tbuckley/cabot-search huggingface dataset:
Use of brain radiotherapy as part of first course of treatment for NSCLC with de novo brain metastasis.
Authors: Rafael Arteta-Bulos, Nadeem Bilani, Leah Elson, Elizabeth Blessing Elimimian, Diana Saravia, Mihir Naik, Zeina A. Nahleh, Evan W. Alley
Journal: Journal of Clinical Oncology (2021)

9118 Background: Loco-regional management of brain metastases from non-small cell lung cancer (NSCLC) are surgery and/or brain radiotherapy, either whole brain (WBRT) or stereotactic (SRS). We used a national registry to evaluate trends in the use of brain radiotherapy as part of the first course of management in patients diagnosed with de novo brain metastasis. Methods: We retrospectively analyzed the National Cancer Database (NCDB) to identify patients with NSCLC and de novo brain metastasis diagnosed from 2004-2016. We described the socio-demographic and clinical characteristics of this population, then used chi-squared testing to evaluate for an association between these variables and the use of brain radiotherapy (either SRS or WBRT). Significant variables (p &lt; 0.05) were included in a multiple logistic regression model. Results: Of n = 41,454 patients with NSCLC and de novo brain metastasis, n = 27,949 (67.4%) received either SRS or WBRT as part of their first course of treatment, while n = 13,505 (32.6%) did not receive primary brain radiation. Of those that did not receive radiation: n = 9,927 (73.5%) were &lt; 70 years old while n = 3,578 (26.5%) were ≥70. N = 11,081 (82.7%) were White, n = 1,550 (11.6%) were Black and n = 768 (5.7%) were Asian. Variables significantly associated with the use of primary brain radiotherapy at the multivariate level were: treatment facility type (p = 0.004), tumor histology (p &lt; 0.001), clinical T-staging (p &lt; 0.001), and clinical N-staging (p &lt; 0.001). Age, sex, race, comorbidity, grade, insurance status, and setting (metro vs. rural vs. urban) were not significantly associated with the use of radiotherapy. Compared to patients treated at community cancer programs (CPs), those treated at comprehensive community CPs (OR 1.152, 95% CI 1.027-1.291, p = 0.015) and academic CPs (OR 1.242, 95% CI 1.104-1.398, p &lt; 0.001) were more likely to receive primary brain radiotherapy. Patients with squamous NSCLC were less likely (OR 0.680, 95% CI 0.619-0.747, p &lt; 0.001) to receive brain radiotherapy compared to those with adenocarcinoma. Finally, patients with advanced T-staging (p &lt; 0.001) and N-staging (p &lt; 0.001) were less likely (OR &lt; 1) to receive brain radiotherapy as part of the first course of treatment. Conclusions: While insurance status and setting were not significantly associated with the use of brain radiotherapy, facility type was. Further research is needed to evaluate whether this is a true disparity in medical practice, or the differences can be explained by characteristics of the patient population undocumented by the NCDB (e.g. severity of brain metastasis). Additionally, patients with larger primary tumors were less likely to receive brain radiation as part of the first course of treatment, which may reflect the need for local therapy prior to treating metastatic sites.
Comprehensive molecular pharmacodynamic assessment identifies response markers of intermediary metabolism associated with BPM 31510-IV treatment in advanced glioblastoma multiforme patients.
Authors: Seema Nagpal, Rangaprasad Sarangarajan, Can Bruce, Greg M Miller, Leonardo O Rodrigues, Punit Shah, Richard Searfoss, Kennedy Ofori-Mensa, Vladimir Tolstikov, Bennett Greenwood, Valerie Bussberg, Michael A. Kiebish, Elder Granger, Niven R. Narain, Lawrence David Recht
Journal: Journal of Clinical Oncology (2021)

