tbuckley/cabot-search huggingface dataset:
A randomized phase II trial of oral vinorelbine as second-line therapy for patients with malignant pleural mesothelioma.
Authors: Dean Anthony Fennell, Angela Claire Casbard, Catharine Porter, Robin Rudd, Jason Francis Lester, Marianne Nicolson, Bruno Morgan, Jeremy Peter Steele, Liz Darlison, Georgina Mary Gardner, Lisette Sheena Nixon, Terri Kitson, Ann White, Gareth Owen Griffiths, Charlotte Poile, Aarti Gaba, Sara Busacca, Catherine Jane Richards
Journal: Journal of Clinical Oncology (2021)

8507 Background: All patients with malignant pleural mesothelioma (MPM) eventually relapse following standard chemotherapy. However, there is no standard treatment option in this setting. Vinorelbine, exhibits useful clinical activity but has not been formally evaluated in a randomised clinical trial, despite its widespread off-label use worldwide. BRCA1 regulates spindle assembly checkpoint in MPM and predicts vinorelbine sensitivity in preclinical models [1,2], suggesting that BRCA1 negative patients may be chemoresistant. Methods: VIM, a Cancer Research UK funded, investigator-initiated randomised controlled phase 2 multi-centre UK trial, enrolled patients with MPM who had progressed after first-line chemotherapy. Pts were randomised 2:1 to either vinorelbine (60mg/m 2 weekly Q21d escalating to 80mg/m 2 from cycle 2) + active supportive care (ASC) versus ASC until disease progression, unacceptable toxicity or withdrawal of consent. The primary outcome was progression free survival (PFS) defined as the time from randomisation to any progression (based on Modified RECIST criteria for assessment of response in malignant pleural mesothelioma) or death. The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints were overall survival (OS), tolerability and safety. Results: Between May 2016 and Oct 2018, 154 patients were recruited from 10 UK sites and randomised to vinorelbine + ASC (n=98) or ASC alone (n=56). In the Intention-to-treat analysis, after 129 events, median PFS was 4.2 months (m) for vinorelbine + ASC compared to 2.8m for ASC alone (Hazard Ratio (HR) 0.59; 95% CI: 0.41 to 0.85; one-sided p = 0.0017). 108 deaths were reported. Median OS was 9.3m for vinorelbine + ASC compared to 9.1m for ASC alone (HR=0.79; 95% CI: 0.53 to 1.17; two-sided p = 0.24). Toxicity data and subgroup analyses including the impact of BRCA1 deficiency will be presented. Conclusion: The trial met its primary endpoint. Vinorelbine demonstrates useful clinical efficacy in relapsed MPM, supporting its off-label use, as a treatment option for patients with relapsed MPM.[1] Busacca et al, J Pathol 2012, 227(2), 200. [2] Busacca et al, Mol Cancer Res, 2021, 20(2) 379. Clinical trial information: NCT02139904.
Fetal Tracheal Occlusion for Congenital Diaphragmatic Hernia
Authors: F. Sessions Cole
Journal: New England Journal of Medicine (2021)

The modern era of fetal surgical interventions began in the 1980s, when improved ultrasonographic imaging enabled prenatal detection of life-limiting birth defects.1 However, the rarity of many severe fetal anomalies, maternal complications associated with open fetal interventions, and the availability of effective, if imperfect, strategies for postnatal infant care restricted the performance of informative clinical trials.1 The Management of Myelomeningocele Study (MOMS),2 the results of which were reported in 2011, served as an early example of the importance of randomized clinical trials in assessing the benefits and risks of fetal interventions that had previously been performed largely on the basis . . .
Analysis of metastatic melanoma treated with immune checkpoint inhibitors and the rates of adverse events of colitis and hepatitis.
Authors: Emily Horan, Melissa Arneil, Wen Xu, Victoria Atkinson
Journal: Journal of Clinical Oncology (2021)

