tbuckley/cabot-search huggingface dataset:
Molecular alterations, tumor microenvironment and clinical correlations in Thai cholangiocarcinoma patients.
Authors: Panuchai Bamrungwong, Songporn Oranratnachai, Pattana Sornmayura, Pimpin Incharoen, Nareenart Iemwimansa, Narumol Trachu, Bhakbhoom Panthan, Nanamon Monnamo, Pakatorn Sae-Lim, Angkana Charoenyingwattana, Ravat Panvichien, Ekaphop Sirachainan, Wasun Chantratita, Thanyanan Reungwetwattana
Journal: Journal of Clinical Oncology (2021)

e16176 Background: The systemic treatment option of unresectable and advanced cholangiocarcinoma (CCA) is limited. The mainstay of treatment is gemcitabine and 5-FU based chemotherapy. Recently, there is the role of promising immunotherapy in MSI-HI CCA. This research aims to study molecular alterations and tumor microenvironment in Thai CCA patients in order to explore the novel treatment and the clinical correlations. Methods: Thirty-six CCA patients in Ramathibodi Hospital between year of 2018 and 2020 with adequate tissue were enrolled. NGS by ThermoFisher (comprehensive panel) for molecular profile and immunohistochemistry (IHC) staining for tumor microenvironment protein expression (CD3, CD4, CD8, CD20, CD138, CD163, FOXP3), and PD-L1 were performed. Clinical data was retrieved from electronic medical record. Survival analysis, univariate and multivariate analysis were performed by Cox-regression analysis. Stata version 16.0 was used for statistical analysis. Results: Intrahepatic CCA was the most common type of CCA in our population (81%). The top 10 common mutations were TP53 (69%), KMT2D 58%), KMT2B (52%), ARID1A (50%), FAT1 (50%), NOTCH3 (44%), FANCA (42%), SMAD4 (42%), EPHA2 (39%), and ARID1B (39%). We also found the interesting targetable genes in our CCA patients, such as, KRAS (33%), MTOR (33%), HER2 (31%), EGFR (31%), FGFR2 (28%), BRCA2 (25%), PIK3CA (22%), NTRK1 (19%), BRCA1 (17%), NTRK3 (11%), and BRAF (8%). Three patients had ALK fusion gene, 1 patient had NTRK1 fusion and the other one had NTRK3 fusion gene. Twelve out of 36 patients (33%) had MSI-HI and 56% of patients had TMB ≥ 10 mutations/megabase. The clinical factors significantly correlated with poor overall survival (OS) were unresectable disease, stage IV, bilirubin &gt; 1.2, and CEA ≥ 22.5. The NF1, MTOR, HER2 mutations, and FOXP3-negative in stromal cells were significantly associated with longer OS, whereas EGFR, APC, FGFR2, and BRCA1 mutations might correlated with better OS. Conclusions: Our study demonstrated the unique molecular profile of Thai CCA patients. We found high prevalence of MSI-HI and high TMB in our population, together with the promising potential of targetable genes for developing targeted therapy in the future. FOXP3 expression was probably one of potential predictive biomarker for immunotherapy. Larger cohort should be explored.
Somatic mutations predict immune-related adverse events (irAEs) and survival following CTLA4 blockade in melanoma patients.
Authors: Savan Shah, Xiaoqing Yu, Jamie K. Teer, Jose Conejo-Garcia, Maureen Lyons, William LaFramboise, Ahmad A. Tarhini
Journal: Journal of Clinical Oncology (2021)

