tbuckley/cabot-search huggingface dataset:
Machine learning based biomarkers to predict CD8 infiltration in non-small cell lung cancers using CT imaging.
Authors: Yan Liu, Danny Francis, Vladimir Groza, Charles Voyton, Afef Baili-Laya, Benoit Huet, Nozha Boujemaa
Journal: Journal of Clinical Oncology (2021)

e21145 Background: Immune-checkpoint inhibitors (ICIs), specifically monoclonal antibodies targeting the programmed cell death protein-1 and programmed death-ligand 1 (PD-1 and PD-L1) have shown promise in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, patients response to ICI is difficult to predict, with cancer stage, treatment line and regimen all affecting response rates. Identification of patients who will be “responsive” to ICI is of great importance to increase treatment efficacy. Current techniques used to identify responsive patients rely on PD-L1/PD-1 expression, microsatellite instability, tumor mutagenic burden and less commonly CD8+ infiltration, all of which are invasive and costly procedures. In this study we aim to develop a machine learning derived CT imaging biomarker that predicts CD8 status of tumors, allowing for non-invasive determination of ICI treatment efficacy. Methods: To study CD8 infiltration we extracted patients that included CT scans and CD8 transcript data from publicly available cohorts (TCGA-LUSC, TCGA-LUAD, NSCLC-Radiogenomics) to produce the Lung3 cohort (104 patients). Using this cohort, we trained (80 patients) and tested (24 patients) an AI model to predict tumor CD8 infiltration using patient CT scans as the sole input. CD8 expression (high and low) was characterized using transcriptomic quantification and served as surrogate for CD8+ infiltration, following previously described methods. Supervised and unsupervised models previously trained to identify lung features were trained to identify CD8 status using the CD8 expression data provided in the Lung3 dataset. Algorithm performance was tested on a randomly chosen subset of the cohort (24 patients) and compared against transcriptomic confirmed CD8 expression. AUC were calculated for supervised and unsupervised models. Results: AUC for the supervised and unsupervised models generated using the Lung3 cohort are shown below. Our results suggest that the derived supervised and unsupervised models could identify the CD8 infiltration status using only patient CT scans in the test dataset. Conclusions: The machine learning based models described here show encouraging results suggesting that CT imaging of NSCLC lung cancers contain sufficient information to predict the CD8 infiltration status of tumors. Although these results are just a proof of concept, the promise of a CT based non-invasive marker for tumor immune status is encouraging to help advance treatment efficacy in the ever-growing field of ICI therapy. References: (1)Wu, X. et al. (2019). (2) Schulze, A. B. et al. (2020). (3) Sun, R. et al. (2018).[Table: see text]
New ways of working will help patients and sustain our profession
Authors: Vasumathy Sivarajasingam
Journal: BMJ (2021)

Salisbury asks whether additional roles could reduce pressure on general practice and how we can create a truly sustainable practice for health service staff.12

During my training and working as a general practitioner for nearly 20 years, I have been made aware of the significance of “increased workload, burnout, and work-life balance.” The covid-19 pandemic has given us a chance to step back, recuperate, and reflect on our working lives. The time has …
The impact of COVID-19 on oncologists: Experience from Egyptian physicians.
Authors: Abeid Mohamed Athman Omar, Marwa Ramadan, Yomna Khamis, Abdelsalam A. Ismail
Journal: Journal of Clinical Oncology (2021)

