bluuebunny/crossref_metadata_2025 huggingface dataset:
The risk of death from prostate cancer in men with Gleason Score 3+4 prostate cancer treated using brachytherapy with or without a short course of androgen deprivation therapy.
Authors: Yang David Dewei , Chen Ming-Hui , Braccioforte Michelle H. , Moran Brian Joseph , D'Amico Anthony Victor
Published: February 2020

330

Background: We evaluated whether the intermediate-risk factors of percentage of positive biopsies (PPB), clinical tumor category, and prostate-specific antigen (PSA) level, in addition to age, were associated with the risk of prostate cancer-specific mortality (PCSM) among men with Gleason 3+4 prostate cancer treated with brachytherapy (BT) alone or BT and a short course of androgen deprivation therapy (ADT). Methods: We conducted a prospective cohort study of 1920 consecutively treated men with Gleason 3+4 adenocarcinoma of the prostate who received BT or BT and a median of 4 months of ADT between 10/14/1997 and 5/28/2013. Separate multivariable Fine and Gray competing risks regression models among men treated with BT or BT and ADT were used to assess whether PPB, cT2b-T2c, and PSA of 10.1-20.0 ng/ml, in addition to age greater than the median of 70 years, were associated with the risk of PCSM after adjustment for comorbidity. Results: After a median follow-up of 7.8 years (interquartile range 5.2-10.4 years), 284 men (14.8%) had died, including 31 (10.9% of deaths) from PC of which 18 (58.1%) and 13 (41.9%) occurred in men treated with BT or BT and ADT, respectively. For men treated with BT alone, increasing PPB, PSA of 10.1-20.0 vs 4.0-10.0 ng/mL, and age >70 vs ≤70 years were significantly associated with an increased risk of PCSM (adjusted hazard ratio [AHR] 1.015 95% confidence interval [CI] 1.000-1.031, P=0.048; AHR 5.55, 95% CI 2.01-15.29, P<0.001; and AHR 3.66, 95% CI 1.16-11.56, P=0.03, respectively). The respective results for men treated with BT and ADT were AHR 1.009, 95% CI 0.987-1.031, P=0.44; AHR 4.17, 95% CI 1.29-13.50, P=0.02; and AHR 3.74, 95% CI 0.87-16.05, P=0.08. The clinical tumor category was not significantly associated with the risk of PCSM. Conclusions: Among men with biopsy Gleason score 3+4 PC, both age >70 years and PSA of 10.1-20.0 ng/ml were significantly associated with an increased risk of PCSM following BT, and adding 4 months of ADT may not be sufficient to mitigate this risk. Advanced imaging and targeted biopsy of suspicious areas should be considered to personalize treatment in order to minimize the risk of PCSM in these men.
Clinical-genomic sub-classification of high-risk prostate cancer: Implications for tailoring therapy and clinical trial design.
Authors: Muralidhar Vinayak , Alshalalfa Mohammed , Spratt Daniel Eidelberg , Liu Yang , Karnes R. Jeffrey , Schaeffer Edward M. , Davicioni Elai , Feng Felix Y , Klein Eric A. , Tosoian Jeffrey J. , Berlin Alejandro , Den Robert Benjamin , Nguyen Paul L.
Published: February 2020

337

Background: Current risk stratification schema have limited prognostic performance in predicting outcome within National Comprehensive Cancer Network (NCCN) high-risk to very high-risk prostate cancer. Methods: Two multicenter high-risk cohorts were used for training (n = 214) and validation (n = 151) of a novel RNA microarray-based integrated clinical-genomic Classifier Optimized for Outcome in High-risk Prostate cancer (COOHP) to classify patients as COOHP favorable high-risk, standard high-risk, or very high-risk. Cox analysis was used to model metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Model performance was compared to prior sub-classification systems using time-dependent c-indices. Results: Among NCCN high/very high-risk patients in the training cohort, 11% were classified as COOHP favorable high-risk, 70% as COOHP standard high-risk, and 18% as COOHP very high-risk. Patients with COOHP favorable high-risk disease had better rates of 5-year MFS compared to those with COOHP standard high-risk disease (94% vs 76%, hazard ratio [HR] 0.10, p = 0.02), and patients with COOHP very high-risk disease had worse 5-year MFS compared to those with COOHP standard high-risk disease (34% vs 76%, HR 3.5, p < 0.0001). Similarly, patients with COOHP very high-risk disease had worse 10-year PCSS compared to those with COOHP standard high-risk disease (36% vs 82%, HR 4.4, p < 0.0001). The c-indices for 5-year MFS and 10-year PCSS in the training cohort were 0.80 and 0.74, significantly improved compared to prior clinical and clinical-genomic risk stratification systems (0.62-0.69 for 5-year MFS and 0.56-0.63 for 10-year PCSS). These results were consistent in the validation cohort, where 5-year MFS significantly varied among the three COOHP subgroups (100% vs 89% vs 79%, p = 0.020), as did 10-year OS (100% vs 71% vs 53%, p = .040). Conclusions: A clinical-genomic risk stratification system specifically designed to discriminate prognosis in high-risk prostate cancer better identified favorable high-risk and very high-risk subsets of disease compared to prior clinical and clinical-genomic stratification systems.
Overall survival of black and white men with metastatic castrate-resistant prostate cancer: A retrospective analysis across 20 years in the largest healthcare trust in the United Kingdom.
Authors: Ng Kenrick , Wilson Peter , Mutsvangwa Katherine , Shamash Jonathan
Published: February 2020

