bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mismatch repair deficiency in metastatic prostate cancer (PC): Response to PD-1 blockade and standard therapies.
Authors: Graham Laura , Montgomery Robert B. , Cheng Heather H. , Yu Evan Y. , Alva Ajjai Shivaram , Schweizer Michael Thomas 
Published: February 2020

194 Background: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant PC (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct, yet clinically relevant subgroup’s natural history and response to treatment. Methods: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic PC. Clinical and pathologic characteristics at time of diagnosis and response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported. Results: 28 men with MMRd and/or MSI-high metastatic PC were identified. 14 (50%) men had M1 disease at diagnosis and 19 (76%) of 25 men that underwent prostate biopsy had a Gleason score (GS) ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.7-NR mos) after median follow up of 43.6 mos (95% CI: 25.8-65.2 mos). PSA responses to standard therapies were similar to historic controls (Table). 17 patients received pembrolizumab and 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who had a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression. Conclusions: MMRd PC is associated with high GS and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high.[Table: see text]
Multiparametric magnetic resonance imaging of multifocal prostate cancer to reveal intra-prostatic genomic heterogeneity and novel radio-genomic correlates: Results of the Smarter Prostate Interventions and Therapeutics (SPIRIT) study.
Authors: Bauman Glenn , Correa Rohann , Aref-Eshghi Erfan , Alfano Ryan , Sadikovic Bekim , Bartlett John , Boutros Paul Christopher , Pautler Stephen E. , Chin Joseph , Gaed Mena , Kassam Zahra , Lemus Jose Gomez , Moussa Madeleine , Ward Aaron 
Published: February 2020

20 Background: Multi-focality and heterogeneity in prostate cancer can confound the selection of appropriate clinical management. Our study aimed to explore radio-genomic correlations using multiparametric magnetic resonance imaging (mpMRI) against a histopathologic reference standard. Methods: Eight men with prostate cancer who underwent mpMRI followed by prostatectomy were selected for this pilot. Whole-mount histopathology was digitized and co-registered to corresponding MRI slices using a validated high-fidelity methodology.(1) Foci, including central/transitional and peripheral zone lesions were identified by a pathologist, and contoured on digitized histopathology specimens and these digitized maps were used to guide macrodissection of the individual foci for genomic copy-number aberration (CNA) analysis. Correlation of radiomics signatures with the histologic findings and genomic analysis was performed. Results: We found a broad range of CNAs revealing inter-patient and intra-prostatic heterogeneity. Recurrently-altered loci ( e.g., 8p21) containing genes of known significance ( e.g., NKX3-1) were observed. Only radiomic features derived from apparent diffusion coefficient (ADC) independently correlated with both Gleason grade (Rho=-0.62, p=0.003) and median CNA burden (Rho=-0.68, p<0.001). While greater CNA burden expectedly correlated with higher grade, intermediate-grade (Gleason score 3+4 or 4+3) lesions appeared more like either high-grade (Gleason scores ≥4+4) or low-grade (Gleason score 3+3) disease when clustered based on CNA and ADC metrics. Conclusions: These findings suggest ADC derived radiomic metrics may be a useful imaging biomarker across both central and peripheral zone lesion and could aid in further characterization of intra-prostatic biologic heterogeneity. These proof-of-principle data reveal novel radio-genomic correlations that could supplement histologic grading and conventional imaging, thus warranting expanded study and validation. 1) Int J Rad Oncol Biol Phys. 2016; 96(1):188-96.
Elevated circulating CCL2 in prostate cancer patients.
Authors: Lin Justin , Caress Amanda , Ahmed Farzana , Taylor Nicole , Gong Yixuan , Oh William K. 
Published: February 2020

