tbuckley/cabot-search huggingface dataset:
Comprehensive genomic and transcriptomic profiling of pediatric malignancies using the Tempus xT Next-Generation Sequencing Assay to identify clinically meaningful alterations.
Authors: Stephanie Toll, Aneta Kwiatkowska-Piwowarczyk, Jeff Schaeffer, Anna Ewa Schwarzbach, Stefanie Marie Thomas, Kristiyana Kaneva
Journal: Journal of Clinical Oncology (2021)

e22002 Background: Our understanding of the genomic makeup of childhood cancers has accelerated over the past decade largely due to next-generation sequencing (NGS) utilized to identify genetic drivers, aid diagnostics and risk stratification, and detect therapeutic targets. Here, we present the genomic and transcriptomic landscape of pediatric malignancies tested with a broad NGS panel at a large commercial CLIA/CAP laboratory, Tempus Labs. Methods: We used the Tempus LENS platform to analyze DNA- and RNA-seq data from a cohort of 150 de-identified records of patients with pediatric cancer aged 0 to 18 years who underwent NGS with the Tempus xT platform. Results: The cohort included 139 solid tumors, 46 of which were central nervous system (CNS) tumors, and 11 hematologic malignancies. A total of 115 samples (77%) had at least one clinically meaningful pathogenic somatic variant detected, with TP53 variants being the most common (n=26; 17.3%). Gene fusions, most commonly EWSR1-FLI1 and KIAA1549-BRAF, were observed in 31 cases (20.7%). Matched tumor/normal testing revealed at least one incidental pathogenic germline variant in six patient records, with two cases harboring two distinct variants. Four cases had tumor mutational burdens (TMBs) greater than 10 mutations/megabase, including two that also exhibited high microsatellite instability (MSI). Conclusions: The Tempus xT tumor/normal-matched platform detects clinically meaningful genomic alterations in pediatric cancers important for diagnosis, prognosis, therapeutic target identification, and incidental germline findings. We continue to accumulate and structure data to meet the need for a large, accessible pediatric cancer clinical and molecular dataset. [Table: see text]
Costs, throughput time, and proportion of valid test results, a model-based analysis of liquid biopsies for stage IV non-small cell lung cancer.
Authors: Simone N. Koole, Robert Schouten, Daan Vessies, Milou Schuurbiers, Linda J.W. Bosch, Michel van den Heuvel, Wim van Harten, Daan van den Broek, Kim Monkhorst, Valesca P. Retel
Journal: Journal of Clinical Oncology (2021)

e18844 Background: Tissue diagnostics for metastasized non-small cell lung cancer (NSCLC) is hampered by the difficulty of obtaining tissue biopsies, and sequential testing. This leads to patient burden, and a time-consuming diagnostic trajectory, sometimes without valid test results. We analyzed the diagnostic process of liquid biopsies (ctDNA) as an addition to tissue diagnostics, for patients with stage IV NSCLC. Methods: Data was retrieved from stage IV patients (N=209) included in the observational, Lung cancer Early Molecular Assessment trial (LEMA; NCT02894853). Within this study, plasma and tissue was collected upfront. Sequencing of ctDNA was performed retrospectively, and compared to results from tissue diagnostics, as performed in the including hospital, including test results, success-rates, and identified targets per patient. Throughput time for tissue, and costs for diagnostics were calculated within a single specialized institute. Because of the retrospective nature of the ctDNA assessment, diagnostics for implementation of ctDNA was modelled (1 run per week), based on estimations for the trajectory and throughput time. A discrete-event simulation model was developed with three scenarios: 1) diagnostics with tissue biopsy alone (comparator); 2) diagnostics with ctDNA first, and tissue biopsy if required; 3) ctDNA if biopsy failed. The process scope ranged from tissue/blood retrieval to outcome in terms of targets. Simulation analysis was performed, calculating mean price per patient (pp), median throughput time pp, and targets found per scenario. Results: In scenario 1, 85% of the patients had a clinically relevant test result, compared to 93% and 92% when ctDNA was added in scenario 2 and 3, respectively. Scenario 2 was the fastest, but also the costliest scenario: median throughput time 15 days pp (IQR 8-30) and mean costs of €2.716 pp (standard deviation [SD] €789) (Table). In this scenario, 9.9% of the biopsies could be cancelled, and in 39.6% a simple biopsy with immunohistochemistry was sufficient. Conclusions: The addition of ctDNA may lead to better informed treatment decisions in patients with stage IV NSCLC. Discrete-event simulation analysis showed that the addition of ctDNA in the diagnostic process increased proportion of patients with a clinically relevant test-result in both scenarios. Throughput time is faster, and additional costs per patient are limited, especially when ctDNA is added after biopsy failure. Clinical trial information: NCT02894853. [Table: see text]
Treatment of metastatic acral lentiginous melanoma: Systematic review.
Authors: Aylen Vanessa Ospina Serrano, Javier Segovia, Luis Eduardo Pino, Ivan Camilo Triana, Santiago Rojas
Journal: Journal of Clinical Oncology (2021)