35

Background: Prostate cancer in Black (B) men has been associated with poorer outcomes than their White (W) counterparts. However, this perception has been derived from studies conducted predominantly in the localized prostate cancer setting, were based on data derived from clinical trials and usually conducted solely within the United States. Methods: We reviewed the outcomes of cases with metastatic castration resistant prostate cancer (mCRPC) treated at St Bartholomew’s Hospital – the UK's largest Healthcare Trust - between 1997-2016. Statistical analyses were conducted using Intercooled Stata 8.2 (State College, TX, USA). Results: We identified 425 cases of mCRPC in the 20 year period. A substantial minority of our patients, 103 (24%) were Black (B), and the remainder White (W). Characteristics were matched in age (73 years in both groups), proportion enrolled in clinical trials (33% in both groups) and median PSA (65.6,B vs 78,W, p=0.86), with a larger proportion of Black patients with a ECOG Performance Status ≥ 2 (19%,B vs 9%,W). In the total cohort analysis, the median Overall Survival (OS) was 25.5 months (B) vs 21.8 months (W), (Hazard Ratio, HR=0.81,p=0.08). For the subpopulation who received chemotherapy at some point of their treatment (n=306), survival was comparable in both groups (median OS 23.8 months, B vs 22.8 months, W, HR=0.97,p=0.82). Interestingly, there was a trend to prolonged survival in the Black population in those who only received hormone therapy (n=106) throughout their treatment course; 39.7 months (B) vs 17.1 months (W), HR=0.54, p=0.019. In a multivariate analysis for prognostic factors for survival from mCRPC therapy considering ethnicity (HR 0.81 p=0.08), time from diagnosis to castrate resistance (HR 1.02, p=0.136), presence of bone metastases at CRPC diagnosis (HR 1.89,p=0.001) – only bone metastases were significant. Conclusions: In the first set of real-world data in a study conducted outside the US, we demonstrate that Black patients do not do worse than White patients with mCRPC. The study suggests that there is a greater margin of benefit of hormone-based therapy in the Black subpopulation.
Early diagnosis of prostate cancer, AABH (Aspartyl Asparaginyl β-hydroxylase), a predictive biomarker: A serum immunoassay and personalized medicine.
Authors: Moshiri Kiarash
Published: February 2020

353

Background: Prostate Cancer (PC) is the most common form of cancer in men in the United States. In their lifetime, approximately 1 out of every 6 American men will develop PC. The chances of developing PC increase dramatically after age 50 with more than 70% of cases occurring in individuals over 65 years of age. Methods: We have investigated the use of aspartyl (asparaginyl) β-hydroxylase (AABH) as a cancer biomarker. We have developed a sandwich ELISA for its detection. Here this assay was utilized to screen sera from patients with prostate cancer and PSA values in various ranges. Results: AABH levels were assessed in sera from 263 individuals with PC and 73 men over 50 years of age not known to have cancer. The levels of AABH in the two groups were >3.00 ng/ml and <3.00 ng/ml, respectively. The overall sensitivity and specificity of the test were 97.5% and 96%. AABH and PSA levels were also compared. The AABH values and sensitivities in individuals with PC and PSA values in the ranges <2 ng/ml, 2-4 ng/ml and >4 ng/ml were >3.00 ng/ml, 99% (n=115); > 3.00 ng/ml, 98% (n=64) and >3.00 ng/ml, 95% (n=114). Conclusions: The present study of AABH indicates that cancer group can be clearly distinguished from normal healthy controls. Moreover, the study indicates that AABH might be used to identify disease in individuals with questionable PSA values. These results support to the establishment of routine screening of serum AABH as a means to detect those who need referral for prostate biopsy. The use of AABH testing may enhance current prostate cancer screening practices by both identifying individuals with low but suspicious PSA values who should be recommended for biopsy and reducing the number of false positive biopsies indicated by positive PSA tests. Serum AABH levels are significantly elevated in individuals with prostate cancer. Using a cutoff value of 3ng/ml, overall sensitivity of the assay for prostate cancer is 97%. The test has a specificity of 96% in healthy men over 50 years of age. AABH is elevated in prostate cancer tissue but NOT in normal prostate or in Benign Prostatic Hyperplasia (BPH). Serum AABH levels are NOT correlate with PSA levels.
Rates and determinants of prostatectomy in prostate cancer (PCa) patients with node-positive disease.
Authors: Sun Lova , Vapiwala Neha , Lee Daniel , Takvorian Samuel U , Haas Naomi B. , Vaughn David J. , Narayan Vivek
Published: February 2020

