bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative healthcare research outcomes of novel Surgery in prostate cancer (IP4-CHRONOS): Pilot RCT assessing feasibility of randomization for focal therapy in localized prostate cancer.
Authors: Reddy Deepika , Dudderidge Tim , Shah Taimur , McCracken Stuart , Arya Manit , Fiorentino Francesca , Day Emily , Prevost Andrew , Emberton Mark , Staffurth John , Sandhu Sarbjinder , Hindley Richard , Arumainayagam Nim , Sydes Matthew R. , Khoo Vincent , Winkler Mathias , Ahmed Hashim Uddin 
Published: June 2022

5086 Background: Randomised comparative data is lacking for focal therapy in localised prostate cancer. Imperial Prostate 4 CHRONOS (IP4- CHRONOS) is an RCT designed to reflect patient and physician equipoise to maximise acceptance to randomisation. Methods: Patients and physicians could opt for CHRONOS-A or CHRONOS-B. CHRONOS-A randomised between focal therapy (HIFU/cryotherapy) and radical therapy (radiation/prostatectomy). Using a multi-arm-multistage design, CHRONOS-B randomised between focal and focal combined with neoadjuvant medication (3 months of either finasteride or bicalutamide). We report the pilot phase outcomes on feasibility of randomisation. IP4-CHRONOS had ethics committee approval and was registered (ISRCTN17796995). Results: Due to impact of COVID-19, the target for CHRONOS-A was modified from 60 to 36; 36 patients were randomised over 24 months from 7 sites (Nov/2019-Nov/2021). CHRONOS-B randomised 64 patients over 14 months across 6 sites (Dec/2019-Feb/2021). Median (IQR) age and PSA (ng/ml) for CHRONOS-A were 69 (65-72) years and 6 (5-7) and for 66 (60.5-70) years and 6 (4-7) for CHRONOS-B, respectively. 34/36 (94%) and 60/64 (94%) had ISUP Grade Group > / = 2, respectively. 4/18 (22%) randomised to radical in CHRONOS-A withdrew consent; 1/22 (5%) randomised to focal withdrew. In CHRONOS-B, only 1/21 (5%) randomised to focal alone, and another randomised to focal with neoadjuvant bicalutamide withdrew. A qualitative recruitment intervention partially improved accrual to CHRONOS-A. Conclusions: IP4-CHRONOS evaluated patient and physician equipoise regarding focal therapy. Randomising between focal and radical therapy is not feasible due to strong patient preferences. A multi-arm, multi-stage RCT investigating the role of neoadjuvant agents combined with focal therapy is feasible. Clinical trial information: 17796995.
Exploring homologous recombination deficiency thresholds for predicting response to platinum-based treatment in triple negative breast cancer.
Authors: Timms Kirsten , Lenz Lauren , Cogan Elizabeth S. , Mayer Erica L. , Kaklamani Virginia G. , Stearns Vered , Abramson Vandana G , Falkson Carla Isadora , Jankowitz Rachel Catherine , Marcom P. Kelly Kelly , Tung Nadine M. , Gradishar William John , Ford James M. , Vinayak Shaveta , Boughey Judy Caroline , Goetz Matthew P. , Storniolo Anna Maria , Connolly Roisin M. , Richardson Andrea L. , Telli Melinda L. 
Published: June 2022

