bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is aggregate use of published case reports as a viable option for augmenting pharmacovigilance? An applied example of pembrolizumab-related adverse events in patients with non-small cell lung cancer receiving first-line treatment.
Authors: Khabbaha Suad , Dempsey Sarah Carder , Anema Aranka , Singh Sonal , Thorlund Kristian 
Published: June 2023

e18840 Background: Pharmacovigilance suffers from considerable underreporting, and causality is rarely confirmed. We aim to examine the validity of the aggregate use of published case reports as a viable option for augmenting pharmacovigilance. We explore the setting of first line pembrolizumab treatment for non-small cell lung cancer as safety signals in this cohort are relatively well documented and because drug-related adverse events are more easily confirmed with no previous drug treatments. Methods: We compared immune-related adverse event rates (Any and Severe) associated with pembrolizumab from three select first non-small lung cancer KEYNOTE clinical trials (024, 042, and 189) to clinician confirmed pembrolizumab-related adverse event rates from a synthetic cohort case report data from a matching population. The latter were retrieved from the OpenCaseTM database and included 126 non-small cell lung cancer patients, of which 110 had received pembrolizumab monotherapy and 16 pembrolizumab in combination with a platinum-based chemotherapy regimen. Baseline characteristics with respect to age, sex, smoking history, non-drug treatment history, PD-L1 tumor proportion score, and key genetic markers (e.g. EGFR, ALK) were acceptably similar (results will be presented in a table). Results: In the synthetic cohort of case reports, Immune-related adverse events, which were clinician confirmed to be related to pembrolizumab, occurred in 86/126 (68.2%). Life threatening and severe treatment-related AEs were 7.4% and 65% respectively. These were substantially higher than reported in clinical trials 8.0%-9.7% experienced severe immune-related events. The majority of the most frequently occurring immune-related AEs in the KEYNOTE trials had similar reported proportions to the case reports. For example, hypothyroidism (any grade) ranged from 6.7% to 9.1% in the KEYNOTE trials compared to 4.9% among the case reports, and pneumonitis (any grade) ranged from 4.4% to 12.0% in the trials compared to 5.5% in the case reports. Other events such as myositis, type 1 diabetes, liver dysfunction, kidney injury, and colitis were frequent in the cohort of case reports (3.1%-7.9%), but rare or unreported in all KEYNOTE trials (0.0%-2.2%). Conclusions: Overall, adverse event rates in the synthetic cohort of case reports were either similar or higher than observed in clinical trials of matching populations. This observation provides rationale for utilizing case reports in pharmacovigilance practice, specifically for rarer events.
Impact of the COVID pandemic on reporting of breast cancer cases and mortality.
Authors: Khorfan Rhami , Namm Jukes P. , Vora Halley P , Solomon Naveenraj Livingstone , Lum Sharon S. 
Published: June 2023

e18842 Background: The National Cancer Database (NCDB) introduced COVID-specific variables in 2020 to assess the impact of the pandemic on cancer care. Variables include (1) any SARS-CoV-2 test and (2) SARS-CoV-2 test result. We evaluated patterns of breast cancer reporting and mortality compared to pre-pandemic. Methods: From the 2020 NCDB breast cancer participant user file, we separately examined reporting and mortality in the years 2017-2020. Pre-pandemic years (2017-2019) were used as a baseline to evaluate secular trends not related to the pandemic. For patients diagnosed in the study period, patient/hospital factors associated with complete reporting (CR) or no reporting (NR) of COVID variables were compared. For patients who died during the study period, yearly mortality rate and overall survival (OS) were examined overall and by stage. Patient/hospital factors were examined for associations with year of death. Results: Fewer breast cancer cases were reported in 2020 (232,023) compared to 2019 (268,210) and 2018 (260,259). In 2020, there were 97,810 (42%) with NR and 116,455 (50%) with CR of COVID variables. On multivariable analysis, patients