tbuckley/cabot-search huggingface dataset:
Analysis of first-line treatment (tx) patterns in advanced non-small cell lung cancer (NSCLC) patients (pts) with compromised performance status (PS), organ dysfunction (dfxn) or other significant comorbidities.
Authors: Julia Judd, Elizabeth A. Handorf, Brinda Gupta, Martin Edelman
Journal: Journal of Clinical Oncology (2021)

e21093 Background: NSCLC is a disease of the elderly and most cases are related to tobacco. Therefore, concomitant organ dfxn, which increases the risk of toxicity with cancer directed therapy, is prevalent. Patterns of care studies have shown that the elderly, those with organ dfxn or compromised PS are frequently not treated, despite prospective studies demonstrating survival benefit with active tx. We hypothesized that the advent of new, more active therapies has resulted in practice changes in these populations. Methods: We conducted a retrospective, observational cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to compare first line tx patterns from 2011 to 2020 in pts with advanced NSCLC meeting at least 1 of the following criteria: age &gt; 70 years, organ dfxn (serum creatinine &gt; 1.5 times the upper limit of normal [ULN] and/or total bilirubin &gt; 2 times ULN), ECOG PS &gt; 2 or documented HIV. Pts were excluded if there was a &gt; 90-day post-diagnosis gap in EHR data. Tx patterns were categorized as having received standard, non-standard or no frontline tx. Tx groups included PD-1/PD-L1 inhibitor single agent, chemoimmunotherapy, platinum-based (Plat) doublet +/- VEGF inhibitors (VEGFi), single agent chemotherapy (chemo) and tyrosine kinase inhibitors (TKIs). Descriptive statistics were used to analyze tx patterns, and the relationship between txs and variables of interest were tested using Chi-squared tests or t-tests. Results: Of the 58,145 pts with advanced NSCLC in the database, 33,701 met at least 1 criterion for inclusion. There was a small but significant increase in the number of pts treated with standard therapy from 2011 to 2020 (p &lt; 0.001). There was rapid uptake of PD-1/PD-L1 inhibitors as well as chemoimmunotherapy upon FDA approvals in 2016 and 2018, respectively. This correlated with a rapid decrease in the use of Plat-doublet chemo +/- VEGFi as well as a decrease in the number of pts receiving single agent chemo or not treated at all (Table). Conclusions: Real world data from 2011 to 2020 demonstrates an increase in the use of standard therapies as well as the rapid incorporation of immunotherapy into first line tx in advanced NSCLC pts who are elderly, have a poor PS, or organ dfxn. However, a substantial proportion of pts (28.9%) still do not receive any documented tx, within the Flatiron Health network.[Table: see text]
The inhibitory effect of cisplatin, paclitaxel, and pemetrexed on the growth of PC9GR cells resistant to NK cell-mediated cytotoxicity during the COVID-19 pandemic.
Authors: Md Mohiuddin, Hideharu Kimura, Satoshi Watanabe, Miki Abo, Takashi Sone, Keigo Saeki, Nanao Terada, Kota Tanimura, Kazuo Kasahara
Journal: Journal of Clinical Oncology (2021)