525 Background: Homologous recombination deficiency (HRD) status can be used to identify patients who are eligible for treatment with DNA damaging agents. Using a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42, studies have previously examined the association between HRD status and outcomes in patients with triple negative breast cancer (TNBC). However, evidence suggests that a GIS threshold of ≥33 may be more appropriate. Here, we conducted an exploratory analysis evaluating the ability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. Methods: Patients across 5 cohorts (TBCRC0301, TBCRC0082, NCT013725793, PrECOG 01054, combined cisplatin cohort4) were included in this analysis if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. GIS was determined by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions.4,5 BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated by comparing binary threshold status and binary pCR status. Results: A total of 204 tumors (158 BRCAwt; 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold producing higher sensitivity values. This was true when thresholds were applied to all samples and to BRCAwt samples only (Table). Among patients who achieved pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. Conclusions: To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors. 1. Ann Oncol. 2020;31(11):1518-25 2. J Nucl Med. 2015;56(1):31-7. 3. Breast Cancer Res Treat. 2015;151(3):629-38. 4. Clin Cancer Res. 2016;22(15):3764-73. 5. Breast Cancer Res Treat. 2014;16(6):1-9. [Table: see text]
Safety and tolerability of olaparib combined with breast radiotherapy in patients with triple-negative breast cancer: Final results of the RADIOPARP phase 1 trial.
Authors: Loap Pierre , Loirat Delphine , Berger Frederique , Rodrigues Manuel , Bazire Louis , Pierga Jean-Yves , Vincent-Salomon Anne , Laki Fatima , Boudali Latifa , Raizonville Laurence , Mosseri Veronique , Jochem Anne , Diallo Mamadou , Stern Marc-Henri , Fourquet Alain , Kirova Youlia M. 
Published: June 2022

534 Background: Preclinical studies have demonstrated that triple-negative breast cancer (TNBC) cells were sensitive to PARP inhibitors when used as radiosensitizers. Combining PARP-inhibitors with radiotherapy may consequently enhance the biological effectiveness of the irradiation, leading to improved locoregional control in TNBC patients. We aimed to establish the appropriate dosing and the safety profile of Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients with residual disease after neoadjuvant chemotherapy. Methods: RADIOPARP (NCT03109080) was a prospective phase I dose-escalation trial establishing the tolerance profile of Olaparib combined with breast radiotherapy in high-risk early TNBC patients. Inclusion criteria were resected TNBC with non-complete pathological response after neoadjuvant chemotherapy, or unresectable TNBC despite prior neoadjuvant chemotherapy. Olaparib was started seven days before irradiation and continued during radiotherapy. A time-to-event continual reassessment method was used to increase Olaparib through four increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day) with a 25% maximum probability rate of dose-limiting toxicities (DLT). Radiotherapy delivered 50 Gy to the breast or to the chest wall, with or without lymph node irradiation. Toxicities were graded according to CTCAE (version 4.03). Homologous recombination (HR) proficiency status was genetically determined based on shallow whole genome sequencing. Results: Twenty-four TNBC patients were enrolled between 09/2017 and 11/2019. Olaparib was escalated to 200 mg twice a day without DLT and the MTD was not reached. With a median follow-up of 34 months, no late treatment-related grade ≥ 3 toxicity was observed, and the maximum observed toxicities were limited to grade 2 breast pain (n=2), fibrosis (n=2), deformity (n=1) and telangiectasia (n=1). Three-year OS and EFS were 83% [95% CI: 70%-100%] and 65% [51%-91%], respectively. HR proficiency status was not associated with OS and EFS. Conclusions: Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients was well-tolerated. The MTD was not reached, and no significant late toxicity was reported. For future trials evaluating the anti-tumor efficacy of this combination, an Olaparib dose of 200 mg twice a day should be considered. Clinical trial information: NCT03109080.
Cisplatin-induced nephrotoxicity in hyperthermic intraperitoneal chemotherapy (HIPEC) is mitigated by sodium thiosulfate: Clinical and toxicotranscriptomic results of a prospective trial.
Authors: Lugo Santiago Nicole , Han Ernest Soyoung , Raoof Mustafa , Wu Xiwei , Cho Hyejin , Lee Stephen , Lin Wei-Chien , Lin Jeff Feng-Hsu , Stewart Daphne B. , Ruel Nora H. , Wang Edward Wenge , Paz Isaac Benjamin , Wakabayashi Mark Tsuneo , Rodriguez-Rodriguez Lorna , Cristea Mihaela C. , Dellinger Thanh Hue 
Published: June 2022

