bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spectrum and characteristics of germline PALB2 pathogenic variants among patients with early-onset breast cancer in China.
Authors: Li Jing , He Peng , Cai Qindong , Chen Lili , Wang Yali , Cai Weifeng , Qiu Yibin , Guo Wenhui , Chen Minyan , Lin Yuxiang , Wang Chuan , Fu Fangmeng 
Published: June 2024

e22536 Background: Partner and localizer of BRCA2 ( PALB2) plays a critical role in homologous recombination repair and recognized as a breast cancer predisposition gene. Early age at onset of breast cancer is considered a hereditary high-risk factor. However, limited information is available about early-onset breast cancer in China. The objective of this study was to investigate the spectrum and characteristics of germline PALB2 pathogenic variants among this population. Methods: A total of 1556 patients with BRCA1/2-negative early-onset breast cancer were included. Peripheral blood samples were collected and all coding regions and exon‒intron boundaries of the PALB2 genes were screened through next-generation sequencing. Results: The prevalence of germline PALB2 pathogenic variants was approximatel 0.77% in entire cohort. Eleven PALB2 pathogenic variants were identified in twelve participants, including five frameshift mutations, four nonsense mutations and one missense mutation. Except for PALB2 c.1056_1057del, which was detected twice, all other variants were detected once. In comparison to non-carriers, PALB2 carriers were more likely to be 30 years old or younger (25% vs. 14.4%), have a positive family history of breast or ovarian cancer (16.7% vs. 6.3%), exhibit metastatic lymph nodes (75% vs. 50.9%), belong to human epidermal growth factor receptor-2 (HER2) -negative and hormone receptor (HR) - positive subtype (75% vs 54.2%), and diagnosed with invasive micropapillary carcinoma (16.7% vs 3.1%). Conclusions: The prevalence of the germline PALB2 pathogenic variants is approximately 0.77% in BRCA1/2 mutation-negative early-onset breast cancer patients in China. Our findings contribute additional insights into the spectrum and characteristics of PALB2 pathogenic variants in Chinese early-onset breast cancer patients, providing valuable information for this population. Key words: PALB2, Germline mutation, Genetic sequencing, early-onset breast cancer, China. [Table: see text]
The value of blinded independent central review (BICR) in recent trials in non-small cell lung cancer (NSCLC).
Authors: Edelman Martin Joseph 
Published: June 2024

e23000 Background: Progression free survival (PFS) is an endpoint that has been increasingly used to obtain approval of new cancer drugs and strategies. However, there are a number of issues that can complicate assessment of PFS. One of these is the potential for investigator bias. This has been addressed by the use of blinded independent central review (BICR). However, BICR increases costs and complexity. Methods: The current study evaluated the results of BICR versus investigator assessment (IA) for phase III randomized clinical trials in thoracic oncology with initial publication from 1.01.2013-12.31.2023. Trials were included if they involved targeted agents, antibody drug conjugates or immunotherapy. Studies with < 100 pts or comparing only cytotoxic chemotherapy or maintenance strategies were excluded. Studies with cytotoxic chemotherapy as part of therapy or within the control arm were included. A search of clinicaltrials.gov with the terms “phase III”, “non-small cell lung cancer” for completed studies was done, supplemented by a bibliographic search. Publications were then reviewed for whether a BICR was utilized and whether both BICR and IA were reported. Hazard Ratios (HR) for PFS between IA vs BICR were compared. Results: 49 randomized phase III trials were identified of which 34 describe BICR of which 21 reported both IA and BICR results. Six studies evaluated immunotherapy and enrolled 3337 pts, 15 evaluated targeted agents and enrolled 6531 pts. All immunotherapy studies were significantly positive for the experimental arm and 14 of 15 of the targeted therapies were positive. PFS data was reported for 17 of the studies (not reached for experimental arms in 2 and not reported in 2 others). HRs were directionally similar in all studies, though were lower (more favorable) in IA vs BICR in 5 of 6 immunotherapy studies and 11 of 15 targeted therapy studies. The mean % difference for immunotherapy studies was 8.9% and the median 10%, range 2-23.5%. For the positive targeted therapies studies the mean/median differences were 14.6%/15.6%, range 1.5-42%. The largest % differences were seen at the lowest HRs (e.g..19 vs .27; 42%). For immunotherapy studies, the median PFS difference was 0.2 and 0.28 months for the control and experimental arms, respectively. For targeted therapy studies, median PFS differences were 0.4 and 0.95 months for the control and experimental arms, respectively. The studies were performed in multiple countries including the United States, European Union, China and Japan. Conclusions: Despite a wide range of agents and settings, no trial for which information is publicly available comparing BICR to IA has demonstrated any qualitative difference in outcome nor more than a marginal numerical difference.
Heterogeneity in methods for estimating renal function in anticancer drug development.
Authors: Karol Alexander B. , Fujiwara Yu , Paredes Rodrigo , Argulian Anna , Joshi Himanshu , Galsky Matt D. 
Published: June 2024

