bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crosstalk among T-cell CX3CR1, immune checkpoints and toll-like receptor 4 signaling pathway in BCG-unresponsive nonmuscle invasive bladder cancer: Mechanism of action of OncoTherad Nano-Immunotherapy.
Authors: Alonso João Carlos Cardoso , Ribeiro de Souza Bianca , Leme Giovana , Brum Reis Ianny , Gonçalves Juliana Mattoso , Cintra Adriano Angelo , Freitas Leandro Luiz Lopes de , Pereira Fabio Gomes , Billis Athanase , Fávaro Wagner José 
Published: June 2022

e16551 Background: This study detailed and characterized the mechanisms of action of OncoTherad nano-immunotherapy based on modulation of Toll-like Receptor 4 (TLR4) signaling pathway, CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation) and immune checkpoints in patients with Bacillus Calmette-Guérin (BCG)-unresponsive high-grade non-muscle invasive bladder cancer. Methods: A single-center open-label (Paulinia Municipal Hospital, Brazil) and single-arm phase 1/2 study (Clinical Trial: RBR-6swqd2) was applied in 44 patients (30 male and 14 female) with BCG-unresponsive NMIBC (≥ 1 prior course of BCG therapy) submitted to OncoTherad immunotherapy for 24 months. Patient follow-ups were performed with systematic mapping biopsies of the bladder every 3 months for the first year and every 6 months thereafter for up to 2 years. Bladder biopsies of each patient (n = 44) were divided into 2 groups: Group 1 (initial biopsy, before OncoTherad treatment); and Group 2 (bladder biopsy after OncoTherad treatment). Subsequently, the samples were submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 CTLA-4) and Regulatory T cells (FOXP3). Results: After 24-months follow-up, pathological complete response rate was 72.7% (95% CI) and recurrence-free survival of 21.4 months. Bladder samples from patients submitted to OncoTherad treatment (Group 2) showed intensified TLR4, TRIF, TBK1, IRF-3 and IFN-γ immunoreactivities when compared (p < 0.01) to initial biopsies (Group 1). Furthermore, as result of interferon signaling pathway (TRIF-dependent pathway) induction by OncoTherad, intensified CX3CR1 immunoreactivities (p < 0.01) were found in the Group 2. In contrast, PD-1/PD-L1 immunoreactivities were decreased (p < 0.01) in the Group 2 when compared to Group 1. No statistical differences were found between the two groups for FOXP3 and CTLA4. Conclusions: OncoTherad nano-immunotherapy led to activation of TLR4-mediated innate immune system, resulting in increased interferon signaling pathway, which was fundamental in the activation of antitumor CD8+ T-cells and decrease of PD-1/PD-L1 expression in the bladder microenvironment. These important findings are relevant concerning the treatment of patients with NMIBC presenting high-risk of progression that are BCG-unresponsive.
Biomarker Exploration for neoadjuvant chemotherapy with gemcitabine combined with cisplatin in muscle-invasive bladder cancer.
Authors: Wang Kun , Chen Xusheng , Zhang Zhenting , Hu Hailong , Zhang Aili , Wang Xin , Chen Lijun , Liu Zhizhong , Yue Changjiu , Zhang Xueying , Zhang Menghuan , Yao Xin 
Published: June 2022

e16556 Background: Neoadjuvant chemotherapy (NCT) is a standard treatment for muscle-invasive bladder cancer (MIBC). However, there is still a considerable proportion of patients who respond suboptimally to available treatments or experience adverse effects. Thus, identifying novel biomarkers to predict response to NCT of MIBC is urgently needed. Methods: A total of 23 patients were enrolled in this study, all of whom were cT2-T4aNxM0 MIBC and received 2̃4 cycles CG (gemcitabine and cisplatin) NCT. Radiographic assessment was performed at the end of each cycle or at the time of progression. Tumor tissue were collected from all patients before NCT. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed for tissue samples. In addition, peripheral blood was collected as a control for WES. Treatment responses were assessed by comparing the imaging data before and after treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with CR and PR were regarded as the responder group, and those with SD and PD were regarded as the non-responder group. Results: Number of patients received 2̃4 cycles NCT were 16 for the responder group and 7 for the non-responder group. Of 19 patients completed WES, 13 patients achieved response and 6 patients did not respond. In the responder group, 6 patients (46%) had variant in any of RB1, ERCC2 and ATM, which were previously reported to predict better response to NCT. Only a patient (16.7%) in the non-responder group had any of those variants. Additionally, our results showed that 3 patients in the non-responder group had MAST4 gene mutations, but not in the responder group, and there was a significant difference between the two groups (p < 0.05). There were no differences in Tumor Mutational Burden (TMB) and Microsatellite instability (MSI) between the two groups. RNA-seq was also completed in 18 patients, of which 14 patients achieved response and 4 patients did not respond. Significant differences in gene expression (eg. UPK3A, CD8B2, TUBB2B) between the two groups were found. The KEGG pathway enrichment analysis revealed that down-regulated DEGs were enriched in the Cytokine-cytokine receptor interaction pathway and up-regulated DEGs were enriched in the Steroid hormone biosynthesis. The infiltration of immune cells in the non-responder group was higher, and the CD4 cells, B cells, Th17 cells, and NK cells in the non-response group were significantly higher than those in the responder group (p < 0.05). Conclusions: Patients with MAST4 mutations may be insensitive to GC NCT. The non-response group had higher levels of immune cell infiltration and may be more sensitive to immunotherapy. These results require further validation in additional sample sets.
