality and costs. BRI zoledronic acid and denosumab are frequently used for the prevention of skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line treatment for men with metastatic CRPC. We sought to evaluate the impact of BRI on time to first SRE (ttSRE) and OS of pts receiving 1st line therapy AA for CRPC with BM. Methods: We identified a cohort of men starting AA as 1st line therapy for CRPC with BM between 2013-2015 from 7 hospitals’ IRB approved registries. Pts were grouped by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. The endpoints were OS, defined as time from AA start to death or last follow-up visit, and ttSRE. Results: Of the 338 pts included, 256 (76%) received AA alone and 82 (24%) AA+BRI. ECOG PS (PS) was ≥1 for 178 pts (52.7%). No statistically significant difference in ttSRE was found between the 2 cohorts [see Table]. Median follow-up for OS was 25.6 months. Pts receiving concomitant BRI showed a significantly longer OS and a 36% decreased risk of death compared to AA alone (HR = 0.64; 95% CI, 0.64 0.46-0.91; p = 0.012). Notably, OS in the AA alone group was shorter than commonly described. The OS benefit with BRI was greater for men with high volume disease (HV) (HR = 0.42; 95% CI, 0.25-0.71; p = 0.001). On MVA, BRI vs. no BRI, low volume of disease vs. HV, PS 0 vs. ≥1, baseline VAS pain ≤3 vs. > 5, and baseline PSA are independently associated with longer OS. Conclusions: Using a multicenter database, the addition of BRI to 1st line AA for CRPC men with BM and poor prognostic factors did not improve prevention of SRE. However, concomitant use of BRI and AA was associated with a significantly improved OS, particularly in HV. Further research to determine the driving factors is needed. [Table: see text]
A phase I dose escalation study of PCUR-101 in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kyriakopoulos Christos , Paller Channing Judith , Verma Ajit , Kader Karim , Kittrelle Jeff , Borgström Per G , Vaishampayan Ulka N. 
Published: May 2019

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.
Evaluation of monovalent versus biparatopic CD3xPSMA bispecific antibodies for t-cell mediated killing of prostate tumor cells with minimal cytokine release.
Authors: Buelow Ben , Clarke Starlynn , Dang Kevin , Li Jacky , Rancan Chiara , Li Yuping , Sankaran Preethi , Pham Duy , Balasubramani Aarti , Davison Laura , Harris Katherine , Jorgensen Brett , Schellenberger Ute , Trinklein Nathan , Ugamraj Harshad , Fong Lawrence , Van Schooten Wim , Force Aldred Shelley 
Published: May 2019

e16519 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new treatments are needed. Therapies directed against Prostate specific membrane antigen (PSMA) -such as radiolabeled antibodies, chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs)- have shown promising efficacy but also induce significant toxicity. In particular T-cell redirection leads to efficient killing of tumor cells but induces cytokine release-related toxicities. We have developed a panel of monovalent and biparatopic CD3xPSMA bispecific antibodies that eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats (UniRat™, OmniFlic™) followed by deep sequencing of the antibody repertoire from draining lymph nodes in immunized animals, and high-throughput gene assembly/expression. PSMA x CD3 T-BsAbs were assembled and evaluated for stability, pharmacokinetics, and T cell activation and ability to eliminate PSMA+ tumor cells in vitro and in vivo. Results: Bispecific CD3xPSMA Abs. incorporating either monovalent or biparatopic anti-PSMA binding domains activated T-cells in the presence of PSMA (plate-bound or cell surface), while no T cell activation occurred in the absence of either PSMA antigen or bispecific antibody. Potent/selective cytotoxicity against PSMA+ cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA T-BsAbs. Similar results were observed in in vivo Xenograft models of prostate cancer. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cytotoxicity compared to those with a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies incorporating both monovalent and biparatopic anti-PSMA binding domains that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.
Are there any significant impacts of patient age and prior treatment profile with docetaxel on the efficacy of cabazitaxel in patient with castration-resistant prostate cancer?
Authors: Kosaka Takeo , Hongo Hiroshi , Mizuno Ryuichi , Tanaka Nobuyuki , Takaeda Toshikazu , Matshumoto Kazuhiro , Oya Mototsugu 
Published: May 2019