e21584 Background: Predicting immune-related adverse events (irAEs) resulting from immune checkpoint inhibitors (ICIs) as well as the likelihood of clinical benefit is an area of great interest. irAEs have been associated with clinical outcome measures and we were interested in examining somatic mutations that may correlate with irAEs and subsequently with relapse free survival (RFS) and overall survival (OS). Methods: Our irAEs of interest for this analysis were rash and colitis based on prior data and these were tested for association with RFS and overall OS. Nonsynonymous somatic mutations were identified utilizing tumor and matched blood samples from 22 metastatic melanoma patients treated with neoadjuvant ipilimumab. Whole exome sequencing was performed using the SOLiD 5500 Next-Generation Sequencing platform. Somatic mutations were identified by subtraction of germline variants. Total mutational burden was assessed, and individual mutations were correlated with irAEs and with clinical outcome. Results: MUC16 was the most commonly mutated gene (82%). Of notable known oncogenic mutations, BRAF was the most common (50%) followed by NRAS (23%). Among known oncogenic signaling pathways, enrichment was most common in RTK-RAS (58%), followed by NOTCH and WNT. Development of colitis showed a strong trend in association with RFS. Development of rash indicated a similar trend. 20 different statistically significant mutations (p &lt; 0.05) were identified among patients with colitis and these were also associated with OS and RFS. Notably, PTPRO mutation status (known to antagonize PDL1 expression) appeared protective against colitis and associated with worse RFS and OS. Similarly, ADGB mutation was significantly associated with developing rash and also associated with improved RFS and OS. Correcting for TMB in a multivariate model confirmed the associations. Conclusions: Somatic mutations were found to be associated with the irAEs of rash and colitis and with clinical outcome following ipilimumab treatment of melanoma. Our findings warrant further investigation and validation in independent cohorts.
Subcutaneous epcoritamab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Safety profile and antitumor activity.
Authors: Michael Roost Clausen, Pieternella Lugtenburg, Martin Hutchings, Peter W. M. Johnson, Kim M. Linton, David John Lewis, Martine Chamuleau, Anna Sureda Balari, David Cunningham, Brian Elliott, Dena DeMarco, Kuo-mei Chen, Rogier Mous
Journal: Journal of Clinical Oncology (2021)

7518 Background: Epcoritamab is a CD20xCD3 bispecific antibody that induces T-cellmediated killing of CD20–positive malignant B-cells. We present updated data, including progression-free survival (PFS) from the dose escalation part of the first-in-human phase 1/2 study of epcoritamab in pts with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT03625037). Methods: Adults with R/R CD20+ B-NHL received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1–2; q2w: cycles 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). Results: At data cut off (1/31/2021), 68 pts with B-NHL were enrolled across histologies including diffuse large B-cell lymphoma (DLBCL; n = 46 [67.6%]; de novo and transformed), follicular lymphoma (FL; 12 [17.6%]), mantle cell lymphoma (MCL; 4 [5.9%]), and others (6 [8.8%]). Majority were heavily pretreated (median [range] prior lines: DLBCL, 3 [1–6]; FL, 4.5 [1–18]); including prior CAR-T (n = 6) and prior ASCT (n = 10). At median follow-up of 14.1 mo (DLBCL, 10.2 mo; FL, 15.2 mo), treatment was ongoing in 15 (22%) pts. Most common treatment-emergent adverse events (AEs) were pyrexia (69%), CRS (59%), and injection site reaction (47%). CRS events were all grade 1 or 2 and most occurred in cycle 1; neurotoxicity was limited (6%; grade 1: 3%; grade 3: 3%; all transient). One case of tumor lysis syndrome was observed (1.5%; grade 3); there were no cases of febrile neutropenia or treatment-related death. Overall response is shown for DLBCL ≥12 mg and ≥48 mg and FL ≥12 mg, corresponding to the minimal efficacy threshold (Table). Responses deepened over time (PR converted to CR: DLBCL, 6 pts; FL, 3 pts). Median time to response was 1.4 mo (DLBCL) and 1.9 mo (FL). Among DLBCL pts achieving CR with ≥6 mg (n = 11), none relapsed while on treatment. The median PFS for pts with DLBCL ≥12 mg (n = 22) was 9.1 mo (95% CI: 1.6, NE; median follow-up 9.3 mo) and for pts with DLBCL ≥48 mg (n = 11) median PFS was not reached (median follow-up 8.8 mo). Updated analyses will be presented. Conclusions: With longer follow-up, SC epcoritamab demonstrated substantial single-agent activity, inducing deep and durable clinically meaningful responses, with a consistent safety profile. Notably no severe (grade ≥3) CRS events, no febrile neutropenia, and limited neurotoxicity was observed. Clinical trial information: NCT03625037. [Table: see text]
Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures
Authors: Laurene S Cheung, Lingling Chen, Teniola F Oke, Thomas B Schaffer, Karim Boudadi, Jillian T Ngo, John McMahon Gross, Holly Kemberling, Luis A Diaz, Evan Lipson, John-WIlliam Sidhom, Janis Taube, Robert Anders, Drew M Pardoll, Dung T Le, Christian F Meyer, Nicolas Llosa
Journal: Journal for ImmunoTherapy of Cancer (2021)

Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.
Analysis of genetic mutations associated with immune-activated microenvironment in lung adenocarcinoma.
Authors: Zhen Liang, Shuhua Zhao, Danni Liu, Tianhao Mu, Jinfeng Chen
Journal: Journal of Clinical Oncology (2021)

e20520 Background: Tumor microenvironment plays an important role in suppressing or enhancing immune response. However, the relationship between genetic mutation and prognosis of lung adenocarcinoma (LUAD) patients, and the molecular mechanism of immune microenvironment are not completely clear. Methods: Expression matrix and somatic mutations of TCGA LUAD (n = 509) were downloaded from UCSC Xena. Immune-related gene list was downloaded from ImmPort. We applied R packages ESTIMATE and CIBERSORT to calculate the proportion of tumor-infiltrating immune cell by mRNA data. Samples were divided into ImmuneScore-High or ImmuneScore-Low depending on upper or lower quartiles of ESTIMATE immune infiltration score. Differential expression analysis between ImmuneScore-High and ImmuneScore-Low was performed with R package DESeq2. Results: Samples were divided into ImmuneScore-High (n = 127) and ImmuneScore-Low (n = 128). The immune cell components of these two groups presented different patterns. 10 most frequently mutated immune-related genes were significantly different between two groups (Chi-Squared test, p value &lt; 0.05). 4,139 differentially expressed genes were obtained (|log2FC| &gt; 1, FDR &lt; 0.05). IL-7R, PIK3R5, TRBC2 and VCAM1 were identified with differential mutation frequency and presented differential expression between two groups. Kaplan-Meier plot in UALCAN cancer database showed IL-7R had a significant influence on the prognosis of patients (log rank test, p value = 0.045). Conclusions: ImmuneScore-High and ImmunScore-Low groups presented different genetic mutation frequency and gene expression. Moreover, mutation and different expression of IL-7R may be used as a potential biomarker in the treatment of patients with lung adenocarcinoma.
Trends in respiratory virus circulation following COVID-19-targeted nonpharmaceutical interventions in Germany, January - September 2020: Analysis of national surveillance data
Authors: Djin-Ye Oh, Silke Buda, Barbara Biere, Janine Reiche, Frank Schlosser, Susanne Duwe, Marianne Wedde, Max von Kleist, Martin Mielke, Thorsten Wolff, Ralf Dürrwald
Journal: The Lancet Regional Health - Europe (2021)

During the initial COVID-19 response, Germany's Federal Government implemented several nonpharmaceutical interventions (NPIs) that were instrumental in suppressing early exponential spread of SARS-CoV-2. NPI effect on the transmission of other respiratory viruses has not been examined at the national level thus far.
Fuzuloparib: First Approval
Authors: Arnold Lee
Journal: Drugs (2021)

Fuzuloparib (AiRuiYi®, 艾瑞颐; formerly fluzoparib) is a small molecule, orally active PARP inhibitor being developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. (formerly Jiangsu Hengrui Medicine Co., Ltd.) for the treatment of solid cancers. Fuzuloparib has been approved in China for the treatment of ovarian cancer (including fallopian tube cancer or primary peritoneal cancer), and phase II and III trials are investigating fuzuloparib for the treatment of other solid cancers, including cancers of the pancreas, breast, prostate and lungs. This article summarizes the milestones in the development of fuzuloparib leading to this first approval for the treatment of platinum-sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer in patients with germline BRCA mutation who have undergone second-line or above chemotherapy.
Similarity network fusion for the integration of multi-omics and microbiomes in respiratory disease
Authors: Jayanth Kumar Narayana, Micheál Mac Aogáin, Nur A'tikah Binte Mohamed Ali, Krasimira Tsaneva-Atanasova, Sanjay H. Chotirmall
Journal: European Respiratory Journal (2021)