e21591 Background: Immune checkpoint inhibitors (CPI) are widely used in metastatic melanoma (MM), where it has markedly improved survival outcomes. ICI induced autoimmune adverse reactions (irAE) manifest in all organ systems and are due to over-activation of the immune system. Clinically relevant irAE are colitis and hepatitis as drivers of morbidity and mortality. Methods: Data was collected from a single centre (Princess Alexandra Hospital) from the electronic medical records system and immunotherapy prescribing software. Patient demographics, treatments, complications and outcomes were recorded from 2016-2019. Eligible patients had to have received immunotherapy (pembrolizumab, ipilimumab, or nivolumab) and experienced colitis or hepatitis toxicity. Trial patients were excluded. Results: The cohort of 337 patients who had received immune therapy, 18% (n = 61) had hepatitis or colitis, mean age was 56 years, 64% male. The majority were stage 4d 28% (n = 17). Braf wildtype accounted for 56% (n = 34). The highest rates of irAE occurred on combination ipilimumab and nivolumab 56% (n = 34), 10% nivolumab (n = 6), 3% (n = 2) ipilimumab, and 31% (n = 19) pembrolizumab monotherapy. Colitis affected 61% of patients (n = 37), 30% (n = 18) were grade 3 severity. Hepatitis affected 48% (n = 29), 18% (n = 32) were grade 1. The majority required oral steroids (80%, n = 49), followed by intravenous steroids (51%, n = 31), infliximab (18%, n = 11) and mycophenolate in 5% (n = 3). Hospitalisation occurred in 56% (n = 34), 20% (n = 12) requiring treatment cessation. Progressive disease occurred in 62% (n = 38), and 13% (n = 8) had a complete response. Conclusions: The findings of this analysis mirror current literature with immunotherapies used, rates and severity of irAE. The management of irAE also aligned with current guidelines. Further research is required to investigate patient factors increasing the risk of developing irAE, and ideal treatment regimens. Analysing this large cohort, the incidence of toxicity was 17%, predominantly colitis followed by hepatitis. Patients were severely impacted requiring significant interventions to manage toxicity, hospitalisation and morbidity.
An automated EHR-based tool to facilitate patient identification for biomarker-driven trials.
Authors: Shailendra Lakhanpal, Kailee Hawkins, Steven G. Dunder, Karri Donahue, Madeline Richey, Edward Liu, Alexandra Brachfeld, Lauren Sutton, Addison Shelley, Dominic Green, Evelyn Siu, James Hamrick
Journal: Journal of Clinical Oncology (2021)

1539 Background: Clinical trial eligibility increasingly requires information found in NGS tests; lack of structured NGS results hinders the automation of trial matching for this criterion, which may be a deterrent to open biomarker-driven trials in certain sites. We developed a machine learning tool that infers the presence of NGS results in the EHR, facilitating clinical trial matching. Methods: The Flatiron Health EHR-derived database contains patient-level pathology and genetic counseling reports from community oncology practices. An internal team of clinical experts reviewed a random sample of patients across this network to generate labels of whether each patient had been NGS tested. A supervised ML model was trained by scanning documents in the EHR and extracting n-gram features from text snippets surrounding relevant keywords (i.e. 'Lung biomarker', 'Biomarker negative'). Through k-fold cross-validation and l2-regularization, we found that a logistic regression was able to classify patients' NGS testing status. The model's offline performance on a 20% hold-out test set was measured with standard classification metrics: sensitivity, specificity, positive predictive value (PPV) and NPV. In an online setting, we integrated the tool into Flatiron's clinical trial matching software OncoTrials by including in each patient's profile an indicator of "likely NGS tested" or "unlikely NGS tested" based on the classifier's prediction. For patients inferred as tested, the model linked users to a test report view in the EHR. In this online setting, we measured sensitivity and specificity of the model after user review in two community oncology practices. Results: This NGS testing status inference model was characterized using a test sample of 15,175 patients. The model sensitivity and specificity (95%CI) were 91.3% (90.2, 92.3) and 96.2% (95.8, 96.5), respectively; PPV was 84.5% (83.2, 85.8) and NPV was 98.0% (97.7, 98.2). In the validation sample (N = 200 originated from 2 distinct care sites), users identified NGS testing status with a sensitivity of 95.2% (88.3%, 98.7%). Conclusions: This machine learning model facilitates the screening for potential patient enrollment in biomarker-driven trials by automatically surfacing patients with NGS test results at high sensitivity and specificity into a trial matching application to identify candidates. This tool could mitigate a key barrier for participation in biomarker-driven trials for community clinics.
Age affects the efficacy of immune checkpoint inhibitors in patients with advanced cancer.
Authors: Yongjie Wang, Ronghua Yang, Dong Wang, Donghua Zhao, Peng Li, Mengjun Li, Yingxue Qi, Ningning Luo, Yaqing Wu, Qin Zhang
Journal: Journal of Clinical Oncology (2021)