362

Background: Consensus guidelines recommend that PCa patients with “regional risk” clinical node positive (cN1) disease undergo EBRT and ADT. However, many of these patients still undergo radical prostatectomy (RP), and the role of clinical node status in predicting benefit from RP is debated. Using National Cancer Database (NCDB), we sought to characterize the rates and determinants of initial RP for cN1 patients, and to assess the prognostic significance of clinical nodal stage for patients undergoing RP with pathologic node involvement (pN1). Methods: Among incident cases of nonmetastatic PCa within NCDB (2004-2012), we identified two cohorts: (1) patients with cN1 disease, and (2) patients with pN1 post-RP. For the cN1 cohort, factors associated with initial RP were evaluated using univariate logistic regression, and post-surgical pathologic staging and adjuvant therapies were described. For the pN1 cohort, multivariate Cox regression was used to compare overall survival (OS) by preoperative clinical stage (cN1 vs cN0). Results: Of 7787 patients with cN1 disease, 2166 underwent initial RP, with consistent annual rates (24-31%) over the study period. Factors independently associated with higher likelihood of RP included age ≤ 65 (HR 1.8), white race (HR 1.4), private insurance (HR 1.8), T stage ≥ T2C (HR 1.3), PSA ≤ 10 (HR 1.6), and Gleason score <8 (HR 1.4). Of cN1 patients who underwent RP, 84% were pN1 and 26% were pN0. 26% of these cN1/pN1 patients later received RT, 49% received ADT, and 20% received both. Separately, among 7396 PCa patients with pN1 disease after RP, 17% were initial cN1 and 83% were cN0. After adjustment for practice setting, patient, and disease variables, initial cN1 clinical stage was associated with significantly worse OS (HR = 1.2, p=0.04). Conclusions: The initial treatment of regional risk cN1 disease is highly variable, with approximately 1 in 4 patients undergoing initial prostatectomy, the vast majority of whom are confirmed pN1. Among all patients with pN1 disease, clinical nodal staging retains prognostic significance for OS. These findings underscore the utility of initial clinical staging when considering initial and adjuvant treatments for regional risk patients.
Adjuvant radiotherapy following radical prostatectomy for prostate cancer: A systematic review and meta-analysis.
Authors: Botrel Tobias Engel Ayer , Clark Otávio , Bretas Francisco Flávio Horta , Sadi Marcus V. , Ferreira Ubirajara , Paladini Luciano , Matheus Wagner Eduardo , Reis Rodolfo , Duraes Ronilson Oliveira , Pompeu Antônio Carlos Lima
Published: February 2020

366

Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing efficacy of adjuvant radiotherapy (AR) versus expectant management (EM) in men who undergo radical prostatectomy for localized prostate cancer (CaP). Methods: To perform this review and meta-analysis,several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included all the studies that compared AR versus EM after radical surgery for CaP. The primary endpoints analyzed were biochemical progression-free survival (bPFS), metastasis-free survival (MPFS), prostate cancer-specific survival (CSS), overall survival (OS) and side effects. The data extracted from the studies were combined by using the Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 68 studies were identified and screened. The final analysis included 7 trials (EORTC 22911, SWOG 8794, ARO 96-02/AUO AP 09/95, RAVES, FINNISH, GETUG-AFU 17 and RADICALS-RT) comprising 4,221 patients. The bPFS was higher in patients who received AR (fixed effect: HR = 0.58, CI95% = 0.52 to 0.66; p < 0.00001) but with significant heterogeneity (Chi2 = 40.34, df = 6 (P < 0.00001); I2 = 85%). We performed a random-effect model analysis to better explore this heterogeneity: in this analysis, the result remained in favor of AR (random effect: HR = 0.64, CI95% = 0.45 to 0.90; p = 0.01). The MPFS also was higher in patients who received AR (HR = 0.77, CI95% = 0.65 to 0.91; p = 0.002). The CSS and OS were not statistically different in patients with or without adjuvant radiotherapy (HR = 0.79, CI95% = 0.47 to 1.32; p = 0.36 and HR = 0.92, CI95% = 0.77 to 1.11; p = 0.38, respectively). The incidence of adverse events (gastrointestinal and genitourinary) were higher in the AR group. Conclusions: This is the first meta-analysis including the seven available RCTs in the literature (the previous meta-analysis reviewed only three), comparing adjuvant radiotherapy versus expectant management following radical prostatectomy for CaP. Adjuvant radiotherapy statistically increased the bPFS and MPFS, but did not have an impact on the OS or CSS.
Long-term health-related quality-of-life outcomes in a racially diverse cohort of prostate cancer patients receiving retropubic versus robotic prostatectomy.
Authors: Conti Galen , Kuo Huai-Ching , Flores John Paul , Frankel Jason , Levie Katherine , Jung Nathan , Caumont Fernando , Brand Timothy C. , Musser John E. , Stroup Sean P. , Rice Kevin R. , Kallingal George , Porter Christopher , Rosner Inger L. , Cullen Jennifer
Published: February 2020

37

Background: This study compared 5-year health-related quality of life (HRQoL) outcomes among prostate cancer (PCa) patients who underwent a robotic-assisted radical prostatectomy (RARP) versus a radical retropubic prostatectomy (RRP), with a focus on race-specific outcomes for Caucasian American (CA) compared to African American (AA) men. RARPs have almost replaced RRPs in recent years, with few long-term studies focused on HRQoL and race. Methods: A prospective cohort study of HRQoL was conducted on patients diagnosed with PCa from 2007 to 2017 and enrolled in the Center for Prostate Disease Research (CPDR) Multicenter National Database. HRQoL was assessed with the EPIC instrument. Temporal changes in urinary and sexual-related quality of life domain scores were compared across surgery type (RARP versus RRP) at pre-treatment (“baseline”), 1-, 2-, 3-, 4-, and 5 years post-baseline. Longitudinal HRQoL patterns were modeled using generalized estimating equations (GEE), adjusting for baseline HRQoL and key clinical characteristics. Results: Of 497 PCa patients who met study inclusion criteria, 68% had RARP and 32% had RRP, with 22% AA men and 88% CA men. Baseline HRQoL domains were comparable across race and surgery type. In adjusted GEE analysis, no differences were noted between AA and CA patients. However, treatment-related differences were observed over time in urinary function (UF) and incontinence (UI) (p=0.02 and p=0.03, respectively), with lower HRQoL scores in RARP vs. RRP patients. Upon dual stratification by surgery type and race, the differences for UF and UI persisted (p=0.01 and p=0.03, respectively) with poorest outcomes observed, and similar trajectories of decline, for AA patients who received RARP. Conclusions: In this 10+ year prospective cohort study, AA patients receiving RARP had the poorest UF and UI outcomes which continued to decline for 5 years post treatment. In light of these findings, AA men considering RARP might benefit from discussions with their providers to set expectations regarding long-term urinary outcomes; though these decrements in HRQoL may be overshadowed by the minimally invasive nature of RARP.
Isotope selection and PSA failure in prostate seed implant: Experience with CS-131 in a community hospital system.
Authors: Booher Jacquelyn G. , Domenig Peter , Chuba Paul J.
Published: February 2020

