tbuckley/cabot-search huggingface dataset:
Nephrotoxicity in patients with cancer treated with immune checkpoint inhibitors.
Authors: Evangelos Eleutherakis Papaiakovou, Efstathios Kastritis, Flora Zagouri, Dimitra Grapsa, Ioannis Ntanassis-Stathopoulos, Dimitra Stefanou, Georgios Evangelou, Ilias Kotteas, Meletios A. Dimopoulos, Konstantinos Syrigos
Journal: Journal of Clinical Oncology (2021)

e14558 Background: Despite their efficacy in various cancer types, administration of immune checkpoint inhibitors (ICIs) may be complicated by the development of immune-related adverse events (IrAE). Nephrotoxicity represents a relatively rare but clinically significant adverse event, associated with the administration of ICI. Methods: The medical records of 294 patients with solid tumors or hematological malignancies that received ICIs for at least 4 weeks were retrospectively reviewed. Demographic, clinicopathological, treatment, toxicity and outcome data were recorded. ICI-associated nephrotoxicity was correlated with the remaining clinicopathological parameters as well as with progression-free survival (PFS) and overall survival (OS). Results: The majority of patients were male (70.4%), with bladder cancer or renal cell carcinoma (38.1% and 27.6%, respectively), and stage IV disease (56.8%), and had received ICI as monotherapy (68,7%). Nephrotoxicity during immunotherapy administration was observed in 20/ 294 (6.8%) patients, was mild (grade 1) and reversible in 55% and 75% of these cases, respectively, and was significantly associated with nephrotoxicity from previously administered therapy (p = 0,008), impaired renal function at initiation of ICIs (p = 0.044). and advanced disease stage at diagnosis (p = 0,028). No correlation between ICI-nephrotoxicity and PFS or OS was observed. Conclusions: ICI-associated nephrotoxicity was a relatively infrequent IrAE in our patient population, most commonly mild and reversible, and with no significant effect on survival. Preexisting treatment-related nephrotoxicity, impaired renal function and/or advanced disease stage at diagnosis may represent significant predisposing factors for its development.
Bone modifying agents and skeletal related events in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.
Authors: Parthib Das, Songzhu Zhao, Lai Wei, Abdul Miah, Mingjia Li, Gabrielle Lopez, Sandip H. Patel, Andrew Johns, Madison Grogan, Erin Marie Bertino, Kai He, Peter G. Shields, David Paul Carbone, Gregory Alan Otterson, Carolyn J Presley, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2021)

e18593 Background: Bone metastases and skeletal related events (SREs) are a common cause of morbidity among patients with metastatic non-small cell lung cancer (mNSCLC). SREs include pathologic bone fractures, spinal cord compression, orthopedic surgery/stabilization, and palliative radiation to bone. Bone modifying agents (BMA) such as bisphosphonates and RANK ligand inhibitors are often used for mNSCLC patients with bone metastases to reduce the incidence of SRE. Data on the associations between BMA use and overall survival (OS) and the development of SRE among patients with mNSCLC treated with immune checkpoint inhibitors (ICI) is limited. Methods: We conducted a retrospective study of patients with mNSCLC treated with first line pembrolizumab or pembrolizumab plus chemotherapy at The Ohio State University from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. The association between BMA and risk of osseous progression was studied using Fisher’s exact test. The association between BMA and OS was examined using a Cox proportional hazard model. Median OS was estimated using the Kaplan-Meier method with 95% CI. OS was calculated from date of ICI initiation to death from any cause or last follow up. Results: We identified a cohort of 228 patients: 107 (47%) treated with pembrolizumab and 121 (53%) treated with pembrolizumab plus chemotherapy; 48 (21%) had squamous histology and 179 (79%) had nonsquamous histology (1 had NSCLC histology not specified); median age 62.6 years; median OS was 26.8 months (95% CI: 17.2 – 34.5 months). A total of 95/228 (42%) patients had bone metastases at time of ICI initiation; 45/95 (42%) had treatment with BMA and 50/95 (58%) were not treated with BMA. Among patients with bone metastases at time of ICI, 45 (42%) developed SRE after ICI initiation and BMA use was not associated with risk of SRE (p = 1). BMA use was not significantly associated with risk of osseous progression (p = 0.21). For patients with baseline bone metastases prior to ICI, the use of BMA was not associated with OS (p = 0.24); the type of BMA used (bisphosphonate vs RANK ligand inhibitor) was also not associated with OS (p = 0.13). Conclusions: In patients with metastatic NSCLC treated with first line pembrolizumab alone or with chemotherapy, bone modifying agents were not associated with OS, decreased risk of osseous progression, or development of SRE in patients with baseline bone metastases prior to ICI initiation. The type of BMA used was also not associated with survival. Further studies evaluating the utility and impact of BMA use in this patient population are needed.
Mortality review as a tool to assess the contribution of healthcare-associated infections to death: results of a multicentre validity and reproducibility study, 11 European Union countries, 2017 to 2018
Authors: Tjallie van der Kooi, Alain Lepape, Pascal Astagneau, Carl Suetens, Mioara Alina Nicolaie, Sabine de Greeff, Ilma Lozoraitiene, Jacek Czepiel, Márta Patyi, Diamantis Plachouras
Journal: Eurosurveillance (2021)