2059 Background: BPM 31510-IV is a drug-lipid conjugate nanodispersion containing oxidized Coenzyme Q10 (CoQ10) in clinical development for glioblastoma multiforme (GBM). In a recently concluded Phase 1 study of BPM 31510-IV (NCT03020602), in addition to safety and tolerability, longitudinal pharmacodynamic samples (20 samples/cycle of 28 days) were collected at various times in patient’s refractory to radiation, temozolomide, and bevacizumab. Methods: Comprehensive multi-omic (proteomic, lipidomic, metabolomic) profiles were generated from buffy coat (proteomics only), plasma, and urine matrices. These data were further analyzed using bAIcis, a Bayesian statistics based artificial intelligence (AI) software, creating causal networks linking clinical information and endpoints to molecular composition of diverse biomatrices of patients prior to, as well as during, treatment with BPM 31510-IV. Twelve subjects comprised the intent to treat population (ITT) which were stratified across days of treatment (DR1; ≤28 days; DLT period; n=6) and (DR2, OS; &gt;28 days; n=6). Bayesian networks and regression analysis were performed on the outputs of the analysis. Molecular analyte panels (combination of proteins, lipids, and metabolites) descriptive of progression free survival (PFS), adverse events (possibly/probably related to BPM 31510-IV), and of overall survival (OS) were generated. Results: Significant alteration (p&lt;0.05) of metabolically associated protein and critical metabolite drivers of intermediary metabolism were identified as causally related to PFS. Significant quantitative changes in levels of several proteins (buffy coat) and metabolites (urine) were identified with probable or possible associations to adverse events in BPM 31510-IV treated subjects. Conclusions: Overall, alterations in proteins and metabolites influencing mitochondrial function and intermediary metabolism that differentiated responders versus non-responders and identified potential markers of adverse events associated with BPM 31510-IV exposure were identified and will be further explored for complementary diagnostic utility.
FDA approves controversial Alzheimer’s drug despite uncertainty over effectiveness
Authors: Elisabeth Mahase
Journal: BMJ (2021)

The US Food and Drug Administration (FDA) has approved aducanumab (Aduhelm)—a drug which aims to delay clinical decline in patients with Alzheimer’s disease—despite concerns over a lack of evidence.1

The treatment—which costs $56 000 (£40 000; €46 000) per year per patient—was approved through the accelerated approval pathway. This is used when there are uncertainties over the drug’s efficacy but it’s believed it could provide “meaningful therapeutic benefit over existing treatments” for serious or life threatening illnesses. As part of this approval, the manufacturer must conduct post-approval studies—known as phase IV confirmatory trials—to “verify the anticipated clinical benefit.” If these trials do not verify the anticipated benefit, the FDA can remove the drug from the market. The FDA did not specify which patients are eligible for treatment with aducanumab. 

Aducanumab has been tested in two phase …
Use of neoadjuvant chemotherapy in elderly patients with muscle invasive bladder cancer: A population-based study, 2006 to 2017.
Authors: Natasza Posielski, Nathan Jung, Hannah Koenig, On Ho, John Paul Flores, Christopher Porter
Journal: Journal of Clinical Oncology (2021)

4536 Background: Current guidelines recommend neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC). NAC has been shown to confer a survival benefit across all ages. Yet, many elderly patients are not offered NAC due to concern regarding physiologic reserve and postoperative complications. Our objective was to evaluate age-based disparity in treatment and outcomes of MIBC. Methods: Using the National Cancer Database, we identified patients with MIBC from 2006-2017. First, use of different treatments, RC, RC and adjuvant chemotherapy, RC with NAC (“optimal treatment”), chemo-radiation, and no treatment, was compared between age groups. A second analysis was performed in the cohort of elderly patients, ≥70, undergoing cystectomy. Propensity weighting was used to compare peri-operative and mortality outcomes in those who received NAC vs. no NAC. Results: In 70,911 patients with non-metastatic MIBC, use of RC with NAC was lower in patients ≥70, 7.2 vs. 20.9%, p&lt;0.001 (Table). Patients receiving RC with NAC were younger, had private insurance, higher high school completion rate and median income, shorter distance to hospital, lower CCI, diagnosis in recent years, and higher stage disease. NAC use was also associated with pelvic lymph node dissection (OR 4.55, p&lt;0.001). In patients ≥70 undergoing RC, NAC was associated with shorter length of stay (LOS) (8.5 vs 9.6 days, p&lt;0.001), decreased 30-day readmission (8.6 vs 10.6%, p=0.003), lower 30- and 90-day mortality (1.9 vs 3.6%, p=0.01 and 4.9 vs 7.7%, p=0.004, respectively), and better overall survival (OS) (43.8% vs. 37.5%, p&lt;0.001). Multivariate logistic regression found NAC as an independent predictor of shorter LOS, lower 30-and 90-day mortality, and improved OS. Conclusions: Despite increased omission of NAC in patients ≥70, NAC is not associated with worse peri-operative outcomes or mortality in elderly patients. Advanced age in properly selected patients should not preclude offering NAC prior to radical cystectomy.[Table: see text]
Clinicopathologic and genomic correlates of tumor-infiltrating immune cells and immunotherapy efficacy in NSCLC.
Authors: Joao Victor Machado Alessi, Biagio Ricciuti, Mizuki Nishino, Jason L. Weirather, Ann-Elisabeth Le, James Lindsay, Bijaya Sharma, Kristen Felt, Lynette M. Sholl, Scott J. Rodig, Mark M. Awad
Journal: Journal of Clinical Oncology (2021)