Treatment patterns and outcomes in prostate cancer patients tested with Decipher in SEER.
Authors: Zaorsky Nicholas George , Proudfoot James Alexander , Vince Randy , Liu Yang , Liu Vinnie YT , Zuhour Raed , Jia Angela Y , Sun Yilun , Hu Jim C. , Shoag Jonathan Evan , Schaeffer Edward M. , Davicioni Elai , Petkov Valentina I. , Spratt Daniel Eidelberg 
Published: June 2022

e17006 Background: In 2021, national data between the Decipher 22-gene prognostic gene expression classifier (GC) for men with prostate cancer and the Surveillance, Epidemiology, and End Results (SEER) cancer registries were linked. The purpose of the work is to report on the linkage by characterizing national GC usage and its association with treatment decisions for men with prostate cancer. Methods: Patients in the SEER registries with primary prostate cancer diagnosis from 2010 to 2018 were included and linked to data from GC testing conducted between 2014 to 2020 (Veracyte, San Diego, CA). GC scores (range 0-1) and GC risk groups (low, intermediate, and high) were used for continuous and categorical analyses. Multivariable logistic regression was used to quantify the association between GC and active surveillance and watchful waiting (AS/WW) use and adverse pathology at radical prostatectomy (RP). Adverse pathology was defined as pathological grade group ≥3, pathological stage ≥pT3b, or lymph node invasion. Results: A total of 575,363 patients were eligible for analysis, of which 10,528 patients underwent GC testing (5,015 GC biopsy test, and 5,513 GC RP test). The median age was 67 for both tested and untested, but more white patients underwent testing (82% vs 76%, p < 0.001). For GC biopsy tested patients, AS/WW was highest for those with GC low risk results (41%) as compared to those with intermediate (32%) or high (17%) GC risk (p < 0.001). RP rates were lower in the tested compared to untested (25% vs. 36%, p < 0.001), and among the tested patients, RP use increased by GC risk group (19% of low, 25% of intermediate, and 34% of high GC risk, p < 0.001). A similar trend by GC risk group in management for radiation therapy was observed (13% of low, 19% of intermediate, and 29% of high GC risk, p < 0.001). In a multivariable logistic regression adjusted for age, race, NCCN risk group, and year of diagnosis, GC tested patients were more likely to undergo AS/WW compared to untested (OR 2.9 [95% CI, 2.8-3.1], p < 0.001). Within the subset of patients classified as NCCN low/favorable intermediate risk at biopsy and who were subsequently treated with RP (n = 594), GC high risk (> 0.6) was associated with more than 3 times the odds of harboring adverse pathology (OR 3.2 [95% CI 1.6-6.4], p < 0.001). Conclusions: Using the first ever linked SEER-Decipher data, we demonstrate that population-based treatment patterns are independently associated with GC test results. Patients with lower GC scores are independently more likely to undergo AS/WW; those with higher scores are more likely to have adverse pathology at time of RP.
Outcomes of second-line therapies in patients with metastatic de novo small cell prostate cancer (SCPC) and treatment-emergent neuroendocrine prostate cancer (tNEPC).
Authors: Eule Corbin , Hu Junxiao , Al-Saadi Sulaiman , Collier Katharine , Boland Patrick James , McKay Rana R. , Narayan Vivek , Bosse Dominick , Mortazavi Amir , Rose Tracy L , Lam Elaine T. 