375

Background: A recent large single institutional study reported excellent long-term biochemical control and survival for Cs-131 prostate implant. This isotope has short half-life (9.7 days) with clinical advantages including shorter duration of symptoms. We previously showed Cs-131 dosimetry to be quantitatively similar to I-125 with improved homogeneity (mean percent V150 36% for I-125 versus 27% for Cs-131 (p < 0.0001). Our objective was to evaluate PSA failure rates and dosimetric outcomes in a multi-institutional community based setting. Methods: Within an IRB approved retrospective study, we compared outcomes for three groups of permanent prostate implant patients treated at Ascension Macomb Oakland, Ascension Saint John, and Ascension Providence Rochester Hospitals over a 10 year time interval. The comparison groups included isotopes Cs-131 (n = 66; t1/2 9.7 days), I-125 (n = 60; t1/2 60 days), and Pd-103 (n = 60; t1/2 17 days). Kaplan Meier estimates of PSA failure used the nadir plus 2 (Phoenix) definition. Results: Standard permanent implant doses employed were 145 Gy for I-125 monotherapy or 109 Gy for combination therapy. The dose for Cs-131 was 115 Gy for monotherapy and 85 Gy for combination therapy. For Pd-103, the doses employed were 125 Gy and 90 Gy for mono- and combination therapy, respectively. Median age at diagnosis was Cs-131; 69 (range 49-80), I-125; 71 (49-78), and Pd-103; 70 (60-82). Mean pretreatment PSA values were Cs-131 5.73 ng/ml, I-125 6.62 ng/ml, and for Pd-103 8.87 ng/ml. Median PSA follow up was 30 months and the median PSA value at 60 months was 0.11 ng/ml. There was excellent PSA control for all three groups of cases (p = NS), however with fewer failures using Cs-131. Conclusions: Permanent interstitial brachytherapy continues to be an attractive option for treatment early stage prostate cancer. Only a few large single institutional studies have examined PSA failure rates or dosimetric aspects of shorter half-life Cs-131 seed implants. This series confirms wide applicability of Cs-131 permanent prostate seed implant in the community hospital setting.
High-dimensional single cell-based immune profiling of the tumor immune microenvironment in prostate cancer.
Authors: Masetti Michela , Portale Federica , Carriero Roberta , Partini Bianca , Morina Nicolò , Ponzetta Andrea , Colombo Piergiuseppe , Elefante Maria Grazia , Saita Alberto , Lughezzani Giovanni , Buffi Nicolo' , Casale Paolo , Peano Clelia , Kunderfranco Paolo , Cibella Javier , Guazzoni Giorgio Ferruccio , Lazzeri Massimo , Di Mitri Diletta
Published: February 2020

376

Background: Genetic lesions that drive prostate cancer (PCa) development are able to modify the immune response and tumor infiltrating immune subsets, resulting in tumor progression. We investigated the profile of the immune microenvironment in PCa by high dimensional single cell analysis. Methods: We conducted an immune profiling study based on integrated RNA single cell sequencing and multiparametric flow cytometry in order to dissect the immune landscape of PCa. CD45+ immune cells infiltrating tumoral and adjacent non tumoral tissues were isolated from patients with PCa who underwent software assisted fusion biopsy, based on MRI, and/or radical prostatectomy, and analyzed by single cell sequencing. The primary endpoint was to evaluate the effectiveness of single cell RNA sequencing on CD45+ cell sorted from tumoral and adjacent non-tumoral tissues. Secondary endpoint was the identification of tumor-driven immune changes in prostatic lesions. Results: The cohort consisted of 3 patients who underwent radical prostatectomy (RP) and 45 patients with positive prostate biopsy; the negative control was checked by pathological assessment. In patients who underwent RP the gene expression analysis identified a modulation in the abundance of several immune subsets infiltrating the tumoral tissue, when compared with the non tumoral, evident for Tumor associated macrophages (TAMs), Natural Killer cells (NK) and T regulatory cells. We then implemented a 22 parameters flow cytometry panel that we tested on fresh prostatic tissue and peripheral blood from positive PCa biopsies. We identified a subset of tumor infiltrating macrophages showing an altered gene expression profile when compared with macrophages infiltrating the non-tumoral tissue. Importantly we derived a genetic signature from this subset of tumoral TAMs that resulted to be associated with cancer progression. Conclusions: Our findings support the effectiveness of single cell RNA sequencing in the dissection of the immune landscape in PCa and identified immune changes in patients when comparing neoplastic tissue with non tumoral areas. Such data may be useful for understanding the role of immune system in PCa carcinogenesis.
Significance of distinct specifically enriched missense TP53 mutations in prostate cancer.
Authors: Vasilevskaya Irina , McCann Jennifer , McNair Christopher , Neupane Neermala Poudel , Gallagher Peter , Knudsen Karen E.
Published: February 2020