9121 Background: Tumor-infiltrating immune cells and PD-L1 expression are associated with improved clinical outcomes in patients (pts) with NSCLC treated with immune checkpoint inhibitors (ICIs). However, as tumor-infiltrating immune cells are not a well-established biomarker for NSCLC, further data are needed to integrate and identify clinicopathological and genomic factors that influence the tumor microenvironment. Methods: We collected clinicopathologic and genomic data from pts with NSCLC who underwent multiplexed immunofluorescence. Uniform Manifold Approximation and Projection (UMAP) was used to identify distinct immunophenotypic clusters according to the number of intratumoral PD-1+ immune cells (ICs), CD8+, and Foxp3+ T cells, as well as PD-L1 on tumor and immune cells. An unbiased recursive partitioning (URP) algorithm was used to investigate an optimal cluster with respect to objective response rate (ORR) in the subset of pts treated with ICIs. Results: Among 304 pts, UMAP identified 5 clusters: PD-L1-high with high vs low CD8+ and PD-1+ ICs (clusters A &amp; B, respectively); PD-L1-low with high vs low CD8+ and PD-1+ ICs (clusters C &amp; D respectively); PD-L1-low and moderate levels of CD8+ and PD-1+ ICs (cluster E). Clinicopathological characteristics of the clusters shown in Table. URP analysis identified immune rich clusters A and C as optimal responders to ICIs. From the start of ICIs, we observed a significantly higher ORR (53.3% vs 4.3%; P&lt;0.001), a significantly longer median progression-free survival (mPFS 25.6 vs 3.7 months; HR: 0.12 [95% CI: 0.05-0.32]; P&lt;0.001), and longer median overall survival (mOS 45.1 vs 22.3 months; HR: 0.25 [95% CI: 0.1-0.68]; P=0.006) in clusters A + C (N=15) vs other clusters (N=23). After adjusting for other variables such as performance status, histology, presence of oncogenic driver mutation, and line of treatment, clusters A + C were significantly associated with improved mPFS (HR: 0.08 [95% CI: 0.03-0.24], P&lt;0.001) and mOS (HR: 0.11 [95% CI: 0.03-0.40], P&lt;0.001). Conclusions: Incorporation of multiplex immunofluorescence may improve prediction of response and resistance to immunotherapy in NSCLC.[Table: see text]
Implementation of insurance marketplaces and changes in diagnosis stage in low-income cancer patients.
Authors: Uriel Kim, Siran M. Koroukian, Kurt C Stange, James Spilsbury, Johnie Rose
Journal: Journal of Clinical Oncology (2021)