Published: June 2022

e17022 Background: De novo SCPC and tNEPC in metastatic castrate resistant prostate cancer (mCRPC) are rare, aggressive cancers with a poor prognosis. After first-line (1L) platinum chemotherapy (PLT), there is no consensus on 2L treatments. This multi-institutional, retrospective study examines practice patterns among clinicians and evaluates the outcomes of patients (pts) with SCPC or tNEPC in the 2L setting. Methods: After IRB approval, pts with a pathologic diagnosis of SCPC or tNEPC (any % of SC or NE histology defined by institutional review) were identified. Pts diagnosed between 2000-2020 who received 1L PLT and any 2L systemic therapy (tx) for SCPC or tNEPC were included. Standardized data collection templates containing demographic, clinical, and pathologic variables were collected. The primary endpoint was objective response rate (ORR) to 2L tx. Secondary endpoints included PSA response, time on 2L treatment, and overall survival (OS) from time of 2L tx. Data was analyzed using descriptive statistics. Results: Forty-two pts (21 SCPC, 21 tNEPC) from 6 institutions were included. At SCPC/tNEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 60.5, 68.0) and median PSA of 3.0 ng/dL (IQR 0.5, 21.8). The most common sites of metastasis included lymph node (78.6%), bone (54.8%), and liver (52.4%). For 1L tx, 37 pts (88.1%) received PLT and 5 (11.9%) had PLT + immunotherapy (IMM). For treatment to the prostate, 21 (51.2%) had none, 7 (17.1%) radiation (RT), 9 (22.0%) surgery, 3 (7.3%) RT + surgery, and 1 (2.4%) brachytherapy alone. Concurrent ADT was given to 32 pts (76.2%) in the 1L and 2L. At last follow-up, 34 pts (81.0%) were dead, 4 (9.5%) were alive, and 4 (9.5%) were lost to follow-up/censored. For 2L tx, 10 pts (23.8%) received PLT, 8 (19.0%) taxane monotherapy (TAX), 10 (23.8%) IMM, 8 (19.0%) other chemotherapy (CHX), and 6 (14.3%) other tx. Among 38 pts evaluable for response, the ORR was 15.8% (6 pts with PR: 4 PLT, 1 IMM, 1 CHX). PSA response ≥ 50% to 2L tx was seen in 5 of 29 pts with PSA data (17.2%). Other outcomes data are reported in Table. Conclusions: In this retrospective study, pts with SCPC or tNEPC who reached 2L tx received a wide variety of treatment regimens, reflecting the lack of consensus in this tx setting. ORR was low and overall prognosis was poor in the 2L regardless of tx choice. Pts on 2L immunotherapy seemed to have the shortest mOS. [Table: see text]
Clinical markers of successful liquid biopsy-based genomic profiling in veterans with prostate cancer.
Authors: Guo Aixia , Ahmed Sara , Rowe Kerry , Pritchard Colin C. , Montgomery Robert B. , Kelley Michael J. , Rettig Matthew 
Published: June 2022

e17031 Background: Liquid biopsy with plasma circulating tumor DNA (ctDNA) is a noninvasive alternative to tissue genomic profiling. The yield of ctDNA is largely dependent upon the total amount and proportion of ctDNA in the total circulating DNA pool. Factors that predict successful genomic profiling via liquid biopsy amongst Veterans with prostate cancer are unknown. Methods: 764 veterans with prostate cancer who received liquid biopsy testing between February 2019-2021 were selected from the VA National Precision Oncology Program (NPOP) database. Baseline patient variables including age at specimen collection date, race, PSA, PSA doubling time (PSADT), sites of metastatic involvement (i.e., bone, brain, liver, lung, and lymph nodes), number of metastatic sites, Gleason score, and Gleason grade group were extracted from the VA Corporate Data Warehouse (CDW). Two independent approaches were used to define a successful liquid biopsy: Approach 1: Liquid biopsies with an alteration detected in one or more prostate cancer related genes ( AR, CDK12, SPOP, MED12, CCND1, BRAF, AKT1, TMPRSS2) (n = 337); Approach 2: Liquid biopsies with alterations detected in any gene detected by the Foundation One Liquid CDx assay (n = 670). We performed univariate and multivariate logistic regression analysis for Odds Ratio (OR), 95% confidence interval (CI), and conducted statistical significance tests to investigate associations between clinical factors and liquid biopsy test outcome. P-value < 0.05 was considered significant. Results: In Approach 1, the OR by univariate analysis was 4.80 (P < 0.001; 95% CI [3.09, 7.47]) for 4th PSA quantile group versus 1st PSA quantile group. The OR was 3.61 (P < 0.001; 95% CI [2.0, 6.5]) for PSADT less than 3 months versus PSADT more than 60 months; brain metastasis had the highest OR value among metastatic sites of 2.47 (P = 0.008; 95% CI [1.27. 4.8]). In multivariate analysis, PSA, PSADT and sites of metastasis remained significant risk factors. Statistical significance tests indicated PSA, PSADT, and sites of metastasis were significantly different between the success and failure groups. In Approach 2, no statistically significant associations were observed between the studied variables and any outcome. Conclusions: Factors such as PSA, PSADT, and metastatic site were significantly associated with a successful liquid biopsy of detecting prostate cancer related gene mutations, while the outcome of detecting any gene mutations was not statistically significant associated with studied variables in this study population. Given the likelihood that a significant number of non-prostate cancer mutations are likely due to clonal hematopoiesis, this finding is expected. Our findings may facilitate clinical decisions around genomic profiling by liquid biopsies in the absence of tumor tissue, thereby increasing the success rate of sequencing efforts for treatment selection.