e23002 Background: Accurate assessment of renal function is critical in oncology clinical trials. Many anti-cancer agents are renally excreted or cleared, and impaired kidney function can significantly impact drug safety and efficacy. In an effort to modernize renal eligibility criteria the American Society of Clinical Oncology–Friends of Cancer Research Organ Dysfunction Working Group recommended that if renal toxicity and clearance are not of direct treatment-related concern, then patients with impaired renal function should be included in trials (Lichtman, JCO, 2017). However, a diversity of approaches are available to determine renal function. Methods: We systematically searched the clinicaltrials.gov database to review renal eligibility criteria for phase III clinical trials. These trials evaluated systemic anti-cancer therapies in adult patients between October 28th 2013, and October 28th 2023. Studies were excluded if they did not include eligibility criteria related to renal function. The demographics of the trials and methods used for estimating renal function were recorded. Results: 436 trials met criteria for review and 231 trials, enrolling 111,424 patients, met our inclusion criteria. Systemic therapies explored included: immunotherapy (98 trials, 42%), targeted therapy (110 trials, 48%), chemotherapy (17 trials, 7%) or other regimens (6 trials, 3%). Renal function exclusion criteria are shown in the Table. Among studies that estimated renal function with a formula, 140 (61%) studies used Cockcroft-Gault, 3 (1%) used Modification of Diet in Renal Disease, 9 (4%) used an institutional standard, 10 (4%) used a heterogenous combination of estimation equations, and 69 (30%) trials did not specify the estimation approach. Conclusions: In phase III clinical trials involving adult cancer patients, there is substantial heterogeneity in methodologies utilized for determining renal function as related to trial eligibility. Harmonization of approaches to estimate renal function in oncology trials may improve trial accessibility, generalizability, and comparability. [Table: see text]
Precision oncology clinical trials: A systematic review of phase II clinical trials with biomarker-driven, adaptive design.
Authors: Lee Hee Yeon , Ha Hyerim , Kang Jin Hyoung , Park Hye-Sung 
Published: June 2024

e23005 Background: Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. Methods: We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Results: Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration’s marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Table. Precision Oncology Trials led to the FDA approval. Conclusions: Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs’ efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape. [Table: see text]
Uptake of recommendations for broadening clinical trial eligibility criteria for patients with brain metastasis and leptomeningeal disease in lung cancer clinical trials: A systematic review.
Authors: Riano Ivy , Velez Maria Antonia , Pomares-Millan Hugo , Velazquez Manana Ana I. 
Published: June 2024