1576 Background: Millions of low-income Americans gained insurance coverage through Medicaid expansion and the “Marketplaces” of the Affordable Care Act (ACA). How Marketplaces have specifically improved cancer outcomes among these individuals is unclear. Thus, we examined changes in insurance status and diagnosis stage following the ACA among low-income (139-250% of the Federal Poverty Level [FPL]), non-elderly patients (ages 30-64). Methods: In Ohio’s cancer registry, we identified patients diagnosed with one of the top 16 cancers before (2011-2013, “Pre-ACA”) and after (Q3 of 2014-2016, “Post-ACA”) the implementation of the ACA’s insurance Marketplaces and either had private insurance or no insurance. Low-income patients were isolated using a novel, geographically-driven approach called probability weighting. Results: The uninsured percentage dropped from 12.9% to 4.9% between the Pre- and Post-ACA periods in the study sample (N = 10,747). An estimated 11.1% of individuals had Marketplace insurance Post-ACA. A significant but modest Post-ACA (versus Pre-ACA) shift toward non-metastatic disease was identified (Adjusted Odds Ratio [AOR]: 0.95, 95%CI: 0.90-0.99). The largest site-specific shifts were observed for thyroid (AOR: 0.50, 95%CI: 0.30-0.83) and ovarian (AOR: 0.74, 95%CI: 0.58-0.93) cancers. In a control analysis of wealthier (400%+ FPL), privately insured individuals, no significant shifts were identified (AOR: 0.97, 95%CI: 0.92-1.02). Conclusions: This is the first study to show an effect in cancer stage at diagnosis from the Affordable Care Act’s Insurance Marketplaces. We found that the Marketplaces greatly reduced the number of low-income, uninsured cancer patients, translating to significant improvements in cancer stage at diagnosis. As policy makers contemplate modifications to the ACA, they should carefully consider the impact of those changes on the highly vulnerable population of low-income cancer patients.
Clinical effectiveness of apatinib at different doses in patients with advanced gastric cancer as the third-line or further treatment: Results from a post-marketing phase IV study.
Authors: Jin Li, Shukui Qin, Lu Wen, Junsheng Wang, Wenying Deng, Weijian Guo, Tongfu Jia, Qun Zhao, Guifang Zhang, Yifu He, Haijun Zhong, Yi Ba, Xiaoyan Lin, Jianwei Yang, Jun Zhao, Yuxian Bai, Guogui Sun, Yongjuan Wu, Meng Wang, Ying Sun
Journal: Journal of Clinical Oncology (2021)

e16037 Background: Apatinib, a highly selective VEGFR2 inhibitor, has shown a clinical benefit as third-line or further-line treatment in patients with gastric cancer in a randomized phase III study with the initial dose of 850mg. However, the study was conducted in a small scale (n = 267) under standardized conditions. Here, we assessed exposure and effectiveness of apatinib at different doses using data collected from a post-marketing phase IV study that included a broader patient population with a larger sample size. Methods: Patients with advanced or metastatic advanced gastric cancer or gastroesophageal junction adenocarcinoma who were aged 18-75 with ECOG performance status of 0-2 and failed at least two lines of chemotherapy were enrolled. Apatinib was recommended with an initial dose of 850 mg q.d orally, while the initial dose was determined at the discretion of the investigators. Administration of apatinib regarding the initial dose, duration of treatment, dose modification, average daily exposure dose (ADED) and its effect on progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 2004 patients were included in the intention-to-treat population. The median age was 59 (range, 19-85) years, 71.8% of patients were male, 84.2% had ECOG performance status of 0-1; 96.4% had stage IV disease, and 98.8% had metastases, among which 34.2% with more than 2 metastases. Five patients did not receive therapy. Compared to 5.5% of patients with the initial dose &gt; 500mg, 94.1% was given at the initial dose≤500mg; 8.6% had ADED &gt; 500mg and 91.1% had ADED ≤500mg. The median duration of treatment was 56 days. Treatment interruption and discontinuation, and dose reduction occurred in 34.4%, 24.5%, and 13.7% of patients due to adverse events, respectively. Survival analyses in the initial dose ≤500mg/ &gt; 500mg subgroups showed median PFS of 2.6 months (95%CI 2.20-2.79) vs 2.7 months (95% CI 1.91-3.32), median OS of 5.6 months (95% CI 5.26-5.95) vs 5.9 months (95% CI 4.40-6.87). In the ADED ≤500mg/ &gt; 500mg subgroups, the median PFS was 2.6 months (95% CI 2.14-2.76) vs 3.0 months (95% CI 2.27-3.61), and median OS was 5.7 months (95% CI 5.32-6.08) vs 6.1 months (95% CI 5.36-7.72). Conclusions: In conclusion, more than 90% of the patients received a lower dose regimen, which indicate dosage of 500mg or lower is a tolerated exposure. Furthermore, dose at 500mg or lower produced similar efficacy to that more than 500mg. Clinical trial information: NCT02426034.
HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research
Authors: Anand Rohatgi, Marit Westerterp, Arnold von Eckardstein, Alan Remaley, Kerry-Anne Rye
Journal: Circulation (2021)