201 Background: Monocyte chemoattractant protein 1 (CCL2 or MCP-1), a chemokine secreted by monocytic cells, is critical in recruiting Treg and MDSCs into the tumor microenvironment and in regulating prostate cancer (PCa) migration and proliferation. In this study, we examined circulating CCL2 levels in healthy vs PCa patients and used an in vitro coculture model to identify the source of the elevated CCL2. Methods: Serum CCL2 concentrations were evaluated via ELISA in 59 patients (19 health controls, 20 “treatment naïve” PCa, 20 mCRPC). Monocytic leukemia cells (U937) were either directly cocultured with PC3 PCa cell line or cultured in the PC3 conditioned medium (CM). The induction of CCL2 mRNA in the cultures was examined by qPCR. The secretion of CCL2 into cell culture supernatants was evaluated via human cytokine array. Neutralizing antibodies to several overexpressed inflammatory cytokines in PC3 cells were added into the PC3 CM to evaluate the contribution of these inflammatory cytokines to CCL2 induction. Results: Circulating CCL2 concentrations were significantly higher in prostate cancer patient serum compared to control patient serum (p=4.4e-6) (Table). To understand the potential source of elevated CCL2, we grew U937 and PC3 in coculture and evaluated with qPCR, revealing that while CCL2 was not expressed in PC3 cells, it was expressed at very low levels in U937 cells. Interestingly, coculture of PC3 with U937 increased CCL2 mRNA expression by over 10-fold, and the result was confirmed at protein levels by human cytokine array. Our results also indicated that IL-6 and GM-SCF were the two major cytokines released by PCa cells to induce CCL2 mRNA in U937 cells and MEK and JAK-STAT signaling were crucial for CCL2 induction. Conclusions: Prostate cancer cells induce CCL2 secretion from monocytes in an IL-6 and GM-CSF dependent manner. Given the critical role of CCL2 in mediating immunosuppressive tumor microenvironments, our study highlighted the CCL2 Concentrations in PCa vs Healthy Serum.[Table: see text]
The impact of time-to-castration resistance on survival in patients with metastatic hormone-naïve prostate cancer: A multicenter retrospective study.
Authors: Okamoto Teppei , Hatakeyama Shingo , Takahashi Masahiro , Narita Shintaro , Ishida Masanori , Hoshi Senji , Kawamura Sadafumi , Ishidoya Shigeto , Shimoda Jiro , Kawaguchi Toshiaki , Tochigi Tatsuo , Mitsuzuka Koji , Tsuchiya Norihiko , Arai Yoichi , Habuchi Tomonori , Ohyama Chikara 
Published: February 2020

213 Background: To evaluate the prognostic impact of time to castration resistance (TCR) in patients with metastatic hormone-naïve prostate cancer (mHNPC). Methods: We retrospectively evaluated 283 mHNPC patients with metastatic castration-resistant prostate cancer (mCRPC) who were initially treated with androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between September 2008 and October 2018. Overall survival (OS) and OS after castration resistance (OS-CR) were compared between the <12 months (TCR <12M) and ≥12 months (TCR ≥12M). The association between the first-line life-prolonging therapy (docetaxel or new androgen receptor-targeted agents: ART) and TCR on OS-CR was investigated using multivariate Cox regression analysis via inverse probability of treatment weighting (IPTW) model. Results: Median age and time to CRPC were 72 years and 12 months, respectively. The number of patients in the TCR<12M and ≥12M groups were 137 and 146, respectively. Of 283, baseline parameters such as age, extent of disease (EOD), hemoglobin (Hgb), lactate dehydrogenase (LDH), and serum albumin levels were significantly differences in between the groups. We observed significantly poor OS and OS-CR in the TCR <12M group than those in the TCR ≥12M group. First-line docetaxel therapy did not significantly improved OS-CR regardless of TCR. Background (age, ECOG PS, GS, Hgb, tumor volume, serum data, and TCR)-adjusted multivariate Cox regression analyses showed that first-line docetaxel therapy was significantly associated with shorter OS-CR than first-line ART therapy in the TCR <12M group. Conclusions: The prognostic impact of TCR on OS was significant. However, the association between the first-line life-prolonging therapy and TCR on OS need further study.
Efficacy of sequential therapy comprising of docetaxel, abiraterone, enzalutamide, and cabazitaxel in patients with castration-resistant prostate cancer.
Authors: Yamamoto Akiyuki , Kato Masashi , Tsuzuki Toyonori , Gotoh Momokazu , Naito Yushi , Hattori Kyosuke , Tochigi Kosuke , Yuba Takuma , Kawanishi Hideji 
Published: February 2020