<b>Similarity network fusion (SNF) is increasingly employed for multi-omics and microbiome data integration and assists patient endotyping. This Methods article describes its performance and explores current and future applications in respiratory medicine.</b>https://bit.ly/3gtoYq9
On-treatment immune prognostic score for patients with relapsed and/or metastatic head and neck squamous cell carcinoma treated with immunotherapy
Authors: Pablo Nenclares, Lucinda Gunn, Heba Soliman, Mateo Bover, Amy Trinh, Isla Leslie, Kee Howe Wong, Alan Melcher, Kate Newbold, Chris M Nutting, Derfel ap Dafydd, Shreerang A Bhide, Kevin Harrington
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Previous studies have suggested that inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and fibrinogen) are prognostic biomarkers in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors (ICIs). We aimed to develop a model that predicts response and survival in patients with relapsed and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy. Methods Analysis of 100 consecutive patients with unresectable R/M HNSCC who were treated with ICI. Baseline and on-treatment (day 28) NLR, fibrinogen and LDH were calculated and correlated with response, progression-free survival (PFS) and overall survival (OS) using univariate and multivariate analyses. The optimal cut-off values were derived using maximally selected log-rank statistics. Results Low baseline NLR and fibrinogen levels were associated with response. There was a statistically significant correlation between on-treatment NLR and fibrinogen and best overall response. On-treatment high NLR and raised fibrinogen were significantly associated with poorer outcome. In multivariate analysis, on-treatment NLR (≥4) and on-treatment fibrinogen (≥4 ng/mL) showed a significant negative correlation with OS and PFS. Using these cut-off points, we generated an on-treatment score for OS and PFS (0–2 points). The derived scoring system shows appropriate discrimination and suitability for OS (HR 2.4, 95% CI 1.7 to 3.4, p&lt;0.0001, Harrell’s C 0.67) and PFS (HR 1.8, 95% CI 1.4 to 2.3, p&lt;0.0001, Harrell’s C 0.68). In the absence of an external validation cohort, results of fivefold cross-validation of the score and evaluation of median OS and PFS on the Kaplan-Meier survival distribution between trained and test data exhibited appropriate accuracy and concordance of the model. Conclusions NLR and fibrinogen levels are simple, inexpensive and readily available biomarkers that could be incorporated into an on-treatment scoring system and used to help predict survival and response to ICI in patients with R/M HNSCC.
Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration
Authors: Belgacem Mihi, Qingqing Gong, Lila S. Nolan, Sarah E. Gale, Martin Goree, Elise Hu, Wyatt E. Lanik, Jamie M. Rimer, Victoria Liu, Olivia B. Parks, Angela N. Lewis, Pranjal Agrawal, Marie L. Laury, Pawan Kumar, Elizabeth Huang, Shay S. Bidani, Cliff J. Luke, Jay K. Kolls, Misty Good
Journal: Cell Reports Medicine (2021)

Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that
Integration and feasibility of symptom burden assessment and early palliative care into an adolescent and young adult leukemia clinic.
Authors: Amy Yuan Wang, Karen Sarah Hoehn, Collin Hanson, Sarah Monick, Fay J. Hlubocky, Jennifer Lynn McNeer, Tara O. Henderson, Wendy Stock, Christopher Daugherty
Journal: Journal of Clinical Oncology (2021)

