tbuckley/cabot-search huggingface dataset:
Cost-effectiveness of subcutaneous pertuzumab, trastuzumab, and hyaluronidase-zzxf for the treatment of high-risk HER2+ early breast cancer.
Authors: Jesse Sussell, Joshua A. Roth, Svenn Hansen, Craig S. Meyer, Anita M. Fung
Journal: Journal of Clinical Oncology (2021)

e18846 Background: Standard therapy for high-risk HER2+ early breast cancer (EBC) begins with neoadjuvant dual targeted therapy with pertuzumab (P) + trastuzumab (T) + chemotherapy (CTX). After surgery, patients who achieve pathological complete response (pCR) should complete one year of dual targeted therapy, while patients with residual disease should receive ado-trastuzumab emtansine (T-DM1). Recently, a subcutaneously administered formulation of P, T, and hyaluronidase-zzxf (Phesgo) was approved for use in the U.S. This study assesses the value of this new formulation in EBC patients vs. a strategy in which patients initiate standard therapy, but discontinue P following ascertainment of pCR. Methods: We developed a six-state Markov model to assess EBC costs and quality-adjusted life years (QALYs) from a healthcare sector perspective over a lifetime time horizon. Two strategies were modeled: 1) Neoadjuvant therapy with subcutaneous P, T, and hyaluronidase-zzxf + CTX with adjuvant continuation if pCR is achieved, and T-DM1 if not (“intervention”), and 2) neoadjuvant therapy with infused P, T + CTX with adjuvant infused T if pCR is achieved, and T-DM1 if not (“comparator”). Event-free and invasive-disease free survival were derived from the PEONY and KATHERINE/APHINITY trials, respectively. Utility values, drug prices, and procedure costs were derived from KATHERINE EQ-5D data, Wholesale Acquisition Costs, and claims analyses, respectively. We assessed comparator costs using both biosimilar and branded T pricing. The primary outcome was the incremental cost-effectiveness ratio (ICER). Outcomes were discounted at 3%/year and costs are presented in 2020 U.S. dollars. Uncertainty in outcomes was assessed through Monte Carlo simulation (1,000 replicates). Results: The table shows key results. The intervention resulted in a gain of 0.092 QALYs. With biosimilar T pricing in the comparator (base case), the intervention increased costs by $7,575 (ICER = $81,793). With branded T pricing in the comparator (scenario analysis), the intervention increased costs by $982 (ICER = $10,602). In probabilistic analyses, the intervention was favored in 52% and 81% of simulations at a willingness-to-pay of $100,000/QALY with biosimilar and branded T pricing, respectively. Conclusions: This study provides additional evidence to support adjuvant continuation of P+T among patients achieving pCR. Neoadjuvant P, T, and hyaluronidase-zzxf + CTX (with adjuvant continuation of dual targeted therapy) is expected to be cost-effective ( &lt; $100,000/QALY) vs. neoadjuvant P and T + CTX (with adjuvant T continuation) for patients with high-risk HER2+ EBC irrespective of whether the comparator uses biosimilar or branded T.[Table: see text]
Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI
Authors: Tao-Tao Tang, Bin Wang, Zuo-Lin Li, Yi Wen, Song-Tao Feng, Min Wu, Dan Liu, Jing-Yuan Cao, Qing Yin, Di Yin, Yu-Qi Fu, Yue-Ming Gao, Zhao-Ying Ding, Jing-Yi Qian, Qiu-Li Wu, Lin-Li Lv, Bi-Cheng Liu
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement AKI is a frequent clinical problem without definitive therapies. We developed an efficient RNAi therapy against AKI by engineering red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs. REVs targeted with Kim-1–binding peptide LTH efficiently delivered P65 and Snai1 siRNAs to the injured tubules, leading to reduced expression of P-p65 and Snai1. Dual suppression of P65 and Snai1 inhibited renal inflammation and fibrosis in mice subjected to ischemia/reperfusion injury and unilateral ureteral obstruction, and blunted the chronic progression of ischemic AKI. This study provides an efficient platform, REV LTH, for the targeted delivery of therapeutics into injured tubular cells, and suggests the viability of targeting P65 and Snai1 as a therapeutic avenue for AKI. Background AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. Methods We engineered red blood cell–derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. Results REVs targeted with Kim-1–binding LTH peptide (REV LTH ) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REV LTH , siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD. Conclusions A red blood cell–derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1 , alleviating inflammation and fibrosis in the tubules.
