tbuckley/cabot-search huggingface dataset:
TNFAIP3 Interacting Protein 3 Is an Activator of Hippo‐YAP Signaling Protecting Against Hepatic Ischemia/Reperfusion Injury
Authors: Junjie Zhou, Manli Hu, Meiling He, Xiaoming Wang, Dating Sun, Yongping Huang, Xu Cheng, Jiajun Fu, Jie Cai, Tengfei Ma, Song Tian, Yufeng Hu, Fengjiao Hu, Dan Liu, Yanqi He, Lanlan Yan, Zhi‐Gang She, Xiao‐Jing Zhang, Yan‐Xiao Ji, Hui Liu, Hongliang Li, Hailong Yang, Peng Zhang
Journal: Hepatology (2021)

Hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, causes a large proportion of early graft failure and organ rejection cases. The identification of key regulators of hepatic I/R injury may provide potential strategies to clinically improve the prognosis of liver surgery. Here, we aimed to identify the role of tumor necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in hepatic I/R injury and further reveal its immanent mechanisms.In the present study, we found that hepatocyte TNIP3 was markedly up-regulated in livers of both persons and mice subjected to I/R surgery. Hepatocyte-specific Tnip3 overexpression effectively attenuated I/R-induced liver necrosis and inflammation, but improved cell proliferation in mice, whereas TNIP3 ablation largely aggravated liver injury. This inhibitory effect of TNIP3 on hepatic I/R injury was found to be dependent on significant activation of the Hippo-YAP signaling pathway. Mechanistically, TNIP3 was found to directly interact with large tumor suppressor 2 (LATS2) and promote neuronal precursor cell-expressed developmentally down-regulated 4-mediated LATS2 ubiquitination, leading to decreased Yes-associated protein (YAP) phosphorylation at serine 112 and the activated transcription of factors downstream of YAP. Notably, adeno-associated virus delivered TNIP3 expression in the liver substantially blocked I/R injury in mice.TNIP3 is a regulator of hepatic I/R injury that alleviates cell death and inflammation by assisting ubiquitination and degradation of LATS2 and the resultant YAP activation.TNIP3 represents a promising therapeutic target for hepatic I/R injury to improve the prognosis of liver surgery.
Relationships of mannitol challenge to methacholine challenge and inflammatory markers in asthmatics receiving inhaled corticosteroids
Authors: William Anderson, Brian Lipworth
Journal: European Respiratory Journal (2012)

BACKGROUND: Mannitol is a novel osmotic indirect bronchial challenge agent thought to reflect underlying inflammation in asthma. We explored relationships of mannitol airway hyper-responsiveness (AHR) to other measures of airway inflammation and to methacholine challenge.  METHODS: Sreening data were analysed of 143 mild to moderate asthmatics, all taking inhaled corticosteroids (ICS), who had mannitol and/or methacholine challenges, fractional exhaled nitric oxide (FeNO) and salivary eosinophilic cationic protein (ECP) measured together. Mannitol AHR was grouped by PD10: mild (315-635mg); moderate (75-315mg); severe (0-75mg).  RESULTS: Mannitol PD10 groups were significantly different overall for FeNO (p=0.023): 43% higher in the severe vs. mild group. There was a significant overall difference for methacholine PC20 (p=0.006): a 2.1 doubling dilution difference between severe vs. mild mannitol groups.  No significant differences were found across groups for: salivary ECP, FEV1%, or ICS dose. Mannitol PD10, methacholine PC20 and FeNO as continuous variables all correlated with each other.  CONCLUSIONS: Mannitol challenge reflects both underlying inflammation using FeNO and direct AHR using methacholine. Thus mannitol may be a useful screening tool for the assessment of asthmatic patients receiving ICS.
An internal review of rates of palliative medicine referral for patients with advanced pancreatic cancer.
Authors: Deanna Huffman, Karthik Shankar, Lynna Alnimer, Yazan Samhouri, Urwat Vusqa, Srividya Srinivasamaharaj, Dulabh K. Monga
Journal: Journal of Clinical Oncology (2021)