with NR were more likely to be > 70 years old, of Asian race, with Medicare coverage, lower education quartile, and treated at community hospitals and those in the Middle Atlantic region. There were 60,933 deaths in 2020, 64,502 in 2019, 63,865 in 2018, and 61,930 in 2017. There were significantly fewer stage 4 deaths in 2020 compared to prior (Table). Although there was a steady trend of increasing OS across the 4-year period, the incremental increase from 2019 to 2020 was higher than expected based on previous years. This finding was particularly true for stage 4 patients (median OS: 31.4 months in 2020, 20.2 months in 2019). On multivariable analysis, 2020 mortalities were less likely in patients > 80 years old (OR 0.88, p < .01) or with stage 3 (0.81, p < .01) or stage 4 (0.64, p < .01) disease, and more likely at academic centers (1.05, p < .01) than in 2017-2019. Conclusions: Non-reporting of COVID data is not at random, and is more common in populations at risk. In addition, fewer breast cancer mortalities were reported in 2020, with higher than expected OS. These findings suggest that OS was artificially increased in 2020 due to underreporting of patients who may be at higher risk of mortality. Accurate and complete data is crucial for evaluating the pandemic's impact on patient care. Underreporting of patients who may be most vulnerable limits our ability to comment on the true impact of the pandemic. These limitations must be considered to avoid blind spots in evaluation of pandemic data and risk deepening disparities. [Table: see text]
Clinical characterization of patients with recurrent glioblastoma in trials involving CED and non-CED treatment.
Authors: Ensign Lisa G. , Boisvert Denis , LaFrance Norman David , Hendershot Jacob , Michalek Joel , Brenner Andrew J. , Davi Ruthanna 
Published: June 2023

e18845 Background: Glioblastoma (GBM) is the most common and aggressive of the primary malignant brain tumors in adults. Bevacizumab (beva) remains the only currently approved therapeutic for recurrent GBM (rGBM) patients who progress on prior therapy. Despite advances in care, rGBM has a median expected progression-free survival (PFS) of < 4 months and overall survival (OS) of ~8 months. NCCN guidelines [Version 2.2022], and other oncology medical societies unanimously recommend patients seek treatment by entering a clinical trial. Since the late 1990’s a number of studies have explored the use of convection-enhanced delivery (CED) of drugs, a well-accepted and widely published delivery option for the treatment of rGBM. This analysis compares the demographics, medical history and survival outcome of patients enrolled into recently completed clinical trials with beva monotherapy to those entered into CED studies. Methods: Data for this analysis was sourced from the Medidata Enterprise Data Store (MEDS), comprised of over 28,000 historical clinical trials for de-identified aggregate patient-level analyses and from the study and patient-level data in the CED studies referenced in D’Amico [J Neurooncol 2021]. Aggregate summary statistics comparing beva and CED patients were based on combined study- and patient-level data using weighted (by sample size) means, incidence and overall survival (OS) rates and median of medians. Results: 163 rGBM beva patients were identified from MEDS. The CED cohort included 636 patients from MEDS and studies referenced in D’Amico. Cohort comparisons (beva vs CED) found median age: 56 vs 55 years; Caucasian race: 91% vs 93%; male sex: 68% vs 65%; not Hispanic or Latino ethnicity: 90% vs 94%; median OS: 7.9 vs 8.4 months. Over the last 2 decades there was a 23% increase in patients with ECOG Performance Status = 0 and 25% decrease in tumor area size at study enrollment, whereas there was no clear temporal OS trend. Conclusions: Patient demographics and most tumor attribute variables were similarly distributed between the beva and CED cohorts. While there is some indication that recent CED studies have enrolled healthier patients with smaller tumors; as expected, this does not appear to have translated to a consistent survival benefit.
Association of cannabis use with real-world time to treatment discontinuation (rwTTD) in patients with advanced cancer initiating immune checkpoint inhibition (ICI).