10052 Background: Patients (pts) diagnosed with hematologic malignancies during adolescence &amp; young adulthood (AYA) are a uniquely challenging population who are understood to have robust supportive care needs. Here, we describe their symptom burdens and the feasibility of integrating palliative care into an outpatient, multi-disciplinary AYA leukemia clinic at an academic medical center. Methods: Palliative care was introduced into the AYA clinic in 8/2020 to provide symptom-focused care. Pre-existing clinic services included psychologists, pharmacists, and social workers. All established pts receiving routine follow up were referred by the oncology team to the Supportive Care team, which provided same-day palliative care consultation in the same clinic space with a telehealth option and as needed follow-up. To describe baseline symptom burdens, a random cross-sectional sample of pts completed a multi-domain symptom assessment (SA) using validated self-report instruments including physical (Edmonton Symptom Assessment Scale [ESAS]); emotional (Brief Symptom Inventory-18 [BSI-18]); financial (FACIT-COST); cognitive (Childhood Cancer Survivor Study – Neurocognitive Questionnaire); spiritual (FACIT -Spiritual Well-being Scale); and quality of life (QOL) (FACT-General) measures. All pts have a diagnosis of acute or chronic leukemia and were on active treatment or in survivorship. Results: Over 6 months, 30 pts (median age 29 years at assessment, range 18-45 years) received symptom-focused palliative care over 16 combined clinics with 81 total encounters averaging 5 pts (range 1-8) per clinic. 47% were female. No pts declined palliative care. Pts received on average 2.7 follow up visits (range 1-6), with 50% of encounters resulting in adjustments to medical management. Common issues addressed included pain, muscle cramps, neuropathy, anxiety, insomnia, depression, nausea, and non-pharmacological symptom control remedies. Of 46 pts, 31 (67%) completed the SA (median age 30 years at assessment, range 18-43 years); 48% were female; 84% were on treatment. 100% of pts reported fatigue, and 48% reported &gt; = 1 severe symptom (range 0-7) based on the ESAS with “poor feeling of well-being” as the most common (23%). 45% met criteria for BSI-18 emotional distress, and 45% reported some neurocognitive impairment. Emotional distress (p &lt; 0.01), financial toxicity (p = 0.03), low spiritual well-being (p &lt; 0.01), and presence of pain, nausea, or depression (p &lt; 0.05) were all associated with lower QOL. Conclusions: AYA pts with leukemia undergoing treatment and in survivorship experience high symptom burden with poor QOL. It is feasible to both assess symptom burden and provide early palliative care focused on symptom management in an outpatient, multi-disciplinary clinic setting.
CP-724714, a novel erbB2 receptor tyrosine kinase inhibitor for cancer therapy
Authors: Jitesh P. Jani, Gabriella Barbacci, Samit Bhattacharya, Mary Campbell, Kevin Coleman, Eric Cox, Erling Emerson, Eugenia Floyd, Shawn Harriman, Ken Iwata, John Kath, Joel Morris, Leslie Pustilnik, Kristina Rafidi, Daniel Richter, Ann Marie Rossi, Stefanus Steyn, Chunyan Su, Carl Thompson, Larry Wagner, Huifen Wang, Steven Winter, Jun Xiao, Xumiao Zhao, James D. Moyer
Journal: Cancer Research (2004)

4637  The erbB2 (neu/HER2) proto-oncogene is over-expressed in various tumor types such as carcinomas of breast, ovary, and stomach. Herceptin, an erbB2 targeted humanized monoclonal antibody produces an increase in survival for patients with breast cancers that overexpress erbB2, and has been approved by the FDA for that indication. CP-724,714 was identified as a potent and selective inhibitor of the erbB2 RTK (IC50 3.8 ng/ml). CP-724714 inhibits erbB2 receptor autophosphorylation in NIH 3T3 cells expressing a chimeric receptor consisting of the EGFR extracellular domain and the erbB2 intracellular domain (IC50 15 ng/ml) and in vitro growth of SKBr3 cells (IC50 25 ng/ml). It inhibits erbB2 autophosphorylation in vivo (ED50 ∼ 19 mg/kg, EC50 ∼ 980 ng/ml), after PO administration to athymic mice bearing FRE erbB2 tumors (Fisher rat embryonic fibroblasts transformed by activated erbB2). Oral administration (QD or BID) of CP-724714 inhibits the growth of FRE erbB2 tumors and human tumor xenografts in athymic female mice. The combination of CP-724,714 and Herceptin provided better anti-tumor efficacy than treatment by either agent alone in the BT-474 human breast carcinoma model. CP-724714 is an orally bio-available, well-tolerated compound that has progressed into clinical development.