e16522 Background: The correlation of the oncological outcomes of patient age in metastatic castration resistant prostate cancer (mCRPC) patients have not been unclear. Materials and Methods: This study included a total of 56 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the prognostic significance of cabazitaxel at Keio University Hospital from 2014 to 2019 were included., focusing on patient age and the correlation of efficacy between docetaxel and cabazitaxel. All patients received cabazitaxel at 20-25 mg/m2 administered intravenously on day 1 of each treatment cycle, together with prednisone 5 mg twice daily. Prophylactic administration of G-CSF was prescribed to all the patients. Results: The median overall survival (OS) periods after the introduction of cabazitaxel was 16.1 months. A 30% PSA response to cabazitaxel was achieved in 5 (50.0%) patients with ≧75 years (n = 10) and 19 (41.3%) patients with less than 75 years (n = 46). There was no significant correlation between the PSA response and patients’ age (p = 0.087). A 30% PSA response to cabazitaxel was achieved in 25 (43.9%) patients. A 30% PSA response to cabazitaxel was achieved in 15 (57.6%) and 10 (33.3%) patients with and without that to docetaxel, respectively. There was no significant correlation of the PSA response between docetaxel and cabazitaxel (p = 0.106). Univariate and multivariate analysis revealed that there were no significant correlation of patient age, the response to prior docetaxel therapyor cycles of docetaxel therapy with shorter OS. Conclusions: These results indicate that the introduction of cabazitaxel for mCRPC patients could result in oncological outcomes without any association with patient’s age and the profiles of previous docetaxel therapy.
Immune-stimulatory gene expression in stroma cells of African-American prostate cancer tissues.
Authors: Mercola Dan , Rahmatpanah Farah , Agrawal Anshu , Jia Zhenyu (Arthur) , Zi Xiaolin , Lilly Michael B. , McClelland Michael 
Published: May 2019

e16544 Background: Prostate cancer (PCa) of African Americans (AA) has a two-fold higher mortality compared to PCa of European Americans (EA). PCa-adjacent stroma cells from these two populations were examined for differences in their cytokine secretion and gene transcription. Methods: Primary PCa-adjacent stroma cells (carcinoma-associated fibroblasts (CAFs)) and PCa-distant normal fibroblasts of the same gland (dNFs) from 15 AA and 27 EA patients were grown to passage 5. A multiplex immunoassay was then used to measure the secretion of 30 cytokines/chemokines in conditioned medium. In addition, RNA-Seq was performed on four AA and four EA CAF lines, and on PCa-adjacent stroma FFPE tissues of seven AA and five EA patients. Self-identified ethnicity was confirmed using the LASER program and SNPs present in the RNA-Seq. Results: Conditioned media from 42 AA and EA CAFs and dNFs were assayed for 30 immuno-regulatory cytokines/chemokines and growth factors, 20 of which (66%) were secreted at lower levels ( p < 0.05) in AA vs. EA CAFs. Remarkably, dNFs did not show this difference. RNA-Seq analysis of AA vs EA CAFs in culture identified 413 upregulated and 893 downregulated genes (FDR < 0.05, ≥ ±1.5 fold). Several interleukins, interferons, and 120 of 154 differentially transcribed interferon-stimulated genes were downregulated in AA vs. EA CAFs. RNA-Seq of PCa-adjacent stroma from FFPE tissues of seven AA and five EA patients revealed significantly reduced transcription of many immunomodulatory genes in AA stroma, including type I IFN-stimulated genes (ISGs). CIBERSORT analysis of the FFPE RNA-Seq data indicated the presence of significantly less numbers of dendritic cells and higher levels of naïve CD4 Th cells in AA vs. EA stroma. Conclusions: We observed reduced transcription of immunomodulators in CAFs of AA vs. EA, accompanied by profound decreases in the levels of many secreted cytokines and chemokines. These differences may indicate reduced innate and adaptive immune responses in AA PCa, compared to EA PCa. The differences observed here in primary cell lines may permit functional studies of the underlying mechanism(s) of the striking dissimilarity in disease outcome of AA PCa compared to EA PCa
Outcomes of men with prostate cancer managed with active surveillance and tested with clinical cell-cycle risk score.
Authors: Ehdaie Behfar , Kaul Sanjeev , Wojno Kirk , Evans Brent , Bernhisel Ryan , Meek Stephanie , D'Anna Richard , Ferguson Jeffrey , Glaser Jeffrey , Morgan Todd Matthew , Lieb Jeremy , Yan Robert , Stone Steven , Cohen Todd 
Published: May 2019

