tbuckley/cabot-search huggingface dataset:
Participation of African Americans in clinical trials supporting FDA approval of cancer drugs.
Authors: Samer Al Hadidi, Martha P. Mims, Courtney Nicole Miller-Chism, Rammurti T. Kamble
Journal: Journal of Clinical Oncology (2019)

e18135 Background: African Americans comprise 12% of the total United States population. Lifetime probability of developing cancer in African Americans is 37.55%. The 5-year relative survival rate is 68% in Caucasians and 61% in African Americans for all cancers combined. Concerns exist that African Americans are underrepresented in trials of cancer medications. We sought to examine African Americans participation for pivotal cancer medications trials submitted to the U.S. Food and Drug Administration (FDA) supporting marketing applications. Methods: On the basis of publicly available FDA reviews, the authors assessed enrollment of African Americans in trials supporting 75 drug approvals from 2014 to 2018. Prevalence-corrected estimates for the participation of African Americans were calculated as the percentage of African Americans among trial participants divided by the percentage of African Americans in the disease population (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting similar representation of African Americans in the trial and disease population. Results: A total of 61763 patients enrolled in clinical trials, which resulted in subsequent FDA approval. The proportion of African Americans enrolled in the clinical trials that led to cancer medication approval in the 5-year period was 7.44%. The calculated PPR for participation of African Americans in clinical trials that led to drug approval for all cancers combined was 0.31. The results were consistent across major cancer subtypes including breast cancer (PPR of 0.29), prostate cancer (PPR of 0.18), and lung cancer (PPR of 0.15). Skin cancer, colorectal cancers and hematological malignancies results were also consistent with low PPR. Conclusions: African Americans were under represented in trials of drugs for all cancer types combined. Efforts should be made to increase the proportion of participation of African Americans in clinical trials.
The host response to immune checkpoint inhibitors: From mechanisms to therapeutic implications.
Authors: Ella Fremder, Eyal Jacob, Irena Khononov, Eran Issler, Shani Raveh, Nili Dahan, Haim Bar, Yuval Shaked
Journal: Journal of Clinical Oncology (2019)

e14584 Background: One of the major challenges in clinical immuno-oncology today is predicting which patients will respond to treatment. Although the use of immune checkpoint inhibitors (ICIs) has significantly improved therapeutic outcomes in a subset of patients with advanced malignancies, the majority of patients do not respond to treatment and some even hyper-progress. This response pattern raises questions regarding the possible mechanisms of resistance to ICIs. In the last decade we and others have shown that the host, in response to almost any type of anti-cancer drug, generates pro-tumorigenic and pro-metastatic effects which in turn contribute to tumor relapse and resistance to therapy despite an initial response. However, such host effects have never been investigated using immune-oncology drugs. Methods: We used functional and computational methods on plasma samples from both mouse models and cancer patients to identify the host-mediated tumor promoting molecular pathways that are induced in response to ICI therapy. Results: We found that these pathways are composed of dominant factors that regulate pro-inflammatory, metastatic and proliferation activities and thus contribute to rapid tumor re-growth. In pre-clinical models, we have found that pharmacological blockade of specific dominant factors overcomes the tumor-promoting effects induced by the host in response to ICI therapy. Conclusions: Based on our collective findings, we propose that therapies inhibiting host-mediated pro-tumorigenic effects could be used in combination with ICIs as a strategy to minimize tumor hyper-progression and increase the susceptibility of resistant tumors to ICI therapy. Furthermore, our studies pave the way towards the discovery of new predictive biomarkers for identifying subjects who will benefit from ICI therapy.
ENGOT-Ov41/GEICO-69-O/ANITA trial: A phase Ill randomized, double-blinded trial of platinum-based chemotherapy (CT) with or without atezolizumab (ATZ) followed by niraparib maintenance with or without ATZ in patients with recurrent ovarian, tubal or peritoneal cancer (OC) and platinum treatment-free interval (TFIp) > 6 months
Authors: Antonio Gonzalez-Martin, Nicoletta Colombo, Florian Heitz, Rene dePont Christensen, Frederic Selle, Ignace Vergote, Ana Oaknin
Journal: Journal of Clinical Oncology (2019)

TPS5599Background: Platinum-based CT is the treatment of choice for OC patients (pts) with TFIp > 6 months suitable for platinum. Niraparib is an oral PARP inhibitor that significantly prolongs the...
Prevalence of maternal mental illness among children and adolescents in the UK between 2005 and 2017: a national retrospective cohort analysis
Authors: Kathryn M Abel, Holly Hope, Eleanor Swift, Rosa Parisi, Darren M Ashcroft, Kyriaki Kosidou, Cemre Su Osam, Christina Dalman, Matthias Pierce
Journal: The Lancet Public Health (2019)

