bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of genetic mutations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.
Authors: Liu Alex John , Kosiorek Heidi E. , Ueberroth Benjamin Edward , Kendi Ayse T. , Tzou Katherine S. , Quevedo Fernando , Choo Richard , Moore Cassandra N. , Ho Thai Huu , Singh Parminder , Keole Sameer R. , Wong William , Bryce Alan Haruo 
Published: May 2020

e17587 Background: Radium (Ra)-223 has become the cornerstone treatment in patients with metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. Ra-223 has been shown to suppress abnormal bone formation by inducing DNA double-strand breaks in tumor cells. This can reduce skeletal-related events, as well as improve survival and quality of life. Studies have indicated mutations that regulate DNA damage response in prostate cancer as susceptible to PARP inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics, genetic mutations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. Results: 239 mCRPC patients treated with Ra-223 were identified. Germline and/or somatic genetic sequencing was available in 50 patients, who had a median age of 61 years at time of diagnosis and 68 years at time of Ra-223 treatment. Median Gleason score at time of diagnosis was 8.0. 100% of patients received prior androgen deprivation therapy. 72% received prior docetaxel, and 18% received prior cabazitaxel. Notable mutations included TP53 (45.2%), TMPRSS2-ERG (28.6%), PTEN (26.2%), BRCA1/2 (14.3%), ATM (9.3%), CDK12 (7.1%), and Rb (4.9%). TMPRSS2-ERG was the second most commonly found mutation, with median OS 12.7 mo versus 15.4 mo in patients without TMPRSS2-ERG mutations (p = 0.099). In patients with CDK12 mutations (2 of 28 tested positive), PFS was 10.4 mo versus 5.6 mo in patients without CDK12 mutations (p = 0.157). The assessment of ALP and PSA response to radium treatment stratified by genetic mutation did not reach statistical significance. Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic, TMPRSS2-ERG was the second most commonly found genetic mutation and had observed worse survival outcomes that approached statistical significance. Prospective studies and increased sample sizes are needed to determine the impact of genetic mutations in response to Ra-223.
Impact of flu vaccine on survival after immunotherapy for metastatic castration resistant prostate cancer (mCRPC): Analysis of Medicare claims data.
Authors: Pachynski Russell Kent , McKay Rana R. , Hafron Jason , Fitch Kate , Flanders Scott , Vogelzang Nicholas J. 
Published: May 2020

e17591 Background: Sipuleucel-T (sip-T) is a cellular immunotherapy that activates a patient’s own immune system to target prostate cancer cells. Flu vaccine contains inactivated virus that stimulates the immune system to induce a response. Hypothetically, influenza vaccines may impact sip-T effectiveness by affecting the apheresis procedure, ex vivo production of sip-T, and/or CD 54+ upregulation. We explored the effect of receiving the flu vaccine on outcomes in men who received first line treatment with sip-T. Methods: Claims data from the 2013-2017 CMS Fee for Service 100% Medicare Identifiable Database for Parts A, B and D Data were examined. Among men with dates of first sip-T doses in 2014 and 2015 (ie, index dates), we identified whether or not they received flu vaccine 30 days before or after based on healthcare common procedure coding system (HCPCS) codes and National Drug Codes (NDCs). Kaplan-Meier methodology was used to assess survival with Cox proportional hazards regression model used to calculate hazard ratios (HR). Three years of follow-up (F/U) were available for men with 2014 index dates; 2 years were available for men with 2014 and 2015 index dates. Results: Approximately 8% of men received the flu vaccine (102 of 1279 with 2 years of F/U; 50 of 656 with 3 years of F/U). Overall, mean age was 76 years. Most ( > 86%) were white. Receipt of flu vaccine did not impact the overall survival of men who received sip-T (HR [95% CI], 0.93 [0.64, 1.35] at 2 years and 0.90 [0.60, 1.37] at 3 years). The resultant Kaplan-Meier curves overlapped (not shown). Conclusions: Based on these claims analyses, concomitant use of flu vaccine did not appear to impact survival outcomes after sip-T administration in men with mCRPC. These data have practical application for clinicians and patients given limited prospective data evaluating the role of flu vaccination in patients receiving immunotherapy. [Table: see text]
Tumor response to a mastermind inhibitor protein.
Authors: Epenetos Agamemnon A. , Prokopi Marianna , Pitsillides Costas , Kapnisis Konstantinos , Deonarain Mahendra , Kousparou Christina , Anayiotos Andreas 
Published: May 2020