Authors: Zylla Dylan M. , Knowlton Greg , Gilmore Grace , Pawloski Pamala A. , Salz Talya , Kulkarni Amit , Cowger Jordan , Kuranz Seth 
Published: June 2023

e18846 Background: Studies suggest that the immunomodulatory effect of cannabis may impair responsiveness to ICI in cancer patients. These studies were limited by small sample size in a heterogeneous group. Determining the impact of cannabis on cancer control in patients receiving ICI is critical to informing patients and clinicians. We assessed the relationship of cannabis with cancer treatment outcomes using a large national healthcare claims database linked to retail cannabis purchase data. Methods: Using the Forian Inc database from 2017-2022, we identified adults (age > 18 years) with advanced cancer who had ≥ 90 days of continuous health plan enrollment and received ≥ 1 ICI treatment. Point-of-sale purchase records from 18 state cannabis programs defined cannabis consumers (CC; any purchase prior to first ICI to last known follow-up) and cannabis non-consumers (CNC; no known cannabis purchases). We abstracted data on patient demographics, cancer history, cannabis utilization (dates of purchases, routes, strains), and all cancer-directed therapy claims. rwTTD was calculated from time of first ICI to a defining discontinuation event (change in therapy, gap of > 120 days, or end of enrollment in health plan). Results: From a database of nearly 68 million patients, 20,675 patients met the inclusion criteria (374 CC and 20,301 CNC). Baseline characteristics were similar between the two groups (e.g., age, diagnosis type, time to first ICI) (Table 1). Lung, melanoma and renal cancers account for nearly half of all identified diagnoses. By day 30 after ICI initiation, 45% of CC had made at least one cannabis purchase. Median time from advanced cancer diagnosis to first ICI and median follow up time were also similar (Table 1). The difference in median rwTTD between CC and CNC groups was small relative to the overall variation of this outcome (Table 1) and remained similar (88 days) when restricting analysis to CC with first purchase within 30 days of ICI. Conclusions: Cannabis use does not appear to be associated with rwTTD in advanced cancer patients initiating ICI. Formal statistical testing using inverse probability treatment propensity weighting and adjustment for confounding factors (opioids/glucocorticoids) to assess rwTTD and real-world overall survival is ongoing. Well designed, prospective cohort studies of CC and CNC are needed to minimize selection bias in studies of cannabis use. [Table: see text]
Safety of same day administration of pegfilgrastim in breast cancer patients.
Authors: Reynolds Kathryn , Katz Julia , Nabell Lisle , Grant Stefan C. 
Published: June 2023

e18850 Background: Myelosuppressive therapy plays a crucial role in the treatment plan of patients with cancer; one common toxicity associated with myelosuppressive regimens is neutropenic fever. Pegfilgrastim is approved for use no sooner than 24 hours after receiving cytotoxic therapy, based on the initial FDA indication, requiring a return to clinic or the use of a patented on-body injector placed at the time of treatment. However, alternative schedules assessing earlier administration were never examined in the FDA registration studies. Small studies have suggested that same-day administration of pegfilgrastim can be carried out safely, including a prior safety study at UAB. The present analysis sought to test the non-inferiority of same day pegfilgrastim compared to administration 24-72 hours after cytotoxic chemotherapy. Methods: We undertook a retrospective analysis of 241 breast cancer patients receiving cytotoxic therapy from May 2016 through October 2018. The patient population was predominately Caucasian women with 28% African American or Asian women, and a median age of 55 (33-81). I2B2 codes identified patients with breast cancer receiving adjuvant or neoadjuvant therapy patients receiving same day versus next day pegfilgrastim were compared. Blood counts, delays in therapy, and neutropenic hospitalizations were analyzed for same day versus 24-hour delayed pegfilgrastim at two separate institutions. Dose reduced metastatic regimens were excluded from this review. Results: We comparedthe rate of neutropenia resulting in dose-delay for breast cancer patients receiving standard chemotherapy with administration of pegfilgrastim on both schedules. Overall, neutropenia with fever resulting in delay of subsequent chemotherapy was similar in both groups with same day administration being non-inferior to the standard administration schedule. Other treatment delays due to non-neutropenic conditions included mucositis, port malfunction, COPD, fatigue, and transportation delays. Conclusions: Policies requiring 24-hour delays following chemotherapy for pegfilgrastrim administration, reduce utilization of biosimilars and make the on-body injector, Onpro, a more convenient, albeit expensive option, for patients and the health system. These data suggest that same day administration of pegfilgastrim are non-inferior to delayed administration and may provide both substantial cost savings and quality of life benefits to patients and health care systems by increasing utilization of biosimilars and removing the need for a return visit after chemotherapy. In addition, same day administration also reduces the risk of complications associated with on body injector use, where failure rates of up to 10% are reported.