e15009 Background: Lung cancer patients have a significantly higher risk of contracting COVID-19, and interactions with the healthcare system during cancer therapy can put patients at risk. Preliminary studies in COVID-19 patients with severe disease found a reduction in the number and function of natural killer (NK) cells. Other studies in COVID-19 patients reported acute respiratory distress syndrome (ARDS) due to the extreme release of inflammatory cytokines. Besides, adverse effects of chemotherapy, such as chemotherapy resistance and the escalation of cellular senescence can worsen the condition of patients with COVID-19. Considering these facts, we evaluated the growth-inhibitory effects of three commonly used chemotherapy drugs, cisplatin, pemetrexed, and paclitaxel, in gefitinib-resistant non-small cell lung cancer (PC9GR) cells and investigated the underlying mechanism. Methods: In this study, flow cytometry (FCM) was used to profile the activity and function of human NK cells. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify cytokine levels. PC9GR cells were treated with cisplatin, paclitaxel, or pemetrexed as monotherapy for 72 h and then evaluated with a cell viability assay, a reactive oxygen species (ROS) assay, a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, SA-β-Gal staining, and Western blotting. Results: We demonstrated that NK cell dysfunction was linked to the reduced NK-mediated elimination of PC9GR cells. The PC9GR cells showed the marked secretion of IL-6, IL-8 and VEGF cytokines, which was connected to the activation of the inhibitory signaling pathway of NK cells. We found that paclitaxel was the most potent growth inhibitor, cisplatin had an intermediate growth inhibitory effect, and pemetrexed induced a minimal growth inhibitory effect in PC9GR cells. These growth inhibitory effects were observed to be associated with ROS-mediated DNA damage, which led to the activation of apoptotic caspases. Surprisingly, paclitaxel was the strongest remover of senescent cells; pemetrexed had an intermediate effect, and cisplatin removed the lowest number of senescent cells. Conclusions: In light of these findings, paclitaxel may have a better therapeutic effect than cisplatin or pemetrexed on PC9GR cells, suggesting that paclitaxel could offer a novel therapeutic approach for the treatment of gefitinib-resistant non-small cell lung cancer during the COVID-19 pandemic.
Differential responses to therapy in Hispanic NSCLC patients with EGFR, KRAS, or TP53 mutations.
Authors: Fahmin Basher, Diana Saravia, Gilberto Lopes
Journal: Journal of Clinical Oncology (2021)

e21027 Background: Hispanic (H) patients with non-small cell lung cancer (NSCLC) tend to have more advanced disease at time of diagnosis and less likely to receive treatment compared to non-Hispanic white (NHW) Americans. While survival outcomes do not differ greatly, Hispanic patients tend to have lower response rates to immunotherapy and to targeted therapy with known EGFR mutations. We sought to determine if Hispanic patients with other common mutations present in NSCLC also demonstrate suboptimal responses to therapy compared to NHW patients. Methods: We performed a retrospective review of 468 patients with advanced stage NSCLC at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) for whom treatment outcomes could be identified. Genomic results were obtained from Guardant360 and Foundation One testing in blood or tissue, respectively. Results: In our cohort, 154 patients (33%) were of Hispanic ethnicity, while 279 patients (60%) were NHW. Median age at time of diagnosis was 59, and 50% were male. PD-L1 status was known for 217 patients, with 110 expressing some level of PD-L1. EGFR mutations were present in 25% of all patients, KRAS mutations in 25%, and TP53 mutations in 61%. Average tumor mutational burden was 4.0 in Hispanic patients and 3.6 in NHW patients. We compared outcomes in patients receiving any therapy as well as those specifically receiving immune checkpoint inhibitors (ICI). No differences in OS were observed in our overall patient cohort between H and NHW patients. However, when stratifying patients with EGFR or KRAS mutations, Hispanic patients exhibit significantly shorter OS than their NHW counterparts. In patients with TP53 mutations, we observed no differences between H and NHW outcomes considering all therapy, but Hispanic patients exhibited improved OS with the use of ICI. Conclusions: Our data suggest that the presence of certain mutations in Hispanic patients with advanced NSCLC may serve some prognostic value in predicting responses to therapy, specifically the use of ICI. Further investigation is indicated to determine mechanisms leading to inferior responses after ICI therapy in Hispanic patients.[Table: see text]
Corneal Microneedles: Single Administration of a Biodegradable, Separable Microneedle Can Substitute for Repeated Application of Eyedrops in the Treatment of Infectious Keratitis (Adv. Healthcare Mater. 11/2021)
Authors: SeungHyun Park, KangJu Lee, Heekyoung Kang, YeJin Lee, JiYong Lee, Jeong Hun Kim, Hyun Beom Song, WonHyoung Ryu
Journal: Advanced Healthcare Materials (2021)