Introduction The contribution of healthcare-associated infections (HAI) to mortality can be estimated using statistical methods, but mortality review (MR) is better suited for routine use in clinical settings. The European Centre for Disease Prevention and Control recently introduced MR into its HAI surveillance. Aim We evaluate validity and reproducibility of three MR measures. Methods The on-site investigator, usually an infection prevention and control doctor, and the clinician in charge of the patient independently reviewed records of deceased patients with bloodstream infection (BSI), pneumonia, Clostridioides difficile infection (CDI) or surgical site infection (SSI), and assessed the contribution to death using 3CAT: definitely/possibly/no contribution to death; WHOCAT: sole cause/part of causal sequence but not sufficient on its own/contributory cause but unrelated to condition causing death/no contribution, based on the World Health Organization’s death certificate; QUANT: Likert scale: 0 (no contribution) to 10 (definitely cause of death). Inter-rater reliability was assessed with weighted kappa (wk) and intra-cluster correlation coefficient (ICC). Reviewers rated the fit of the measures. Results From 2017 to 2018, 24 hospitals (11 countries) recorded 291 cases: 87 BSI, 113 pneumonia , 71 CDI and 20 SSI. The inter-rater reliability was: 3CAT wk 0.68 (95% confidence interval (CI): 0.61–0.75); WHOCAT wk 0.65 (95% CI: 0.58–0.73); QUANT ICC 0.76 (95% CI: 0.71–0.81). Inter-rater reliability ranged from 0.72 for pneumonia to 0.52 for CDI. All three measures fitted ‘reasonably’ or ‘well’ in &gt; 88%. Conclusion Feasibility, validity and reproducibility of these MR measures was acceptable for use in HAI surveillance.
Therapeutic options for CTLA-4 insufficiency
Authors: David Egg, Ina Caroline Rump, Noriko Mitsuiki, Jessica Rojas-Restrepo, Maria-Elena Maccari, Charlotte Schwab, Annemarie Gabrysch, Klaus Warnatz, Sigune Goldacker, Virginia Patiño, Daniel Wolff, Satoshi Okada, Seiichi Hayakawa, Yoshiaki Shikama, Kenji Kanda, Kohsuke Imai, Manabu Sotomatsu, Makoto Kuwashima, Takahiro Kamiya, Tomohiro Morio, Kazuaki Matsumoto, Takeshi Mori, Yuri Yoshimoto, Ingunn Dybedal, Maria Kanariou, Zeynep Yesim Kucuk, Hugo Chapdelaine, Lenka Petruzelkova, Hanns-Martin Lorenz, Kathleen E. Sullivan, Jennifer Heimall, Michel Moutschen, Jiri Litzman, Mike Recher, Michael H. Albert, Fabian Hauck, Suranjith Seneviratne, Jana Pachlopnik Schmid, Antonios Kolios, Gary Unglik, Christian Klemann, Scott Snapper, Lisa Giulino-Roth, Michael Svaton, Craig D. Platt, Sophie Hambleton, Olaf Neth, Geraldine Gosse, Steffen Reinsch, Dirk Holzinger, Yae-Jean Kim, Shahrzad Bakhtiar, Faranaz Atschekzei, Reinhold Schmidt, Georgios Sogkas, Shanmuganathan Chandrakasan, William Rae, Beata Derfalvi, Hanne Vibeke Marquart, Ahmet Ozen, Ayca Kiykim, Elif Karakoc-Aydiner, Pavlína Králíčková, Godelieve de Bree, Dimitra Kiritsi, Markus G. Seidel, Robin Kobbe, Jennifer Dantzer, Laia Alsina, Thais Armangue, Vassilios Lougaris, Philipp Agyeman, Sofia Nyström, David Buchbinder, Peter D. Arkwright, Bodo Grimbacher
Journal: Journal of Allergy and Clinical Immunology (2021)
Transition of dose-adjusted EPOCH therapy into the outpatient healthcare setting, quality and cost considerations under an alternate payment model.
Authors: Sandra Savaya, Joselyn Villanueva, Atefeh Sharif, Neda AlRawashdh, Andrew Garcia, Ivo Abraham, Daniel O Persky, Ali McBride
Journal: Journal of Clinical Oncology (2021)