Evaluating patient adherence and persistence to first-line tyrosine-kinase inhibitors for metastatic renal cell carcinoma.
Authors: Arter Zhaohui , Benjamin David Joseph , Cao Yen , Forsyth Michael , Thirumaran Ranjit , Farias Jorge , Rezazadeh Arash 
Published: June 2023

e18856 Background: Tyrosine kinase inhibitors (TKIs) have been approved in treating advanced renal cell carcinoma (RCC) since 2005. More recently, combination therapy with an immune checkpoint inhibitor (ICI) and a kinase inhibitor (TKI) is considered standard of care in the first-line setting of metastatic RCC. While oral neoplastic therapies such as TKIs promote patient autonomy, these therapies pose unique challenges including ensuring patients take medications as indicated (i.e., adherence) and for the recommended duration (i.e., persistence). Persistence and adherence data from prescription dispensing and refill patterns are important to health care providers, systems, and payers in order to assess and/or optimize the therapeutic goal(s) of anticancer treatment. Therefore, we sought to explore adherence and persistence of first-line TKIs when used in combination with ICIs for treating metastatic RCC. Methods: Adults with metastatic RCC who received at least two prescriptions for FDA-approved TKIs used in combination with ICIs between April 29, 2019 and August 29,2022 were identified at University of California Irvine Medical Center. Adherence was determined by calculating the Medication Possession Ratio (MPR) and the Proportion of Days Covered (PDC). TKI persistence was evaluated using the Kaplan-Meier method. Also evaluated was the average length of therapy. We examined additional dispensing and refill pattern indicators, including the monthly total number of prescriptions filled. Results: A total of 66 individuals and 849 prescriptions were discovered. The mean duration of treatment for all patients was 237 days, and the median duration was 201 days (Table 1). The mean persistence was 303 days, whereas the median persistence was 233 days. Over 180 days, the median MPR was 83%, whereas the median PDC was 72%. The median variable PDC was 86%, while the median variable MPR was 105%. September was historically the month with the lowest prescription counts (16 +/- 2). Conclusions: We observed a significantly longer median duration of oral TKIs therapy (201 days) in an academic medical center than the national average ( < 100 days). This analysis of real-world data reveals that lengthier treatment durations for TKI+ICI combinations are feasible. Further research is warranted to identify possible factors such as clinical monitoring or adverse effect management that may prolong adherence and persistence. [Table: see text]
Correlation of survival in colorectal cancer with tumor mutational burden and mutations identified by next-generation sequencing.
