bluuebunny/crossref_metadata_2025_split huggingface dataset:
Express-diagnosing of acute kidney injury among patients with the localized kidney cancer after partial nephrectomy under warm ischemia: A role of biomarkers.
Authors: Dimitriadi Sergey N , Kit Oleg I. , Frantsiyants Elena M. , Velichko A. V. , Rozenko Dmitry A. , Faenson Aleksandr V. , Filatova Elena V. , Shvyrev Dmitry A. , Rozenko A. D. , Omelchuk Ekaterina P. 
Published: May 2019

e16108 Background: The specialists consider partial nephrectomy (PN) under warm ischemia (WI) as a standard treatment option for localized renal cell carcinoma (RCC) patients. However, clinical use of the method is restricted by acute kidney injury (AKI) development among patients with high R.E.N.A.L. score, which usually demands long warm ischemia time (WIT). The purpose of the study consists in assessing of the diagnostic ability of cystatin С, IL-18, KIM-1, L-FABP and NGAL in express-diagnosing of AKI among patients with the localized kidney cancer after PN under WI. Methods: The sample of the examined patients consists data of the retrospective research of 100 cases with a localized RCC who underwent PN for elective indications using WI. The WIT was about 15-21 minutes. 24 hours prior to and 16 hours after the surgery, using the ELISA technique and standard test-systems the serum concentration of the following “early markers of AKI” was tested: cystatin С (BioVendor, Czech Republic), КIМ-1 (BCMDiagnostics, USA), NGAL (BCMDiagnostics, USA), L-FABP (Hycult Biotechnology, Netherlands), IL-18 (BenderMedsystems, USA). The WIT and diuresis rate were also registered. AKI was diagnosed based on the serum creatinine level measuring in accordance with the KDIGO guidelines. The clinical and laboratory data were processed using MS Excel software; the Wilcoxon test was used. Simultaneously the expert analysis of the data was carried out. Results: The AKI was registered in 24 patients having a preoperative serum cystatin С level higher than 1000 ng/ml. Another risk factor was WIT lasting 15-21 min. All patients with AKI had an increase of serum concentrations of all 3 following markers: cystatin С, NGAL and L-FABP by more than 10 per cent each (in relation to a preoperative level by each patient). In 5 patients (among the 24 ones) an elevation of creatinine serum concentration was registered just after 40 hours after the surgery – much later than the markers’ reaction appeared. Based on the expert analysis of the clinical and laboratory data the personified scale of early AKI diagnosing and its graphical representation in a form of three-dimensional model was developed. Conclusions: The new method allows diagnosing the AKI development after 16 hours in patients who underwent PN under WI on occasion of RCC. The method has good perspectives of clinical use as it allows identifying the AKI development before elevation of a serum creatinine concentration.
Full adaptome repertoire analysis of immunotherapy to predict responsiveness and correlation with CD8-LAG3, sLAG3, and hepatocyte growth factor levels in patients with renal cancer.