e23007 Background: Brain metastasis (BM) in patients with lung cancer are relatively frequent (~20%). Clinical trials (CTs) often exclude patients with BM due to concerns about life expectancy, functional status, and toxicity. Restrictive eligibility criteria deter patients with BM from receiving investigational treatments that may be beneficial. In 2017, ASCO, Friends of Cancer Research (FoCR), and the US FDA recommended to expand eligibility criteria to assist in design more representative trials. We examined the uptake of these guidelines in BM/leptomeningeal disease (LMD) inclusion criteria among registered lung cancer CTs. Methods: We extracted eligibility criteria of US-based, phase I/II/III interventional CTs for patients with metastatic lung cancer registered in ClinicalTrials.gov between 10/2012 to 01/2024. CTs registered one year within ASCO/FoCR/FDA published their recommendations were excluded. For each trial, two independent reviewers screened eligibility criteria and classified patients with BM as fully included (active/untreated disease), partially included (treated/stable disease), or excluded, and LMD as included or excluded. Discrepancies were resolved by a third reviewer. Fisher’s exact tests and odds ratio (OR) were obtained by logistic regression. Results: Among 307 CTs, patients with BM were partially included in most CTs (228, 74.3%), excluded in 9 (2.9%) and not mentioned in 35 trials (11.4%). Patients with active BM were included in 35 trials (11.4%). The use of steroids was accepted in 69 trials (22.5%). Only 18 trials (5.8%) included patients with LMD. Most patients with LMD were excluded (135, 44.0%) or not mentioned as criterion (154, 50.2%). A statistically significant difference was observed in the inclusion of patients with BM pre- vs post-recommendations ( p= 0.046). Yet, there was not significant difference in trials with active BM and LMD pre- vs post-recommendations. CTs including patients with active BM or LMD were more likely to appear in CTs explicitly measuring central nervous system outcomes (OR = 4.3; p= 0.002; OR = 14.3; p= 7e-5, respectively). Conclusions: Although existing recommendations to broaden CTs eligibility criteria to include patients with BM showed a significant change, patients with active BM and LMD remained excluded from lung cancer trials. Designing CTs including patients with active BM/LMD is likely to improve patient accrual, increase access to clinical trials and further characterize the investigational drug’s safety and efficacy in this patient population. Exclusion criteria should be clearly justified, and expected toxicity should be reflected in the rationale. As new targeted therapies emerge in lung cancer realm, eligibility criteria should be modernized to fit patients who will be using novel therapies once they are available.
MetaAnalysisOnline.com: A new easy-to-use bioinformatic tool for the meta-analysis of clinical trials.
Authors: Gyorffy Balazs , Fekete Janos Tibor 
Published: June 2024

e23012 Background: A meta-analysis is a formal, quantitative study design in epidemiology and clinical medicine that systematically assesses and consolidates previous research findings to derive comprehensive conclusions on a specific topic. Here, we aimed to establish a new tool for the visualization options useful for conducting a meta-analysis specifically designed for oncology trials. Methods: A meta-analysis can be based on binary data, continuous data, or time-to-event data. The most crucial statistical models, including the random effect model and the fixed effect model, are outlined alongside their respective statistical methods. Furthermore, we implemented graphical representations such as the forest plot, funnel plots, and Z-scope plots. While the forest plot effectively illustrates heterogeneity and pooled results, a funnel plot can reveal potential publication bias, and a Z-score plot shows the robustness of the used sample number. Results: The models and visualization options outlined have been integrated into a new, online web portal which can be accessed without the need for registration. The web application operates on an Ubuntu server running Apache and enables users to conduct meta-analyses using results typically used in oncology trials including binary (total and event numbers), continuous (mean and standard deviation data), and time-to-event data (hazard rate and CI data). Study results from common spreadsheet applications like Excel can be directly input into the system. The online platform utilizes the meta and metafor packages in the R programming environment (R version 4.2.2) for calculations and plots. The Shiny user interface is powered by shinyjs, shinydashboard, and rhandsontable R packages. The portal generates a forest plot to summarize meta-analysis results, a funnel plot for visual detection of potential bias, and a Z-score plot showing the sufficiency of the cumulative sample number. The analysis results of the tool were validated using IBM SPSS v28. The new bioinformatic tool is available at www.metaanalysisonline.com and requires no programming knowledge or command line use. Conclusions: Our platform aims to provide a user-friendly meta-analysis tool for epidemiological studies and oncology clinical trials, offering a swift and reproducible way to integrate the results from multiple studies.
Reduced time to efficacy signals in advanced cancer trials using Chauhan weighted trajectory analysis.
Authors: Chauhan Utkarsh , Mackey Daylen , Mackey John Robert 
Published: June 2024