5570 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC). Unfortunately, cisplatin is associated with significant renal toxicities. Sodium thiosulfate (ST) has been suggested as a nephroprotectant for patients undergoing HIPEC with cisplatin. Methods: A feasibility trial ( ClinicalTrials.gov: NCT01970722) evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during optimal cytoreductive surgery (CRS) in patients with EOC and endometrial cancer (n = 40), with or without ST. Twenty-one patients received no sodium-thiosulfate (nST group), and nineteen patients received sodium thiosulfate (ST group). Toxicities were reported according to CTCAE v. 5. Progression-free survival was followed. Normal tissue biopsies were collected intra-operatively immediately following HIPEC and cisplatin exposure in a subset of patients (n = 21), and profiled with transcriptomic sequencing to identify RNAseq signatures correlating with toxicities. Hierarchical cluster analyses identified distinct transcriptomic signatures in post-HIPEC normal samples of patients with renal AEs (rAEs) compared to no renal AEs (nrAEs). KEGG pathway analysis identified up- or downregulated gene sets using GSEA. Results: Forty patients had HIPEC at time of optimal CRS. Renal toxicities were higher in the nST group (no sodium thiosulfate) compared to the ST group. nST patients had 17% any grade, and 9% Grade 3 AEs for acute and chronic kidney injuries. In contrast, ST patients suffered 0% renal AEs. rAE patients demonstrated upregulation of immune signaling pathways (Toll-like receptor, Natural killer cell, Nod-like receptor); and downregulation of metabolic pathways. Top upregulated genes in rAE patients included immune (e.g. neutrophil) related genes, while downregulated genes included metabolism genes. Kaplan-Meier curves demonstrated improved PFS in primary ovarian cancer patients undergoing HIPEC who were treated with ST vs no ST (p = 0.04, NR vs 13.4 mo). Conclusions: HIPEC with cisplatin results in significant renal toxicities. The mechanisms of cisplatin-induced nephrotoxicity in HIPEC are immune-related and reflect reduced metabolism. Sodium thiosulfate abrogated renal toxicities and did not decrease PFS. Clinical trial information: NCT01970722.
Mutational landscape of low-grade serous carcinoma of the ovary.
Authors: Schink Julian C. , Garg Ruchi , Elvin Julia Andrea , Godbee Natalie , Moran Amber , Doctor Vicki , Tan Bradford A. , Farley John H. , Markman Maurie 
Published: June 2022

5578 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that are potential therapeutic targets. We present an analysis of comprehensive genomic profiling (CGP) of a large series of low grade serous ovarian carcinoma patients assayed in a nationwide cancer network. Methods: 40 Pts with advanced low grade serous ovarian carcinoma (LGSOC) underwent hybrid-capture based CGP for up to 324 cancer-related genes on archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 thru 06-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 44 years (range, 25-65), 68% were White and 23% were Black. Genomic alterations (GA) were identified in 80% (32/40) of LGSOC, of which 22 (55%) had a clinically relevant genomic alteration (CRGA). There were no apparent racial differences between mutation frequencies. The table below details the frequency of the most common of these clinically relevant mutations. Additionally, 1 patient had an ESR1 activating mutation commonly seen in acquired hormone therapy resistance in breast cancer; and single cases of the following mutations were also noted: TSC1, PTCH1, PTEN, FGFR1, and AKT2. Conclusions: In a large series of Low Grade Serous Ovarian Cancer patients assayed with CGP, 55% of pts had mutations potentially targeted by precision medicine therapy. The most common target is KRAS, seen in 33% of patients, these are potentially treatable with FAK and MEK inhibitors. Another 10% of patients had either a BRCA or ATM mutations making PARP inhibitor therapy an additional targeted treatment option. While mutations in the RAS pathway are most common in LGSOC they are not the only actionable target. Furthermore, this approach might also help identify baseline or acquired resistance to the hormone therapies often used to treat this cancer. The results of this study demonstrate the significant heterogeneity of genomic alterations in this rare cancer and highlight the importance of genomic profiling in this cancer which has a marked propensity for recurrence. [Table: see text]
HER2 in uterine carcinosarcoma: Testing platforms and implications for targeted therapy.
Authors: Maredia Navin , Wu Sharon , Farrell Alex , Oberley Matthew James , Thomaier Lauren , Jones Nathaniel L. , Herzog Thomas J. , Thaker Premal H. , Powell Matthew A. , Klc Tenley , Erickson Britt Kristina 
Published: June 2022