In article number 2002287 by WonHyoung Ryu, Hyun Beom Song, and co-workers, a biodegradable and separable microneedle into the cornea is studied as a substitute for multiple eyedrops in the treatment of infectious keratitis. This study showcases the mechanical integrity and release optimization with three different formulations of drug-tip and demonstrates that a single microneedle injection can be used instead of an initial three days of multiple eyedrops in vivo.
DNA-damage response-umbrella study of the combination of ceralasertib and olaparib, or ceralasertib and durvalumab in advanced biliary tract cancer: A phase 2 trial-in-progress.
Authors: Jee Sun Yoon, Jin Won Kim, Ji-Won Kim, Tae-Yong Kim, Ah-Rong Nam, Ju-Hee Bang, Hye-Rim Seo, Jae-Min Kim, Kyoung Seok Oh, Peter G. Mortimer, Simon Smith, Do-Youn Oh
Journal: Journal of Clinical Oncology (2021)

TPS4166 Background: Ceralasertib (AZD6738) is a selective ATR inhibitor that causes stalled replication forks to collapse, leading to accumulation of double-strand DNA breaks, which is expected to have synergistic anti-tumor effects with immune checkpoint inhibitors (ICI) or PARP inhibitors. First, accumulation of DNA damage by ceralasertib induces tumor cell death, leads to the release of tumor-specific antigen, changing the tumor microenvironment to promote antigen presentation and enhances the anti-tumor effect of ICI. Second, by simultaneously inhibiting two DNA-damage response (DDR) pathways downstream of PARP and ATR, cancer cells are unable to repair damaged DNA, leading to cell death. Ceralasertib has demonstrated promising anti-tumor activity and manageable toxicity in combination with durvalumab or olaparib in solid tumors in a phase 1 study (NCT02264678). In preclinical studies, ceralasertib has shown potent anti-tumor effects in biliary tract cancer (BTC) as a monotherapy and in combination with chemotherapy (Nam, et al, 2019). Methods: This is an open-label, phase 2 umbrella study assessing the efficacy of ceralasertib in combination with durvalumab or olaparib in patients with advanced BTC. Eligible patients have histologically confirmed BTC (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), have failed at least one chemotherapy and have ECOG performance status of 0-1. Patients who have received prior ICI, ATR or PARP inhibitor are excluded. Each cycle consists of 4 weeks. In ceralasertib /durvalumab cohort, 37 patients will receive durvalumab 1.5g on day 1 and ceralasertib 240mg twice daily on days 15-28. In ceralasertib /olaparib cohort, 37 patients receive ceralasertib 160mg once daily on days 1-7 and olaparib 300mg twice daily on days 1-28. The primary endpoint is disease control rate, with key secondary endpoints including overall response rate, progression-free survival, overall survival, and safety. Tissue and blood samples are being collected for translational biomarker studies. Clinical trial information: NCT04298021.
The impact of aircraft noise on the health of population living near six Italian airports.
Authors: C Ancona, F Forastiere, Anconac, E Cadum, D Camerino, G Cattani, T Fabozzi, G Licitra, F Mataloni, M Ottino, S Pisani, S Simonato, R Sozzi, M Vigotti
Journal: Environmental Health Perspectives (2013)

Background: Aircraft noise has been associated with several health effects. Because of the great success of low cost flights, small airports have been turned into international airports thus exposi...
Patient-reported outcomes predicting non-fatal self-injury after a cancer diagnosis: A population-based case-control study.
Authors: Julie Hallet, Rinku Sutradhar, Elie Isenberg-Grzeda, Christopher Noel, Alyson Mahar, Simone Vigod, James Bolton, Julie Deleemans, Wing Chan, Victoria Zuk, Natalie G. Coburn, Antoine Eskander
Journal: Journal of Clinical Oncology (2021)