e17601 Background: Notch signalling is implicated in tumorigenesis prompting scientists to research and develop anti-Notch therapeutics. Drugging the Notch pathway has been a challenge due to severe G-I toxicity seen by many small-molecule inhibitors. Mastermind is a key nuclear factor that mediates Notch activity. We generated a novel protein drug, Syntana-4, that inhibits the Notch pathway at the Mastermind transcriptional level. Syntana-4 consists of the cell penetrating domain of Antennapedia, fused to a truncated peptide from Mastermind-like (MAML) that behaves in a dominant-negative fashion inhibiting Notch. Syntana-4 translocates into the cell nucleus, suppressing Notch activity and inducing apoptosis in Notch-driven cancer cells. Methods: We have conducted pharmacokinetics (PK), pharmacodynamics (PD) and toxicology studies, in combination with innovative imaging including in vivo flow cytometry and whole-body fluorescence reflectance imaging to define the behaviour of Syntana-4, determine its mode of action and establish a safety and efficacy profile in an orthotopic model of breast cancer in SCID mice based on the implantation of MDA-MB-231 cells into mammary fat pads. Samples of blood and tissues were examined for toxicity, apoptosis and immunogenicity. Results: We found that Syntana-4 was well-tolerated by normal cells and organs and was not immunogenic. Also, it was shown that free, non-internalized drug was rapidly cleared from the circulation. Whole body imaging showed that the drug in tissues was cleared within 24 hrs. Assessment of tumor growth demonstrated a reduction in tumor growth as evidenced by an overall increase of less than 50% in the intensity of fluorescence signal in the treated group compared to a 3-fold increase in signal and thus tumour size in untreated group by day 14. Conclusions: Syntana-4, a Mastermind inhibitor, was found to be well-tolerated and non-immunogenic in healthy animals. This drug targets the oncogenic Notch mechanism and can be applied across tumours with genetic defects in Notch signalling including breast, prostate, etc. We have demonstrated the utility of an innovative molecular imaging system emulating a clinical ‘phase I/II’ study in an orthotopic cancer model in order to measure the biodistribution, PK, PD, mode of action, toxicity and efficacy of a first-in-class biological therapy prior to entering the clinic. This innovative approach could be useful for accurate selection of lead drug candidates prior to entering clinical development.
Efficacy of androgen receptor antagonists in combination with androgen deprivation therapy in nonmetastatic, castration-resistant prostate cancer: A systematic review and meta-analysis of published phase III randomized controlled trials.
Authors: Jahan Nusrat , Rehman Shabnam , Mogollon-Duffo Francis , Ball Somedeb , Wongsaengsak Sariya , Tijani Lukman Aderoju 
Published: May 2020