2638 Background: Immune checkpoint inhibitors (ICIs), such as programmed death(ligand)1 (PD-(L)1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, have dramatic effects on treatment in patients with various malignancies. High tumor mutation burden (TMB) is predictive of clinical response to ICI in multiple cancer types. Although age-related immune dysfunction might induce difference on the efficacy of ICIs between younger and older patients, the potential effect of age on the efficacy of ICIs remains little known and controversial. Herein, we aimed to analysis the association between age and the efficacy of ICIs based on MSKCC cohort. Methods: We screened out 1661 patients having complete information with advanced cancer, whose tumors underwent next-generation sequencing (NGS) detection and who were treated with at least one dose of ICI in MSKCC cohort. All patients were divided into two groups according to age, the younger group (age ≤50-year old) and the older group (age &gt; 50-year old). We further analyzed the differences in overall survival (OS) and TMB between the two groups. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated via Cox regression model for OS and P-values were calculated via the Wilcoxon sign test for TMB. We analyzed the effect of age on ICI in lung cancer using the same way. Results: In 1661 patients with cancer in our study, 312 (19%) younger and 1349 (81%) older patients were found. The pooled HRs for OS was 1.28 (95% CI: 1.09-1.52) in younger group compared with older group. In 1661 patients with cancer, there was 350 (21%) patients with lung cancer, including 30 (9%) younger and 320 (91%) older patients. The pooled HRs for OS was 1.45 (95% CI: 0.95-2.23) in younger group compared with older group in lung cancer. In addition, TMB in older group was higher than in younger group and significant difference of TMB was found via the Wilcoxon sign test (p = 2.6e-10) between the two groups, especially in lung cancer (p = 1e-4). Conclusions: Our study assessed the impact of age on the efficacy of ICIs using the threshold of 50 years old for the first time and we founded that patients in older group had higher TMB and longer OS than younger group.
Nutritional status and outcomes of veterans undergoing curative surgery for colorectal cancer.
Authors: Urvashi Mitbander, Timothy Frankel, Irina Y. Dobrosotskaya
Journal: Journal of Clinical Oncology (2021)

e18585 Background: Malnutrition is highly prevalent within the cancer population. Malnourishment has various negative surgical and oncologic impacts. The Veterans Health Administration (VHA) provides comprehensive care to patients in a single-payer system allowing for capture of peri-operative data and the opportunity for focused pre-operative (pre-op) interventions to improve outcomes. We sought to study the effect of pre-op weight and albumin on post-operative (post-op) complications in a contemporaneous group of veterans with colorectal cancer (CRC) at a tertiary care Veterans Affairs (VA) hospital. Methods: This is a retrospective review of 105 patients with colorectal malignancies treated with curative intent surgery at the VA Ann Arbor Healthcare System between January 2015 and January 2020. Patients with distant metastatic disease, neoadjuvant therapy, non-adenocarcinoma histology, or those receiving majority of care outside of the VHA were excluded. We examined BMI trends from one year prior to one year post surgery, rates of nutrition consults, and post-op complications defined as abnormal clinical developments such as, but not limited to, infection and delayed wound healing. Fisher’s exact test was used for analysis. Results: At time of CRC diagnosis, the mean age was 70.3 ± 9.1 and the median stage was T2N0. Surgical resections were 65% (n = 68) laparoscopic. Pre-op weight loss from 6 months prior to diagnosis to time of surgery was observed in the majority of patients (n = 47, 64%). Significant weight loss, defined as ≥3% weight reduction, was seen in 45% (n = 33) of patients. A quarter of patients were identified to have a low pre-op albumin of less than 3.5 (n = 25, 25%). Significant weight loss and low pre-op albumin were each independently associated with increased post-op complications (p &lt; 0.01). Post-op weight loss was seen in 81% (n = 73) and 69% (n = 48) of patients at 30- and 60-days post-op, respectively, and was not associated with post-op complications. Inpatient post-op nutrition consultation was performed in 96% (n = 101) of patients; nutritional supplements were recommended in only 23% (n = 23) of cases. In patients with significant weight loss, pre-op nutrition evaluation was performed in 15% (n = 5) of cases and post-op outpatient nutrition follow up occurred in 18% (n = 6) of cases. Conclusions: 45% of patients had ≥3% weight loss 6 months prior to diagnosis of CRC and 25% of patients had low albumin levels. These led to greater post-operative complications. An intensive nutrition pre-habilitation program to address weight loss and low albumin prior to surgery for CRC is needed and may reduce associated complications.
“What if I’m not trans enough? What if I’m not man enough?”: Transgender young adults’ experiences of gender-affirming healthcare readiness assessments in Aotearoa New Zealand
Authors: G. Fraser, A. Brady, M. S. Wilson
Journal: International Journal of Transgender Health (2021)