e16245 Background: Patients diagnosed with advanced pancreatic cancer face many challenges in addition to symptom burden including psychological stressors and often the need for supportive care at home. In recent years, both clinical trials and retrospective reviews have confirmed the benefits of early integration of palliative care services such as improved quality of life and reduced symptom intensity. The American College of Clinical Oncology recommends patients with advanced cancer receive directed palliative care services early after diagnosis and in concurrence with active treatment. While the benefit of palliative care services is clear, the best way to integrate palliative services has not been determined. Our project aims to review the rates of palliative care consultation in patients with advanced pancreatic cancer intending to improve patient outcomes. Methods: We retrospectively reviewed the electronic medical records of all patients diagnosed with pancreatic cancer at Allegheny General Hospital diagnosed between 2009-2020. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Results: Of the 171 patients reviewed, 121 competed all treatment and evaluation within our health network. Median age was 63 years (IQR 40-91 years); 55 patients (45%) were male. The majority were white (88%). At the time of diagnosis, 28% of our patients had stage IV disease and 19.8% of patients with stage IV disease had documented palliative care referrals. Eight patients had pain documented at diagnosis, six patients underwent celiac plexus neurolysis, 31 underwent palliative radiation and 43 patients had documented opiate use. Of the 6 patients who underwent celiac plexus neurolysis, only 4 documented pain at 6-month follow-up. Of the 31 patients who underwent palliative radiation, 6 documented pain at 6-month follow-up. Conclusions: Palliative care is an integral part of usual care for pancreatic cancer. Our analysis showed that palliative care is underutilized in our hospital with only 19.8% of patients having documented palliative care visits. While patients may refuse palliative care consult, other contributing factors are likely the lack of access or lack of early involvement of palliative care team members. Integration of palliative care has been proven repeatedly to improve quality of life in patients diagnosed with advanced pancreatic cancer. We aim to improve palliative care integration in out patients’ care by adding a hard stop to electronic medical records to remind physicians to offer palliaitive care to the patients, in addition to arranging medical grand rounds and various lectures to increase awareness of the importance of palliative care in this setting.
Prospective genomic testing of unselected cancer patients yields insights about cancer susceptibility and noncancer disease with therapeutic implications.
Authors: Stacy W. Gray, Kevin McDonnell, MD, PhD, Gregory Idos, Christine Hong, Ilana Solomon, Duveen Sturgeon, Joseph D. Bonner, Sidney A. Smith, Jennifer Morales Pichardo, Melissa Woodhouse, Elise Sobotka, Elyssa Zukin, Samir Courdy, Elisabeth King, Xiaoyu Xia, Szabolcs Szelinger, Janine LoBello, Stanley R. Hamilton, Jeffrey M. Trent, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2021)

10603 Background: Clinicians have used strict criteria to determine eligibility for cancer susceptibility (CS) testing and have limited genetic assessment to cancer-related genes. However, half of all CS mutation carriers are missed by criteria-based testing and there may be an unrecognized opportunity to modify care for patients who have rare but actionable genetic disorders as defined by the American College of Medical Genetics (ACMG). With the aim of improving patient outcomes through precision genomics, we initiated an enterprise-wide program to offer somatic and germline sequencing to all patients. Methods: We offer consented patients clinical grade paired somatic &amp; germline WES/ RNA seq and panel germline testing for cancer (156 genes) and ACMG disorders (59 genes). Results are reviewed by a Precision Oncology Tumor Board. Somatic results are returned by the treating team. Germline results are returned by phone (genetic counselor, GC) followed by a clinic visit (GC+MD) for those with pathogenic/likely pathogenic (P/LP) mutations and selected variants of uncertain significant. We evaluated the proportions of patients with somatic findings suggestive of germline conditions and those carrying P/LP mutations in CS and ACMG genes. Results: 1,804 patients enrolled and received somatic sequencing: 52% female; 51% non-Hispanic White/ 20% Hispanic White/ 18% Asian/ 4% Black/ 7% other; median age 64. Review of somatic data suggest that 14% have findings suggestive of germline conditions based on factors such as TMB, MSI, and young age. Of the patients offered germline testing, &gt;95% opted to receive CS/ACMG results. To date, we have sequenced 684 patients for CS and 647 for ACMG. 18% of patients had P/LP mutations in CS genes and 4% had P/LP mutations in ACMG non-cancer genes (Table). Conclusions: Prospective somatic/germline sequencing of unselected cancer patients reveals tumor findings suggestive of germline disorders and identifies patients with CS and non-cancer genetic conditions. These findings highlight the promise of a comprehensive sequencing approach to help guide cancer treatment, management of unrecognized cancer risk and the need for concomitant management of rare disorders such as arrhythmogenic cardiomyopathy and susceptibility to adverse reactions with anesthesia.[Table: see text]
Single center observational study of the efficacy of chemotherapy in breast cancer patients treated before and after the widespread use age of CD4/6 inhibitors: Is there evidence that chemotherapy response is impacted by prior use of CD4/6 inhibitors?
Authors: Martin S. Hogg, Tweisge Mugisa, Smriti Gaur
Journal: Journal of Clinical Oncology (2021)