5590 Background: Uterine carcinosarcomas (UCS) are rare, aggressive tumors accounting for 5% of all uterine cancers. Recurrence rates are high and 5-year survival is only 18-39%. HER2 is an emerging prognostic and therapeutic target in uterine cancer including UCS. Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to determine HER2 prevalence in UCS and the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of UCS specific testing guidelines. We also evaluated the rate of downstream mutations and immune biomarkers that may affect response to HER2 directed therapy. Methods: Eight hundred and seventy-five UCS tumor samples (primary 81.4%; metastatic 17.1%; unknown 1.5%) were analyzed using NGS (592, NextSeq; WES, NovaSeq, Caris Life Sciences, Phoenix, AZ). A subset of tumors with HER2 positivity were tested with IHC (4B5, Ventana) and/or CISH (INFORM DUAL HER2 ISH Assay, Ventana) based on 2018 ASCO/CAP HER2 Breast Cancer guidelines. Amplification of ERBB2/HER2 by NGS used a copy number cut-off >6. PD-L1 expression was analyzed by IHC (SP142, positive cut-off ≥1%, Ventana). Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (TMB high cut-off > 10 mutations per Mb). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Results: Rates of HER2 positivity were 3.4% (28/820) by NGS. Among the IHC/CISH-tested cohort, 7.2% was positive (10/139) by IHC, and 19.5% (27/133) by CISH. In the 105 samples tested with both IHC and CISH, the concordance was 100%. Specifically, 9/105 patients (8.6%) were IHC+/CISH+ and 96 patients (91.4%) were IHC-/CISH-. The concordance between CISH and NGS (N = 127) was 90.6% (sensitivity 100% and specificity 89.3%). Common gene alterations in CISH HER2+ UCS tumors that may implicate resistance to HER2 targeted therapy included mutations in TP53 (100%), FBXW7 (22.2%), PIK3CA (33.3%), PIK3R1 (18.5%), PTEN (3.7%) and KRAS (3.7%) and gene amplification of KRAS (11.1%). CISH+ HER2+ UCS tumors had low immunotherapy biomarker prevalence (0% MSI-H, 0% TMB high, 7.7% PD-L1+). Conclusions: Increased HER2 positivity was detected via CISH testing compared to IHC and NGS, which may reflect the heterogeneity of HER2 amplification due to mixed histology between the sarcoma and carcinoma portion of the tumor. High concordance rates were observed between CISH and IHC. These testing platforms need to be validated by response to HER2 targeted therapies in order to develop UCS specific testing guidelines.
Impact of travel burden on overall survival in patients with lung cancer.
Authors: Stoyanov Dragomir Svetozarov , Tonev Ivan , Dimitrova Eleonora , Panayotova Teodorika , Manev Rostislav , Donev Ivan , Conev Nikolay 
Published: June 2022

6522 Background: High-volume specialized centers are more efficient at managing patients with lung cancer than low-volume centers. Centralization of cancer treatment has the potential to improve patient outcomes and quality of treatment. However, the growing centralization also increases patient’s travel burden (measured as travel distance or travel time) and may negatively impact access to specialist services. The aim of our study was to evaluate the potential impact of travel burden on clinical outcomes in patients with lung cancer. Methods: A retrospective analysis of a single Bulgarian center was performed. A total of 9240 lung cancer patients treated between 2005-2020 were included in the study. Travel distance between patients’ city of residence and the treating facility was calculated with an online tool to determine the shortest route for travel using the existing road network. The mean of travel time values for every workday of the week was calculated to control for daily changes in typical traffic. The probability of survival was estimated using the Kaplan-Meier method and differences in survival in each subgroup were evaluated with a log-rank test. Results: About one third of all included patients were living in the same city as the treating facility (n = 2746, 29.7%). The medians for travel distance and travel time were used to stratify patients into subgroups. According to travel distance the patients were grouped into three strata – same city, < 50 km and ≥ 50 km. A cut-off of 60 min was used to stratify patients into three groups by travel time – same city, < 60 min and ≥ 60 min. Overall survival in our patient population was significantly lower with increasing travel distance (p < 0.001, Mantel-Cox log rank) and travel time (p < 0.001, Mantel-Cox log rank). The 1-year OS rate according to travel distance was 27.1% in the same city group, 22.4% in < 50 km group and 20.5% in ≥ 50 km group (p < 0.001). The corresponding values for the 5-year OS rate were: 2.9%, 2.6% and 1.4% (p < 0.001). Conclusions: In this retrospective study we discovered significant differences in overall survival of patients with lung cancer depending on travel distance and travel time to the treating oncological facility. Despite having similar clinical and pathological characteristics (age, sex, stage at initial diagnosis, histologic subtype), the median overall survival was significantly lower in those subgroups of patients with a higher travel burden. [Table: see text]
Analysis of demographic characteristics and disparities of enrollment in cancer clinical research at the U.S. National Cancer Institute (NCI): A 15-year experience.
Authors: Choradia Nirmal , Gulley James L. , Floudas Charalampos S. 
Published: June 2022