Authors: Lotze Michael T. , Appleman Leonard Joseph , Zhai Shuyan , Wang Yue Yolanda , Forte Alexa , Pan Wenjing , Byrne-Steele Miranda L. , Han Jian 
Published: May 2019

e16116 Background: Aldesleukin (recombinant interleukin-2, IL-2), the first checkpoint inhibitor overcoming Tregs, was FDA-approved for mRCC with a 5-10% rate of durable CRs and 25% ORR. Hydroxychloroquine (HCQ) inhibits autophagy, promoting tumor apoptosis. In murine models, IL-2 and HCQ is associated with diminished toxicity and increased efficacy. We hypothesized that a novel deep seven chain analysis of the TCR and BCR repertoire would correlate with sLAG3, CD8 cytosolic LAG3, and HGF levels, associated with outcomes in RCC patients treated with this regimen. Methods: Patients (pts) received high dose IL-2, 600,000 IU/kg, every 8 hours up to 14 doses/cycle. HCQ was administered orally, starting 2 weeks prior to IL-2 and continued up to one year. The HCQ dose was 600 mg (17pts) or 1200 mg (13pts) daily. A newly available seven chain TCR/BCR Adaptome dimer avoidance multiplex-PCR followed by NextGen Sequencing allowed identification of CDR3’s associated with response and increasing clonal diversity. Results: Of 30 pts in the study, 29 were evaluable for response (3CR, 3PR) with serum samples and seven chain analysis of PBMC with 330x106 total reads of the TCR αβ, TCR γδ, IgH, and κλ light chains. HGF (p < .009) was a significant negative predictor of OS at Day 1 after IL-2 and OS at Day -14 (p < .005). Surprisingly this correlated with the TCRδ/γ ratio (p < .01). Similarly serum sLAG3 and CD8LAG3+ both > median predicted improved PFS (p = 0.019) correlating with total TCRδγ expression, p < .01. Diversity of the TCR αβ but not the TCR γδ nor the IgH, and κλ light chains predicted response, p = .005. Conclusions: IL-2 plus HCQ was well tolerated and clinically active with encouraging increase in the PFS of > 17 months at the 600 mg HCQ dose ( > 4x greater than historical controls). Powerful new technology identifying enhanced responsiveness correlating significantly with diversity of the TCR αβ identifies a novel method for predicting responsiveness to immunotherapy. This unbiased examination of the full repertoire ('Adaptome') measured in the same bioassay correlates with other novel biomarkers and should be widely applicable in the further evolution of immunotherapy. NCT01550367 ; approved as IRB 11-074. Clinical trial information: NCT01550367.
Docetaxel dose-intensity effect on overall survival in patients with metastatic castrate-sensitive prostate cancer.
Authors: Kushnir Igal , Mallick Ranjeeta , Ong Michael , Canil Christina , Bossé Dominick , Koczka Kim , Reaume M. Neil 
Published: May 2019

e16501 Background: Several studies assessed the association of docetaxel dose intensity (DI) and efficacy in metastatic castrate-resistant prostate cancer (mCRPC) patients with contradicting conclusions. In this retrospective analysis we will assess whether the docetaxel DI used in patients with metastatic castrate-sensitive prostate cancer (mCSPC) is associated with overall survival (OS). Methods: We have identified all the patients with mCSPC treated at The Ottawa Hospital Cancer Centre that received docetaxel chemotherapy between June 2014 - September 2017. For each patient we calculated the relative dose intensity (RDI) and assessed whether it’s associated with OS using univariate and multivariate cox-proportional hazards analysis. Results: Eighty-0ne patients were included in the analysis. Nineteen patients (23.5%) had their body surface area capped at 2 which resulted with de facto median dose reduction of 7% (IQR 6% - 9%). Ten patients had upfront dose reduction (usually due to significant co-morbidities) with a median dose reduction of 20% (IQR 19.25 – 20.75). Only 35 patients (43.2%) were able to complete the planned treatment with a RDI of at least 90%. After a median follow-up of 29.4 months, 32 patients (39.5%) died. The median OS was 43.9 months. On a univariate analysis RDI and number of cycles of docetaxel received were found to be statistically significant associated with OS. For every 10% decrease in RDI the risk of death increased by 23% (HR 1.23, 95% CI 1.09 – 1.4, P = 0.0011). For every incremental cycle (up to a total of 6) the risk of death decreased by 27% (HR 0.73, 95% CI 0.61- 0.88, P = 0.001). On multivariate analysis we included age, Gleason score, burden of disease, visceral involvement and baseline PSA. Reduced RDI remained the only significant variable associated with OS (HR 1.2, 95% CI 1.04 – 1.39, P = 0.0117). Conclusions: Reduced docetaxel DI administrated to mCSPC patients is associated with worse survival. Therefore unnecessary docetaxel dose reductions, treatments delays and early discontinuation should be avoided. Granulocyte-colony stimulating factor should be considered in order help maintain standard DI.