377

Background: The most common TP53 alterations are missense mutations occurring in the DNA binding domain. The majority of missense p53 mutants (mut-p53) demonstrate oncogenic gain-of-function (GOF) abilities, irrespective of wild-type p53 presence, and thus contribute to a more aggressive disease. In prostate cancer (PCa), characterized by comparatively low overall mutational burden, TP53 is frequently mutated in both primary and advanced disease. Despite significant progress made in the field, detailed mechanisms of GOF in PCa remain undefined due to differing features of p53 mutants. Methods: Analysis of available datasets was performed to assess TP53 mutational status in PCa patient samples and its correlation with the clinical outcome. Using hormone therapy sensitive and CRPC cells, a panel of cell lines was generated to model the two most frequently occurring mutations in the presence or absence of wild-type TP53, as occurs clinically. CHIP-seq, gene expression arrays, and in vitro and in vivo biological assays were performed to interrogate the significance of mut-p53 in PCa. Results: In PCa, missense mutations are significantly associated with decreased progression-free and overall survival. In PCa patient samples these mutations most commonly occur at the R273 residue, demonstrating specific enrichment when compared to other cancers, with R273C alteration being the most frequent. Using our cell panel, CHIP-seq data revealed an expansion of the p53 cistrome upon expression of R273C and R273H mutants in a manner distinct from p53 stabilization in the presence of wt-p53. Moreover, analysis of the TP53 missense mutant-sensitive transcriptomes demonstrated differential gene expression between these mutants, related to the expression of wild-type TP53 in those cells. Finally, R273C and R273H p53 mutants elicited context dependent effects on canonical p53 functions, thereby modulating distinct downstream biological outcomes. Conclusions: These data expand our knowledge of the underlying mechanisms by which distinct gain-of-function p53 mutants affect prostate cancer, and can lead to identification of novel therapeutic targets to improve clinical outcomes in PCa patients harboring these mutations.
Consistency of patient versus investigator reporting of symptomatic adverse events (AEs) in international trials.
Authors: Chang Elaine , Gong Yutao , Weinstock Chana , Suzman Daniel L. , Ibrahim Amna , Beaver Julia A. , Kluetz Paul Gustav
Published: February 2020

38

Background: FDA approved 3 androgen receptor inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on global randomized trials with control arms of placebo + ADT. Despite similar enrolled populations, grade 1 or higher investigator-reported, Common Terminology Criteria for Adverse Events (CTCAE)-graded fatigue ranged 11-25% in the placebo arms. We sought to characterize variability in investigator-reported, CTCAE-graded fatigue across geographic regions and compare this with the variability in patient-reported fatigue. Methods: Data from patients receiving ≥ 1 placebo dose were reviewed from control arms of 3 nmCRPC double-blind, placebo-controlled trials submitted to FDA. We determined worst grade clinician-reported (ClinRO) CTCAE fatigue, and most severe fatigue reported by patient-reported outcome (PRO) for each patient at any time during treatment or within 30 days of last dose in each trial by geographic region: North America/Western Europe (NAWE) versus rest of the world (ROW). We compared variability in fatigue rates to those of a more objective AE, CTCAE-defined anemia. Results: NAWE enrollment comprised 46-75% of placebo cohorts. Median age was comparable across trials and regions. ClinRO CTCAE fatigue was higher in NAWE (15-33%) compared to ROW (8-14%) in each of the 3 placebo cohorts (see Table). Rates of PRO fatigue varied by region (50-73% in NAWE compared to 42-59% in ROW), and the regional differential was present at baseline. Anemia rates were similar in NAWE and ROW in each trial ( < 5%) per CTCAE. Conclusions: CTCAE reporting of fatigue, a subjective symptom, was inconsistent across sites. Anemia, an objective AE, was more consistently reported. ROW investigators less frequently reported fatigue compared to NAWE investigators. Reasons for this are unclear, but could include cultural and language factors. PRO fatigue was relatively consistent across trials and regions. These results should be interpreted with caution, as we acknowledge the limitations of cross-trial comparison.[Table: see text]
Validation of the two best models to predict “benign” pathohistology in patients with advanced nonseminomatous germ cell tumors (NSGCT) undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Authors: Nestler Tim , Paffenholz Pia , Baeßler Bettina , Hellmich Martin , Hiester Andreas , Nini Alessandro , Pfister David , Albers Peter , Heidenreich Axel
Published: February 2020

