tbuckley/cabot-search huggingface dataset:
Dosing, drug reduction, drug interruption, and drug discontinuation rates among U.S. FDA approved tyrosine kinase inhibitors.
Authors: Neha K. Reddy, Jason Roszik, David Carl Norris, Roman Groisberg, Niamh Coleman, Omar Alhalabi, Ethan B. Ludmir, Cullen M. Taniguchi, Ishwaria Mohan Subbiah, Vivek Subbiah
Journal: Journal of Clinical Oncology (2021)

3112 Background: The advent of tyrosine kinase inhibitors (TKIs) has altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. Since many of these drugs are continuously dosed, ongoing toxicities may lead to drug reductions and drug discontinuations. Hence in practice, many patients are started on lower doses due to tolerability concerns or are dose-reduced subsequently for toxicity. Herein, we assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: TKIs were approved for 143 different indications, ranging from 1 indication to 11 indications (eg. Imatinib) from data arising from 7 patients to 2816 patients for a specific indication. Among all TKIs, median dose was 150 mg and average dose was 237 mg; 34 (23.8%) were approved bid vs 71 (49.7%) qd. Specifically for oncology, 54 indications were biomarker based (eg. EGFR mutant NSCLC) and 52 were non-biomarker based for specific diseases (eg. metastatic RCC). Among approved indications range of dose reduction rate (DRR), drug interruption rates (DIR), drug discontinuations rates (DDR) were 0.80-89%, 3%-89%, and 1-39% respectively. Most common reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Geriatric use was listed in 99 indications ( &gt; 65 yrs, 6-68%; &gt; 75 yrs, 0.50-24%). Patient reported outcomes were not available. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients. Future studies are warranted to look into flat dosing vs alternative dosing, like weight-based dosing for TKIs, and to report patient reported outcomes.
The global burden of 29 cancer groups from 2010 to 2019: A systematic analysis for the Global Burden of Disease study 2019.
Authors: Jonathan M Kocarnik, Kelly Compton, Franny Dean, Weijia Fu, Brian Gaw, James Harvey, Hannah Henrikson, Dan Lu, Alyssa Pennini, Rixing Xu, Force Lisa
Journal: Journal of Clinical Oncology (2021)

10577 Background: Cancer is a major cause of morbidity and mortality worldwide, and global efforts to reduce health loss from cancer require systematic estimates that can measure progress from national to global levels. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019), we examined global cancer burden in order to highlight areas where cancer burden is inequitably distributed and to inform cancer control efforts around the world. Methods: Using estimation methods from GBD 2019, we analyzed the incidence, mortality, years lived with disability, years of life lost (YLLs), and disability-adjusted life years (DALYs) for 29 cancer groups and 204 countries and territories from 2010 to 2019. Cancer burden was compared to health burden from other categories of diseases and injuries in the GBD. Results were assessed globally and by socio-demographic index (SDI), a summary measure of income per capita, average educational attainment, and total fertility rate. Point estimates and 95% Uncertainty Intervals (UIs) are reported. Results: There were 23.6 million (95% UI 22.2-24.9 million) incident cancer cases globally in 2019 (17.2 [15.9-18.5] million excluding non-melanoma skin cancer), and 10.0 (9.36-10.6) million cancer deaths. There were 250 (235-264) million DALYs globally due to cancer, 97% of which came from years of life lost. The leading five cancers by DALYs in 2019 were: tracheal, bronchus, and lung cancer (45.9 [42.3-49.3] million); colon and rectum cancer (24.3 [22.6-25.7] million); stomach cancer (22.2 [20.3-24.1] million); breast cancer (20.6 [19.0-22.2] million; and liver cancer (12.5 [11.4-13.7] million). Compared to other diseases and injuries in the GBD, cancer was responsible for the second-highest number of deaths, YLLs, and DALYs globally in 2019. These rankings of cancer burden differed by SDI quintile: cancer was the leading cause of absolute DALYs in high SDI countries but was ranked 10th in low SDI countries. From 2010-2019, the number of global cancer cases increased by 26.3% (20.3-32.3%), deaths by 20.9% (14.2-27.6%), and DALYs by 16.0% (9.29-22.8%). The largest annualized rate of change in absolute cases and deaths over this period occurred in the low and low-middle SDI quintiles. Conclusions: Cancer cases and deaths are growing globally, with the largest relative growth over the last decade occurring in low to middle SDI countries. Improvements in cancer prevention efforts and ensuring access to timely diagnosis and care will be necessary to make equitable progress in reducing the global burden of cancer.
Atherosclerotic Cardiovascular Disease, Cancer, and Financial Toxicity Among Adults in the United States
Authors: Javier Valero-Elizondo, Fouad Chouairi, Rohan Khera, Gowtham R. Grandhi, Anshul Saxena, Haider J. Warraich, Salim S. Virani, Nihar R. Desai, Farzan Sasangohar, Harlan M. Krumholz, Nestor F. Esnaola, Khurram Nasir
Journal: JACC CardioOncology (2021)