e16566 Background: The indolent nature of many prostate cancers (PC) makes some men eligible to undergo active surveillance (AS) rather than immediate definitive treatment. Accurate risk classification is critical for selection of appropriate candidates for AS. The clinical cell-cycle risk (CCR) score, a combined clinical and molecular score, provides improved prognostic information about tumor aggressiveness over clinical parameters alone. This study aimed to evaluate the clinical outcomes of men with low-risk PC by NCCN guidelines and CCR score who selected AS. Methods: This study retrospectively reviewed men with localized PC who received CCR testing (2013-2017) and had low-risk disease according to NCCN guidelines and CCR score (N = 664). Low-risk by CCR score was defined as having a risk of disease-specific mortality < 3.2%. Men selected AS (no definitive treatment within 6 months of diagnosis) or underwent immediate definitive treatment. Durability of AS was evaluated beginning from diagnosis. Clinical outcomes were determined by reporting adverse events (biochemical recurrence (BCR), progression to metastasis as confirmed by radiographic imaging, prostate cancer specific mortality). Results: In this study, 547 men (82%) selected AS (median follow-up time 2.2 years [1.5, 3.1]). Of those managed by AS, two (0.4%) men experienced an adverse event. One man experienced BCR 3.7 years after diagnosis, and the other experienced metastasis 0.9 years after diagnosis. There were no reported cases of disease-specific mortality. The probability of remaining on AS for 3 years was 69.6%. Common reasons for exiting AS were patient choice (27.1%), increase in Gleason score (23.3%), and change in prostate specific antigen (PSA) (10.5%). Of those patients that left AS due to change in PSA (N = 14), only 4 exhibited a clinically significant increase in PSA ( > 10 ng/mL). Conclusions: The majority of men with molecularly-confirmed (CCR), NCCN low-risk PC selected AS in both academic and community settings. The incidence of metastatic disease or BCR after definitive treatment for disease progression was rare. The majority of men who selected AS remained on AS for the duration of the study.
Association of disease prognostic model (PM) with baseline quality of life (QOL) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Prizment Anna , Halabi Susan , McSweeney Sean , Eisenberg Amy , Rao Arpit , Gupta Shilpa , Morgans Alicia K. , Ryan Charles J. 
Published: May 2019

e16579 Background: PM’s in mCRPC accurately predict survival, but little is known about their association with QOL. We hypothesize that pre-treatment QOL is inversely correlated with PM derived scores. Our study explored associations between baseline Halabi PM derived risk score (including metastatic site, opioid use, ECOG performance status (ECOG PS), Alk phos, albumin, hemoglobin, LDH, and PSA) and multiple QOL domains at treatment initiation with docetaxel and prednisone (DP). Methods: The DP arm of MAINSAIL, a multicenter, randomized Phase 3 study of DP +/- lenalidomide in mCRPC, was analyzed via ProjectDataSphere. Halabi PM score was computed as continuous with higher score reflecting worse survival and classified as low- ( < 140 points), intermediate- (140-194.96) or high-risk groups ( > 194.96 points). QOL tests included FACT-P (higher score = better QOL), BPI-SF Severity score (BPI-SFSS; higher score = higher pain severity); and BPI-SF Interference score (BPI-SFIS, higher score = worse pain). General linear regression model was used to calculate beta estimates and 95% confidence intervals. Results: The sample included 526 mCPRC pts (median 68 years, White: 91.9%, Black: 5.3%, median PSA 75.95 ng/ml). Median [range] for FACT-P, BPI-SFSS and BPI-SFIS were 111 [0-152], 1.8 [0-9.3], and 1.4 [0-10], respectively. PM score was correlated with BPI-SFIS and BPI-SFSS and inversely correlated with FACT-P with correlation of 0.36, 0.31 and -0.33, respectively (all p < 0.0001). For each unit increase in the PM score, BPI-SFIS increased by 2.1 points), BPI-SFSS increased by 1.5 points, and FACT-P decreased by 16.4 points. Using the three-risk groups, pts in the intermediate and high-risk groups had worse FACT-P QOL and higher BPI-SFIS and BPI-SFSS than pts in the low-risk group. In multivariate analysis, factors negatively impacting FACT-P QOL, BPI-SFSS and BPI-SFIS were higher ECOG PS, visceral metastases and opioid use. Declining hemoglobin levels were associated with increased BPI-SFSS and BPS-SFIS. Conclusions: Higher PM scores are associated with a lower baseline QOL overall, higher pain and higher pain interference. These results should be validated prospectively.