e23028 Background: As Kaplan-Meier (KM) analyzes single unidirectional endpoints, most advanced cancer randomized clinical trials (RCTs) are powered for a 10 endpoint of either progression free survival (PFS) or overall survival (OS). This disregards efficacy information carried by stable disease (SD), partial response (PR), and complete response (CR) that may precede progressive disease (PD) and death. Chauhan Weighted Trajectory Analysis (CWTA), a generalization of KM, permits simultaneous evaluation of multiple rank ordered endpoints. We hypothesized that using CWTA with all efficacy inputs could expedite RCT efficacy signals. Methods: We performed 100-fold simulations of RCTs in advanced cancer and determined the time to first significant efficacy signal (p < 0.05) for KM PFS and OS (logrank test) and CWTA (weighted logrank test). RCTs were stochastically generated at defined sample size (SS) allocated 1:1 to control or intervention and run for 60 months. Rank ordered health statuses were CR = 0, PR = 1, SD = 2, PD = 3, and Death = 4. All patients we assigned SD at time 0 and, each month, were capable of response (PR then CR), maintained SD, or irreversible exacerbation to PD or Death. Event probabilities were modified between groups as defined by a hazard ratio (HR). We modeled a control group CR rate of ~10% and a PR rate of ~50% to reflect first-line advanced cancer RCTs with a dropout rate of 10% over 60 months. At increments of SS and HR, we determined the mean and standard deviation of time-to-efficacy signals. Results: CWTA markedly reduced the time-to-efficacy signals when compared to KM PFS (23% to 67%) and KM OS (43% to 82%) (Table 1). Conclusions: CWTA, by incorporating the entirety of the cancer trajectory including disease response, progression, and death, meaningfully expedites the efficacy signals of cancer treatments compared to KM PFS and OS. We have previously reported CWTA increases trial power and reduces sample size requirements (Chauhan U, Zhao K, Walker J, Mackey JR; 2023. DOI: 10.3390/biomedinformatics3040052). Using CWTA rather than KM reduces trial duration, cost, and numbers of patients needed to evaluate therapies in advanced cancer, while reducing the regulatory risk inherent in powering a trial for a single KM primary endpoint. [Table: see text]
Compliance with Centers for Medicare & Medicaid Services (CMS) 2021 price transparency requirements among proton therapy centers.
Authors: Feder Noah Maxwell , Cargill Kasey , Wilhite Tyler , Skinner Heath Devin , Mowery Yvonne Marie , Wilke Christopher 
Published: June 2024

e23034 Background: Since 2019, the Centers for Medicare & Medicaid Services (CMS) has required hospitals to publish gross charges for all goods and services provided. In 2021, CMS amended this requirement to include publishing standard charge files, which include cash and payer-negotiated prices for all goods and services provided. This was enacted in an attempt to reduce healthcare prices by reducing information asymmetry and generating competition among both insurers and hospitals. Since complex proton therapy is one of the most expensive modalities of cancer treatment, we aimed to determine proton therapy center compliance with CMS price transparency requirements. Methods: We searched for online standard charge files for the 44 proton therapy centers in the United States. To assess compliance with the nine CMS price transparency criteria, we obtained prices for proton therapy using keyword searches and billing code 77525, the CPT code for the per fraction technical charge billed for complex proton treatment delivery. Results: Out of 44 operating proton therapy centers, 5 (11.4%) are free-standing private practice centers that are not affiliated with a hospital system, and thus not required to publish standard charge files per CMS policy. Of the 39 centers required to publish, 39 (100%) published their standard charge files free of charge with appropriately named files, thus meeting Criteria 1-3. Twenty-seven (69.2%) centers met Criteria 4 by including data on complex proton therapy (CPT code 77525) and Criteria 5a by including the gross charge for the service. One (2.6%) center partially met Criteria 4. Seventeen (43.6%) centers included negotiated prices for commercial insurers, thus meeting Criteria 5b, while 3 (7.7%) partially met this criterion. Twenty-two (56.4%) centers met Criteria 5c and 5d by including the deidentified minimum and maximum negotiated commercial prices, respectively. Twenty-six (66.7%) centers met Criteria 5e by listing the cash price for complex proton therapy, which is typically paid out-of-pocket by patients. One (2.6%) center partially met Criteria 5c-e. In total, 17 (43.6%) out of 39 proton therapy centers were in complete compliance with the 2021 CMS price transparency requirements. Conclusions: In summary, 17 out of 39 eligible proton centers were fully compliant with the 2021 CMS price transparency requirements in regard to complex proton radiation therapy. This suggests that deficiencies exist among hospital compliance and the CMS review process used to identify non-compliance. Future directions are aimed at expanding this analysis to include evaluation of proton center compliance with other billing codes, such as simple and intermediate proton treatment delivery. [Table: see text]
COVID vs. non-COVID oncology patient cohorts: Demographics and cancer variables.
Authors: Sajith Bilja Kurian , Cesario Sandra K. , Fadol Anecita P. , Fredland Nina M. , Dello Stritto Rita A. , Day Lakeisha R. , Reddy Dereddi Raja , Nates Joseph ,   D3CODE Team
Published: June 2024