6529 Background: Racial, gender, and socioeconomic disparities in cancer clinical trials participation have been well documented. The intramural program of the NCI in the National Institutes of Health (NIH) Bethesda campus conducts clinical research where participants are referred by their physician or self-referred, treated without charge and receive aid in travel expenses. We sought to describe the demographics of participants and identify potential disparities. Methods: We used the clinical research data repository of the NIH, Biomedical Translational Research Information System (BTRIS), to extract self-reported demographic data of enrollees in NCI protocols from 2005-2020. Comparisons were made with the U.S. population of patients with cancer as captured in the Surveillance, Epidemiology, and End Results (SEER) Program (2005-2018). The average household income per zip code was derived from the American Community Survey at five-year increments from 2011, 2015, and 2019. Results: We obtained data on 40,007 participants; 38,531 (95%) came from the U.S., of which 18,606 (48%) from DC, Maryland, or Virginia (DMV). Median age at consent was 54 years (range 2 – 89). Proportions of basic demographic attributes and corresponding values from SEER data were presented. Notably, Hispanic male, non-Hispanic female, and white female participants were under-represented in NCI clinical research compared to SEER data. African Americans were under-represented in the non-DMV population (5%) vs. the DMV (19%). Also, for patients from the DMV area, median income was consistently less for African American participants compared to White and Asian participants. Conclusions: The identified disparities may be partially due to the specific research activities available at the NCI, but strategies aiming at increasing the participation and representation of under-represented groups are required. [Table: see text]
Are pivotal clinical trials for lymphomas that led to drug approval representative of the population affected by these diseases?
Authors: Casey Mycal , Odhiambo Lorriane Achieng , Shoukier Mahran , Islam KM , Aggarwal Nidhi , Cortes Jorge E. 
Published: June 2022

6531 Background: There are significant inequities in cancer care and outcomes in the United States (US) and worldwide. Race, ethnicity, and sex all define sub-groups affected by these inequities. Randomized controlled trials (RCTs) provide new therapies in cancer care. Many new drugs have been recently approved for the management of lymphoma. We examined whether pivotal clinical trials included populations representative of those affected. Methods: Lymphoma clinical trials were collected from the US Food and Drug Administration (FDA) Databases ‘Oncology (cancer)/Hematologic Malignancies approval notifications’ and ‘Novel Drug Approvals’ between 2011 and 2021. Trials were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature related to the drug approval. Only studies for adult patients were included; one study was excluded due to inconsistencies in the total patients enrolled and the totals by race. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) RCTs were not included. The burden of diseases based on Surveillance, Epidemiology, and End Results (SEER) data was used as a comparison for US participants. Results: Thirty-three pivotal trials were identified from the FDA databases (2011-2021); 18 (54.5%) had available race data on CT.gov or in Primary Literature. Three trials focused on classical Hodgkin’s Lymphoma (cHL) and 15 on Non-Hodgkin’s Lymphoma (NHL). Two of the three trials for cHL with available data for race reported ethnicity data. Only 10 of 15 NHL trials that reported race demographics had available ethnicity data. Table 1 shows trials that had available data for race and ethnicity along with proportions from the SEER data. There was underrepresentation of Blacks and to some extent Hispanics in both cHL and NHL trials. Females were also underrepresented, particularly in NHL trials. Conclusions: There is racial, ethnic, and sex misrepresentation within clinical trials that led to approval of drugs for lymphomas in the US between 2011 and 2021. In addition, there was significant underreporting of racial and ethnic subgroups noted in the clinical trials.[Table: see text]