Low high-density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect high-density lipoprotein (HDL) function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target. HDLs comprise distinct subpopulations of particles of varying size, charge, and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and antidiabetic properties. HDLs can be anti-inflammatory (which may protect against atherosclerosis and diabetes) and proinflammatory (which may help clear pathogens in sepsis). The molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and noncoding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A through I) have revealed nonlinear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus noncoronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers (namely, cholesterol efflux capacity) are associated with coronary disease, but they remain research tools. Therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None has proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.
Genomic markers associated with hyperprogression in patients with lung cancer treated with immune checkpoint inhibitors.
Authors: Eyob ale Tadesse, Kayla Heslin, Mohamed Hendawi, Luke Peterson, Frank M. Wolf, Thomas D. Brown, Michael A. Thompson
Journal: Journal of Clinical Oncology (2021)

9105 Background: Immune checkpoint inhibitor (ICI) therapy has become a mainstay of non-small cell lung cancer (NSCLC) treatment. However, not all patients (pts) benefit with a subset paradoxically experiencing accelerated tumor growth while on ICI. Hyperprogression (HP) refers to accelerated tumor growth on ICI with worsening clinical status. Various gene alterations may be associated with HP including MDM2/MDM4 amplifications, EGFR alterations, and STK11/LKB1 mutations. Kato et al. (doi: 10.1158/1078-0432.CCR-16-3133 ) showed HP in 6/6 pts with MDM2/MDM4 amplification and in 2/10 pts with EGFR alterations. This report describes HP in pts with NSCLC treated with ICIs in a large health system. Methods: Pts with NSCLC treated with ICIs from Jan 2012 to Jan 2021 at Advocate Aurora Health were reviewed after IRB approval. Pts with NSCLC histology (ICD diagnosis codes and/or manual chart review), ICI treatment, and molecular testing were identified via the real world data integrated within the Syapse Learning Health Network platform. Additional chart review to ascertain HP was performed, and molecular results were analyzed. HP criteria include: 1) time-to-treatment failure &lt; 2 months (from start to discontinuation of ICI for any reason), 2) &gt; 50% increase in tumor burden by RECIST, 3) spread of the disease to a new organ between baseline and first radiologic evaluation or clinical deterioration, and 4) ECOG PS ≥ 2 during the first 2 months of treatment. Based on the number of criteria fulfilled, HP = &gt; 3, Progression = 1-2, and non-progressor = 0. Pts with and without HP were compared using Chi-squared and Fisher Exact tests. T-tests were performed for continuous variables. Results: Out of 7,078 NSCLC pts, 1,389 (20%) were treated with ICI including atezolizumab (40 pts, 3%), durvalumab (17 pts, 1%), nivolumab (167 pts, 12%), pembrolizumab (190 pts, 14%), and multiple ICIs (12 pts, 1%). Of those pts treated with ICIs, molecular testing was performed in 427 (31%). 98 of 427 pts (23%)had HP and an additional 86 pts (20%) had progressive disease without meeting the definition of HP. Biomarker associations with HP are shown in the table. By tumor gene alterations, HP was seen in pts with: EGFR (20/60), STK11/LKB1 (16/25); and MDM2/4 (4/7). Conclusions: EGFR, STK11/LKB1, and MDM2/4 gene alterations were all statistically significantly associated with HP. Clinical and molecular predictors of HP need to be explored in order to optimize selection of pts for ICI therapy.[Table: see text]