Novel approach to improve the diagnosis of pediatric cancer in Kenya via telehealth education.
Authors: Tyler Severance, Gilbert Kipruto Olbara, Festus Njuguna, Marjorie Treff, Patrick J. Loehrer, Terry A. Vik
Journal: Journal of Clinical Oncology (2021)

11000 Background: Childhood cancer has an annual incidence of 150-160 cases per million children worldwide but remains vastly under-diagnosed in low to middle income countries (LMIC) such as in Sub-Saharan Africa. Moi Teaching and Referral Hospital (MTRH) is the only tertiary referral hospital in western Kenya and serves a population of 25 million people, including 10 million children. The average number of pediatric cancer diagnoses was 216 cases annually in 2017-2019, well below the anticipated 1500 cases based on cancer epidemiology data. We recently completed a comprehensive Needs Assessment suggesting that due to inadequate pediatric oncology education, many clinical diagnoses are missed and correct diagnostic tests are not obtained at county hospitals. Local medical staff expressed interest in educational programs to help augment their understanding and diagnostic evaluation of pediatric oncology. Methods: To address these disparities in medical knowledge, we implemented Project ECHO – a validated virtual guided practice and telementoring model – to connect multidisciplinary specialists at MTRH with staff in medically underserved communities in western Kenya for ongoing training, technical assistance, and mentorship. The ECHO program follows a Hub-and-Spoke design where the specialists at MTRH and pediatric oncologists at Riley Hospital functioned as the “hub” team and the health care workers at county hospitals were the “spokes”. Sessions were freely available on Zoom twice monthly and featured both a didactic topic presented by experts and a spoke-led case-based discussion. The discussion utilized dialogue education to promote learning and engagement among the spokes with mentorship from the hub team. Results: The ECHO program launched successfully in January 2020 with a curriculum focused on pediatric oncology for general health care workers. A total of 22 sessions occurred with an average of 23 learners (primarily staff at community hospitals within the referral region) per session. Despite the COVID-19 pandemic, the year-end analysis in January 2021 demonstrated 286 new pediatric patients were diagnosed with cancer at MTRH representing a 33% increase over the 3-year average. Conclusions: The implementation of a telehealth education platform – Project ECHO – focused on diagnosing pediatric cancer in medically underserved communities in Kenya, is a useful model to increase the recognition and earlier referral of childhood cancer in LMICs.
Social determinants of health, genetic ancestry, and mortality in ECOG-ACRIN E5103.
Authors: Samilia Obeng-Gyasi, Anne M. O'Neill, Kathy Miller, Bryan P. Schneider, Ann H. Partridge, Lava R Timsina, George W. Sledge, Lynne I. Wagner, Ruth Carlos
Journal: Journal of Clinical Oncology (2021)

6527 Background: Social determinants of health (SDH) and genetic ancestry have been independently implicated in breast cancer presentation, treatment and mortality. However, little is known about the relationship between SDH and genetic ancestry on clinical trial outcomes. The objective of this study is to assess the association between SDH, genetic ancestry and clinical outcomes in patients enrolled in an adjuvant breast cancer clinical trial. Methods: ECOG-ACRIN (EA) 5103 randomized patients to receive AC + taxane + bevacizumab or placebo. SDH were operationalized as insurance status at trial registration (individual SES) and neighborhood socioeconomic status (nSES). Insurance categories included: (1) Private, 2) Medicare including private/Medicare, military, 3) Medicaid including Medicaid/Medicare, uninsured, 4) self-pay). The nSES index was calculated using zip codes linked to county level data on occupation, income, poverty, wealth, education and crowding. Genome-wide single-nucleotide polymorphism arrays were used to define African ancestry (AA), European ancestry (EA) and other (OA). Multivariable regression and Cox-Proportional Hazard