e21536 Background: Acral lentiginous melanoma (AML) is infrequent malignant melanoma subtype (5%) .It does not have specific treatment. The objective of this article is to summarize the best available evidence regarding the specific treatment of metastatic acral lentiginous melanoma. Methods: A systematic review of the literature was proposed. A search was carried out in the databases of Pubmed, Embase, Scopus, Lilacs in English and Spanish, during the last 20 years. The equation used was ((“acral lentiginous melanoma”) AND (“Treatment”)). For quality assessment, the JAMA guidelines for qualifying and globally through the GRADE system, the Cochrane guideline for evaluation of clinical trial bias was used. The review process involved 3 researchers and differents filters for evaluating the scientific evidence. The primary outcome was overall survival (OSm) and progression-free survival (PFS) as a secondary outcome. Results: 208 articles were found, only 3 articles were included. No phase 3 clinical trial. The summary of the data and qualification of evidence are in Table. In total there were 63 patients. It was found high heterogeneity in the 3 studies. The outcomes were those reported directly from each study, a subgroup analysis was not required. In first study, overall survival 21.1m was found with Dasatinib and PFS 2.8m. The second clinical trial, found OS with Nivolumab of 28.7% at 3 years. The last study was observational, and included three different treatment options, the outcomes were: Chemotherapy OSm 8.3m and PFS 2.1m, Immunotherapy OSm 16.6m and PFS 11.4m and Targeted therapy OSm 21.7m and PFS 11.4m. Conclusions: Worldwide, there is no good quality scientific information to define the best specific treatment for acral lentiginous melanoma. Current available evidence suggests that treatment with targeted therapies such as c-kit, V600E or immunotherapy as some useful options. Link Prospero: CRD42020171528.[Table: see text]
Development of a DNA damage response (DDR) therapeutics platform for oncology.
Authors: Debanu Das, Matthew Duncton, Patricia Pellicena, Ashley Deacon, David Wilson, Millie Georgiadis
Journal: Journal of Clinical Oncology (2021)

e15036 Background: Cancer cells respond to increases in DNA damage by deploying their DNA damage response (DDR) pathways. We are building a platform for the discovery and development of target-specific DDR therapeutics, including small molecule inhibitors and targeted protein degradation warheads, founded on fragment- and structure-based drug discovery. Methods: Our DDR platform, which includes hit-to-lead, lead optimization and candidate selection, starts with hit generation from a new technology that uses high-throughput protein X-ray crystallography to directly screen compound libraries. Our hit generation process produces empirical evidence of direct target engagement. The elucidation of high-quality ligand-bound 3D structures reveals the location and pose of the ligand and details of the protein-ligand interactions. Thus we can predict the structure-function consequences of the hit molecule engagement, which sets the stage for rapid assessment of synthetic tractability and intellectual property. After hit identification, we apply a multi-pronged approach in hit-to-lead conversion and lead optimization using iterative biophysical and biochemical assays, coupled with crystallography. We are applying our approach to several new targets in DDR and will present some early progress in this space. Results: Apurinic/apyrimidinic endonuclease 1 (APE1) is the major repair enzyme for abasic sites in DNA and contributes to DNA strand break processing. Many studies have associated increased APE1 levels with enhanced growth, migration, and drug resistance in human tumor cells, and with decreased patient survival. APE1 has been implicated in over 20 human cancers, including glioblastoma, making the protein an attractive target for the development of anticancer therapeutics. Despite intensive effort, there are no clinical endonuclease inhibitors of APE1. We have identified 25 diverse small molecule fragments that bind to APE1 at two distinct sites, including the endonuclease site. Pol eta (or PolH) is a DNA polymerase implicated, among other things, in the development of cisplatin resistance in a subset of ovarian cancers. In our quest to develop PolH inhibitors, we have identified 5 diverse fragments that bind to two distinct sites in the polymerase including a new potential allosteric site. Our results on APE1 and PolH represent the first known cases of crystal structures of small molecules bound to these proteins. Flap endonuclease (FEN1) is implicated in several cancers including for example ER/tamoxifen-resistant breast cancer. We are developing a targeted protein degradation approach using PROTACs (Proteolysis-Targeting Chimeras) toward the development of novel therapeutics against FEN1. Conclusions: Our results will help us develop small molecule inhibitors and targeted protein degradation against DDR targets that may be effective as single therapies or be used to make existing therapies more effective.
Feasibility of a telemedicine lifestyle-based rehabilitation program (HEAL) for gynecologic cancer patients.
Authors: Nathalie Dauphin McKenzie, Nnamdi Ifekandu Gwacham, Julie W. Pepe, Sarfraz Ahmad, James Erasmus Kendrick, Robert W. Holloway
Journal: Journal of Clinical Oncology (2021)