e13019 Background: Recently CD4/6 inhibitors have radically changed treatment pathways, leading to a deferment of chemotherapy for advanced disease. Patients still relapse following this treatment; we wish to share our experience of chemotherapy both before and after this change and explore whether there is a change in efficacy. In England CD4/6 inhibitors are prescribed according to the guidelines set out by NHS England (NICE), and are generally utilised in the first line setting unless there is visceral crisis. Methods: This is a retrospective double cohort observational single centre study comparing the efficacy of a chemotherapy regimen (vinorelbine and capecitabine vin cap) before and after the incorporation of CD4/6 inhibitors into breast cancer treatment (Jan 2017- Nov 20). The doublet chemotherapy is widely used at our centre providing a well tolerated and effective alternative to intravenous treatments such as taxanes or single agent capecitabine. Data was collected contemporaneously using e prescribing software and audited retrospectively Results: In the audit period n=19 treated with cap, n= 97 with vin cap, n= 24 treated with CD4/6, (of whom 5 relapsed). 5 patients received abemaciclib first line, as initial therapy, all G3, stage 11A or above, median number of cycles 4.2, I received ribociclib, G2, stage 111A, 7 cycles and 17 received palbociclib, 10 first line, 4 following 1 course chemo, 2 after 2 courses and 1 and after 3 courses, 30% G3 and 70% G2, mean number of cycles 11.06. Patients who received first line cap progressed after a median of 3.5 cycles, with a range of 0-22 months (RR= 47%), for cape vin a median of 8.6, a range of 0-60 months (RR=77%), post CD4/6 mean of 8, median of 9, a range of 0-17 (RR=80%). Conclusions: Those post CD4/6 requiring chemo relapsed far short of the median TTP of around 26months and may have specific characteristics predicting poor response to CD4/6. Despite small numbers salvage chemotherapy remains effective with similar responses. First line vin cap is more efficacious and better tolerated than Cap.[Table: see text]
Association of <i>MUC16</i> mutations with immunotherapy biomarkers in Chinese non-small cell lung cancer patients.
Authors: Tao Han, Taiyan Guo, Xia You, Qianru He, Qin Zhang, Chuang Qi
Journal: Journal of Clinical Oncology (2021)

e21061 Background: MUC16 is frequently mutated in non-small cell lung cancer (NSCLC). Previous studies showed MUC16 mutation were associated with TMB and prognostic outcome in gastric cancer patients and may benefits for patients with immunotherapy. Herein, we aimed to characterize the association of MUC16 with immunotherapy biomarkers in Chinese and Western NSCLC patients. Methods: Next-generation sequencing data and clinical data were collected from 1053 TCGA NSCLC patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 1056 Chinese pan-cancer patients (Chinese cohort). Both MUC16 mutation ratio and TMB were calculated on the two cohorts following the same criteria. Results: In total, 269 (25%) of the 1056 Chinese patients and 494 (47%) of the 1053 Western patients had at least one mutation of MUC16 genes ( MUC16 mutant group). The Chinese cohort had a higher mutation frequency of MUC16 gene than the Western cohort (25% vs. 47%, p＜0.001). In both cohorts, TMB was higher in the MUC16 mutant group compared to non- MUC16 mutant group. In Chinese cohort, PD-L1 positive was not associated with MUC16 mutation. However, patients with MUC16 mutation were not associated with prolonged survival in Western immunotherapy cohort. Conclusions: Our study provided a landscape of MUC16 mutations in a much larger Chinese NSCLC group, which could be a valuable complement to TCGA dataset. Both in Chinese and Western cohorts, the higher TMB in MUC16 mutant patients suggested potential efficacy from immunotherapy of MUC16 mutant group. A larger validation cohort of MUC16 mutant is required to confirm these findings in the further.
Combining hematoxylin and eosin (H&amp;E) stained images and RNA sequencing (RNA-Seq) data to predict overall survival (OS) in patients with non-small cell lung cancer (NSCLC).
Authors: Teresa M Karrer, Marius Garmhausen, Xiao Li, Gunther Jansen
Journal: Journal of Clinical Oncology (2021)