A growing body of transgender health research reports that transgender people often feel pressure to conform to a dominant narrative during gender-affirming readiness assessments. In New Zealand, however, no study to date has specifically examined transgender people's experiences of readiness assessments for gender-affirming healthcare.This study aimed to explore the experiences of transgender young adults (aged 16-30) during gender-affirming readiness assessments in New Zealand. We also sought participants' views on improving transgender healthcare provision.Thirteen transgender young adults took part in individual interviews or focus groups. Participants were asked to describe how they felt about the questions asked during readiness assessments and how the readiness assessment process could be improved. We used thematic analysis to identify patterns of meaning across the dataset.We identified two themes. Firstly, proving gender explores participants' views of readiness assessments as designed to establish whether they were "trans enough" or "truly" transgender, and why readiness assessments are conducted in this manner. Secondly, the trans narrative describes the pressure participants felt to adhere to a dominant transgender narrative in order to gain access to the healthcare they needed.Our findings call attention to the importance of a trans-affirmative approach and the need to clarify the purpose of gender-affirming healthcare readiness assessments in New Zealand.
Oropharyngoesophageal Scintigraphy in a Case of Complex Swallowing Disorders After a Major Oral Surgery
Authors: Daria Maccora, Claudio Parrilla, Valerio Lanni, Jacopo Galli, Ylenia Longobardi, Venanzio Valenza
Journal: Clinical Nuclear Medicine (2021)

Abstract A 75-year-old woman had an occasional finding of a left tonsil mass for dysphagia, which resulted a high-grade squamous carcinoma. Therefore, the patient was sent to have a left pharyngectomy. After the pharyngectomy, the patient reported persistent swallowing disorders and nasal reflux. Consequently, she had an oropharyngoesophageal scintigraphy, demonstrating irregular oral and pharyngeal swallowing phases and confirming reflux episodes into the rhinopharynx and into the oropharynx. In line with these findings, the patient was send to rehabilitation; the abnormal functional mechanisms, previously identified by the scintigraphy, allowed to guide the speech therapy, with a progressive clinical improvement.
Artificial intelligence-powered spatial analysis of tumor infiltrating lymphocytes (TIL) to reflect target gene expressions of novel immuno-oncology agents.
Authors: Chan-Young Ock, Seunghwan Shin, Wonkyung Jung, Sangheon Ahn, Haejoon Kim, Chunggi Lee, Jaehong Aum, Daim Tak, Ahyoung Ryu, Taiwon Chung, Eunji Baek, Jisoo Shin, Seungje Lee, Jiwon Shin, Minuk Ma, Seonwook Park, Sergio Pereira, Jeongseok Kang, Donggeun Yoo, Kyunghyun Paeng
Journal: Journal of Clinical Oncology (2021)

e14534 Background: Novel immuno-oncology (IO) agents are promising but showing their efficacy in early phase clinical trials has been challenging due to limited enrichment strategies using practical biomarker platforms. We hypothesize that an artificial intelligence (AI)-powered spatial analysis of TIL using practically feasible H&amp;E slides, can reflect a specific target gene expression derived from RNA sequencing. This enhances its potential application in early development of novel IO agents. Methods: An AI-powered spatial TIL analyzer, namely Lunit SCOPE IO, was developed with data from 2.8 x 10 9 micrometer 2 H&amp;E-stained tissue regions and 5.9 x 10 6 TILs from 3,166 whole slide images of multiple cancer types, annotated by board-certified pathologists. Inflamed Score and Immune-Excluded Score was defined as the proportion of all tumor-containing 1 mm 2 -size tiles within a WSI classified as being of inflamed immune phenotype (high TIL density within cancer epithelium) and immune-excluded phenotype (low TIL density within cancer epithelium, but high TIL density within stroma), respectively. We used RNA sequencing data and H&amp;E images from The Cancer Genome Atlas database, excluding those of mesenchymal origin (n = 7,467). Spearman's rank correlation between each gene expression and IS or IES, respectively, was calculated. Correlation coefficient &gt; 0.2 and false discovery rate (FDR) &lt; 1% was considered as a significant correlation. Results: In a total of 20,304 genes, 871 (4.3%) and 1,155 (5.7%) genes were significantly correlated with Inflamed Score (IS) and Immune-Excluded Score (IES), respectively. The IS was highly related to genes reflecting immune cytolytic activity and targets of approved immune checkpoint inhibitors (Table). Interestingly, it was also significantly correlated with target genes of novel IO such as TIGIT, LAG3, TIM3, IDO, Adenosine receptor A2A, OX40, ICOS, M-CSF, IL2, IL7, and IL12. Moreover, the IES was exclusively correlated with the target genes of CEACAM, TGFB, and IL1. Conclusions: Expression levels of novel I-O target genes are correlated with three scores derived from AI-powered TIL analysis using H&amp;E slides, which can be easily applied to clinical research.[Table: see text]
T-cell clonality in peripheral blood as a predictor of progression to systemic treatment in patients with stage IB mycosis fungoides (MF).
Authors: Suravi Raychaudhuri, Charli-Joseph Yann, Michelle Mintz, Laura Pincus, Chiung-Yu Huang, Weiyun Z. Ai
Journal: Journal of Clinical Oncology (2021)