models (odds ratios (OR) and hazard ratios (HR) with corresponding 95% confidence intervals (CI)) were used to assess associations with chemotherapy completion and overall mortality. Estimates were adjusted for the following clinical covariates: age, tumor size, nodal status, hormone receptor status, and primary surgery at randomization. Results: The study cohort included 2453 EA (79.2%), 381 AA (12.2%) and 265 OA (8.6%). Medicaid patients (OR 0.76(0.59-0.99); ref private) and those with AA (OR 0.62(0.49-0.78); ref EA) were less likely to complete chemotherapy. Regarding overall mortality, Medicaid insurance (HR 1.42(1.05-1.92) was associated with a higher mortality than private insurance. Conversely, there was no significant difference in mortality by ancestry (AA HR 1.27 (0.97-1.66); OA HR 0.90 (0.63-1.29): ref EA). Neighborhood socioeconomic status did not appear to be associated with chemotherapy completion or mortality. Conclusions: SDH reflective of individual SES, such as insurance, appear to be stronger drivers of trial completion and mortality compared to nSES among patients enrolled in E5103. Moreover, study results suggest an interplay between ancestry and individual proxies for SDH in trial completion. Nevertheless, the relationship between ancestry and lower rates of chemotherapy completion do not appear to translate into higher mortality rates among patients of AA.
Abstract 12765: Meta-Analysis of Secondary Prevention of Cryptogenic Stroke
Authors: Babikir Kheiri, Harsh Golwala, Mohammed Osman, Khidir Dalouk, Eric Stecker, Firas Zahr, Babak Nazer, Hind W Rahmouni
Journal: Circulation (2019)

Introduction: Cryptogenic stroke and embolic stroke of undetermined source (ESUS) represent a subtype of ischemic stroke with an uncertain cause. The best anti-thrombotic therapy in this population...
Mutant <i>PPM1D</i> and <i>TP53</i> populate the hematopoietic compartment after peptide receptor radionuclide therapy (PRRT) exposure.
Authors: Abhay Singh, Nuria Mencia-Trinchant, Elizabeth A. Griffiths, Medhavi Gupta, Matthew Gravina, Rutaba Tajammal, Mark G Faber, LunBiao Yan, Eti Sinha, Duane C. Hassane, Monica L. Guzman, Renuka V. Iyer, Eunice S. Wang, Swapna Thota
Journal: Journal of Clinical Oncology (2021)

10605 Background: Mutations in TP53 and PPM1D are putative drivers associated with therapy related-myeloid neoplasm (T-MN) and have been identified in pre-treatment blood samples obtained at the time of primary malignancy, predating clinically evident T-MN. Genomic analysis of patients(pts) who undergo leukemogenic therapies will help understand T-MN biology and devise risk mitigation strategies. PRRT (Lu 177) for neuroendocrine tumors is associated with enhanced risk of T-MNs. The mechanism for T-MN induced by PRRT is largely elusive due to the novelty of this drug. Methods: We analyzed initial (n=13) and serial blood samples (n=4) prior to and following PRRT for clonal mutations in order to elucidate the role of PRRT in exerting selective pressures on HSCs. Genomic DNA was analyzed using a targeted myeloid 100-gene panel and a variant allele frequency (VAF) cutoff 1% was used to call clonal hematopoiesis (CH). Results: Fifty-four percent pts had CH, despite relatively young age of cohort (median age 58 years, range 41-75) and minimal chemo-radiotherapy exposure; baseline characteristics and molecular profile of cohort is published [Singh et al. Blood 2020; 136 (Supplement 1): 35–36]. Serial sample analysis in 4 pts (Table 1) demonstrates that PRRT exposure is associated with clonal evolution and accompanying cytopenias in 75% (3/4) pts. Pt-1 (age 67) with normal baseline hemogram developed persistent cytopenias after PRRT, accompanied by emergence and expansion of mutant- PPM1D (m PPM1D; VAF 20%). These data suggest that cytopenias result from repopulation of the HSC compartment by m PPM1D cells. In Pts 2 and 3 (age 74 and 75), we note expansion of m TP53 and m PPM1D clones respectively, also associated with the development of cytopenias. Pt-4 was younger (age 59) and developed no cytopenias. Exposure to PRRT was associated with loss of m TET2 and m DDX41, possibly due to lack of clonal fitness of m TET2/DDX41 