239 Background: The sequence of use of life-prolonging therapy (docetaxel, abiraterone, enzalutamide, and cabazitaxel) is unclear in patients with castration-resistant prostate cancer (CRPC). Methods: We retrospectively identified a total of 316 patients diagnosed with CRPC from September 2003 to April 2019 at Nagoya University and its affiliated hospitals. All patients were treated with >2 life-prolonging therapies. We divided these patients into four groups based on the sequence of drug administration. The group of patients who were treated using the sequence of abiraterone to enzalutamide or enzalutamide to abiraterone was termed as AA. The group treated using the sequence of abiraterone or enzalutamide to docetaxel was termed as AD. The group treated using the sequence of docetaxel to abiraterone or enzalutamide was termed as DA. Lastly, the group treated using the sequence of docetaxel to cabazitaxel was termed as DC. We investigated the overall survival (OS) from the time of diagnosis of CRPC. In addition, we estimated combined progression-free survival (combined PFS) defined as the sum of the PFS of each agent. Results: The number of patients in AA, AD, DA, and DC was 106, 69, 130, and 11, respectively. Regarding AA, AD, DA, and DC, the median ages were 72, 70, 68, and 64 years, respectively. The proportion of patients who had de novo distant metastasis was 66%, 65%, 58%, and 73% in AA, AD, DA, and DC, respectively. Further, the median OS was 68.7, 54.5, 68.6, and 22.0 months for AA, AD, DA, and DC, respectively. Notably, no significant differences related to OS were observed between AA and AD ( p = 0.06), AA and DA ( p = 0.24), as well as AD and DA ( p = 0.46). The median combined PFS was 8.6, 10.1, 13.9, and 5.6 months for AA, AD, DA, and DC, respectively. In terms of combined PFS, a significant difference was observed between AA and DA ( p < 0.001) as well as AD and DA ( p = 0.003). OS and combined PFS were significantly poor in DC compared with those in the other groups. Conclusions: No significant differences related to OS were observed regarding the sequence of use of docetaxel, abiraterone, and enzalutamide. Notably, combined PFS was comparatively better in DA than in any other group.
Non-prostate cancer malignancies detected by 18F-Fluciclovine PET/CT.
Authors: Barsky Andrew R. , Ahn Grace S. , Pantel Austin A. , Vapiwala Neha 
Published: February 2020

28 Background: Novel imaging modalities such as 18F-fluciclovine PET/CT provide additional sensitivity over conventional imaging modalities in the workup of recurrent prostate cancer (PC). The range of published sensitivity and specificity values for 18F-fluciclovine is broad, however, and NCCN guidelines note the scan’s high false-positive rate. Prior case reports have described incidental detection of non-PC using this modality, including melanoma, oropharyngeal, pancreatic, penile, liver, and breast cancers. Herein, we surveyed our institutional 18F-fluciclovine PET/CT results to assess the rate and histologies of incidentally-detected non-PC. Methods: We retrospectively identified consecutive men with PC who underwent 18F-fluciclovine PET/CT as part of their disease workup. After identifying studies with unequivocal PET-avidity, we assessed for subsequent tissue sampling and/or imaging to confirm a non-PC malignancy. We report these patients’ clinicopathologic data. Results: Three-hundred thirty-six men underwent 18F-fluciclovine PET/CT for PC at our institution between 6/2017-7/2019. Seven (2%) were found to have non-PC malignancies. The diagnoses were: meningioma (n=3, 43%), non-small cell lung cancer (NSCLC) (n=2, 29%), gastric adenocarcinoma (n=1, 14%), and pancreatic neuroendocrine tumor (n=1, 14%). One of the patients with meningioma underwent resection as a result, while the other two were surveilled by MRI. Both cases of NSCLC were biopsied and resected. Tissue sampling was not performed in the gastric or pancreatic cases, as these patients were already known to have these malignancies. Conclusions: In this large institutional series, we found a low rate (2%) yet broad range of non-PC malignancies incidentally detected by 18F-fluciclovine PET/CT performed for PC, including diagnoses not previously reported in the literature. Such detection allowed patients to receive definitive management or appropriate surveillance for the non-PC malignancies. These findings underscore the importance of clinical and/or pathological correlation of positive scan results.
Integrating comprehensive genomic profiling into the clinical management of prostate cancer patients: A single institution community practice experience.
Authors: Shore Neal D. , Haberberger James , Severson Eric Allan , Alexander Brian Michael , Sathyan Pratheesh , Reddy Prasanth , Ramkissoon Shakti H. 
Published: February 2020

