bluuebunny/crossref_metadata_2025_split huggingface dataset:
AUCtox: A new method to evaluate the safety of anticancer drugs in metastatic prostate cancer.
Authors: Launay-Vacher Vincent , Helissey Carole , Laguerre Brigitte , Spaeth Dominique , Lloret Thomas , Stevens Jerome , Bossi Paolo , Scotte Florian ,   OptiSoins Prostate Study Group
Published: March 2019

290 Background: The evaluation of anticancer drugs safety currently relies on the NCI-CTCAE classification. Most often in clinical trials, attention is focused on severe adverse events (AE) i.e.grade 3 or more. However, AE of lower grades can have a significant deleterious impact, especially when recurrent or permanent. We aimed at defining a new method to better describe the impact of treatment on quality of life (QoL). Methods: The oncology patient monitoring program OptiSoins prospectively records treatment, number of cycles, and toxicities (NCI-CTCAE). Patients with metastatic prostate cancer treated with either docetaxel (DOC) or cabazitaxel (CABA) were identified in the database. For each patient, toxicities and their grade reported in medical records were plotted against time under treatment, to calculate the area under the curve of toxicities (AUCtox) that takes into account both the intensity and duration of toxicities, and the number of events. AUCtox was calculated for any toxicity reported at least once. The association with QoL, evaluated by EQ-5D-3L. Results: In total, 146 patients were evaluable [DOC 85 (58%), CABA 61 (42%)]. Median age was 70.5 years (Q1-Q3: 64.7; 76.0). Median follow-up was 4.0 months. Patients underwent a median number of 6 cycles, with a median number of 15.0 evaluations (monitoring calls). At least one grade ≥3 AE was reported by 45.2% of patients, most frequently fatigue (20.6%) and pain (12.3%). A negative impact on global health status, assessed by the VAS of EQ-5D-3L, was identified for 3 AEs based on grade alone vs. 8 when considering AUCtox. Conclusions: Current evaluation of toxicity based on grade alone underestimates the impact of anticancer drugs on QoL. Our method, using AUCtox, can better detect this impact, allowing a more patient-oriented evaluation of drug safety. [Table: see text]
German health service research with the focus on effectiveness of secondary-antiandrogen deprivation therapy (s-ADT) in prostate cancer patients with buserelin in daily practice.
Authors: Luedecke Gerson , Geiges Goetz , Schulze Matthias , Lange Monica ,   Interessenverband zur Qualitätssicherung der Arbeit niedergelassener Uro-Onkologen in Deutschland e.V.
Published: March 2019

291 Background: Aim of the health service research was to answer the questions: 1.) Is the s-ADT with buserelin a successful therapy perspective in biochemical progressive PCA patients after any ADT therapy performed prior? 2.) What is the response rate over all and with a PSA decline more than 50% from the starting level? Methods: In a time period of 2.5 years (2013-2016) a study collective of 1233 PCA patients was treated with buserelin of which 355 got a s-ADT therapy after biochemical progress. In follow-up controls the effectiveness was proven in respect to PSA decline after 6 and 12 months. Results: The cohort of 355 men had an age of 77.3 years with a risk distribution of 26.2% low risk, 33% intermediate and 40.8% high risk PCA. The initial PSA level before ADT change ranged from < 0.4 up to > 1000 ng/ml. Therapy effects over 12 month: 17.7% stayed unchanged, 49.7% progressed, 32.7% remitted and 23.8% declined in PSA more than 50% (effective). During the 12 month of follow-up 7.5% showed an initial PSA flair with a following remission, 15.6% an initial remission switching to progression. The PSA progression varied from 10 to 5229% increase and 40% had a PSA increase of more than 100% over 12 month. Conclusions: The s-ADT manipulation by buserelin after any prior ADT therapy induced in 33% over 1 year a positive PSA response and over all in 24% an effective PSA remission ( > 50% PSA decline) over 1 year. On the other hand 50% of the patients will progress with buserelin in s-ADT. The decision if s-ADT will succeed can be maid after 6 month of therapy with buserelin until a treatment change must be decided. Today, in respect to the early onset of abiraterone and docetaxcel in PCA management since 2017 the value of s-ADT must be discussed critically and again re-evaluated.
Integration of radium-223 dichloride (Xofigo) into clinical practice for the treatment of castration-resistant prostate cancer.
Authors: Doyle Catherine Mary , Mills Matthew , Damgaci Sultan , Smith Johnna , Zhang Jingsong , Fishman Mayer N. , El-Haddad Ghassan 
Published: March 2019