389

Background: The aim of our study is to validate and evaluate the two currently best performing prediction models (Vergouwe and Leao) for final pathohistology in NSGCT patients undergoing PC-RPLND and we introduce a new radiomics approach. Methods: We performed a retrospective analysis including 496 patients who underwent a PC-RPLND between 2008 and 2018 to validate the two prediction models using published formulas and thresholds. ROC were plotted and AUC was calculated. We determined the optimal cut point and used bootstrapping (1,000 replications) to estimate its variability. For radiomics, lymph nodes of 80 patients were identified on CT images, semiautomatically segmented with 93 radiographic features (pyRadiomics package). A linear support vector machine algorithm was applied to analyze reproducible radiomics features. A continuous reduction of features analyzed was performed using Random Forest algorithms and ROC analysis. Results: In our validation cohort, the Vergouwe model had a significantly better AUC compared to Leao model (0.749 [CI 0.706-0.792] vs. 0.689 [0.642-0.736], p=0.004) to predict benign histology. At a threshold of > 70% for the probability of benign disease, the Leao model would have avoided PC-RPLND in 8.6% with benign disease with an error rate of 5.6% for viable tumor. The Vergouwe model would avoid PC-RPLND in 23.4% with benign disease with an error rate of 12.7% for viable tumor/teratoma. Of the 93 radiomic features analyzed, 51 features were reproducible. Applying the trained algorithm on the training dataset resulted in an accuracy of 0.96 (93% sensitivity, 100% specificity, 100% PPV), on an independent validation cohort the accuracy was 0.81 (88% sensitivity, 72% specificity, 78% PPV). Conclusions: According to our data, the discriminatory accuracy of both models is not sufficient to safely select patients for surveillance strategy instead of PC-RPLND. The radiomics model is promising but needs prospective validation. Further studies including new biomarkers are needed to optimize the accuracy of potential prediction models.
Performance characteristics of 18F-Fluciclovine positron emission tomography/computed tomography prior to retroperitoneal lymph node dissection.
Authors: Meng Xiaosong , Woldu Solomon L. , Wong Daniel , Lafin John T. , Ghandour Rashed , Margulis Vitaly , Conyers Jesse , Xi Yin , Subramaniam Rathan M. , Bagrodia Aditya
Published: February 2020

390

Background: There is no reliable way to differentiate between fibrosis/necrosis, teratoma, and viable germ cell tumor in patients receiving post-chemotherapy retroperitoneal lymph node dissection (RPLND) for non-seminomatous germ cell tumor (NSGCT). Functional imaging, including 18F-FDG positron emission tomography/computed tomography (PET/CT), has been disappointing. Due to the need for better imaging modalities, our prospective, pilot study aims to investigate the accuracy of 18F-Fluciclovine PET/CT in detecting residual tumor prior to RPLND. Methods: From Mar 18 – May 19, 10 eligible patients underwent pre-operative 18F-Fluciclovine PET/CT prior to undergoing bilateral full template RPLND or excision of mass (for one re-do retroperitoneal lymph node dissection) in a prospective phase II study. Correlation between PET/CT findings and pathology were evaluated on per patient level. Results: A total of 10 patients underwent 18F-Fluciclovine PET/CT prior to surgery. 9/10 patients received chemotherapy prior to RPLND. Correlation between 18F-Fluciclovine PET/CT and RPLND pathology was seen in 3/10 patients. 5/10 patients with negative anti-18F-FACBC PET/CT were found to have residual disease/teratoma on RPLND. Compared to the reference standard of RPLND, 18F-Fluciclovine PET/CT demonstrated 29% sensitivity and 33% specificity. Conclusions: Current management of NSGCT is heavily reliant on sub-optimal imaging modalities that are unable to accurately distinguish between post-chemotherapy necrosis/fibrosis versus residual disease and/or teratoma. Despite a different mechanism of action from 18F-FDG, 18F-Fluciclovine has low sensitivity and specificity for residual teratoma in the retroperitoneum. Clinical trial information: NCT03426865. [Table: see text]
Overcoming sociodemographic factors in the care of testicular cancer patients at a safety net hospital.
Authors: Chertack Nathan , Ghandour Rashed , Singla Nirmish , Freifeld Yuval N. , Hutchinson Ryan C. , Courtney Kevin Dale , Moore Joseph Allen , Aydin Ahmet , Margulis Vitaly , Lotan Yair , Woldu Solomon L. , Bagrodia Aditya
Published: February 2020

398

Background: Optimal treatment of GCT in underserved populations is subject to barriers that are associated with worse clinical outcomes. We determine whether standardized treatment of GCT can overcome such sociodemographic factors limiting patient care. Methods: The records of all patients undergoing primary treatment for GCT were analyzed from both a public safety net hospital and an academic tertiary care center in the same metropolitan area. Patients at both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center and clinicopathologic features, practice patterns, and outcomes were analyzed. Results: 106 and 95 patients underwent initial treatment for GCT between 2006 and 2018 in the safety net hospital and tertiary care center, respectively. Safety net patients were younger (29 vs 33 years, p=0.005), more likely to be Hispanic (79% vs 11%), more likely to be uninsured (80% vs 12%, p<0.001), and present via the emergency department (76% vs 8%, p<0.001). They were more likely to have metastatic (stage II/III) disease (42% vs 26%, p=0.025). On multivariable analysis, presence of lymphovascular invasion (OR=0.30, p=0.008) and embryonal carcinoma component (OR=0.36, p=0.02) were associated with surveillance vs adjuvant treatment for Stage I patients; hospital setting was not (OR=0.67, p=0.55). For patients with Stage II/III NSGCT, there was no difference in performance of PC-RPLND at the safety net hospital vs tertiary care center (52% vs 64%, p=0.53). No difference in recurrence rates between cohorts (5% vs 6%, p=0.76) was observed. Conclusions: Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCT; this may be overcome with integrated, standardized management of testicular cancer.
Validation and implementation of a mobile app decision support system for quality assurance of tumor boards: Analyzing the concordance rates for testis cancer at a multidisciplinary tumor board of a tertiary referral center.
Authors: Ural Yasemin , Heidenreich Axel , Elter Thomas , Yilmaz Yasemin , Pfister David A.
Published: February 2020