e24033 Background: General health related factors such as obesity, unhealthy diets disproportionate with sugary and highly processed foods, inactivity, and smoking have repeatedly been shown to negatively impact survival and quality of life outcomes in cancer survivors. The Healthy Eating Active Lifestyle (HEAL) – GYN “rehabilitation” cancer program was developed to provide intensive group lifestyle training on exercise, nutrition, sleep, social integration, and stress management via a telemedicine platform. The aim of this study was to determine the feasibility of such an intervention and its tolerability, in addition to its impact on short-term quality of life for gynecologic cancer patients. Methods: HEAL – GYN consists of 8 weekly group sessions offering experiential instruction and personalized goal setting for patients with diagnosis of gynecologic cancer. Components are drawn from the tenets of lifestyle medicine. An oncologist certified in lifestyle medicine along with a multidisciplinary rehabilitation team addressed diet, physical activity, strategies for sleep and stress management, smoking cessation, and alcohol intake. The intervention included training to address unmet psychologic, emotional, physical, sexual, social, and spiritual needs common to cancer survivors. American College of Lifestyle Medicine questionnaires were administered, utilizing Likert scales (1-5) in a pre- and post- fashion to assess improvements in physical activity levels, dietary habits, sleep hygiene, and quality of life. Medical records were reviewed including anthropometric data. Results: 26 patients have enrolled thus far, and we report outcomes on the first 20 participants. The mean age was 58.8 years; 22 were Caucasian, and 7 were on maintenance therapies for gynecologic cancers. Average total severity of reported symptoms (scale = 100 points) on a general medical symptom questionnaire (MSQ) decreased by 22% (61 vs 48). Eight patients reported increased perceived levels of health and 6 had stable perception of health. There were also notable improvements from baseline in item assessments of eating behavior (34%), perceived stress (20%), and resilience (21%). Patients also reported a notable trend towards improvement in anxiety (35%) and depression (34%), as well as social integration and connectedness (30%). 100% of participants would “highly recommend the program” and none complained of stress or altered mood associated with online instruction. Conclusions: The telemedicine HEAL – GYN peri-habilitation program is feasible and well tolerated. In addition, the program may improve quality of life and may prevent further decline for those on treatment or maintenance therapy. These preliminary findings support continued investigation of a telemedicine healthy lifestyle peri-habilitative program.
Transcriptional Repression of RASSF2 Impairs Hippo Kinase-Dependent p53 Activation and Tumor Suppression in t(8;21) AML
Authors: Samuel A Stoner, Elizabeth T Andrews, Kei-Ichiro Arimoto, Ming Yan, Stephanie Weng, Russell Dekelver, Miao-Chia Lo, Kun-Liang Guan, Dong-Er Zhang
Journal: Blood (2017)
Treatment outcomes in patients (pts) with melanoma brain metastases (MBM) treated with systemic therapy: A systematic literature review (SLR) and meta-analysis.
Authors: Hussein Abdul-Hassan Tawbi, Georgina V. Long, Nicolas Meyer, Boris Breznen, Charmy Vyas, Lisa Leung, Andriy Moshyk, Divya Pushkarna, Pratik K. Thakkar, Mir Sohail Fazeli, SRIVIDYA KOTAPATI, Dirk Schadendorf
Journal: Journal of Clinical Oncology (2021)