312 Background: Radium-223 dichloride (Xofigo) is an FDA-approved radionuclide used to treat symptomatic bone metastases in patients with castration-resistant prostate cancer (CRPC) with no known visceral metastases. Outside of clinical trial, the benefits of Radium-223 dichloride (Ra-223) in the treatment of CRPC have not yet been fully delineated in real life setting. Therefore, the purpose of this study was to evaluate the outcome of patients with CRPC who were treated with Ra-223, especially studying the variables associated with completion of 6 cycles of therapy. Methods: A total of 114 patients with CRPC and bone metastases referred for treatment with Ra-223 between March 2010 and February 2018 were identified for retrospective analysis. A chart review was conducted to analyze clinical characteristics, treatments, and outcomes including radiologic bone scans. Categorical variables were compared using Chi-square and independent student t test, and survival rates were generated using Kaplan-Meier analysis. Multivariate analysis (MVA) Cox proportional hazard ratios (HR) model was used in the assessment of OS and PFS. Results: Of the 114 patients referred for treatment, the overall median OS was 12.6 months. In MVA, improved OS was most strongly associated with completion of all six doses (p < 0.001). Median OS for the 56 patients who received full treatment was 24 months, while median OS for the 107 patients who did not complete treatment was 5.9 months. In univariate analysis, treatment completion was significantly associated with prior Sipuleucel-T (p = 0.002), concurrent Denosumab (p = 0.027), and baseline PSA < 30 ng/mL (p = 0.004). Conclusions: Completion of treatment with Ra-223 is a significant factor associated with improved OS. Therefore it is clinically important to delineate which patients are to the most appropriate candidates to complete treatment. Factors notable for treatment completion suggest patients might benefit from initiating Ra-223 treatment after receiving Sipuleucel-T and while their PSA remains low. Further consideration should be given to the sequence of Ra-223 in clinical practice, including use of concurrent Abiraterone and Enzalutamide.
A novel CD3xPSMA bispecific antibody for efficient T cell mediated killing of prostate tumor cells with minimal cytokine release.
Authors: Clarke Starlynn , Dang Kevin , Li Yuping , Sankaran Preethi , Pham Duy , Balasubramani Aarti , Davison Laura , Harris Katherine , Jorgensen Brett , Schellenberger Ute , Trinklein Nathan , Ugamraj Harshad , Buelow Roland , Van Schooten Wim , Force Aldred Shelley , Buelow Ben 
Published: March 2019

324 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new therapeutics are urgently needed. Prostate specific membrane antigen (PSMA) is expressed on the surface of prostate cancer cells and expression increases with disease progression. Therapies directed against PSMA such as radiolabeled antibodies and T cell redirecting therapies including chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs) have shown promising efficacy in clinical trials but also induce significant toxicity. In particular CAR-Ts and T-BsAbs potently kill tumor cells but induce cytokine release-related toxicities. Novel anti-CD3 engaging domains may be required to create T-BsAbs with a broader therapeutic window. We have developed fully human CD3xPSMA bispecific antibodies that efficiently eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats that produce human antibodies (UniRat, OmniFlic) followed by repertoire deep sequencing of lymph nodes isolated from immunized animals and high-throughput gene assembly/expression. CD3xPSMA T-BsAbs were assembled and evaluated for T cell activation and ability to eliminate PSMA+ tumor cells in vitro. Results: Primary human T cells were activated only in the presence of both bispecific CD3xPSMA antibodies and PSMA (either plate-bound or on the surface of tumor cells). Potent and selective cytotoxicity against PSMA+ prostate tumor cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA bispecific antibodies. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cell cytotoxicity compared to CD3xPSMA bispecifics containing a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies 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.
A study into the pharmacodynamic biomarker effects of olaparib (PARP Inhibitor) ± degarelix (GnRH antagonist) given prior to radical prostatectomy (RP) CANCAP03.
Authors: Pacey Simon , Linch Mark David , Kynaston Howard , Warren Anne , Freeman Alex , Tysoe Ruth , Shaw Greg , Narahari Krishna , Kumar Satish , Martin Henno , Kularatne Bihani , Gnanapragasam Vincent , Davies Barry , Khan Josephine , Bratt Ola , Dev Harveer , Massie Charles , Shah Nimish 
Published: March 2019