Financial toxicity (FT) is a well-established side-effect of the high costs associated with cancer care. In recent years, studies have suggested that a significant proportion of those with atherosclerotic cardiovascular disease (ASCVD) experience FT and its consequences.This study aimed to compare FT for individuals with neither ASCVD nor cancer, ASCVD only, cancer only, and both ASCVD and cancer.From the National Health Interview Survey, we identified adults with self-reported ASCVD and/or cancer between 2013 and 2018, stratifying results by nonelderly (age <65 years) and elderly (age ≥65 years). We defined FT if any of the following were present: any difficulty paying medical bills, high financial distress, cost-related medication nonadherence, food insecurity, and/or foregone/delayed care due to cost.The prevalence of FT was higher among those with ASCVD when compared with cancer (54% vs. 41%; p < 0.001). When studying the individual components of FT, in adjusted analyses, those with ASCVD had higher odds of any difficulty paying medical bills (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.09 to 1.36), inability to pay bills (OR: 1.25; 95% CI: 1.04 to 1.50), cost-related medication nonadherence (OR: 1.28; 95% CI: 1.08 to 1.51), food insecurity (OR: 1.39; 95% CI: 1.17 to 1.64), and foregone/delayed care due to cost (OR: 1.17; 95% CI: 1.01 to 1.36). The presence of ≥3 of these factors was significantly higher among those with ASCVD and those with both ASCVD and cancer when compared with those with cancer (23% vs. 30% vs. 13%, respectively; p < 0.001). These results remained similar in the elderly population.Our study highlights that FT is greater among patients with ASCVD compared with those with cancer, with the highest burden among those with both conditions.
Synergistic enhancement of immunological responses triggered by hyperthermia sensitive Pt NPs via NIR laser to inhibit cancer relapse and metastasis
Authors: Jie Yu, Sha Liu, Yupeng Wang, Xidong He, Qingfei Zhang, Yanxin Qi, Dongfang Zhou, Zhigang Xie, Xiaoyuan Li, Yubin Huang
Journal: Bioactive Materials (2021)

The combination of tumor ablation and immunotherapy is a promising strategy against tumor relapse and metastasis. Photothermal therapy (PTT) triggers the release of tumor-specific antigens and damage associated molecular patterns (DAMPs) in-situ. However, the immunosuppressive tumor microenvironment restrains the activity of the effector immune cells. Therefore, systematic immunomodulation is critical to stimulate the tumor microenvironment and augment the anti-tumor therapeutic effect. To this end, polyethylene glycol (PEG)-stabilized platinum (Pt) nanoparticles (Pt NPs) conjugated with a PD-L1 inhibitor (BMS-1) through a thermo-sensitive linkage were constructed. Upon near-infrared (NIR) exposure, BMS-1 was released and maleimide (Mal) was exposed on the surface of Pt NPs, which captured the antigens released from the ablated tumor cells, resulting in the enhanced antigen internalization and presentation. In addition, the Pt NPs acted as immune adjuvants by stimulating dendritic cells (DCs) maturation. Furthermore, BMS-1 relieved T cell exhaustion and induced the infiltration of effector T cells into the tumor tissues. Thus, Pt NPs can ablate tumors through PTT, and augment the anti-tumor immune response through enhanced antigen presentation and T cells infiltration, thereby preventing tumor relapse and metastasis.
How representative is a point-of-care randomized trial? Clinical outcomes of patients excluded from a point-of-care randomized controlled trial evaluating antibiotic duration for Gram-negative bacteraemia: a multicentre prospective observational cohort study
Authors: Anne Rossel, Kimberly P.M. Zandberg, Werner C. Albrich, Angela Huttner
Journal: Clinical Microbiology and Infection (2021)
Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans
Authors: Christopher L. Axelrod, Ciaran E. Fealy, Melissa L. Erickson, Gangarao Davuluri, Hisashi Fujioka, Wagner S. Dantas, Emily Huang, Kathryn Pergola, Jacob T. Mey, William T. King, Anny Mulya, Daniel Hsia, Bartolome Burguera, Bernard Tandler, Charles L. Hoppel, John P. Kirwan
Journal: Metabolism (2021)
Bispecific CART cells in the treatment of relapsed and refractory multiple myeloma: A review of literature.
Authors: Joshua Christy, Abdul Rafae, Nazma Hanif, Pranali Santhoshini Pachika, Emad Kandah, Hamid Ehsan, Ahsan Wahab, Tabinda Saleem, Rabia Ali, Mustafa Nadeem Malik, Faiz Anwer
Journal: Journal of Clinical Oncology (2021)