281 Background: Prostate cancer is a leading cause of cancer-related mortality with a 5-year survival rate of 69%. In this study, we examine the role of integrating CGP, including tissue and liquid biopsy testing, into the clinical management of prostate cancer patients. Methods: We analyzed 140 cases of advanced prostate carcinoma with tissue and ctDNA based Comprehensive Genomic Profiling (CGP). CGP analysis revealed genomic alterations (GAs), TMB and MSI status. Germline testing, using multiple commercially assays was also obtained. Results: The median age of patients tested by tissue-based and liquid-based CGP was 65 years (46 to 85 yrs) and 69 years (51 to > 89 years), respectively. CGP analysis of tissue samples revealed the most commonly altered genes to be TP53 (34.6%), TMPRSS2- ERG (25.9%), PTEN (23.5%), NBN (14.8%), MYC (13.6%), BRCA2 (14.3%) and CDKN2A (13.3%). TMB analysis determined in 77 tissue samples showed a median (mean) value of 2.61 (5.00) mutations/Mb. 3.9% cases (3/77) were found to be hypermutated. MSI status was determined in 74 cases of which 2.7% (2/74) were found to be MSI-High. Of the tissue-based samples tested, 30.9% (25/81) were derived from metastatic sites. Analysis of commonly altered genes between primary vs metastatic tissue samples revealed TP53 mutations were significantly enriched in metastatic tumors. CGP analysis of the 59 liquid biopsy samples revealed the most commonly altered genes to be TP53 (37.3%), NF1 (10.2%), ATM (10.2%), CHEK2 (8.5%) and GNAS (8.5%). Germline testing was performed as described above on a clinically indicated subset of patients, which revealed alterations in BRCA, ATM, CHEK2, BRIP1 and TP53, among others. We are evaluating additional patient samples as part of the data set, which will be added to the final abstract presentation with a cutoff date of 12-31-2019. Conclusions: Genomic testing for high risk and advanced prostate cancer patients per the NCCN recommendations, with somatic testing, using tissue and liquid biopsy testing, as well as germline testing in selected cases, identifies DNA alterations which have potential clinical utility for clinical trial enrollment.
GLUT1 expression in high-risk prostate cancer: Correlation with 18F-FDG-PET/CT and clinical outcome.
Authors: Pouliot Frederic , Meizou Salma , Ringuette Goulet Cassandra , Hovington Helene , Lefebvre Veronique , Lavallée Etienne , Bergeron Michelle , Brisson Hervé , Champagne Audrey , Neveu Bertrand , Lacombe Didier , Beauregard Jean-Mathieu , Buteau François-Alexandre , Riopel Julie 
Published: February 2020

291 Background: Tumour FDG-uptake is of prognostic value in high-risk and metastatic prostate cancer (PCa). The aim of this study is to investigate the underlying glucose metabolism mechanisms of 18F-FDG-uptake on PET/CT imaging in PCa. Methods: Retrospective analysis was conducted for 94 patients diagnosed with a Gleason sum ≥8 at biopsy who underwent 18F-FDG-PET/CT imaging before radical prostatectomy. GLUT1, GLUT12 and HK2 expression were blindly scored after immunohistochemistry on radical prostatectomy specimens by 3 pathologists. 18F-FDG-uptake in primary lesion was measured by a blinded reader using maximum standardized uptake value (SUVmax). Correlations between GLUT1, GLUT12 and HK2 and SUVmax were assessed using Spearman’s rank correlation test. Survival probabilities were based on the Kaplan-Meier method. Results: With a median follow-up of 4.5 years, 56% (n=53) of patients had biochemical recurrence, 7% (n=7) progressed to castration-resistant PCa (CRPC) disease, 13% (n=12) developed metastasis and 6% (n=6) died. Correlation was found between GLUT1 expression and SUVmax level (r=0.2512, p=0.0182). In addition, SUVmax was significantly higher in tumours with high GLUT1 expression (n=17, 5.74±1.67) than tumours with low GLUT1 expression (n=71, 2.68±0.31, P=0.0037). Also, contrary to GLUT12 and HEX2 expression, a significant association was found between GLUT-1 expression levels and SUVmax index (p=0.004), lymph node status (p=0.046), volume of cancer (P=0.013), CRPC-free survival (p=0.02) and metastasis-free survival (p=0.04). Conclusions: GLUT1 expression in PCa tumours correlates with 18F-FDG-uptake and poor prognostic factors. These results suggest that this transporter is involved in the molecular mechanism of 18F-FDG-uptake in high-risk PCa and raise interest in targeting metabolic dependencies of PCa cells as a selective anticancer strategy.
PSA status after neoadjuvant androgen deprivation therapy before high-dose-rate brachytherapy as biomarker for prediction of long-term outcome in high-risk prostate cancer patients.
Authors: Wedde Trude , Cvancarova Milada , Hayman Jonathan S. , Tran Phuoc T. , Tafjord Gunnar , DeWeese Theodore L. , Lilleby Wolfgang 
Published: February 2020