35 Background: Novel agents given prior to RP allows the study of drug effect(s) in primary human prostate cancer (PC), supporting future clinical study development. Pre-clinical and clinical data (mostly in setting of castration resistant PC) support PARP ± androgen inhibition as therapy for some patients (pt). We undertook a study of olaparib (O) ± degarelix (D) prior to RP. Methods: 20 evaluable (pre and post RP tissue available with 86% dose compliance) pt randomised 1:1 to O or O+D. Primary endpoint: measure PARP inhibition by IHC. Secondary endpoints were feasibility, safety, tolerability. Exploratory objectives: changes PSA, circulating tumour DNA & intra-tumoral immune cells. Men, due for RP, with high volume or aggressive PC, consented and were treated with O (300mg bd) 15 days ± D (240mg once), prior to RP. Diagnostic biopsy and RP tissue were collected. Adverse events (AE) were graded according to CTCAE v4 and followed up to resolution or 6-weeks post RP. Results: 24 men recruited, 4 not evaluable (opted radiotherapy, surgery date altered, not by AE). Interim results are presented of available data. Conclusions: 2 weeks of O (± D) can be given prior to RP with acceptable safety profile. Exploratory analyses of tumour tissue are ongoing however, preliminary data confirm PSA drop noted for pt on both regimens. While expected for O+D this is the first report of PSA changes following a short course of single agent PARPi (O) in pt with local/ hormone sensitive PC. Clinical trial information: NCT02324998. [Table: see text]
Ramucirumab (RAM) exposure-response (ER) relationship in RANGE: A randomized phase III trial of RAM plus docetaxel (DOC) versus placebo (P) plus DOC in advanced platinum-refractory urothelial carcinoma (UC) patients (pts).
Authors: De Wit Ronald , Powles Thomas , Castellano Daniel E. , Necchi Andrea , Lee Jae-Lyun , Van Der Heijden Michiel Simon , Matsubara Nobuaki , Bamias Aristotelis , Flechon Aude , Sternberg Cora N. , Drakaki Alexandra , Yu Evan Y. , Hamid Oday , Zimmermann Annamaria H. , Gao Ling , Long Amanda , Walgren Richard A. , Bell-McGuinn Katherine M , Petrylak Daniel Peter 
Published: March 2019

353 Background: Recent RANGE results showed significant improvement in PFS, a non-significant positive trend in OS, increased ORR and acceptable safety with RAM+DOC vs P+DOC in UC pts (Petrylak et al. Lancet 2017; Petrylak et al. ESMO 2018, abstr 865PD). RAM ER-OS relationships in RANGE are reported here. Methods: Pts received RAM (10 mg/kg) + DOC or P + DOC (Day 1 of a 21 day cycle) until discontinuation criteria were met. Population pharmacokinetic analysis predicted RAM minimum concentrations after first dose (RAM Cmin, 1). Multivariate Cox regression & matched case control (MCC) analyses using exposure treated as a continuous covariate, or grouped as quartiles, evaluated the ER-OS relationship. Results: Several poor prognostic factors, including Bellmunt risk factors, appeared to be more frequent in the lower exposure quartiles, suggesting a possible disease-PK interaction. Increasing RAM exposure as a continuous covariate in an ER population of n=246 pts significantly ( p=0.01) associated with improvements in OS. Higher exposure quartiles trended toward longer survival & smaller HRs compared to P (Table, Q1=lowest). Conclusions: OS and ORR benefits favored Q4, a group which was associated with more favorable prognostic features and higher exposure. The observed disease-PK interaction may confound the interpretation of the ER results and warrants further exploration. Clinical trial information: NCT02426125. [Table: see text]
Long-term outcomes of hypoxia modification in bladder preservation: Update from BCON trial.
Authors: Song Yee Pei , Mistry Hitesh , Choudhury Ananya , Hoskin Peter 
Published: March 2019