clones and the relatively young HSC microenvironment. Conclusions: We conclude that mutations in PPM1D and TP53 are clinically relevant, contribute to clonal cytopenias and may increase risk of future T-MN. The temporal association of m TP53 and m PPM1D expansion with PRRT exposure in our analysis suggests selection of these clones in response to PRRT-induced stress, outcompeting wild type and less therapy-resistant HSCs. Our study along with others will inform future efforts to strategize methods of surveillance and early detection for clonality assessment and chemoprevention, to reduce adverse effects of leukemogenic therapies.[Table: see text]
RARE-23. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR: A CASE SERIES
Authors: Ashley Aaroe, Alexander Ou, Susan McGovern, Arnold Paulino, Jason Johnson, Jason Huse, Gregory Fuller, John de Groot, Andrew Walter, Wafik Zaky
Journal: Neuro-Oncology (2021)

Abstract Introduction Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis first incorporated into the WHO Classification of Tumors of the Central Nervous System in 2016. Though historically considered indolent, emerging evidence suggests that the biological behavior of these tumors may be further classified by molecular features of prognostic significance. Methods A retrospective review was conducted in accordance with IRB approval of patients with the histologic diagnosis of DLGNT. Demographic, clinical, and molecular data where abstracted from the medical record when available. Results 10 patients were identified (M = 8, F = 2). Median age at diagnosis was 6 years (range 0.3–21 years), and the most common symptoms at diagnosis were related to obstructive hydrocephalus, for which 3 patients required CSF diversion. MRI findings included diffuse leptomeningeal thickening, nodularity, or coating of the subarachnoid or ependymal surfaces. Histologically, these tumors expressed variable features of neuronal and/or glial differentiation. Four patients (40%) were treated with radiation therapy (all craniospinal), which was upfront for 2 patients. Chemotherapy regimens used included temozolomide, carboplatin and vincristine and vinblastine. NTRK or BRAF-targeted therapy were used upon progression. At follow-up, 6/10 had stable disease (4/6 of whom were on second line therapy), 1 had partial response, 1 passed away from sepsis and 2 were lost to follow-up. The median progression-free survival for the four patients who developed disease progression was 26 months (range 12–34 months). Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel detected BRAF-KIAA1549 (4 patients) and NTRK (1 patient) fusions. Conclusions DLGNT are rare tumors with scarce data about imaging characteristic and standard of care treatment. Our case series reinforces current literature that although these tumors appear low-grade, they can be clinically aggressive. Further study is needed regarding molecular diagnosis and profiling treatment strategies.
Clinical accuracy of information extracted from prostate needle biopsy pathology reports using natural language processing.
Authors: Risa Liang Wong, Medha Sagar, Jacob Hoffman, Claire Huang, Angelica Lerma, Diboro Kanabolo, Joshua Caldwell, John L. Gore
Journal: Journal of Clinical Oncology (2021)

1557 Background: Patients with prostate cancer are diagnosed through a prostate needle biopsy (PNB). Information contained in PNB pathology reports is critical for informing clinical risk stratification and treatment; however, patient comprehension of PNB pathology reports is low, and formats vary widely by institution. Natural language processing (NLP) models trained to automatically extract key information from unstructured PNB pathology reports could be used to generate personalized educational materials for patients in a scalable fashion and expedite the process of collecting registry data or screening patients for clinical trials. As proof of concept, we trained and tested four NLP models for accuracy of information extraction. Methods: Using 403 positive PNB pathology reports from over 80 institutions, we converted portable document formats (PDFs) into text using the Tesseract optical character recognition (OCR) engine, removed protected health information using the Philter open-source tool, cleaned the text with rule-based methods, and annotated clinically relevant attributes as well as structural attributes relevant to information extraction using the Brat Rapid Annotation Tool. Text pre-processing for classification and extraction was done using Scispacy and rule-based methods. Using a 75:25 train:test split (N = 302, 101), we tested conditional random field (CRF), support vector machine (SVM), bidirectional long-short term memory network (Bi-LSTM), and Bi-LSTM-CRF models, reserving 46 training reports as a validation subset for the latter two models. Model-extracted variables were compared with values manually obtained from the unprocessed PDF reports for clinical accuracy. Results: Clinical accuracy of model-extracted variables is reported in the Table. CRF was the highest performing model, with accuracies of 97% for Gleason grade, 82% for percentage of positive cores ( &lt; 50% vs. ≥50%), 90% for perineural or lymphovascular invasion, and 100% for presence of non-acinar carcinoma histology. On manual review of inaccurate results, model performance was limited by PDF image quality, errors in OCR processing of tables or columns, and practice variability in reporting number of biopsy cores. Conclusions: Our results demonstrate successful proof of concept for the use of NLP models in accurately extracting information from PNB pathology reports, though further optimization is needed before use in clinical practice.[Table: see text]
Abrogating Treatment Resistance By Mir-451 in FLT3-ITD-Positive Acute Myeloid Leukemia
Authors: Rosanna H.E. Krakowsky, Alexander Arthur Wurm, Dennis Gerloff, Christiane Katzerke, Jens-Uwe Hartmann, Daniela Bräuer-Hartmann, Franziska Wilke, Christian Thiede, Carsten Müller-Tidow, Dietger Niederwieser, Gerhard Behre
Journal: Blood (2017)
Genomic profiling of Chinese esophageal squamous cell carcinoma patients and difference of genomic mutation between Chinese and American cohorts.
Authors: Lin Li, Kefeng Wang, Binghua Tan, Yingcheng Lyu, Xiaotian He, Wenjian Wang, Xueting Hu, Duoguang Wu, Huayue Lin, Minghui Wang
Journal: Journal of Clinical Oncology (2021)

e16108 Background: Esophageal squamous cell carcinoma (ESCC) remains an aggressive malignancy and most patients are diagnosed at advantage stage with limited treatments. Large amount of evidence has demonstrated that immune biomarkers such as PD-l/PD-L1 and tumor mutational burden (TMB) are associated with clinical outcomes and disease prognosis. Methods: A total of 475 ECSS patients enrolled in this study. Deep sequencing of 450 cancer genes performed on formalin-fixed paraffin-embedded tumor tissues and matched blood. Results: Genomic mutation landscape indicated the top five mutated genes are TP53 (95.0%), CCND1 (42%), FGF3 (42%), FGF19 (41%), FGF4（41%. We found that CCHD2, FOXL2 and PIK3CA were tumor-driver genes in 475 ECSS patients. BCL6 ( p&lt; 0.02), CCND1 ( p&lt; 0.03), FGF12 ( p&lt; 0.04), FGF19 ( p&lt; 0.04), FGF3 ( p&lt; 0.02) and FGF4 ( p&lt; 0.05) mutations are significantly associated with high expression of PD-L1 Moreover, we found that BCL6 ( p&lt; 0.04), BRD4 ( p&lt; 0.03), EP300 ( p&lt; 0.03), HGF ( p&lt; 0.02), KMT2C ( p&lt; 0.005), KMT2D ( p&lt; 0.04), MET ( p&lt; 0.006), NSD1 ( p&lt; 0.04), PBRM1 ( p&lt; 0.003), PTCH1 ( p&lt; 0.01), SPEN ( p&lt; 0.006), SPTA ( p&lt; 0.02), ZHF750 ( p&lt; 0.004), TP53 ( p&lt; 0.01) mutation are significantly associated with high TMB as well. The cutoff for TMB is set for 6.9 mut/Mb. The target gene analysis indicated that over half of Chinese ECSS patient might benefit from gene target therapy. By comparison between Chinese and TCGA cohorts, EBFR ( p&lt; 0.05), FGRF1 ( p&lt; 0.05) and CDKN2A ( p&lt; 0.001) have significantly mutated frequency, which indicated the gene mutated profiling is significantly different between Chinese and American ECSS patients. Conclusions: This study identified certain gene alteration associated with PD-L1 and TMB status. It is necessary to conduct large clinical study to identify biomarker for evaluation the efficacy of novel adjunct immunochemotherapy.