Oncolytic HSV and PI3K inhibitor BKM120 synergize to promote killing of prostate cancer stem-like cells.
Authors: Wang Lei 
Published: May 2019

e16503 Background: Novel therapies to override chemo-radiation resistance in prostate cancer (PCa) are needed. Prostate cancer sphere-forming cells (PCSCs) (also termed prostate cancer stem-like cells) likely participate in tumor progression and recurrence and are important therapeutic targets. Methods: We established PCSC-enriched spheres by culturing human (DU145) and murine (TRAMP-C2) PCa cells in growth factor-defined serum-free medium, and characterized stem-like properties of clonogenicity and tumorigenicity in vivo. The efficacy of two different oHSVs (G47∆ and MG18L) in PCSCs was tested alone and in combination with radiation, chemotherapy, and inhibitors of PI3K, Wnt, and NOTCH in vitro, and G47∆ with BKM120 in a PCSC-derived tumor model in vivo. Results: PCSCs were more tumorigenic than serum-cultured parental cells. Human and murine PCSCs were sensitive to oHSV and BKM120 killing in vitro, while the combination was synergistic. In contrast, oHSV combined with radiation, docetaxel, Wnt, or NOTCH inhibitors was not. In athymic mice bearing DU145 PCSC-derived tumors, combination intra-tumoral G47∆ and systemic BKM120 induced complete regression of tumors in 2 of 7 animals, and exhibited superior anti-tumor activity compared to either monotherapy alone, with no detectable toxicity. Conclusions: oHSV synergizes with BKM120 in killing PCSCs in vitro and the combination markedly inhibits tumor growth even inducing regression in vivo.
Association between circulating miRNA-141 and miRNA-375 and treatment outcome in metastatic castration-resistant prostate cancer.
Authors: Zedan Ahmed Hussien , Osther Palle Jörn Sloth , Assenholt Jannie , Madsen Jonna Skov , Hansen Torben 
Published: May 2019

e16507 Background: Metastatic castration resistant prostate cancer (mCRPC) is associated with high mortality. Monitoring of disease activity at this stage, with lack of validated prognostic models, is still a major clinical challenge. The role of microRNAs (miRNAs) has been widely investigated in prostate cancer with both diagnostic and prognostic potential. The aim of this study was to investigate the relationship between circulating miRNAs and treatment outcome in mCRPC patients. Methods: The relative expression of four miRNAs was investigated in plasma samples from 84 mCRPC patients; 40 patients were treated with docetaxel and 44 patients with abiraterone. Real-time polymerase chain reaction was used for analysis. Blood was sampled at baseline, before the second treatment cycle, and at radiological progression (RP). Associations to prognoses were analyzed using the Cox Regression analyses. Results: The plasma levels of all four miRNAs decreased significantly after treatment initiation in patients receiving docetaxel, and for miRNA-141 and miRNA-375 the level increased again at the time of RP. High baseline levels of miRNA-141 were significantly associated with a shorter time to RP in patients receiving both abiraterone, hazard ratio (HR) 3.18 (95% confidence interval (CI) 1.31-7.32), p < 0.01, and docetaxel HR 2.56 (95% CI 1.45-4.50), p < 0.01, and a shorter overall survival (OS), HR 3.20 (95% CI 1.25-9.37), p = 0.02, and HR 1.77 (95% CI 1.07-2.83), p = 0.02, respectively. Likewise, high baseline levels of miRNA-375 were also significantly associated with a shorter time to RP in both cohorts and OS in patients receiving docetaxel. Conclusions: Plasma levels of miRNA-141 and miRNA-375 were of prognostic importance in patients with mCRPC receiving both abiraterone and docetaxel and may be used in treatment monitoring irrespective of treatment modality.