356 Background: The mainstay of radical organ preserving treatment in muscle-invasive bladder cancer is radiotherapy (RT). Radiosensitising agents have been shown to improve treatment response and survival. Chemoradiotherapy is the most commonly used regime, however, hypoxia modification has also been shown to be effective. BCON is a phase III clinical trial which showed that the addition of carbogen and nicotinamide (CON) significantly improved recurrence-free survival (RFS) and overall survival (OS) (Hoskin et al, 2010). The long term outcomes twelve years after the trial closed to recruitment are reported. Methods: Outcomes from the original BCON trial were updated and analysed. Patients excluded from the original analysis were excluded once again. Cox regression analysis adjusted for known prognostic factors was performed. Results: 333 patients were randomized to receive RT alone or RT+CON. 9 patients from the RT+CON arm and 3 from RT alone arm were excluded from the analysis. The median age of patients in both arms was 74 (51-90) and the median follow-up was 10.3 years. There was a statistically significant improvement in 5 year RFS (41% vs 33%, p = 0.04) with the difference maintained at 10 years (27% vs 20%). The 5 year OS was 49% vs 40% (p = 0.068) with a continued effect seen at 10 years when OS was 32% vs 24%. These differences remained following adjustment for known prognostic factors. Conclusions: The survival advantage for CON in the original analysis which demonstrated a significantly improved 3 years OS (59% vs 47%, p = 0.020) is maintained in long term follow up. At 5 years there is a statistically significant improvement in RFS and at 5 and 10 years the addition of hypoxia modification to radiotherapy continues to show an impact on overall survival, These results confirm a sustained benefit of hypoxia modification in bladder preservation treatment for muscle-invasive bladder cancer. Clinical trial information: NCT00033436.
Molecular profiling of aggressive variant urothelial carcinoma.
Authors: Ramamurthy Chethan , Arguello David , Anari Fern , Ghatalia Pooja , Zibelman Matthew R. , Plimack Elizabeth R. , Burgess Earle Frederick , Hogan Thomas F. , Dawson Nancy Ann , Hauke Ralph J. , Aragon-Ching Jeanny B. , Vaena Daniel A. , Heath Elisabeth I. , Geynisman Daniel M. 
Published: March 2019

378 Background: The WHO recognizes multiple variant histologies of urothelial carcinoma (vUC), many of which have been associated with poor outcomes compared with urothelial carcinoma (UC). We aimed to explore molecular differences between aggressive vUC and UC. Methods: 23 micropapillary (MP), 16 plasmacytoid (P), 23 sarcomatoid (S), 7 nested (N), 6 clear cell (CC), and 2 giant cell (GC) vUC specimens were tested between 2012 to 2018 via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (next generation sequencing [NGS]), gene amplification (CISH or NGS), and protein expression (immunohistochemistry [IHC]). Findings were compared to 435 control UC specimens using the Chi-square test. Results: 84% of samples were from primary tumor. Alterations identified are summarized in Table 1, and are notable for high rates of TP53 mutations across histologic subtypes, varying rates of RB1, ERBB2 and FGFR mutations, and overall low rates of DNA damage repair (DDR) mutations (29 genes reported) except in S. There were more ARID1A mutations detected in MP than UC (100% [3 specimens] v. 41.3%, p=0.044), and more CDH1 mutations in P than UC (50% [4 specimens] v. 2%, p<0.001). CISH ERBB2 (HER2) amplification was seen in 27.3% MP compared with only 10.4% in UC (p=0.005). Compared to UC, PD-L1 IHC (SP142 assay) was positive (>5%) in a high proportion of S (55.6%, p=0.002) but in a lower proportion of other vUC (e.g. absent in P). Tumor mutational burden (TMB) was high in a lower proportion of vUC: 18.4% UC vs. 14.3% MP, 0% P, 16.7% S. Conclusions: Aggressive variant histology UCs have a differential profile of molecular aberrations compared to UC, with notable differences in potential targets such as HER2 and DDR genes as well as immunotherapy biomarkers. Further studies are needed to confirm these findings, and may support therapy development for these rare, aggressive UC subtypes. Aberrations (%) in Variant Histology UC. [Table: see text]
Do elderly men (>75) harbor more aggressive prostate cancer? Comparison of decipher and PAM50 TESTS among different age groups.
Authors: Goldberg Hanan , Herrera Cáceres Jaime Omar , Santiago-Jimenez Maria , Fishbane Nicholas , Davicioni Elai , Klaassen Zachary William Abraham , Chandrasekar Thenappan , Wallis Christopher , Woon Teck Sing , Hamilton Robert James , Kulkarni Girish S. , Berlin Alejandro , Fleshner Neil Eric 
Published: March 2019