e18583 Background: Psychological distress is key in cancer care. Non-fatal self-injury (NFSI) represents a patient-centred, objectively measured manifestation of the greatest level of distress occurring in 3 out of 1,000 patients after a new cancer diagnosis. How to identify patients at high risk for NFSI remains unknown. We examined the relationships between routinely collected patient-reported outcomes measures and the risk of subsequent NFSI following a cancer diagnosis. Methods: We conducted a population-based case-control study of patients with a new cancer diagnosis (2007-2019) reporting a Edmonton Symptom Assessment (ESAS) score within 36 months of diagnosis. Cases were patients with NFSI within 36 months of diagnosis and controls those without NFSI (assigned a dummy index date corresponding to the case’s NFSI). Cases and controls were matched 1:4 on time from cancer diagnosis, ESAS record in 180 days prior index, age, sex, cancer site, and history of self-injury. Multivariable conditional logistic regression assessed the association between moderate-to-severe ESAS symptoms and total ESAS (t-ESAS) score with NFSI within 180 days. Results: Of 408,858 patients reporting &gt;1 ESAS within 36 months of cancer diagnosis, 748 patients had a NFSI, including 425 patients with an ESAS score within 180 days preceding the NFSI event. Of those 406 cases were matched to 1,624 controls without NFSI. Cases reported a higher proportion of moderate-to-severe symptoms and higher t-ESAS than controls prior to the event (p &lt; 0.01 for all). After adjusting for psychiatric illness history and cancer therapy received, reporting of moderate-to-severe anxiety (odds ratio – OR 1.61, 95%CI 1.14-2.27), depression (OR 1.66, 95%CI 1.2-2.31), and shortness of breath (OR 1.65, 955CI 1.18-2.31) were independently associated with higher risk of NFSI within 180 days. Each 10-point increase in t-ESAS (score 0-90) was independently associated with increased risk of NFSI within 180 days (OR 1.51; 95%CI 1.40-1.63). Conclusions: Reporting moderate-to-severe anxiety, depression, and shortness of breath, and increasing t-ESAS after cancer diagnosis are associated with higher odds of NFSI in the following 180 days. These data support the prospective identification of patients at high risk for NFSI via routine ESAS screening to improve supportive care. Patients with at-risk ESAS scores should receive tailored assessment, management, and longitudinal follow-up.
Cardiovascular phenotypes predict clinical outcomes in sickle cell disease: An echocardiography‐based cluster analysis
Authors: Thomas d'Humières, Laurent Savale, Jocelyn Inamo, Jean‐François Deux, Simon Deswarte, Francois Lionnet, Gylna Loko, Christelle Chantalat, Thibaud Damy, Henri Guillet, Anne Laure Pham Hung d'Alexandry d'Orengiani, Frédéric Galactéros, Etienne Audureau, Bernard Maitre, Marc Humbert, Geneviève Derumeaux, Pablo Bartolucci
Journal: American Journal of Hematology (2021)

This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Three clusters were identified. Cluster 1 (n = 123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n = 102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n = 154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n = 33) included the majority of pre-capillary PH whilst cluster 2 (n = 34) included post-capillary PH. No PH was found in cluster 3 (n = 27). After a follow-up of 11.4 ± 2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate versus 12% in cluster 1 and 5% in cluster 3 (p log-rank = 0.003). Cluster analysis of echocardiography variables identified three hemodynamic and clinical phenotypes among SCD patients, each predicting a different prognosis.
ZEB1 expression in different stages of colorectal cancer.
Authors: Evgeniya M. Nepomnyashchaya, Elena P. Ulianova, Inna A. Novikova, Aleksandr B. Sagakyants, Maksim N. Chernyak, M. A. Gappoeva, Maria O. Ezhova
Journal: Journal of Clinical Oncology (2021)