9561 Background: The introduction of immunotherapy and targeted therapy has revolutionized the treatment landscape for metastatic melanoma. However, clinical trial data in pts with MBM are scarce; here we summarize the available clinical evidence. Methods: An SLR was conducted by searching EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials databases through November 13, 2020. When available, Kaplan-Meier (K-M) curves for overall survival (OS) were digitized and converted to pseudo-individual pt data using the Guyot algorithm. A meta-analysis of the pooled K-M curves was performed for selected interventions, including immunotherapies and targeted therapies. Median OS was calculated either through the meta-analysis of K-M curves or as a weighted average of median OS (table). When interventions were reported in only 1 study, the value reported was used instead of the weighted average and compared qualitatively with the other results. Results for treatment modalities other than systemic agents will also be presented. Results: The SLR included 70 publications that evaluated systemic therapies in pts with MBM for qualitative evidence synthesis: 12 pertaining to 7 randomized controlled trials, 55 pertaining to 46 single-arm studies, and 3 involving nonrandomized comparative studies. The pt population was highly heterogeneous with respect to prior therapies, pt characteristics, and neurological symptoms. For the meta-analysis, a total of 25 K-M curves from 12 studies representing 6 interventions and 1043 pts were digitized. Based on the pooled K-M curves, median OS was numerically longer with nivolumab plus ipilimumab (NIVO + IPI; 28.3 mo; 95% CI, 19.7-31.9) than with the other interventions (range 5.7-11.8 mo; table). Similar OS benefit was also observed with NIVO + IPI when the weighted average of the median was used (in a long-term study, median OS was 29.2 mo) compared with the other interventions. Conclusions: Given the lack of comparative clinical trial data in pts with MBM, there remains an unmet need to determine the best approach to treat these pts. This analysis suggested a clinical advantage with NIVO + IPI compared with other systemic agents analyzed. The heterogeneity of the available data added uncertainty to our treatment assessments. Therefore, these findings warrant further research into the best approach to improve outcomes in pts with MBM.[Table: see text]
Effects of tobacco smoking on recurrent hospitalisation with pneumonia: a population-based cohort study
Authors: Vadsala Baskaran, Wei Shen Lim, Tricia M McKeever
Journal: Thorax (2021)

The incidence of and risk factors for recurrent hospitalisation for pneumonia were investigated using data from Hospital Episode Statistics, linked to a UK primary care database. Within 90 days and 1 year of follow-up, 1733 (3.1%) and 5064 (9.0%), developed recurrent pneumonia respectively. Smoking status at the time of hospitalisation with index pneumonia was associated with the risk of readmission with recurrent pneumonia within a year of discharge: current versus never smokers: adjusted subhazard ratio (sHR) 1.42, 95% CI 1.32 to 1.53, p&lt;0.001, and ex smokers versus never smokers: adjusted sHR 1.24, 95% CI 1.15 to 1.34, p&lt;0.001. Other independent risk factors associated with recurrent pneumonia were age, gender, deprivation and underlying comorbidities.
Mitigating the risk of transfusion-transmitted bacterial infections in hematology oncology patients.
Authors: Harold Alvarez, Marion Lanteri, Guenther Koehne
Journal: Journal of Clinical Oncology (2021)