e20038 Background: Chimeric antigen receptor T cells (CART) have shown promising results in the treatment of relapsed and refractory multiple myeloma (RRMM). Recently, bispecific-CART cells targeting 2 antigens are being evaluated in various clinical trials. Methods: A comprehensive literature search was done of Pubmed, Embase, and Cochrane. Data presented at annual hematology and oncology conferences were also included. Results: We included 4 phase I clinical trials with a total of 77 RRMM patients between the ages of 18 to 71 years. The median follow-up duration ranged from 1 month to 27.5 months. All were lymphodepleted with Cyclophosphamide and Fludarabine before receiving CAR-T cell therapy. The CAR-T cell targets include BCMA and CD38 (dose range 0.5 x 10^6 - 4 x 10^6 cells/kg), BCMA and TACI (dose range 15 - 900 x 10e6 CAR-T cells), BCMA and CD19 (1 x 10e5/kg - 3 x 10e5 CAR-T cells/kg), and BCMA and CD19 (dose 1 x 10e6 cells/kg). Overall response rate (ORR) was reported by 4 trials (87.5%, 43%, 93.8%, 95%). Complete response (CR) was also reported in 4 trials as 50%, 64%, 56.3% and 14% and partial response (PR) reported as 25%, 28%, 16.6%, 14%, 18% in 5 trials (table). The most common grade 3-4 adverse effects that were reported include cytokine release syndrome, neurotoxicity, neutropenia, lymphopenia, anemia, thrombocytopenia, diarrhea, increased LDH, lower respiratory tract infections (LRTI), dehydration, renal failure (table). Yan et al. reported one death due to cerebral hemorrhage which was considered unrelated to treatment. Jiang et al. reported one death from unknown cause of a patient who presented with fever during the COVID- 19 pandemic. Conclusions: Bispecific CART cells have shown promising results in the treatment of RRMM. However, the clinical trials are ongoing, and a longer follow-up is needed.[Table: see text]
acelERA Breast Cancer (BC): Phase II study evaluating efficacy and safety of giredestrant (GDC-9545) versus physician’s choice of endocrine monotherapy in patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2-) locally advanced or metastatic breast cancer (LA/mBC).
Authors: Miguel Martin, Elgene Lim, Mariana Chavez Mac Gregor, Mahesh Shivhare, Graham Ross, Monika Patre, Laura Roncoroni, Maria Louka, Joohyuk Sohn
Journal: Journal of Clinical Oncology (2021)