e17606 Background: Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often heralds metastatic disease which is responsible for majority of the morbidity and mortality associated with prostate cancer. Hence, delaying metastasis is an expedient therapeutic goal for the patients with nmCRPC. Three androgen receptor (AR) antagonists — apalutamide, enzalutamide, and darolutamide — have been approved recently for nmCRPC on the basis of prolongation of metastasis-free survival. The purpose of our meta-analysis is to consolidate the efficacy data of AR-antagonists prolonging metastasis-free survival in nmCRPC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Phase 3 RCTs using AR-antagonists for nmCRPC were included in the final analysis. We used generic inverse variance method and random effects model to calculate the pooled hazard ratio (HR) for distant metastasis or death with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) randomizing 2694 patients in the AR-antagonist arms and 1423 patients in the control arms are included in the final analysis. All studies enrolled only patients with prostate specific antigen (PSA) doubling time of 10 months or less. AR-antagonists used in the study arms were — ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. The pooled HR for distant metastasis or death was highly significant at 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 79%) in the favor of AR-antagonist arm in overall population. The pooled HR remained significant when patients were stratified according to PSA doubling time. For patients with PSA doubling time > 6months, the pooled HR was 0.34 (95% CI: 0.27 - 0.43; P < 0.00001, I2 = 0%); for patients with PSA doubling time ≤6 months, the pooled HR was 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 73%). Conclusions: Our meta-analysis demonstrated addition of AR-antagonists to ADT significantly prolongs the metastasis-free survival in patients with nmCRPC — an exciting new development in the management of prostate cancer.
Dissection of primary prostate cancer to determine the clonal origin of synchronous lymph node metastasis.
Authors: Nallandhighal Srinivas , Tosoian Jeffrey J. , Singhal Udit , Karim Razeen , Mathieu Romain , Plouffe Komal , Rioux-Leclercq Nathalie , Siddiqui Javed , Liu Chia-Jen , Hovelson Daniel H. , Doglioni Claudio , Morgan Todd Matthew , Susani Martin , Luciano Luciano Roberta , Shariat Shahrokh F. , Tomlins Scott A. , Briganti Alberto , Palapattu Ganesh S. , Udager Aaron M. , Salami Simpa Samuel 
Published: May 2020

e17614 Background: Primary prostate cancer often consists of multiple, genomically-distinct clones. The clonal source of lymph node metastasis in multifocal disease is unknown. We sought to analyze and determine the histopathologic and molecular characteristics of the tumor sub-clones capable of metastasis in primary prostate cancers with synchronous lymph node metastasis. Methods: We identified patients with primary prostate cancer found to have lymph node (LN) metastasis at the time of radical prostatectomy, including those with multifocal disease. Punch biopsies were obtained from multiple regions of primary tumors and LN metastases. Targeted next generation sequencing to assess somatic DNA mutations, copy number alterations (CNA), and TMPRSS2:ERG fusion status. Bioinformatic analyses were performed using in-house developed pipelines. Phylogenetic evolutionary analyses were performed to delineate the primary cancer clone responsible for LN metastasis. Results: We identified 2 patients with LN cancer regions. In one patient, while all four Grade Group (GG) 5 primary tumor (PT) regions showed concordant TP53 and TPR non-synonymous mutations and broad copy number alterations (CNAs) with two LN foci, only two regions shared high level CNAs with both lymph node foci. In this case, a GG1 tumor focus showed no TP53 somatic mutation or CNA overlap with the high-grade tumor or lymph node samples. Critically, phylogenetic analysis revealed that the GG5 PT with extra-prostatic extension (EPE) showed higher concordance with the LN metastases than regions confined to the prostate. In another patient with four PT, phylogenetic analysis revealed that the PT with EPE closely resembled the LN metastasis; both were TMPRSS2:ERG fusion positive share PTEN copy number loss. Two PT (GG1 and 2) appeared to be independent clones and were TMPRSS2:ERG fusion negative. One of the six circulating tumor cells (isolated pre-prostatectomy) from this patient demonstrated a significant PTEN copy loss consistent with the findings in the region of EPE and the LN metastasis. Conclusions: Our findings confirm molecular heterogeneity of primary prostate cancers and homogeneity of LN metastases supporting the use of shared molecular alterations to infer clonal lineage. Our results highlight the critical role of adverse pathologic features, such as grade and EPE, in prostate cancer with synchronous lymph node metastasis.
Possibilities for improving the diagnosis of clinically significant prostate cancer based on 3D modeling.
Authors: Dimitriadi Sergey N. , Frantsiyants Elena M. , Demchenko Nikolay S. , Iozefi Dmitry Ya. , Vinidchenko Mikhail A. , Kit Oleg I. 
Published: May 2020