Profiling of clinically relevant subgroups of asymptomatic or mild-symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients using PSA and testosterone levels and deep learning.
Authors: Dominguez Correa Juan Manuel , Gomez del Campo Pablo , Galmarini Carlos Maria 
Published: June 2022

e17032 Background: The optimal time to begin therapy in mCRPC patients who have either no, or minimal symptoms is not defined yet. Estimating prognosis of these patients can avoid undertreatment or overtreatment and guide the follow-up intensity. This study has investigated the ability of a deep learning framework (DLF) to identify asymptomatic or mildly symptomatic mCRPC patients with high risk of disease progression and mortality using PSA and testosterone levels. Methods: Data from the control arm of the NCT00554229 trial was obtained from www.projectdatasphere.org . These mCRPC patients were treated with placebo alone. The dataset consisted of more than 150 clinical variables. We generated synthetic fingerprints (SF) for each patient through the integration of PSA values collected at baseline and during the first 90 days of follow-up and testosterone levels at baseline. These SF were then input into a DLF to identify subgroup of patients based on their similarities. The resultant subgroups were correlated with progression-free survival (PFS) and overall survival (OS). Feature contribution analysis identified the significant predictive clinical variables in each subgroup. Results: After discarding missing data, 189 patients were eligible for this exploratory study. Median PFS and OS for the total population were 8.7 months and 24.5 months, respectively. DLF identified two different subpopulations, SPA (n = 89) and SPB (n = 100), with significantly different survival outcome. Patients in SPA had a lower risk of progression (median PFS 12.2 months vs. 7.2 months; hazard ratio 0.54, 95% CI 0.41-0.71; p < .0001) and death (median OS not reached vs. 20.3 months; hazard ratio 0.33, 95% CI 0.21-0.52; p < .0001) compared to patients in SPB. SPA signature was significantly correlated to leuprolide treatment. These patients also had higher levels of haemoglobin, red blood cells, haematocrit, total bilirubin, Ca, phosphate, and K. Instead, SPB signature was significantly correlated with presence of > 3 bone metastasis, lack of energy or forced time to bed in the FACT-P and moderate problems in selfcare in the EQ-5D, and treatment with goserelin, tamsulosin, opioids and contact laxatives. In addition, these patients had higher levels of platelets, basophils, monocytes, ALP, AST, LDH, PSA, free PSA, Mg, Na, and specific gravity. Conclusions: DLF identifies mCRPC subtypes that correlate with higher risk of progression and death according to PSA and testosterone levels. Model predictions also suggest complex interactions among many clinical features that might be important modulators of key clinical traits and outcome. Further work is required to validate this approach to anticipate the clinical course of asymptomatic or mildly symptomatic mCRPC patients and help to better decide when to start appropriate therapy.
Real-world associations between bone-targeted agents and palliative bone radiotherapy in prostate cancer decedents: A province-wide population study.