TPS1100 Background: The standard-of-care therapy for ER+ BC typically involves modulation of estrogen synthesis and/or ER activity. Despite disease progression with standard treatments, growth and survival of the majority of tumors are thought to remain dependent on ER signaling; therefore, pts with ER+ BC can still respond to second- or third-line endocrine treatment (ET) after progression on prior therapy (Di Leo 2010; Baselga 2012). ESR1 mutations may drive estrogen-independent transcription and proliferation leading to resistance. The highly potent, nonsteroidal oral selective ER degrader, giredestrant, achieves robust ER occupancy and is active regardless of ESR1 mutation status. Phase I data have shown that giredestrant is well tolerated and active both as a single agent and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), palbociclib (Lim 2020). Single-agent giredestrant has also shown encouraging antitumor activity in pts previously treated with fulvestrant and/or a CDK4/6i. Methods: acelERA BC (NCT04576455) is a randomized, open-label, multicenter phase II study evaluating the efficacy and safety of giredestrant vs. physician’s choice of ET (fulvestrant or aromatase inhibitor) in males, or postmenopausal or pre/perimenopausal females with ER+/HER2– LA/mBC who have received 1–2 prior lines of systemic therapy in the LA or mBC settings, at least one of which must be ET. Randomization: 1:1 to receive giredestrant (30 mg PO QD on Days 1–28 of each 28-day cycle) or physician’s choice of ET per local guidelines. Men and pre-/perimenopausal women will receive a luteinizing hormone-releasing hormone agonist. Eligibility: ≥18 years, ECOG PS 0–1, histologically or cytologically confirmed diagnosis of LA (recurrent or progressed) or metastatic adenocarcinoma of the breast, measurable disease (per modified RECIST v1.1) or evaluable bone lesions, and ER+/HER2– tumors (locally assessed). Primary endpoint: progression-free survival (PFS; investigator-assessed per RECIST v1.1). Secondary endpoints: overall survival, objective response rate, duration of response, clinical benefit rate, PFS in pts with baseline ESR1 mutations, and quality of life. Safety, pharmacokinetics, biomarkers, and health status utility will also be assessed. Stratification: site of disease (visceral vs. nonvisceral), prior treatment with CDK4/6i (yes vs. no), and prior treatment with fulvestrant (yes vs. no). PFS will be compared using a stratified log-rank test; median PFS, using Kaplan–Meier analyses. Recruitment for the global enrollment phase is ongoing, the first patient was enrolled November 27, 2020. Clinical trial information: NCT04576455 .
TMOD-01. A PROGNOSTIC NOMOGRAM MODEL AND ONLINE SOFTWARE FOR PATIENTS WITH NEWLY DIAGNOSED LOWER-GRADE GLIOMAS
Authors: Mingzhi Han
Journal: Neuro-Oncology (2021)

Abstract The nomogram represents a statistical model that incorporates multiple risk factors to estimate individualized survival probabilities. In this study, we developed a nomogram which provides an important tool for individulized survival predicition for newly diagnosed low-grade gliomas (LGG). A total number of 582 newly diagnosed LGG patients were included; the median age was 39.93 years and 42% were female. Cox regression analysis showed that younger age at diagnosis, WHO grade II vs. III, the IDHmut-codel vs. the IDHwt, and the IDHmut-non-codel vs. the IDHwt were significantly associated with better prognosis. The adjuvant treatment following surgery showed a trend towards improved survival. Subsequently, the nomogram to estimate 60-, 90-, and 120-month survival probabilities was established. Our data showed that the age at diagnosis was the largest contributor to patient survival, followed by molecular subtype, WHO grade, treatment and gender. The calibration plot showed that the observed and the nomogram predicted OS curves were well-aligned. In addition, we also validated our nomogram for LGG patients who received postsurgical adjuvant therapy through cross-validation and the calibration plot. Finally, we developed a free online tool for this nomogram (softwarewebsite:https://rrlnnomogram.shinyapps.io/LGG_Nom_Asian/). Overall, this model should be a useful tool for counseling patients in clinical practice including treatment decisions, follow-up, and prognosis.
<i><i>PIK3CA</i></i>-<i><i>TP53</i></i> co-mutation as a biomarker of overall survival in malignant tumor.
Authors: Hongyan Wang, Xiaopeng Zhao, Xu He, Miao Wang, Haoran Zhang, Jingge Cheng, Yaqing Wu, Ningning Luo, Yingxue Qi, Qianqian Duan
Journal: Journal of Clinical Oncology (2021)