e18655 Background: Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin DA-(EPOCH)-containing regimens are frequently utilized in lymphoma, however, outpatient EPOCH or modified inpatient/outpatient EPOCH has not been described extensively. We transitioned inpatient EPOCH to the outpatient setting and modified EPOCH to be given in the inpatient setting with rituximab outpatient to improve quality of care and access to patient assistance programs. Methods: A single-center, institutional review board-approved retrospective study was conducted for adults receiving EPOCH-based regimens. Data were collected by chart review for each patient between January 2013 and September 2020. The primary outcomes were to determine the incidence of chemotherapy delays due to disease-related reasons as febrile neutropenia (FN), adverse events or abnormal labs and the incidence of FN between patients receiving inpatient (IP), outpatient (OP), or combination inpatient/outpatient DA-EPOCH +/- R (hybrid). Secondary cost analysis including hospital stay cost, chemotherapy and laboratory monitoring costs was performed for the three settings. Results: A total of 43 patients received 175 cycles of an EPOCH regimen (18 [10.3%] IP), 90 [51.4%] OP, and 67 [38.3%] hybrid). The mean maximum dose level achieved with DA-EPOCH+/-R was dose level 2 with the average number of cycles at 4.1 cycles/patient. A total of 15 cycles were delayed due to disease related reasons: 1 (6%) in IP, 12 (18%) in hybrid (P = 0.196, when compared with IP) and 2 (2%) in OP (P = 0.432 when compared with IP). A total of 166 cycles received granulocyte-colony stimulating factor (G-CSF); 16 cycles (9.6%) administered IP with a FN incidence of two (12.5%), 62 cycles (37.4%) administered in the hybrid setting with a FN incidence of seven (11.3%) (P = 0.893 when compared with IP) and 88 cycles (53%) administered OP with a FN incidence of ten (11.3%) (P = 0.896 when compared with IP). The incidence of FN was 9.3% and 12.7% in patients received pegfilgrastim same day versus next day, respectively, P = 0.558. The incidence of FN in patients received reference pegfilgrastim was 9.5% vs 7.7% for patients received pegfilgrastim-cbqv in OP setting (P = 1.00). Transitioning EPOCH to a hybrid IP/OP or OP setting yielded a total cost savings to the health-system of $3,523,174 with 607 hospital bed days saved. Conclusions: EPOCH-containing regimens can be safely transitioned into the outpatient setting or utilized as a hybrid of EPCOH and outpatient Rituximab after chemotherapy side effects can be monitored and outcomes optimized, to better adapt treatment strategies for individualized patient therapies. As new healthcare payment models are developed, outpatient treatments allow for adaptive financial options both for the payor and the patient.
Place Matters: Residential Racial Segregation and Chronic Obstructive Pulmonary Disease
Authors: John R. Balmes
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