Authors: Phillips William James , Jooya Alborz , Mahdavi Roshanak , Leigh Jennifer , Tawagi Karine , Webber Colleen , Milani Christina , Morgan Scott Carlyle , MacRae Robert Malcolm , Bourque Jean-Marc , Tanuseputro Peter , Ong Michael 
Published: June 2022

e17043 Background: Palliative bone radiation is the predominant skeletal-related event (SRE) reported in advanced prostate cancer. Bone targeted agents (BTA), such as denosumab and zoledronic acid, are shown to both prevent and delay SREs including bone radiation. This study evaluated real-world use of BTA in a large provincial database in relation to palliative bone radiotherapy prior to prostate-cancer related death. Methods: Linked, province-wide administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98646), who received continuous androgen deprivation therapy (n = 29453), died between 2013-2018 (n = 4184), and qualified for Ontario Drug Benefits (OBD; 65 years or older, n = 3788). Patients receiving novel life prolonging therapy (LPT) for metastatic castration-resistant prostate cancer (mCRPC; abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223) were selected, and use of BTA (denosumab, zoledronic acid) was identified. Demographic, health, and treatment characteristics were collected over a 2-year observation window looking back from the date of death. Multivariable analyses were conducted to identify factors important in use of palliative bone radiation. Results: 1769 patients received LPT for mCRPC, including abiraterone (n = 1094, 62%), docetaxel (n = 881, 60%), enzalutamide (n = 480, 27%), radium-223 (n = 250, 14%) and cabazitaxel (n = 108, 6%). Amongst patients receiving LPT, 57% received BTA and 60% received palliative radiation to bone. Factors associated with palliative bone radiation were receipt of BTA (OR 1.46; 95% confidence interval [CI] 1.13-1.91), metastatic disease at diagnosis (OR 1.48; CI: 1.11-1.97), radiation oncologist involvement (OR 103.11; CI: 47.03-226.25), whereas patients with fewer chronic diseases (OR 0.73; CI: 0.54-0.98) and who had prior prostatectomy (OR 0.54; CI: 0.36-0.84) were less likely to receive radiation. This relationship was maintained for both zoledronic acid (OR 1.68; CI: 1.09-2.58) and denosumab (OR 1.35, CI: 1.03-1.77). No specific LPT was associated with use of palliative bone radiation. Conclusions: Despite clinicians prescribing BTAs to prevent SREs, in this cohort, radiotherapy to bone was more likely in patients receiving BTAs. This suggests that clinicians are prescribing BTAs to patients at greater risk of SREs, but that patients dying of prostate cancer continue to have significant bone-related morbidity despite contemporary prostate cancer treatment. An analysis of primary (before bone radiotherapy) versus secondary (after bone radiotherapy) BTA prescriptions will be presented, as well as timing of BTA initiation in relation to death.
Impact of therapeutic strategy on disease-free and overall survival of early-stage cervical cancer: Surgery alone versus preoperative radiotherapy.
Authors: Mahiou Katia , Vincent Laura , Peignaux-Casasnovas Karine , Costaz Hélène , Padeano Marie-Martine , Amet Alix , Dabakuyo Tienhan Sandrine , Bengrine-Lefevre Leila , Coutant Charles 
Published: June 2022

e17517 Background: At present, there is no international consensus for management of early-stage cervical cancer. This study aimed to retrospectively investigate disease-free survival (DFS) and overall survival (OS) in patients with early cervical cancer according to the therapeutic strategy used, surgery alone versus pre-operative radiotherapy following by surgery. Methods: Data from patients with early-stage cervical cancer were retrospectively collected from January 1998 to December 2015 using the Breast & Gynecological Cancer Registry of the Côte d’Or, regrouping data from 7 centers. The inclusion criteria were: FIGO 2009 stage IB1 or lower; epidermoid, adenocarcinoma or adenosquamous type. The exclusion criteria were: history of pelvic radiation; concomitant radiochemotherapy; adjuvant radiotherapy; total radiation dose less than 50 Gy, or more than 66 Gy or not documented. In the surgery group, patients had only a surgical treatment for early-stage cervical cancer. The surgical treatment was either a hysterectomy, a trachelectomy or a conization. In the radiation group; patients had radiotherapy, brachytherapy and/or radiotherapy followed by surgery. DFS and OS were determined using the Kaplan-Meier method .Survival curves were compared using the log-rank test. Results: A total of 126 patients were included. Median survival in the whole population was 90 months (47-148); 72 months for those receiving primary surgery, and 135.5 months for those receiving primary radiation therapy. There was no significant difference in DFS between the surgery and radiation groups (HR=2.82, 95%CI (0.82-9.65), p=0.08). Similarly, there was no significant difference in OS between groups (HR=1.35, 95%CI (0.6-3.05), p=0.5). In the sub-group of patients with stage IB1 (FIGO 2009), there was no significant difference in DFS (HR=3.26, 95%CI (0.4-26.76), p=0.2) or in OS (HR=3.87, 95%CI (0.49-30.35), p=0.2) between groups. Conclusions: Cervical cancer counts among the only solid tumors for which increasing mortality has been observed in recent years. Radiation therapy is still a major source of morbidity for young patients. Therefore, key issues remain outstanding for the future management of young patients with cervical cancer and include reducing the morbidity of existing therapeutic options by identifying subgroups of patients at low or intermediate risk, and facilitating fertility-sparing surgery.