e15526 Background: Colorectal cancer (CRC) is among the most common cancers. The leading cause of high mortality is tumor progression developed due to the epithelial to mesenchymal transition (EMT). The ZEB1 protein is one of the critical regulators of this process. In this regard, our study aimed to assess the ZEB1 expression in different stages of colorectal cancer. Methods: This study included samples of 206 patients with stage II-IV CRC aged 42 to 86 years (mean age 64.2±1.7). All patients were divided into three groups: group 1 - patients with T3-4 N0 M0 (stage II) with high-risk factors for recurrence, n = 6; group 2 - patients with T1-4 N1-2 M0 (stage III), n = 88; group 3 - patients with T1-4 N0-2 M1 (stage IV), n = 58. IHC study was performed using polyclonal rabbit antibodies to ZEB1 (Biorbyt Ltd.) diluted 1:200 and a Reveal Polyvalent HRP-DAB Detection System. The staining percentage and intensity were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. The nuclear reaction of the ZEB1 protein was considered positive when staining was detected in more than 10% (cut-off) of tumor cells with intensities of 2+ and 3+. Statistical analysis of the results was carried out using the STATISTICA 13.0 software (StatSoft Inc., USA). Results: A positive nuclear reaction for ZEB1 was detected in 80.6% (166 of 206 patients), while negative in 19.4% (40 of 206 patients). The maximal percentage of patients with positive staining for ZEB1 was among those with stage IV (94.8%), the minimal percentage - stage II (60%). The prevalence of ZEB1+ in patients with stages III and IV significantly increased the risk of tumor progression by 3.5 (95% CI 1.8-8.4) and 12.2 (95% CI 3.4-43.6) times, respectively, compared with stage II patients. No statistical significance was observed in the comparison between patients with stages III and IV (95% CI 0.9-11.7). The percentage of ZEB1+ samples increased in more advanced tumors. The ratio of ZEB1+/ZEB1- tumors in stage II was 1.5, in stage III - 5.8, in stage IV - 18.3 (p &lt; 0.05). Conclusions: The immunohistochemical study revealed the features of ZEB1 expression in different stages of colorectal cancer, which can serve as prognostic factors that determine the disease progression.
A novel, computer-aided, scanning platform agnostic solution for grading carcinomas in breast biopsy whole slide images.
Authors: Nicolas M Orsi, Tathagata Dasgupta, Satabhisa Mukhopadhyay, Michele Cummings, Angelene Berwick
Journal: Journal of Clinical Oncology (2021)

e12575 Background: The determination of breast cancer grade remains a problematic diagnostic issue in biopsies due to limited tissue sampling and the inherent inter-observer variability associated with the Nottingham (histologic) score. Significantly, biopsy grading corresponds only moderately with that based on excision specimens, with discordance rates of 21-30.0%, which is a concern for cases managed neoadjuvantly or with minimally ablative therapy. Although the advent of digital pathology has encouraged endeavors to automate breast cancer detection and grading, no method has yet received regulatory approval for clinical use or proven to be a platform agnostic solution. Methods: This study was the blinded clinical validation a novel, FDA breakthrough designation approved automated device-based predictive solution which uses a surrogate scale to determine breast carcinoma grade in core biopsies using H&amp;E slide whole slide images (WSIs) only. Non-preselected malignant breast core biopsy clinical cases (n=173 WSIs; 107 cases) covering a broad spectrum of breast cancer morphological subtypes were scanned at x20 magnification on both on Aperio high-throughput T2/T3 systems (.SVS files) and Roche-Ventana DP200 scanners (.BIF files). The diagnostic gold standard reference was the reports of tertiary referral center breast subspecialty consultant histopathologists. Diagnostic outputs were also compared to case-matched resection specimen grades. Comparison of diagnostic outcomes with pathologists as gold standard was done using inter observer agreement (cohen kappa) with 95% CI and statistically significant chi-squared test p-value for two different scanner platforms. Results: Although biopsy-based diagnostic concordance with pathologists was very good, the device actually delivered a much better concordance between case-matched biopsy and resection specimen (accuracy: 95%, cohen kappa: 0.91) relative to pathologists’ assessments (accuracy: 80%). Conclusions: This indicates that the use of a single continuous surrogate grading scale is much less affected by limited tissue sampling than conventional ordinal morphological scales. This level of performance was independent of file format analyzed, demonstrating the device’s platform agnosia.