Real-world cardiovascular outcomes with novel anti-androgen agents in prostate cancer patients.
Authors: Kulkarni Amit , Rubin Nathan , Tholkes Tony , Prizment Anna , Ryan Charles J. , Rao Arpit 
Published: May 2019

e16510 Background: Abiraterone use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude of this morbidity in contemporary US prostate cancer (PC) population remains unknown. We examined a large medical claims database to answer this important question. Methods: We retrospectively reviewed Marketscan claims database (1/1/2013 to 9/30/2015) to identify adults with diagnosis of localized PC, recurrent localized PC, biochemically recurrent non-metastatic PC and metastatic PC who received treatment with androgen deprivation therapy (ADT) alone or ADT with novel antiandrogen agents (abiraterone or enzalutamide). The primary outcome measure was composite severe CV outcome of acute myocardial infarction (MI), stroke or heart failure (HF). We used Cox regression model with time dependent covariates to estimate the CV risk of various therapies. Results: A total of 7030 patients of PC were identified- 1285 received ADT for localized PC, 424 received ADT for recurrent localized PC, 554 received ADT for biochemically recurrent non-metastatic PC, 256 received ADT alone for metastatic PC and 1366 received abiraterone or enzalutamide with ADT for metastatic PC. During the study period, 143 severe CV events occurred, resulting in an incidence rate of 0.74 per 100 patient-years. In multivariate analysis, abiraterone use was associated with a trend towards increased risk of severe CV compared to non-abiraterone users (HR = 1.58; 95% CI: 0.98-2.59, p= 0.06). No such increased risk was detected for ADT (HR = 1.35; 95% CI: 0.92-2.00, p= 0.12) or enzalutamide (HR = 0.84 95% CI: 0.34-2.11, p= 0.71). Conclusions: To our knowledge, this is the first study to present real-world data on CV outcomes of PC patients receiving novel anti-androgens. Our findings support the trend towards increased severe CV risk seen in abiraterone trials. No such association was seen for enzalutamide. Additional analyses with a longer follow-up duration are planned.
Intratumoral and subcutaneous injection of HVJ-E (GEN0101) for metastatic castration-resistant prostate cancer: Open-label, phase I, dose escalation study.
Authors: Fujita Kazutoshi , Nakai Yasutomo , Kato Taigo , Kawashima Atsunari , Ujike Takeshi , Nagahara Akira , Uemura Motohide , Imamura Ryoichi , Okihara Koji , Ukimura Osamu , Miki Tsuneharu , Kaneda Yasufumi , Nonomura Norio 
Published: May 2019

e16511 Background: Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E (GEN0101). Methods: Patients with CRPC who were resistant to standard of care or could not receive standard of care were eligible. GEN0101 was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a modified 3+3 dose-escalation design to determine the recommended dose of GEN0101. The primary end points were to evaluate safety and tolerability of GEN0101 and determine the recommended dose. The secondary end points were to analyze antitumor effect and tumor immunity. The study is registered at UMIN Clinical Trials Registry, number UMIN000017092. Results: Of the 9 patients treated, 3 received 30,000mNAU of GEN0101 and 6 received 60,000mNAU. There were no dose-limiting toxicities, and the recommended dose of GEN0101 was defined as 60,000mNAU. Radiographically, one patient had stable disease and 2 had progressive disease in the low-dose group, and 5 patients had stable disease and one had progressive disease in the high-dose group. Four patients in high dose group had reductions in lymph node metastasis after 2 treatment cycles. Final PSA increase rates in high-dose group were more suppressed than those in low-dose group. NK cell activity was enhanced in 2 patients (66%) in low-dose group and 5 patients (83%) in high-dose group, Serum interleukin-6, and IFN-γ levels were not affected by GEN0101 treatment. Conclusions: Intratumoral and subcutaneous injections of GEN0101 were well tolerated and feasible. Antitumor effect in lymph node metastasis were observed in CRPC patients. It is necessary to test whether the treatment with GEN0101 improves the survival of CRPC patients. Clinical trial information: UMIN000017092.