38 Background: Age is an important prognostic factor in oncology. Over 20% of men diagnosed with prostate cancer (PC) are ≥ 75 years old. In the growing elderly population, objective methods for predicting outcomes beyond chronologic age are necessary in order minimize the likelihood of withholding curative treatment when warranted. Herein, we describe and analyze age-related differences in clinico-genomic prognostic indices of aggressiveness in localized PC. Methods: Clinical and genomic data for 8,355 patients from the Decipher Genomic Resource Information Database was obtained. Conventional and genomic prognostic indices including Decipher GC scores, PAM50 molecular subtypes (e.g. luminal A/B or basal) NCCN risk groups and Gleason groups (GG) were stratified by age using multivariable logistic regression analyses (MLRA). Results: With increasing decile of age, we observed a higher proportion of high GG and higher Decipher scores. There was a statistically significant increase in the proportion of patients with high Decipher scores with increasing age among GG1 and GG2 (< 55-10.2%, 30.7%, 55-60-15.4%, 25.6%, 60-65-15.9%, 29.7%, 65-70-16.9%, 28.2%, 70-75-17.9%, 30%, and > 75-20.3%, 37.3%, respectively). Furthermore, the prevalence of the PAM50 luminal B subtype (associated with worse prognosis) increased with age among GG1 and GG2 (< 60-22.2%, 40%, 60-65-29.1%, 41.7%, 65-70-28.2%, 39.2%, 70-75-30%, 43.4%, 75-80-33.5%, 44.3%, > 80-34.2%, 52%, respectively). Among higher grade tumors (GG 3-5), no statistically significant differences between the different age groups were observed. MLRA demonstrated that in addition to higher T stage, PSA and GG, each age decile entailed a 20% increased risk for a high Decipher score (OR 1.2, 95% C.I 1.11-1.3, p < 0.001). Conclusions: Older men with lower grade tumors, as opposed to higher grade tumors, harbored worse disease based on genomic risk models. The accepted paradigm of elderly PC patients being treated conservatively based solely on chronologic age, needs to be changed. We provide evidence suggesting the utility of clinical-genomic characterization for better treatment individualization decisions. (GRID; NCT02609269).
Treatment (tx) characteristics of patients (pts) with locally advanced or metastatic urothelial cancer (mUC) receiving atezolizumab (atezo) monotherapy in United States clinical practice.
Authors: Mhatre Shivani K. , Chuo Ching-Yi , Morgans Alicia K. , Rahma Osama E. , Pachynski Russell Kent , Martinalbo Jorge , Davarpanah Nicole N. , Davies Jessica 
Published: March 2019

381 Background: Atezo (anti–PD-L1) was the first immune checkpoint inhibitor approved for mUC. Here, we describe pt characteristics, time on tx (TOT) and distribution of tx cycles for pts receiving atezo in clinical practice, to complement data from clinical trial setting. Methods: Pts diagnosed with mUC who initiated atezo monotherapy in the first-line (1L) or second-line and beyond (2L+; prior platinum tx) settings on or before Jun 30, 2017, were identified from the US-based Flatiron Health electronic health record–derived database. Tx data were analyzed through Mar 31, 2018. TOT was defined as time from first to last atezo administration, plus 1 cycle length. Median TOT was calculated by tx line using the Kaplan-Meier method. Tx cycles were calculated by the number of atezo doses received during TOT. Corresponding results from global atezo clinical trials are presented. Results: Real-world data (RWD) from 312 pts (n = 102, 1L; n = 210, 2L+) met the study selection criteria (Table). Median TOT was 3 and 3.5 months in the 1L and 2L+ settings, respectively, with 95% CIs overlapping with the trial TOT data. A median of 4 cycles (IQR, 2-7, 1L; 2-9, 2L+) was administered in both settings. Conclusions: This is the first study of RW atezo use in mUC. The TOT with atezo observed in a US RW setting and the clinical setting (IMvigor210/IMvigor211) was similar. [Table: see text]