Authors: Taflin Nicholas , Sandow Lyndsey , Thawani Rajat , Kardosh Adel , Corless Christopher L. , Chen Emerson Yu-sheng 
Published: June 2023

e18861 Background: Next-generation sequencing (NGS) can identify specific mutations and molecular abnormalities such as high tumor mutational burden (TMB), defined as 10 or more mutations per megabase. Immune checkpoint inhibitors (ICI) have been approved for all solid tumors with high TMB, including colorectal cancer (CRC), though studies have been inconclusive regarding prognosis of high TMB as well as the efficacy of ICI’s in treating CRC specifically. We aimed to use data collected from next-generation sequencing (NGS) of CRC at our institution to correlate survival to TMB, correlate survival to presence of mutations of interest, and to investigate efficacy of ICI in this patient population. Methods: This was a retrospective cohort analysis of patients at a single institution, analyzing NGS of patients who were identified as TMB-high and microsatellite stable (MSS) (n = 161) from January 20218 to December 2020.Demographics, clinical-pathological factors, and NGS results were extracted along with clinical outcomes. We conducted a survival analysis looking at TMB status and selected mutations of interest. A descriptive subset analysis of the patients who underwent treatment with immunotherapy was performed. Results: Patients with high TMB MSS CRC trended to have worse survival with a HR of 1.45, though this was not significant (p = 0.22). Median survival for high TMB patients was 28.1 months and was 77.5 months for non-high TMB. Analysis of NGS revealed 112 unique mutations, with TP53 (82.0%), APC (80.1%), and KRAS (43.5%) occurring the most frequently. Patients were found to have statistically significant worse overall survival with KRAS (HR = 1.81, p = 0.023), CDKN2A (HR = 4.81, p = 0.0002), RB1 (HR = 2.83, p = 0.047), and SMAD4 (HR = 1.858, p = 0.039) mutations. Twelve patients underwent treatment with ICI with nine patients having between 0.7 to 4.1 months of progression-free survival (PFS) and three patients with long PFS of 13.2, 24.7, and 26.3 months. The two patients with the longest PFS were not high TMB. Conclusions: Presence of high TMB in MSS CRC did not show a statistically significant difference in outcome. Presence of KRAS, CDKN2A, RB1, and SMAD4 correlated with significantly worse prognosis. Treatment with ICI’s was effective in some CRC patients though survival did not correlate with high TMB. There is a need to identify a marker beyond TMB which better indicates which patients with MSS CRC will have good response to ICI therapy.
Association of weight loss with risk of myelodysplastic syndromes (MDS) in adults with obesity: Insights from the SPLENDID cohort.
Authors: Mishra Rahul , Wilson Rickesha , Tu Chao , Milinovich Alex , Carraway Hetty E , Abraham Jame , Aminian Ali , Singh Abhay 
Published: June 2023

e18865 Background: MDS arises from pre-existing somatic mutations or clonal hematopoiesis (CH). A normal body mass index (BMI) is strongly associated with a lower prevalence of CH. We hypothesized that intentional weight loss (IWL) might be associated with lower incidence of MDS and studied this in the context of bariatric surgery (BSx) among adults with obesity. Methods: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adults with BMI ≥35Kg/m2 who had BSx (ages 18-80) during 2004-2017 were included. Each patient (pt) who underwent BSx was matched with propensity score by the nearest-neighbor method to five pts who did not undergo BSx for their obesity, resulting in a total of 30318 pts. MDS diagnosis was made using contemporary WHO criteria and myeloid sequencing mutation data were analyzed. Multivariable cox regression analysis estimated time to MDS as the primary endpoint. Results: 5053 adults with obesity had BSx while 25265 adults underwent nonsurgical (NS) care. Median age and BMI were 46 years (y) and 45kg/m2. The majority were females (77%); and had white (73%) race. Follow-up was over 17y period with median (IQR) of 6.1 (3.8-8.9)y for the entire cohort. BSx-group had 19.2% greater WL at 10-y [mean between-group difference: 24.8 (95% CI, 24.6-25.1) kg]. One patient (male) in the BSx-group vs twenty-four patients (twelve females) in the NS-group developed MDS (incidence rate: 0.03 vs 0.14, per 1000 person-years). A fully adjusted hazard ratio was 0.14 (95%CI 0.02-1.14), which did not reach conventional level of statistical significance (p = 0.066) due to small number of events. A third of MDS pts had high-risk disease per IPSS-R prognostic score (7/20 evaluable pts). 10 (of 11 NS MDS pts with available NGS data) pts had ≥1 nonsynonymous mutations and most pts (6/11) harbored multiple [Median (IQR): 2 (1-3)] high-risk mutations despite a younger median age of the cohort. Conclusions: In this large cohort of adults with obesity, we observed a lower incidence of MDS after IWL achieved with BSx. Higher prevalence of high-risk-MDS mutations in a relatively young NS-cohort with obesity warrants further investigation of effects of IWL on clonal evolution, its clinical relevance, and role of screening in halting progression of CH to MDS via early detection and targeted intervention. [Table: see text]