1547 Background: IMpower150 was a phase 3 clinical trial that evaluated the efficacy of atezolizumab in patients with metastatic nonsquamous NSCLC; it demonstrated no significant OS benefit in the ACP (atezolizumab+carboplatin+paclitaxel) arm vs the BCP (bevacizumab+carboplatin+paclitaxel) control arm (hazard ratio [HR]=0.85; 95%CI, 0.71-1.03). The objective of this analysis was to identify a subpopulation of patients that benefits from ACP using H&amp;E stained images and RNA-Seq data. Methods: Spatial statistics algorithms were applied to the coordinates of tumor cells and lymphocytes of the H&amp;E stained images to capture spatial heterogeneity of the tumor microenvironment. The normalized and log-transformed RNA-Seq data underwent a nested feature selection procedure using a Cox proportional hazard model with L1 regularization and stability selection. Cutoffs for gene selection were determined using a permutation strategy with a false discovery rate &lt;0.001. To investigate the association between the 41 derived spatial features, significant genes and OS, a Cox proportional hazard model with L2 regularization was fitted only for the ACP group. Survival groups were further identified using nested Monte Carlo Cross Validation to prevent over-fitting. Results: A total of 236 ACP and 235 BCP patients who had both H&amp;E stained images and RNA-Seq data were analyzed. In the predicted long survival group, ACP patients had significantly longer median OS vs BCP patients based on H&amp;E stained images (HR=0.61; 95%CI, 0.41-0.90; P=0.013) and RNA-Seq data (HR=0.64; 95%CI, 0.41-0.99; P=0.042). The combination of both modalities further improved the OS benefit between the arms (HR=0.44; 95%CI, 0.27-0.73; P=0.001). Data-driven selection of genes relevant for the prediction of OS included MAML3, AC024475.4, RGPD1, LCE3D and AC004156.1. Conclusions: Our approach was able to stratify a subpopulation of patients that significantly benefited from ACP compared with BCP treatment, particularly when integrating both H&amp;E stained images and RNA-Seq data, which demonstrated the complementary value of both modalities. Our results could inform the development of a companion diagnostic that predicts individualized treatment response. Clinical trial information: NCT02366143.
Perceptions of cancer patients and their caregivers regarding COVID-19 pandemic in Ethiopia.
Authors: Aynalem Abraha Woldemariam, Nataliya Berbyuk Lindström, Rune Andersson, Adamu Addissie
Journal: Journal of Clinical Oncology (2021)