301 Background: The aim is to investigate the clinical significance of biochemical response after Androgen Deprivation Therapy (ADT) prior to high-dose-rate brachytherapy (HDR-BT) for early identification of patients at increased risk of recurrence. Measured outcomes included biochemical relapse free survival (bRFS), distant metastasis free survival (DMFS) and overall survival (OS). Methods: A total of 324 patients with high-risk Prostate Cancer (PCa) were identified in the Norwegian Radium Hospital brachytherapy database. Neo-adjuvant ADT was administered for 3-6 months, followed by two 10 Gy HDR-BT treatments to the prostate, each spaced by two weeks, followed by conformal external beam radiation to 50 Gy to the prostate gland and seminal vesicles. Total length of ADT ranged from 12 to 36 months. PSA (ng/mL) and testosterone values (T, nmol/L) after 3-6 months of neo-adjuvant ADT were measured. Kaplan Meier and Cox regression analyses were performed. Results: Median age at diagnosis was 66 years and median follow-up was 10 years. At last follow-up, 277 patients (85,2%) were alive, 10 patients (3.1%) had died of prostate cancer and 37 patients (11.4%) died of other causes. 24 patients (7.4%) had biochemical relapse and 9 patients (2.8%) had distant metastasis within the first 5 years. Patients with PSA > 1 after neo-adjuvant therapy had 4.3 (95%CI 1.7 to 11.1) higher odds of biochemical relapse within 5 years compared to patients with PSA < 1 (p = 0.002). ROC analysis confirmed that PSA < 1 had a prediction accuracy of 0.76 (sensitivity 68% and specificity 67%). T < 0.7 and PSA < 1 after neo-adjuvant therapy were associated with improved bRFS, DMFS and OS (p < 0.001). Neither the length of neo-adjuvant nor total ADT treatment impacted outcomes (p > 0.05). Conclusions: Dose intensification with 2 HDR-BT boosts resulted in excellent survival in our cohort. PSA > 1 after neo-adjuvant ADT may be able to predict patients at increased risk of relapse and worse OS and identify patients in whom increased monitoring and/or intervention is warranted. ADT > 1 year did not improve outcome, indicating that shorter course of ADT may be used.
Deep learning using preoperative MRI information to predict early recovery of urinary continence after robot-assisted radical prostatectomy.
Authors: Sumitomo Makoto , Teramoto Atsushi , Fukami Naohiko , Fukaya Kosuke , Zennami Kenji , Ichino Manabu , Takahara Kiyoshi , Kusaka Mamoru , Shiroki Ryoichi 
Published: February 2020

310 Background: Urinary incontinence remains one of the most bothersome postoperative complications even after robot-assisted radical prostatectomy (RARP). We aimed to make a novel prediction system that can be used preoperatively to inform patients of the accuracy of early recovery of urinary continence after RARP using a deep learning (DL) model from magnetic resonance imaging (MRI) information and preoperative clinicopathological parameters. Methods: A retrospective cohort study was conducted on prostate cancer (PC) patients who had undergone RARP at our hospital between August 2015 and July 2019. Patients using no pads/no leakage of urine or the use of a safety pad within 3 months after RARP is categorized into “good” continence and others into “no good” continence. MRI DICOM data from axial, coronal and sagittal imaging as well as preoperative clinicopathological covariates (age, BMI, prostate volume, serum PSA level, Gleason score, clinical stage) were assessed. Supervised DL algorithms, which included AdaBoost, Naive Bayes, Neural Network, Random Forest, and SVM were trained and tested as binary classifiers (good or no good). To evaluate the DL models from the testing data set, their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), as well as area under the receiver operating characteristic curve (AUC) were analyzed. Results: Data were available for 497 patients in the study period. The AdaBoost DL algorithm using MRI information in addition to clinicopathological parameters had the highest performance with sensitivity at 92%, specificity at 77%, PPV at 79%, NPV at 91%, and AUC at 84% for predicting good continence, while that using clinicopathological parameters only had the performance with sensitivity at 50%, specificity at 69%, PPV at 60%, NPV at 60%, and AUC at 60%. Conclusions: Our results suggest that the DL algorithms using MRI imaging information are highlighted as an accurate method for strongly predicting early recovery of urinary continence after RARP. Thus, DL predictions may help allocation of treatment strategies for PC patients who dislike prolonged urinary incontinence after RARP.