e15001 Background: Overall survival (OS) is an important endpoint, with the advantage that there is minimal ambiguity in defining an OS event; the patient is either alive or dead. Some single gene mutations, such as TP53, were identified as important predictors of shorter OS in malignant tumors. However, the relationship between gene co-mutation and OS of malignant tumors is poorly defined. Methods: Genomic and OS data were derived from The Cancer Genome Atlas (TCGA) databases. We defined the double-mutant gene pair as “hit pair” in the specific cancer type if statistically significant OS difference was observed in at least one of three comparison (double-mutant samples vs gene A-only-mutant samples; double-mutant samples vs gene B-only-mutant samples; gene A-only-mutant samples vs gene B-only-mutant samples). Results: PIK3CA-TP53 co-mutation was evaluated as “hit pair” in seven cancer types: GBM (Glioblastoma multiforme), HNSC (Head and neck squamous cell carcinoma), LUSC (Lung squamous cell carcinoma), SARC (Sarcoma), SKCM (Skin cutaneous melanoma), UCEC (Uterine corpus endometrial carcinoma), and UCS (Uterine carcinosarcoma). In SARC and SKCM, the expected hazard ratio was higher in both-mutant group than TP53-only-mutant group, and neither genes were correlated with OS. Especially in SKCM, after we took “neither” group (both genes were wild-type) into comparison, hazard ratio of both-mutant group was significantly higher than neither group. Single-gene mutation didn’t make difference on hazard ratio, which indicated that the both-mutant interaction made the leading contribution. In GBM, LUSC, and UCS, the significant difference of hazard ratio between TP53-only-mutant group and PIK3CA-only-mutant group was neutralized in the both-mutant group, to some extent equivalent to “average effect (OS curve of double-mutant group was between that of only single gene mutant groups)". For PIK3CA-TP53 in HNSC, both-mutant group and TP53-only-mutant group carried with a higher hazard ratio than PIK3CA-only-mutant group. It suggested that the increasing hazard ratio in both-mutant group might be resulted from TP53 mutation. For the circumstance in UCEC, TP53 and PIK3CA were testified to be correlated with higher and lower hazard ratio, respectively and both-mutant group and TP53-only-mutant group both with significantly higher hazard ratio than PIK3CA-only-mutant group, which further verified the greater strength of TP53 than PIK3CA in both-mutant group. Conclusions: In summary, our study identified PIK3CA-TP53 co-mutation as a predictor of OS in seven cancer types: GBM, HNSC, LUSC, SARC, SKCM, UCEC, and UCS, especially in SARC and SKCM.
Type of recurrence, cause of death and second neoplasms among 737 patients with ductal carcinoma in situ of the breast: 15-year follow-up.
Authors: Anna Niwinska, Michal Kunkiel, Katarzyna Wardzynska
Journal: Journal of Clinical Oncology (2021)

e12592 Background: The aim of the study is to assess the results of the treatment of 737 consecutive patients with DCIS with particular attention to the character of recurrences, other neoplasms and causes of deaths. Methods: A retrospective analysis was carried out of 737 consecutive DCIS patients treated in one institution in the years 1996-2011. The percentage of failures, causes of death, cumulated recurrence risk, DFS, OS depending on the method of treatment (mastectomy, breast conserving treatment BCT, breast conserving surgery BCS), was calculated. Results: 66 recurrences (42% DCIS, 58% invasive) were reported: 61 recurrences in the breast, 5 outside the breast. The comparison of mammography images before the initial treatment and after local recurrence revealed the true recurrence in the breast in 48/61 (79%) of cases. The cumulated recurrence risk after 15-year observation, after mastectomy, BCT and BCS was 3.2%, 19.5% and 31.2 %, respectively (p &lt; 0.001). 15-year DFS after mastectomy, BCT and BCS was 72%, 65% and 48%, respectively (p &lt; 0.001). 15-year OS after mastectomy, BCT and BCS was 75%, 83% and 70%, respectively, p = 0.329. In the course of the whole observation period 124 other neoplastic lesions in 121 patients (16%) were reported including 58 (8%) contralateral breast cancers. Deaths due to DCIS progression were reported in 4 (0.5%) of patients. An overwhelming majority (74/86) of deaths was linked to the age of the patients or other diseases, including other neoplasms. Conclusions: The highest recurrence risk reported in patients after BCS was unacceptable and, moreover, it kept growing over the fifteen years of observation. 79% of recurrences in the treated breast were true recurrences. Local recurrences were effectively treated without influence on OS. The percentage of deaths due to DCIS was low.