BAL neutrophils, allergic sensitization, and different bacterial detection may lay the foundation for therapeutic decisions for this difficult-tomanage population.Unbiased phenotype clustering has helped redefine the framework of severe asthma (12), although even "unbiased" approaches are constrained by the selection of variables (13).Acknowledging the difficulty in procuring airway samples in preschool children, validation of these findings in similar cohorts is needed.Although these clusters have face validity, baseline and predictive validity (i.e., association with important health outcomes), long-term prognosis, or differential treatment response in the clinical setting is needed.Longer-term follow-up of this unique cohort will be critical to answer many of these questions.Fully understanding the mechanisms and optimal treatment approaches for preschool children with recurrent wheeze remains a significant research challenge.Robinson and colleagues begin to chart a different course highlighting the discordance between current clinical labels and airway pathology and identifying clusters of clinicalpathologic features that may lay the foundation for future prognostic studies and therapeutic trials in this heterogenous condition.
Circulating genetically abnormal cells combined with artificial intelligence for accurate and non-invasive early detection on NSCLC.
Authors: Han Yang, Hongjie Chen, Ran Ni, Guorui Zhang, Yongjie Huang, Xin Ye, Xianjun Fan, Yinglan Kuang, Juncheng Zhang, Chuoji Huang, Hong Liu
Journal: Journal of Clinical Oncology (2021)

3056 Background: Non-small-cell carcinoma (NCSLC) is the most common type of early lung cancer. Early detection of NSCLC is still a diagnostic challenge. Current clinical management of patients with pulmonary nodule is inefficient and may lead to misclassification, thus increasing healthcare expenses. Further, a few previous studies showed liquid biopsy and artificial intelligence (AI) platform on computed tomography (CT) imaging contributes to early NSCLC detection. Still, there is something lacking in a precise and authorized lung nodule classifier to minimize discomfort of patients. This study aims to evaluate the possibility and effectiveness of combining circulating genetically abnormal cells (CACs) with an AI platform on CT imaging to improve the diagnostic route for NSCLC. Methods: A prospective cohort of 101 in-patients was enrolled from Sep. 1, 2020 to Jan. 15, 2021, with non-calcified pulmonary nodules, ranging from 0.5 to 3 cm in diameter, indicated by CT. The participants' pulmonary nodules will be assessed by two evaluation tools: CAC detection on full blood and AI platform on CT imaging. The diagnostic performances of the two tools were evaluated in a blinded validation study respectively and combined in an open-label retrospective analysis. Results: 68 of enrolled patients were confirmed as NSCLC by pathology. The diagnostic performance of CACs for NSCLC detection was 80.9% for sensitivity and 87.3% for positive predictive value (PPV) while overall accuracy reaches 79.2%. AI platform showed a slight disadvantage as 78.6% for PPV and 73.5% for accuracy. 9 false-negative patients on CAC results could be reversed with a combination of AI platform on CT imaging, while sensitivity rises to 94.1%. However, of 33 benign nodules patients, 8 wrong diagnoses by CAC detection could decrease to 2 when combined with the results from the AI platform, which may avoid unnecessary biopsies. Conclusions: Coupling CAC with an AI platform on CT imaging could be a useful strategy to improve the diagnostic route for NSCLC and avoid unnecessary biopsies.[Table: see text]
Expanding the molecular taxonomy of NUT midline carcinomas with multiomic analyses.
Authors: Henry G. Kaplan, Alex Barrett, Jiaxin Niu, Somasundaram Subramaniam, Maria Matsangou
Journal: Journal of Clinical Oncology (2021)