e23046 Background: This study aimed to compare demographics and cancer-specific variables in oncology patients hospitalized with (n = 551) and without COVID-19 (n = 3674) during the first year of the pandemic. Methods: We analyzed prospectively collected data from March 2020 to February 2021 at a major US cancer center, comparing age, sex, cancer category, race, metastasis, treatments within one month prior to admission, and smoking history. Results: The study found no significant difference in mean age between COVID and non-COVID cohorts (60.7% vs. 60.9%; p = 0.830). Significant differences (p = 0.002) in cancer categories were noted between COVID and non-COVID cohorts. Hematological cancers had the highest hospitalization rates in both groups (38.8% vs 29.2%). Statistically significant racial differences were observed between COVID and non-COVID cohorts (p < 0.001). Whites had the highest hospitalization rates in both groups, yet COVID-related admissions were lower for Whites (COVID cohort: 51.2% vs non-COVID cohort: 61.9%) and Asians (COVID cohort: 2.7% vs non-COVID cohort: 5.9%) compared to non-COVID admissions, while higher for Blacks (COVID cohort: 15.4% vs non-COVID cohort: 14%) and Hispanics (COVID cohort: 28.3% vs non-COVID cohort: 15.7). Significant differences (p < 0.001) were noted in metastasis prevalence between COVID and non-COVID hospitalizations, with rates of 81.3% and 86.0%, respectively. Conversely, non-metastatic cancer was more prevalent in COVID hospitalizations (18.1%) than in the non-COVID cohort (8.7%). In the COVID cohort, 30.5% received chemotherapy within one month before admission, compared to 43.8% in the non-COVID cohort, showing a significant difference in admission rates (p < 0.001). Similarly, recent immunotherapy (8.0% vs. 10.9%) and recent surgery (3.6% vs. 6.6%) were associated with higher hospitalization rates in the non-COVID cohort (p = 0.046 and p = 0.010, respectively). We observed significant differences (p < 0.001) in the smoking history of the COVID and. non-COVID cohorts. While 2.5% of COVID patients were current smokers, 5.4% of non-COVID patients were, more than double the COVID rate. In the COVID cohort, 36.3% were former smokers, slightly lower than the 37.6% in the non-COVID cohort. Additionally, 59.3% of COVID patients were never smokers, compared to 56.3% in the non-COVID group. Conclusions: COVID-related admissions were lower for Whites and Asians compared to non-COVID admissions, while higher for Blacks and Hispanics. Lower rates of metastasis were noted in COVID cohort. Lower rates of hospitalizations among patients who received chemotherapy, immunotherapy, and surgery were observed in the COVID cohort. The smoking prevalence was higher in the non-COVID group, former smoking rates were similar across cohorts, and a higher proportion of COVID patients were never smokers.