e13514 Background: The unprecedented emergence of coronavirus disease (COVID-19) has disrupted the patients' and physicians' daily activities, including cancer care. However, little is known on how COVID-19 has impacted oncologists from low and middle-income countries. Methods: We conducted a cross-sectional survey among eighty-eight practicing oncologists in Alexandria governorate, Egypt. An electronic, anonymized self-reporting survey was distributed in February 2020 to collect information on occupational safety measures, the prevalence of COVID-19 among respondents, workload, and family support during the pandemic Results: Out of 88 contacted oncologists, 75% completed the survey (n=66). Nearly half (45%) of respondents were residents, 36% were specialists, and 18% were consultants. The mean age of respondents was 34.79 years (SD ±10.42). More than half of the respondents were not comfortable managing cancer patients during the pandemic (56%) and did not feel well-protected at the workplace (58%). However, most (79%) had managed a cancer patient with COVID-19 more than once. Furthermore, almost all participants (98%) have worked with an infected colleague. Nevertheless, to more than half (54%), it made no difference working with a colleague who was previously infected. Most physicians (79%) felt overwhelmed with workload than the pre-pandemic period. Despite being COVID-19 negative, nearly half reported their family members had reduced contact with them due to the fear of being infected. In contrast, 24% are now getting more family support, whereas 27% are experiencing the same contact level as before the COVID-19 era. Physicians lacking family support had a significantly higher burnout rate than those who had family support (p=0.038). However, the burnout rate was similar regardless of doctors' rank, or treating COVID-19 patients, or feeling protected at work. The majority of the participants (75%) had experienced COVID-19 like symptoms, and one third (n=21) were confirmed COVID-19 infected: residents - 52%, specialists - 33%, and consultants - 14%. Nevertheless, we found no association between the rank and being infected with COVID-19 (p=0.632). Most participants thought they were infected at the hospital (38% by patients; 24% by colleagues), and 14% by family members. However, there was no significant association between being infected and feeling protected at work (p=0.823). Most of the infected physicians (61%) received moral support from both the family and colleagues, and 33% received family support only. There was no association between burnout rate and being COVID-19 infected (p=0.719). Conclusions: One-third of the oncologists were COVID-19 positive. Besides, most oncologists feel overwhelmed with workload and experience more burnout than before the COVID-19 era, and it worsens if one lacks family support.
Identification and analysis of immune microenvironment characterization and key signal pathways in liver metastasis.
Authors: Xiaoxia Zhu, Zhihao Zheng, Yuhang Jiang, Luyao Li
Journal: Journal of Clinical Oncology (2021)

e15004 Background: The liver represents a common site for metastatic disease, patients with advanced malignancies were usually associated with worse prognostic outcomes once liver metastasis has occurred. The aim of this study was to explore the immune microenvironment characterization and key signal pathways of liver metastasis in colorectal cancer (CRC) and breast cancer (BRCA), and to provide potential targets and decision-making basis for the diagnosis and treatment of patients with liver metastasis. Methods: Two datasets (GSE49355 and GSE58708) were downloaded from the Gene Expression Omnibus (GEO) database, and patients with primary tumors and paired liver metastases were enrolled. Data were processed by the limma and Deseq2 package and the differentially expressed genes (DEGs) were identified. Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG) and Reactome pathway analysis was performed using clusterProfiler package. Prognosis markers were identified via survival analysis of The Cancer Genome Atlas (TCGA) databases. CIBERSORT algorithm was used to calculate the proportions of 22 types of infiltrated immune cells. We used Spearman’s correlation analysis to describe the correlation between gene expression and microsatellite instability (MSI) or tumor mutational burden (TMB) score. Results: We investigated 16 patients with paired specimens (3 patients with BRCA and 13 patients with CRC). A total of 424 and 49 DEGs were identified in the BRCA and CRC samples. Only 26 DEGs were shared by the two kinds of cancers. The functional enrichment analysis suggested that the functions of DEGs were mainly related to cholesterol metabolism, complement and coagulation cascades, platelet activation etc. The survival analysis indicated that high expression levels of SERPINA3 was associated with a better prognosis in TCGA-BRCA (P = 0.01), while high ITIH2 and COLEC11 expression correlated with poor prognosis in TCGA-COAD (P = 0.045 and P = 0.013, respectively). CIBERSORT analysis revealed a significantly increased proportion of M2-macrophages and decreased proportion of activated mast cells in liver metastases. The Spearman correlation analysis showed that the SERPINA3 expression had a significantly negative relationship with the TMB (r = -0.26, P＜0.001) in TCGA-BRCA, but not significantly associated with the MSI (r = -0.02, P = 0.520), while the COLEC11 expression was significantly correlate negatively with the MSI and TMB (r = -0.15, P &lt; 0.001 and r = -0.23, P &lt; 0.001, respectively) in TCGA-COAD. Conclusions: The immune microenvironment of liver metastases exhibits a significant increase in the proportion of M2-macrophages and a significant decrease in the proportion of activated mast cells, and the key signal pathways implicate cholesterol metabolism and platelet activation. The specific mechanism needs to be further elucidated. Support: 81972853, 81572279, LC2019ZD009.
Thiazolidinediones and Glucagon‐Like Peptide‐1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study
Authors: Judith van Dalem, Johanna H. M. Driessen, Andrea M. Burden, Coen D. A. Stehouwer, Olaf H. Klungel, Frank de Vries, Martijn C. G. J. Brouwers
Journal: Hepatology (2021)

Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists.We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63).Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings.
Molecular subtypes of pancreatic adenocarcinoma stratified based on copy number variation profile.
Authors: Qian Zhan, Chenlei Wen, Zhao Yi, Henghui Zhang, Baiyong Shen
Journal: Journal of Clinical Oncology (2021)

e16232 Background: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas all over the world, with an estimate of 60,430 new cases and 48,220 deaths in United States according to the cancer statistics of 2021. It is important and urgent to identify molecular subtypes for stratifying PAAD into different groups with respective genomic footprint, appropriate treatment and prognosis status. Methods: We profiled a comprehensive landscape of genomic alterations for 608 PAAD patients in a Chinese cohort, including somatic mutations, pathogenic germline variants and copy number variations (CNVs). 233 out of 608 PAAD had disease-free survival (DFS) information with at least 6-month follow-up. Focusing on this subset of PAAD, we explored prognostic values for several kinds of genomic alterations and finally identified four molecular subtypes based on CNV profile. Results: For point mutations in highly mutated genes ( KRAS, TP53, CDKN2A and SMAD4) or homologous recombination repair (HRR) genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, NBN, PALB2, RAD50/ 51B/ 51C/ 51D/54L and MRE11A), we found no associations between them and prognosis of PAAD patients. Instead, PAAD could be stratified into four molecular subtypes based on CNV profile through unsupervised clustering and CNV score defined by principle component analysis (PCA). According to amplification and deletion pattern of genes in DNA repair and receptor tyrosine kinase related signaling pathways, we named these four subtypes as repair-deficient, proliferation-active, repair-proficient and repair-enhanced ones. Among them, repair-deficient PAAD had the best prognosis with median DFS of 410 days, repair-proficient and proliferation-active one had median DFS of 239 and 197 days, respectively, while repair-enhanced one had the worst prognosis with DFS of 48 days. Genomic footprint analysis showed that both of repair-deficient and proliferation-active subtypes of PAAD possessed higher copy number instability (CNI), while both of repair-proficient and repair-enhanced subtypes possessed higher tumor mutational burden (TMB), implying that the former two subtypes suited for DNA damage therapies (such as platinum-based chemotherapy and PARPi) and the latter two subtypes suited for immunotherapy. Conclusions: We identified four molecular subtypes for PAAD based on CNV profile and found their respective genomic footprint, suited treatment and prognosis status, pacing key steps to precision medicine in PAAD field.
Preliminary results of V-FAST, a phase 1b master trial to investigate CPX-351 combined with targeted agents in newly diagnosed AML.
Authors: Vinod Pullarkat, Mark J. Levis, Gabriel N. Mannis, Stephen Anthony Strickland, Tara L. Lin, Stefan Faderl, Divya Chakravarthy, Vijayalakshmi Chandrasekaran, Ronald Cheung, Harry Paul Erba
Journal: Journal of Clinical Oncology (2021)

7026 Background: CPX-351 (US: Vyxeos; EU: Vyxeos Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio, is approved by the US FDA and EMA for adults with newly diagnosed t-AML or AML with myelodysplasia-related changes. Preclinical data suggest CPX-351 may exert synergistic activity when combined with agents such as the BCL-2 inhibitor venetoclax (VEN) or FLT3 inhibitor midostaurin (MIDO). Methods: V-FAST (Vyxeos – First Phase Assessment With Targeted Agents) is an open-label, multicenter, phase 1b master trial (NCT04075747) to evaluate safety and establish the recommended phase 2 dose (RP2D) of CPX-351 combined with targeted agents in patients (pts) aged 18-75 y with untreated AML who are fit for intensive chemotherapy. The study includes a dose-exploration phase (3+3 design) and subsequent expansion phase. Pts received CPX-351 (dose level 1 for first induction [DL1]: 100 units/m 2 on Days 1, 3, and 5) plus VEN (Arm A; DL1: 400 mg on Days 1-14), MIDO (Arm B; DL1: 50 mg BID on Days 8-21), or the IDH2 inhibitor enasidenib ([ENA] Arm C; DL1: 100 mg on Days 8-28) based on mutation testing. Results: Among 21 pts with available data enrolled by 11/06/20 (24 pts enrolled total; data cut-off: 01/19/21), the median age was 54 y (range: 35, 69). In Arm A (n = 17), 11 (65%) pts had de novo AML, 5 (29%) had an antecedent hematologic disorder (2 [12%] had myelofibrosis), and 2 (12%) had t-AML; 12 (71%) had adverse-risk AML; and 6 (35%) had mutated TP53. In Arms B (n = 3) and C (n = 1), all pts had intermediate-risk de novo AML. DL1 was the RP2D in Arms A and B; the RP2D in Arm C is still under investigation. In Arm A, 1/6 pts in the dose-exploration phase had 2 dose-limiting toxicities (DLTs) of grade 4 neutropenia and thrombocytopenia that extended beyond 49 days; no DLTs have occurred for Arms B and C. The combinations exhibited manageable safety profiles (Table). Of pts with available response data, complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) pts in Arm A, including 4 (29%) with CR. All pts in Arms B and C achieved CR. Conclusions: These preliminary results suggest CPX-351 can be combined with VEN and MIDO with manageable toxicities in newly diagnosed AML pts, with DL1 determined to be the RP2D. The study is ongoing and actively enrolling pts; updated results will be presented at the meeting. Clinical trial information: NCT04075747. [Table: see text]
The effect of household wealth on financial debt after cancer diagnosis.
Authors: Syed Hussaini, Mia Dana, Lauren Nicholas
Journal: Journal of Clinical Oncology (2021)