Addition of docetaxel or abiraterone to androgen deprivation therapy in metastatic castration-naive prostate cancer in South Asian population.
Authors: Sonthwal Neha , Hussain Shaik Maheboob , Arya Devavrat , Batra Sandeep , Chaturvedi Harit Kumar , Gupta Alok 
Published: May 2019

e16514 Background: Clinical trials have shown that addition of Docetaxel or Abiraterone to androgen deprivation therapy (ADT) achieves superior survival outcome in metastatic castration naive prostate cancer (mCNPC) in predominantly western population. We sought to evaluate treatment outcomes of adding Docetaxel or Abiraterone to ADT in South Asian population. Methods: 90 mCNPC patients who received treatment between January 2015 and June 2018 were prospectively followed. Diagnosis was established by TRUS guided prostate biopsy and staging was done by Ga68 PSMA PET CT scan in all patients. Patients who were unfit for combination therapy received ADT alone. Patients diagnosed before June 2017 & fit to receive chemo-hormonal therapy, received ADT+Docetaxel. Patients diagnosed after June 2017 and fit to receive combination were offered ADT+Docetaxel or ADT+Abiraterone and therapy selected based on patient’s choice. Monthly clinical evaluation and PSA measurement was done. Outcome measures analyzed included PSA decline > 90%, serological complete response (PSA < 0.2 ng/ml) and progression to CRPC. 76 patients with atleast 6 months follow-up were included in outcome analysis. Results: Patients received ADT alone (N = 37) or ADT+Docetaxel (N = 31) or ADT+Abiraterone (N = 22). Median age was 72, 64 & 70 years, median PSA was 88, 95 & 38 ng/ml, Gleason score was ≥8 in 57%, 71% & 77% patients in ADT alone, ADT+Docetaxel & ADT+Abiraterone group, respectively. Bone & visceral metastasis were present in 62% & 24%, 74% & 26%, 68% & 23% patients in ADT alone, ADT+Docetaxel & ADT+Abiraterone group, respectively. Outcome analysis in 76 evaluable patients is shown in Table. Conclusions: ADT+Docetaxel & ADT+Abiraterone achieve deeper serological response and reduced progression to CRPC compared to ADT alone in metastatic castration naive prostate cancer patients with South Asian ethnicity. Longer follow up is required to comment on overall survival and also to determine which combination (ADT+Docetaxel or ADT+Abiraterone) is superior to other, if at all.[Table: see text]
Early PSA progression in abiraterone/enzalutamide-treated patients with metastatic castration-resistant prostate cancer.
Authors: López-Campos Fernando , Gomez-Iturriaga Alfonso , Llacer Perez Casilda , Henriquez Ivan , Peleteiro Paula , Lozano Rebeca , Castaño Ana , Romero-Laorden Nuria , Molina-Cerrillo Javier , Alvarez-Rodríguez Sara , Piquer Teresa , Navarro-Castellón Joaquin , Conde-Moreno Antonio José , Ramirez-Backhaus Miguel , Barrionuevo Patricia , García Raquel , Pérez-Haro María de los Llanos , Castro Elena , Olmos David , Lorente David 
Published: May 2019

e16530 Background: Changes in PSA are widely used as a biomarker for the monitoring of treatment outcome in Metastatic Castration-Resistant Prostate Cancer (mCRPC) in the clinical real-world setting. Early PSA changes (before 12 weeks) are not considered in the definition of PSA Progression (PSAProg) due to the potential for spurious “flare” reactions. We aimed to evaluate the significance of an early PSA increase in Abiraterone/Enzalutamide (Abi/Enz)-treated mCRPC patients (pts). Methods: We retrospectively evaluated Abi/Enz-treated mCRPC pts from 11 hospitals between 2011-2018. Early PSAProg was defined as a 25% increase in PSA from baseline at 4 (PSAProg4) or 8 (PSAProg8) weeks after treatment initiation. PSA progression at 12 weeks (PSAProg12) was confirmed by a second reading. Uni- and multivariable (MV) Cox regression models were conducted to explore the association of PSAProg and overall (OS) and radiographic progression-free (rPFS) survival. Sensitivity (Se), specificity (Sp) and predictive values (PPV, NPV) for the association of early PSAProg with PSAProg12 were calculated. Results: We analyzed 581 mCRPC pts; median follow-up: 19.1 months. 