399

Background: Guideline-compliance in the management of GCT is suboptimal concerning and it results in significantly impaired long-term survival. To facilitating guideline concordant decisions even in less experienced MTD, we developed an algorithm-driven and validated mobile App to provide evidence-based recommendations. This App contains latest guideline versions and it is continuously updated to include practice changing clinical trials. It is the purpose of this study to analyse treatment decision made by MTD compared to guideline recommended therapy. Methods: 302 patients with GCT and MTD decision were randomly selected from our database. Concordance rates of MTD recommendations were compared to query results of the digital APP “Easy Oncology” performed by 2 independent, blinded reviewers. Descriptive statistics and data analysis included IBM´s statistics software SPSS Version 25. Correlation analysis of cancer case characteristics was performed by Kendalls Tau, Gamma, Pearson and Spearman tests. Results: Median age was 35 (18-82) years. Clinical stages I, IIA-C, and III were identified in 32%, 37%, and 31%, resp. According to IGCCCG 56%, 18%, and 25% demonstrated good, intermediate, and poor prognosis, resp. 56% were non-seminomas and 44% were seminomas. 60%, 16%, and 7% of MTD decisions were related to 1st-line, 2nd, and 3rd line therapy and 18% dealt with follow up. Overall concordance rate was 99% (301/302). Concordance rates in CS I, IIA-C, and III were 100%, 98% and 99%, resp. Concordance rates with regard to 1st, 2nd and 3rd line therapy were 99% (135/136), 100%, and 88% (13/14). Conclusions: Our validated expert-created mobile decision support system demonstrates easy and reliable application in daily routine in an expert tertiary referral centre. The APP relies on guideline and trial based information and avoids MTD decisions by expert opinions. It might improve the MTD decision in less experienced MTDs which is currently evaluated in a prospective study.
Effect of increasing Medicaid coverage in Medicaid expansion states on stage at presentation for urologic malignancies.
Authors: Meng Xiaosong , Trivedi Hersh , Kenigsberg Alexander P. , Ghandour Rashed , Margulis Vitaly , Bagrodia Aditya , Lotan Yair , Woldu Solomon L.
Published: February 2020

400

Background: Medicaid Expansion (ME) was introduced by the Affordable Care Act to improve access to care for low income individuals by increasing the annual income limits to 138% of the poverty line. However, not all states have elected to participate in ME. Using the National Cancer Database (NCDB), we sought to assess the effects of participation in ME on the four most common urologic malignancies. Methods: The NCDB was queried for bladder, prostate, kidney and testis cancer from 2012-2016, to span the time period two years before and two years after the main ME which took place in 2014. Trends in insurance status at time of diagnosis and effects on stage at presentation before and after ME were analyzed. Results: The percentage of patients with Medicaid coverage at the time of diagnosis for all four urologic malignancies increased significantly after 2014, with a commiserate decrease in the percentage of uninsured patients (Table). By 2016, significantly more patients had Medicaid coverage at diagnosis in ME states compared to those in Non-ME states (bladder 5.0% vs 2.5%, prostate 5.9% vs 2.2%, kidney 9.7% vs 4.1%, 19.5% vs 7.2%, all p < 0.01). However, the stage at presentation for all four urologic malignancies did not significantly differ for patients in ME versus non-ME states. Conclusions: Despite an increase in the proportion of patients with Medicaid coverage after 2014, surprisingly, there was not an associated change in stage at presentation for urologic malignancies in ME states. Further long-term analysis is necessary to evaluate if expanded Medicaid coverage impacts overall survival in this patient population.[Table: see text]
High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) for relapsed metastatic germ cell tumors (mGCTs): The Alberta experience from 2001 to 2018.
Authors: Zhang Hanbo , Alimohamed Nimira S. , Basappa Naveen S. , Cheng Tina , Chu Michael , Cox-Kennett Nanette , Ernst D. Scott , Fontaine Amelie , Ghosh Sunita , Heng Daniel Yick Chin , Littleton Richard , North Scott A. , Railton Cindy , Sandhu Irwindeep , Stewart Douglas Allan , Venner Chris , Venner Peter M. , Kolinsky Michael Paul
Published: February 2020