e18552 Background: Cancer is the 2 nd most common cause of death in the country, eclipsed only by heart disease. Cancer care is increasingly characterized by financial toxicity related to high-cost treatments, though it is unknown whether other chronic conditions impose similar financial harms. Methods: We conducted a retrospective analysis of the Health and Retirement Study participants interviewed between 2012-2018. This is a national, longitudinal survey conducted every two years of adults 50 and older and their spouses. We used fixed effect regression models to compare changes in financial debt among households with new diagnosis of cancer, other major chronic conditions (diabetes, stroke, or heart disease), and no new health diagnosis (or health shock). Since more affluent households may respond to health shocks differently, we estimated separate comparisons for households above versus below median wealth in 2012, prior to new health conditions. We assessed use of any non-housing financial debt, credit card debt, and home equity lines of credit among the subset of homeowning households. Results: In this study of 14,153 households, average age at interview was 62 years, with 43% male, 70% White, 22% Black, 13% Hispanic, and 70% with up to high school education. Of this population, 25% held credit card debt, 70% owned a home, 18% had a home equity line of credit, and 9% used a home equity line of credit. Among households with below median wealth when they entered the study in 2012 ( &lt; $23,000 in $2016), a new cancer diagnosis was associated with a 4.7 percentage point increase in financial debt (12.5% effect size, p &lt; 0.05). Participants diagnosed with a chronic condition (heart condition, stroke or diabetes) were 3.6 percentage points more likely to develop financial debt (9.6%, p &lt; 0.05) compared to households that did not develop a new chronic condition. Such differences were eliminated in participants in a house with above median wealth. There was no difference in credit card debt, availability of home equity line of credit, or use of home equity line of credit for participants with a new diagnosis. Conclusions: New diagnosis of cancer or a chronic condition were associated with increased financial debt for older Americans living in a household that were below median wealth.
AUREA study: Atezolizumab (Atezo) combined with split-dose gemcitabine plus cisplatin (s-GC) in locally advanced or metastatic urothelial cancer (LA/mUC): A SOGUG study.
Authors: Alfonso Gomez De Liano Lista, Georgia Anguera, Emilio Esteban, Ovidio Fernandez Calvo, Iciar García-Carbonero, Xavier Garcia del Muro, Iria González Maeso, David Lorente-Estelles, Esther Martínez Ortega, Alvaro Pinto, Javier Puente, Guillermo de Velasco
Journal: Journal of Clinical Oncology (2021)

TPS4589 Background: First-line cisplatin-based chemotherapy (70 mg/m 2 ) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky´s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression ≥5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age &gt; 70 years, PS ECOG 0-2, creatinine Clearance &gt;30 and &lt;60 mL/min per Cockroft-Gault formula or by 24-hour urine collection. Other reasons for cisplatin ineligibility as considered by investigator, including those uncovered by Galsky´s criteria, will be allowed, prior discussion with PI. Exclusion criteria include prior systemic therapy for LA/mUC (adjuvant/neoadjuvant allowed if finished &gt; 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078.
Interest of extracellular vesicles in regards to lipid nanoparticle based systems for intracellular protein delivery
Authors: Sarah Le Saux, Anne Aubert-Pouëssel, Khaled Elhady Mohamed, Pierre Martineau, Laurence Guglielmi, Jean-Marie Devoisselle, Philippe Legrand, Joël Chopineau, Marie Morille
Journal: Advanced Drug Delivery Reviews (2021)