96 (17.1%); 105 (21.6%) and 85 (16.9%) pts had PSAprog at 4, 8 and 12 wks. PSAProg4 and PSAProg8 were significantly associated with confirmed PSAProg12. 55.3% of pts with PSAProg4 and 66.7% of pts with PSAProg8 had a confirmed PSAProg12. Only 9% of pts with no PSA prog at 4 wks and 4.1% of pts with no PSAProg8 had a confirmed PSAProg12. PSAProg4 had Se: 56.6%, Sp: 90.5%, PPV: 55.2%, NPV: 91% for the detection of PSAProg12. PSAProg8 had Se: 81.9%, Sp: 91.2%, PPV: 66.7%, NPV: 95.9% for the detection of PSAProg12. PSAprog at 4, 8 and 12 wks was significantly associated with OS and rPFS in uni- and MV Cox models (Table). Conclusions: Early PSAProg after Abi/Enz is significantly associated with both confirmed PSA Prog at 12 wks and outcome, and may help identify pts not benefitting from Abi/Enz before clinical or radiographic progression. Prospective validation studies are needed. [Table: see text]
Association between nutritional status (NS) and health-related quality of life (HRQoL) in men with early metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Cavka Luka , Perme Maja Pohar , Kozjek Nada Rotovnik , Seruga Bostjan 
Published: May 2019

e16539 Background: HRQoL is of paramount importance in men with mCRPC. It is not known how NS affects HRQoL in this population of patients. We hypothesized that NS is associated with HRQoL in men with early mCRPC and that NS outperforms body mass index (BMI) in this association. Methods: We prospectively enrolled men with early mCRPC into this study. Patients were assessed, and on the basis of established criteria, four NS categories were defined: normal NS (nNS), nutritional risk without cachexia/sarcopenia (NR), sarcopenia (S) (handgrip strength < 30 kg) and cachexia (C) (Evans`s criteria). HRQoL was assessed by the validated questionnaire Functional Assessment of Cancer Treatment (FACT-P); higher score reflects better HRQoL. After checking for normal distribution, we performed a linear regression model for HRQoL with NS as a dummy variable (with nNS as the reference group). Age, duration of previous androgen deprivation therapy (ADT), hemoglobin level (Hb), prostate-specific antigen (PSA) and BMI were included as covariates into the multivariate model. Results: One hundred forty-one patients were enrolled in our study. At presentation, their mean age was 74.2 years (SD 7.1), and 18 (12.4 %) had visceral metastases. Fifty-eight (41.3%) had nNS, 43 (30.8 %) had sarcopenia, 24 (16.8 %) NR and 16 (11.2 %) C. Mean FACT-P score [SD] in nNS was 115.3 points [22.2], following by 97 [24.6], 98.3 [22.4] and 78.8 [25] points in NR, S and C groups, respectively. We found a significant and consistent association between better NS and worse HRQoL (β [NR:nNS] = -18.2 points; β [S:nNS] = -17 points; β [C:nNS] = -36.5 points; p < 0.001; R² = 0.2). The association remained significant after adjustments (R² = 0.27). Conclusions: Suboptimal NS but not BMI is significantly associated with worse HRQoL in men with early mCRPC. Interventional trials focused on the optimization of NS in men with mCRPC are warranted.[Table: see text]