e19538 Background: A major unmet clinical need in the care of early-stage MF patients is the identification of those with a high risk of failing skin directed therapy or progressing to advanced disease. Herein, we inquired if the identification of a clonal T-cell receptor (TCR) gene rearrangement by PCR in peripheral blood could predict the clinical outcome, particularly the need for systemic treatment, in patients with stage IB MF. Methods: This is a retrospective cohort study of patients with stage IB MF who underwent peripheral blood TCR clonality analysis by PCR. The primary outcome of the study was time from diagnosis to initiation of systemic treatment. Secondary outcomes were: (1) time to progression to advanced-stage disease (stages IIB-IV) and (2) overall survival. Patients were censored at time of last clinical follow up. Log rank test was used to compare the survival distributions of the two groups; p value &lt; 0.05 was considered significant. Results: From May 2014 to October 2019, 56 consecutive stage IB pts with &gt; 6 months follow up were included in this analysis. Peripheral blood TCR clonality status was available in 42 patients: 18 pts had a positive TCR clone and 24 did not. Median follow up time was 36 months (range 8.5 – 198 months). At 3 years, 39% of patients with peripheral clone had progressed to systemic treatment versus 8% of those without a peripheral clone (log rank test, p-value = 0.003). For the secondary outcomes, at 3 years 17% of patients with peripheral clone had progressed to advanced stage versus 4% of those without (log rank test, p-value = 0.10); 5% of patients with peripheral clone had died versus 0% of those without (log rank test, p-value = 0.03). Conclusions: Detection of a predominant TCR clone by PCR in the peripheral blood is an important prognostic marker in the initial workup of MF, as its presence is highly correlated with subsequent progression to systemic treatment and death. If this finding is validated, it can be used to risk stratify and individualize therapy for MF patients.[Table: see text]
Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression marks human obesity
Authors: Maria P. Clemente-Olivo, Jayron J. Habibe, Mariska Vos, Roelof Ottenhoff, Aldo Jongejan, Hilde Herrema, Noam Zelcer, Sander Kooijman, Patrick C.N. Rensen, Daniël H. van Raalte, Max Nieuwdorp, Etto C. Eringa, Carlie J. de Vries
Journal: Metabolism (2021)

ObjectiveFour-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and expression of the FHL2 gene increases with age, and high FHL2 expression is associated with increased body weight in humans and mice. This led us to hypothesize that FHL2 is a determinant of diet-induced obesity.MethodsFHL2-deficient (FHL2−/−) and wild type male mice were fed a high-fat diet. Metabolic phenotyping of these mice, as well as transcriptional analysis of key metabolic tissues was performed. Correlation of the expression of FHL2 and relevant genes was assessed in datasets from white adipose tissue of individuals with and without obesity.ResultsFHL2 Deficiency protects mice from high-fat diet-induced weight gain, whereas glucose handling is normal. We observed enhanced energy expenditure, which may be explained by a combination of changes in multiple tissues; mild activation of brown adipose tissue with increased fatty acid uptake, increased cardiac glucose uptake and browning of white adipose tissue. Corroborating our findings in mice, expression of FHL2 in human white adipose tissue positively correlates with obesity and negatively with expression of browning-associated genes.ConclusionOur results position FHL2 as a novel regulator of obesity and energy expenditure in mice and human. Given that FHL2 expression increases during aging, we now show that low FHL2 expression associates with a healthy metabolic state.