e17617 Background: The purpose of the study was improving the accuracy of diagnosis of clinically significant prostate cancer, using 3D models based on multiparametric MRI. Methods: We examined a total of 126 patients using a 12-point transrectal biopsy supplemented with an MRI targeted biopsy. The study included patients with a PSA in plasma of 1-20 ng / ml and symptoms of the lower urinary tract. We used a GE Signa HD 1.5T tomograph and an Advantage workstation. The scanning protocol included DWI, T2-FS, T2, 3D-Cube and a multiphase series with contrast. We evalueted focal changes in the structure of the prostate during MRI, using the PiRads v2.0 system, the results were processed at the GEAW 4.7 workstation, the prostate gland, urethra, seminal vesicles and sections were separated in layers. In the final 3D model, the prostate was labeled transparent, the urethra and seminal vesicles were labeled white. This model was saved and used as a visual three-dimensional image of the volume, size and localization of the foci of the prostate gland. When conducting a standard 12-point biopsy of the prostate under ultrasound control, based on a visual analysis of the 3D model, 2 additional injections were made into each part of the prostate, graded according to the PiRads≥ 3 scale. Results: We compared MRI with the histological results of a 12-point biopsy on the main 3D models of the prostate gland Among 126 patients, changes in MRI using the PiRads v2.0 system had 3 points in 48, PiRads 4 points - 32, PiRads 5 in 46 Among patients with PiRads 3 who underwent a standard 12-point biopsy, supplemented by targeted biopsy based on analysis of 3D models after MRI in 4 (8.3%) revealed clinically significant prostate cancer. Among patients with PiRads 4, clinically significant cancer was found in 11 (34.4%). In patients with PiRads 5, clinically significant cancer was found in 33 (71.7%). Conclusions: A transrectal biopsy of the prostate (using 3D modeling based on MRI with focal marking according to PI-RADS v2.0) allows to effectively identify clinically significant prostate cancer. Performing a transrectal biopsy of the prostate based on 3D modeling is the result of the effective application of an interdisciplinary approach to solving the problem of diagnosing clinically significant prostate cancer.
Molecular profiles and immune checkpoint inhibitor-related biomarkers analysis in advanced cervical cancer.
Authors: Xu Qin , Chen Chuanben , Sun Yang , Lin Yibin , Liu Jing , Li Li , Chang Lianpeng , Xu Yaping , Li Lifeng , Huang Bin , Zhu Chenchen 
Published: May 2020

e18003 Background: Treatment options for advanced cervical cancer (ACC) are limited and patients experiencing recurrence after first-line chemotherapy and bevacizumab have a poor prognosis. Checkpoint inhibitors targeting the PD-1/PD-L1 are promising treatment option. However, related genomic biomarker study is rare reported in ACC. Methods: We prospectively enrolled 102 pts with ACC. Tumor and plasma samples were obtained to analysis genomic profiles. DNA was sequenced by target-capture deep sequencing with the pan-cancer panel. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1. Results: The median age of enrolled pts was 63 yrs, and most (84.3 %, 86/102 pts) weresquamous carcinoma. A total of 93 tissues and 96 plasma were collected from 102 pts. The most frequently mutated genes were PIK3CA (40.9%, 38/93 pts), KMT2D (35.5%, 33/93 pts), and KMT2C (28.0%, 26/93 pts) in tissues. 80% (77/96 pts) of plasma was detected positive, with PIK3CA (23.4%, 18/77 pts), KMT2D (20.8%, 16/77 pts), KMT2C (20.8%, 17/77 pts) mutant frequently. Among 87 pts with paired samples, at least a tumor-derived mutation was detected in 35 (40.2%)plasma. Median of tTMB was 11.9 mut/Mb, and 45% pts were TMB-H. Significant correlation was found between tTMB and bTMB (Pearson r = 0.39, P = 0.001). Higher tTMB was identified in KMT2D- or KMT2C-mut pts (P = 0.002 or P = 0.01, respectively). tTMB showed no relation with clinic characteristics, including pathological subtype, FIGO stage, and status of distant metastasis. PD-L1 expression (CPS≥1) was identified in 53 pts (93 %, 53/57) and mutually independent with TMB status. Conclusions: Molecular profiles and TMB in plama showed high consistence with that in tissue. Prospective clinical trial is ongoing to determine the genomic biomarkers and the PD-L1 expression as predictive factors for the ICI efficacy in ACC (ChiCTR1900023015).
Identification of risk factors associated with pelvic lymph node metastasis in patients with stage IB1 cervical cancer.
Authors: Jiang Ping , Cai Jing , He Xiaoqi , Wang Hongbo , Dong Weihong , Zhang Yuan , Dunst Juergen , Willborn Kay C , Huang Bangxing , Wang Zehua 
Published: May 2020