e19047 Background: Hospital acquired infections create major logistical, financial, and patient safety concerns within the healthcare system. Bacterial contamination (BC) of platelet components (PCs) can lead to transfusion-transmitted bacterial infections (TTBI), central line-associated bloodstream infections, and sepsis, with long-term complications and/or death. In the US, hematopoietic stem cell transplant (HSCT) recipients require transfusion support until engraftment and together with hematology/oncology (hemonc.) patients receive the highest number of PCs/patient. FDA’s Guidance recommends approaches to reduce BC risk including the use of enhanced bacterial culture screening (EBSC) or pathogen reduction (PR) of platelets. Methods: The Miami Cancer Institute (MCI) implemented PR-PCs for all allogeneic HSCT patients. Irradiation, CMV testing, and bacterial screening have been discontinued for PR-PCs. Transfusion outcomes are being monitored using active hemovigilance (HV) reporting. Results: Considering the fatality risk associated with BC of PCs (1:200,000 – 1:1,000,000) despite the use of optimal skin cleansing, initial sample diversion, and primary bacterial culture, 1/2,880 PCs are still contaminated (Bloch et al.); further steps towards BC mitigation are needed. As the UK and US reported a residual BC risk of 5.4-9.4/million PCs after implementation of EBSC, PR may represent an alternative approach with other cumulative benefits. Indeed, national HV data from France, Switzerland and Belgium reported no sepsis transfusion reactions since PR implementation (Benjamin et al.). In addition, the risk of TA-GVHD and other TTI including emerging infectious diseases (EID) may be decreased after the inactivation of pathogens and leukocytes (Lanteri et al.). At MCI, the percentage of transfused PR-PCs has been increasing steadily from 7.9% in July 2019 to 22.2% in January 2021. Over a 19 month-period, a total of 9,296 PC were transfused including 1,677 PR-PCs. While non-PR-PCs were all irradiated and bacterially screened, PR-PC were neither irradiated nor bacterially screened. No cases of TA-GVHD or TTI were reported. A total of 27 mild, non-life-threatening platelet transfusion reactions were reported including 22 (81.5%) after non-PR PCs transfusion and 5 (18.5%) after PR-PC transfusion. In addition, the early release of transfusion-ready fresh PR-PCs 24-48 hours after collection has proven invaluable in providing clinicians and patients with blood continuity during the COVID-19 pandemic. Conclusions: Though certain measures have improved blood safety, the risk of TTI associated with PC transfusion remains a concern for vulnerable hemonc. patients. Using PR-PC is especially important to consider when patients undergo extensive life-saving therapies such as bone marrow transplants.
An injectable, self-healing, electroconductive extracellular matrix-based hydrogel for enhancing tissue repair after traumatic spinal cord injury
Authors: Yian Luo, Lei Fan, Can Liu, Huiquan Wen, Shihuan Wang, Pengfei Guan, Dafu Chen, Chengyun Ning, Lei Zhou, Guoxin Tan
Journal: Bioactive Materials (2021)

Injectable biomaterial-based treatment is a promising strategy to enhance tissue repair after traumatic spinal cord injury (SCI) by bridging cavity spaces. However, there are limited reports of injectable, electroconductive hydrogels with self-healing properties being employed for the treatment of traumatic SCI. Hence, a natural extracellular matrix (ECM) biopolymer (chondroitin sulphate and gelatin)-based hydrogel containing polypyrrole, which imparted electroconductive properties, is developed for traumatic SCI repair. The resulting hydrogels showed mechanical (~928 Pa) and conductive properties (4.49 mS/cm) similar to natural spinal cord tissues. Moreover, the hydrogels exhibited shear-thinning and self-healing abilities, which allows it to be effectively injected into the injury site and to fill the lesion cavity to accelerate the tissue repair of traumatic SCI. In vitro, electroconductive ECM hydrogels promoted neuronal differentiation, enhanced axon outgrowth, and inhibited astrocyte differentiation. The electroconductive ECM hydrogel activated endogenous neural stem cell neurogenesis in vivo (n = 6), and induced myelinated axon regeneration into the lesion site via activation of the PI3K/AKT and MEK/ERK pathways, thereby achieving significant locomotor function restoration in rats with spinal cord injury (p < 0.001, compared to SCI group). Overall, the injectable self-healing electroconductive ECM-based hydrogels developed in this study are ideal biomaterials for treatment of traumatic SCI.
Reply to: Digging mediastinal holes with vigour: a word of caution
Authors: Jing Zhang, Zan-Sheng Huang, Felix J.F. Herth, Ye Fan
Journal: European Respiratory Journal (2021)

We thank T.K. Tournoy and K.G.Tournoy for their thoughtful letter in response to our manuscript on transbronchial mediastinal cryobiopsy [1].We agree that our study shows no differences in the diagnostic yield of lung cancer between endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and mediastinal cryobiopsy, thus it would be premature to consider mediastinal cryobiopsy as the standard nodal staging strategy in lung cancer.In our cohort, a diagnosis of non-small cell lung cancer is established by EBUS-TBNA but not cryobiopsy in three patients, which might be attributed to the relatively fixed biopsy location of mediastinal cryobiopsy.Nevertheless, it should be noted that there were six lung cancer cases only diagnosed by mediastinal cryobiopsy.