406

Background: HDC-ASCT is a standard therapy for patients (pts) with mGCTs whose disease progresses on or after conventional dose chemotherapy. We conducted a retrospective review of HDC-ASCT in pts with relapsed mCGT in Alberta over the past two decades. Methods: Pts with mGCTs who received HDC-ASCT at two provincial referral cancer centers in Alberta, Canada from 2001-2018 were identified. Baseline clinical and treatment characteristics were collected as well as overall survival (OS) and disease-free survival (DFS). Relevant prognostic variables were analyzed. Results: Forty three pts were identified. Median age was 28 years (range 19 – 56). Majority (95%) had non-seminoma histology and testis/retroperitoneal primary (84%). Twenty pts (47%) had poor risk disease as per IGCCC at start of first-line chemotherapy. HDC-ASCT was used as second-line therapy in 65% and 58% received tandem HDC-ASCT. Median follow-up from ASCT was 22 months (range 2 – 181). At last follow-up, 42% of pts are alive without disease, including 3/7 (43%) of pts with primary mediastinal disease. Two-year and 5-year DFS/OS were 44%/51% and 41%/43%, respectively. Median OS and DFS for all pts were 27.9 months (10.2 – NR) and 9.3 months (4.2 – 124), respectively. Conclusions: We found that HDC-ASCT is an effective salvage therapy in mGCT, consistent with existing literature. Pts appeared to benefit regardless of primary site. Though limited by small sample size, we found a numerical difference in DFS and OS between 2nd and 3rd line HDC-ASCT and single vs. tandem ASCT.[Table: see text]
Genomic analysis for potential targetable mutations in relapsed and refractory germ cell tumors.
Authors: Kern Sean Q. , Einhorn Lawrence H. , Adra Nabil
Published: February 2020

407

Background: A large number of metastatic germ cell tumors (GCTs) are cured with platinum-based chemotherapy. Patients that have relapsed or refractory disease can be cured with salvage therapy including salvage surgery, standard dose or high-dose chemotherapy with stem-cell transplant. However, 15-20% of patients with metastatic GCT are incurable with current therapeutic options. We sought to perform a genetic analysis on a cohort of these incurable patients to determine the presence of therapeutically targetable genetic mutations. Methods: After obtaining IRB approval, patients treated at Indiana University for refractory or relapsed GCT from 2016-2019 were analyzed with a next-generation sequencing (NGS) platform. Clinically relevant genomic alterations were reviewed to determine the potential for targeted therapies. Results: 10 patients with testicular (9) or ovarian (1) GCT underwent an analysis of tissue (7), blood (1), or both (2) with a mean 2.9 potential targetable mutations per patient. Four patients had NGS from preserved gonadal tissue removed prior to chemotherapy while 6/10 sample specimens were obtained post standard (1) or high-dose (5) chemotherapy. Potential known therapeutic targets were found in 80% (8/10). Of the platforms that tested biomarkers, high microsatellite instability (MSI) (1/5), intermediate tumor mutational burden (1/4), and high PD-L1 expression of 90% (1/3) was appreciated. The MSI-high patient did not respond to pembrolizumab. A patient with a KIT only mutation did not achieve a response to imatinib. One patient with KRAS, KIT, RAF1, CCND2, MET, AR, CDK6, PDGFRA, EGFR, and BRAF mutations was treated with brentuximab and was progression free for 2.5 months. Common mutations were CCND2 (4/10), RAF1 (2/10), KIT (2/10), and KRAS (2/10). Other mutations actionable in non-GCT tumors included ERCC1, TUBB3, RRMI, PIK3CA, TOPO1 and TP53. Conclusions: NGS identifies potential clinically relevant genomic alterations. Genetic mutations may enable future effective therapies as our understanding of platinum-resistant disease evolves. To our knowledge, this is among the first reports utilizing next-generation sequencing in GCT to direct potential therapeutic agents.
A phase I study of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors.
Authors: Albany Costantine , Spinella Michael J. , Adra Nabil , Hanna Nasser H. , Einhorn Lawrence
Published: February 2020

408

Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m2 x 5 days and cisplatin 100 mg/m2. We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m2 x 5 days and cisplatin 100 mg/m2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.
Origin of somatic transformation in germ cell tumor of testis (TGCT): Role of differentiation versus dedifferentiation in a mature teratoma.
Authors: Umbreit Eric , Joon Aron , Westerman Mary E. , Vyas Shikhar Gautam , Maity Tapati , Uthup Joma , Hofstetter Wayne Lewis , Ward John Francis , Karam Jose A. , Zhang Miao , Pisters Louis L. , Wood Christopher G. , Tu Shi-Ming
Published: February 2020

410

Background: TGCT is a prototype stem-cell malignancy recapitulating the ontogeny of solid tumors. We studied the roles of differentiation versus dedifferentiation in a bona fide well-differentiated tumor, namely mature teratomas, associated with or without somatic transformation. Methods: Between 2001 and 2013, we identified 7 out of 13 cases in which teratoma and somatic transformation were present within the same residual tumor after chemotherapy and resected at our institution with sufficient quantity and quality for DNA and RNA analysis. We performed primary cell culture, flow cytometry, and xenografts to evaluate stem-ness biomarkers and tumor phenotypes of freshly resected mature teratomas. Results: We detected very few mutations within a preselected gene pool (T200) in all tumor samples. The "within patient mutation agreement" from a mutation matrix of 57 genes, in which at least one mutation occurred between teratoma and somatic transformation, was 86.2 to 94.8%. There was disparity in gene expression, including miR7-3HG, ARHGEF35, and DLX6, between the 7 matched tumor pairs (log2 fold change of about 2). Prospective primary cell culture studies using cell surface stem-ness markers (SSEA3, TRA1-60, Cripto-1, CD90, CD133, CD44) indicate presence of stem cells embedded within residual mature teratomas (n = 3) after chemotherapy. Conclusions: Molecular profiling confirms a common clonal origin between teratoma and somatic transformation but refutes the idea of dedifferentiation of teratoma to somatic transformation. Presence of stem cells embedded within mature teratomas and capable of differentiation into separate ontogenetic lineages could account for the origin of somatic transformation in TGCT.[Table: see text]