e21008 Background: NUT midline carcinoma (NMC) is an aggressive squamous cell carcinoma molecularly defined by a chromosomal rearrangement of nuclear protein in testis (NUTM1) with bromodomain-containing protein 3 or 4 (BRD3/4). While NMCs are characterized by this rare canonical gene rearrangement little is known about the transcriptome and proteosome of this rare disease. As such, we set out to comprehensively characterize five NMC cases in which we attained targeted DNA sequencing, full-transcriptome RNA sequencing, and targeted proteomics. We further examine and integrate these results in order to better understand the relationship between gene expression and protein abundance within the context of NMC. Methods: All cases were analyzed for genomic and transcriptomic alterations against a custom panel via the Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth and full-transcriptome RNA sequencing) for germline and/or somatic mutations. The xT assay detects single nucleotide variants, specific insertion/deletions, amplifications and gene fusions, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. Proteomic data were obtained utilizing digital spatial profiling through Nanostring immune, MAPK and PI3/AKT, and pan tumor nCounter GeoMix panels. Results: Clinical characteristics, histology, and genomic/proteomic alterations for 5 NMC cases are presented. Cases were defined by pathological assessment and the identification of the canonical NUTM1 fusion, further broken down by fusion partner with three patients having NUTM1-BRD4 fusions, one NUT-BRD3, and one NUT-ZMYND8. TMBs ranged for 0.8-.6 mutations/megabases (n=5). All patients were MSI stable (5/5). Of three patients with available PD-L1 IHC result, one had elevated PD-L1 tumor staining at 70%. Results will be presented from full-transcriptome RNA expression analysis indicating overexpression of BRAF, MYC, mTOR, and EGFR, among others. Targeted proteomics were performed to assess relative abundance at the protein level (results to be presented). Clinical follow up for the five patients revealed that two have survived beyond 7 months. A lung primary patient treated with surgical resection and post op radiation (XRT) is NED at 63 months. A sinus primary patient is NED at 16 months after a partial response (PR) to taxotere/5FU/Cisplatin followed by resection and XRT/cis platin. One patient had a brief PR from ifosphamide/etoposide/vorinostat. One patient's tumor grew through XRT/cisplatin. Conclusions: Multi-omic analysis has the potential to further elucidate the mechanisms of tumor growth in NMC and identify new targets for the treatment of this aggressive and poor prognosis disease.
Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).
Authors: Lucy Xiaolu Ma, Gun Ho Jang, Amy Zhang, Robert Edward Denroche, Anna Dodd, Stephanie Ramotar, Shawn Hutchinson, Yifan Wang, Mustapha Tehfe, Ravi Ramjeesingh, James Joseph Biagi, Bernard Lam, Julie Wilson, Faiyaz Notta, Sandra Fischer, Robert C Grant, George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane
Journal: Journal of Clinical Oncology (2021)

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3 rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p &lt; 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p &lt; 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.
Correlation analysis of gene and immune microenvironment for 87 melanoma cases.
Authors: Lanqun Qin, Yu Ren, Lianjun Zhao, Yirong Wu, Mengke Zhao, Rong Huang, Zhengyun Zou
Journal: Journal of Clinical Oncology (2021)

e21555 Background: To map the genome of Chinese melanoma patients and explore its correlation with the expression of tumor immune microenvironmental indicators. Methods: Next generation sequencing was performed on 87 cases of primary melanoma that had been surgically removed from Nanjing Drum Tower Hospital from July 2010 to May 2017. Immunohistochemistry was carried out to detect the expressions of PD1, PDL1, CD3+TIL, MSH2, MSH6, PMS2 and MLH1. Results: BRAF mutations were the most common (26.4%), followed by KIT mutations (12.6%) in melanoma patients. RB1 gene copy number deletion (55%) and CDK4 (25%)/CCND1 (22.5%) gene copy number amplification were also common. The prognosis of patients could be distinguished by grouping the expression of PDL1 and TIL, and the difference may be related to the expression of PD1. There were more copy number amplication of genes with poor prognosis in PDL1-TIL- patients. Conclusions: The classification of tumors into four microenvironmental subtypes based on PDL1 and TIL expression is an appropriate method to stratify patients with different clinical outcomes. At the genetic level, there are more copy number amplification of the genes with poor prognosis in patients with TIL-PDL1- type, so the prognosis is always worse than that of patients with TIL+PDL1+ type. Gene may affect the prognosis of patients by affecting the tumor immune microenvironment.