e18005 Background: Evaluation the distribution of nodal metastases in the stage IB1 cervical cancer and the risk factors associated with pelvic lymph node metastasis (LNM) at each anatomic location. Methods: 728 patients with stage IB1 cervical cancer who underwent radical hysterectomies and systemic pelvic lymphadenectomies from January 2008 to December 2017 were retrospectively studied. All removed pelvic lymph nodes were pathologically examined, and the risk factors for LNM at the obturator, internal iliac, external iliac, and common iliac regions were evaluated by univariate and multivariate logistic regression analyses. Results: 20,134 lymph nodes were analysed with the average number of 27.80 (± SD 9.43) lymph nodes per patient. Nodal metastases were present in 266 (14.6%) patients. The obturator was the most common site for nodal metastasis (42.5%) followed by the internal iliac nodes (20.3%) and the external iliac nodes (19.9%), while the common iliac (9.8%) and parametrial (7.5%) nodes were the least likely to be involved. Tumor size more than 2 cm, histologically proven lymphovascular space involvement (LVSI) and parametrial invasion correlated independently significantly with the higher risk of the lymphatic metastasis. Obesity (BMI≥25) was independently significantly negatively correlated with the risk of lymphatic metastases. All the positive common iliac nodes were found in patients with tumors greater than 2 cm. The multivariate analysis showed that tumor size greater than 3 cm was associated with a 16.6-fold increase in the risk for common iliac LNM. Interestingly, tumor size was not an independent risk factor for pelvic LNM in the lower regions, i.e., the obturator, internal iliac and external iliac areas, where LVSI was the most significant predictor for LNM. In addition, parametrial invasion was related to external and internal iliac LNM; deep stromal invasion and age less than 50 years were associated with obturator LNM. Conclusions: The incidence of lymph node metastasis in patients with stage IB1 cervical cancer is low but prognostically relevant. The data offer the opportunity for tailored individual treatment in selected patients with small tumors and obesity.
Treatment patterns in cervical cancer patients initiating systemic therapy.
Authors: Shah Anuj , Kebede Nehemiah , Shah Ruchit , Corman Shelby , Nwankwo Chizoba 
Published: May 2020

e18009 Background: NCCN recommends the use of systemic treatment for advanced cervical cancer patients. However, no study has assessed treatment patterns in this population. This study described real-world treatments patterns among women with cervical cancer newly initiating a systemic therapy. Methods: Cervical cancer patients with ≥2 claims for systemic therapy (i.e., chemo- or immunotherapy) within a 4-week period between June 2014 – October 2018, no claims within 6 months prior to systemic treatment initiation (baseline period), and continuously enrolled within the baseline period and 3 months post therapy initiation were identified from the Optum Clinformatics DataMart database. Patients who had a cervical cancer-related surgery within ±3 months of therapy initiation were excluded to exclude adjuvant use. All claims for the same systemic therapy without a > 90-day gap or new systemic therapy started within 28 days of a previous treatment were considered to be part of the same LOT. Descriptive analysis, stratified for presence of non-cervical cancers during the baseline period, were conducted to identify most common treatments, durations, and use of mono versus combination therapy within each LOT. Results: 1,229 women newly initiated systemic therapy, 357 (29.0%) received LOT2 and 141 (11.5%) had a LOT3. Treatments received within each LOT are described in the table below. The proportion receiving radiation reduced from LOT1 (49.9%) to LOT2 (12.0%). The mean duration of LOT1 and LOT2 were 2.9 and 3.7 months. The proportion of patients receiving monotherapy in LOT1 and LOT2 were 77.8% and 64.1% respectively. Conclusions: The treatment received by patients in this analysis suggested receipt of guideline concordant care. [Table: see text]