e24116 Background: Limited research is available about COVID 19 pandemic in Ethiopia in general and in relation to cancer care in particular. Ethiopia reported the first COVID-19 in March, 2020. The number of cases is increasing, putting much pressure on oncology care. This study examines what the Ethiopian cancer patients and their caregivers knew about COVID 19 after the initial stages of the pandemic. It also assesses the information needs, psychological experiences as well as the impact of pandemic on oncologist-patient-caregiver communication and treatment process. Methods: A cross-sectional study was conducted among 200 participants (100 cancer patients and 100 caregivers) at the initial stage of pandemic (May 1 - June 30, 2020) at Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia. Data was collected using a pre-tested, structured questionnaire to assess knowledge and perceptions on COVID-19. Ethics approval was obtained from the Ethical Review Board of TASH (04/14/2015) and the Ethical Review Board of Western Sweden (DNR 520-18). Results: The results indicate that though both cancer patients and their caregivers show a high awareness of and knowledge about COVID 19, they need more information about the risks specific to cancer patients. The respondents are also concerned about the risks of pandemic outbreak in Ethiopia and its impact on availability of cancer care treatments in the country. The respondents report experiencing psychological concerns in relation to the pandemic. The higher educated patients and caregivers report being more concerned than the lower educated respondents. Delays in appointments and therapy are the main concerns in relation to cancer care. Further, both patients and caregivers experience that the restrictions on the number of caregivers present during interactions with oncologists negatively influence communication, resulting in relatives being excluded and patients experiencing loneliness and lack of support. Conclusions: Getting a better insight into knowledge and awareness of COVID-19 among cancer patients and their caregivers is essential for managing the effects of pandemic in cancer care. To our knowledge, there was no similar study in Ethiopia. The results of the study contribute to insights into patient and caregiver awareness of COVID 19, essential for adoption of health care protective practices, providing information and managing oncologist-patient-caregiver communication.
Survival outcomes with the use of immunotherapy (IO) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC) at a large hybrid cancer institute.
Authors: Joanna Alyse Young, Christina Clarkson, Jiaxian He, Daniel Slaughter, Daniel Ernest Haggstrom, Daniel R. Carrizosa, Kathryn Finch Mileham
Journal: Journal of Clinical Oncology (2021)

e21192 Background: Landmark trials have shown increased survival in pts who receive IO for NSCLC as compared to chemotherapy (chemo). Median overall survival (mOS) ranged from 17-26 months (mo); however, mOS in several published “real-world” retrospective studies are lower, ranging from 8-12 mo, with about 4-5 months on IO treatment. We sought to define mOS of pts with mNSCLC who received IO as monotherapy or in combination with chemo as first line therapy at Levine Cancer Institute. Methods: We retrospectively reviewed 315 adult pts with mNSCLC without driver mutations diagnosed between 2016 and 2019. The Kaplan-Meier method was used to estimate and compare OS between IO and IO + chemo. Univariate and multivariate Cox models were used to evaluate risk factors (RF) for OS. RFs considered included age, sex, race, smoking status, histology, first-line treatment type, and metastatic (mets) sites. Results: Baseline pt characteristics were: 40% female, 77% white, 20% Black, 34% current smokers and 60% former smokers. Median age was 69 years (45-88) in pts receiving IO alone and 63 years (28-84) in pts receiving IO + chemo. Tumor characteristics were: 76% adenocarcinoma and 17% squamous cell carcinoma. PD-L1 TPS distribution was: 39% for 0%, 22% for 1-49%, and 39% for ≥50%. Distribution of mets was 10% adrenal, 40% bone, 30% brain, 14% liver, 31% lung. mOS for pts receiving IO and IO + chemo as first line therapy was 17 and 14.8 mos, respectively (P = .209). Median duration of IO received was 4.25 months (0 to 43.6). mOS as stratified by PD-L1 TPS was 14.5 mos for PD-L1 0%, 13.3 mos for PD-L1 1-49%, and 19.5 mos for PD-L1 ≥50% (P = .163). OS was significantly different between IO and IO + chemo after adjusting for age. No OS differences were seen between white and Black or between all pts vs pts with brain mets (brain-specific interventions not reviewed). The table summarizes significant findings only (P &lt; 0.05). Conclusions: Pts with mNSCLC treated first-line with IO either alone or with chemo at Levine Cancer Institute lived longer than those in similar published “real-world” cohorts. Median OS was highest in patients with PD-L1 TPS ≥50%, although not statistically significant. While not unusual to identify worse outcomes in those with bone and liver mets, interestingly brain metastasis was not associated with worse survival. In this cohort, when adjusted for age, IO alone trends toward improved survival. Although there was no OS difference based on race, further investigation will seek to uncover any other disparities contributing to outcomes, such as insurance status and zip code mapping. To our knowledge, this provides the largest analysis of this patient population outside of a clinical trial.[Table: see text]