<h2>Summary</h2><h3>Background</h3> Little information exists about the prevalence of children exposed to maternal mental illness. We aimed to estimate the prevalence of children and adolescents exposed to maternal mental illness in the UK between 2005 and 2017 using primary care data. <h3>Methods</h3> In this national retrospective cohort study, we included children aged 0–16 years born between Jan 1, 1991, and Dec 31, 2015, who were linked to their mothers and registered on the primary care Clinical Practice Research Datalink (CPRD) between 2005 and 2017. We extracted data on diagnosis, symptoms, and therapy from the CRPD to define the following maternal mental illnesses: depression, anxiety, non-affective psychosis, affective psychosis, eating disorders, personality disorders, alcohol misuse disorder, and substance misuse disorder. We also extracted data on socioeconomic status from the Index of Multiple Deprivation 2010 and data on ethnicity from the Hospital Episode Statistics dataset. The main outcome was prevalence of maternal mental illness. Prevalence was calculated for each 2-year period of childhood (from age 0–<2 to 14–<16 years) using marginal predictions from a logistic regression model. We used survival analysis to estimate the incidence and cumulative risk of children experiencing maternal mental illness by age 16 years. <h3>Findings</h3> We identified 783 710 children registered in the UK CPRD mother-baby link database, and included 547 747 children (381 685 mothers) in our analysis. Overall prevalence of maternal mental illness was 23·2% (95% CI 23·1–23·4), which increased during childhood (21·9%, 21·7–22·1 among the 0–<2 year age group <i>vs</i> 27·3%, 26·8–27·8 among the 14–<16 year age group). Depression and anxiety were the most prevalent maternal mental illnesses. The proportion of children exposed to maternal mental illness increased from 22·2% (21·9–22·4) between 2005 and 2007 to 25·1% (24·8–25·5) between 2015 and 2017. Geographically, the highest prevalence of maternal mental illness was observed in Northern Ireland (29·8%, 29·0–30·5). In England, prevalence of maternal mental illness was highest among children in the most deprived areas (28·3%, 27·8–28·8). The incidence of maternal mental illness was highest between 0–3 months (26·7 per 100 person years, 26·4–27·1). By age 16 years, the cumulative risk of maternal mental illness was 53·1% (52·8–53·3). <h3>Interpretation</h3> One in four children aged 0–16 years are exposed to maternal mental illness and the prevalence of diagnosed and treated maternal mental illness is increasing. Policy makers and commissioners should consider this information and channel resources to target individuals in greatest need. <h3>Funding</h3> The European Research Council and the National Institute for Health Research.
<i>Notes from the Field</i>: Acute Intoxications from Consumption of <i>Amanita muscaria</i> Mushrooms — Minnesota, 2018
Authors: Joanne Taylor, Stacy Holzbauer, Danushka Wanduragala, Alexander Ivaskovic, Ron Spinosa, Kirk Smith, Justin Corcoran, Ashley Jensen
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

In October, 2018, a middle-aged ethnic Karen* man from Burma was evaluated at a hospital emergency department with altered mental status, vomiting, diarrhea, incontinence, sweating, swelling of the lip and tongue, and excessive salivation.Signs and symptoms began approximately 2-3 hours after eating mushrooms at home.The patient was admitted for supportive treatment, including endotracheal intubation for airway protection and mechanical ventilation because of acute respiratory failure and hypoxia for 4 days.His daughter, who also ate the mushrooms, was evaluated for similar, but milder symptoms, including mild sweating and nausea; she was admitted overnight for observation, and was discharged the following day.The father recovered and was discharged 8 days after admission.An emergency department physician suspected possible cholinergic mushroom toxicosis and notified the Minnesota Poison Control System (MPCS).MPCS notified the Minnesota Department of Health (MDH), and, together with the Minnesota Mycological Society (MMS), they initiated an investigation.The patient's medical records and exposure history were obtained and reviewed, and he was interviewed through a Karen language interpreter.He described the mushroom and collection location and later sent a photo of a mushroom that he said looked similar to the one he picked.He reported that he had picked mushrooms from an area near his workplace and cooked them in turmeric, oil, and water; only he and his daughter had eaten the mushrooms, and she reportedly consumed substantially fewer mushrooms than he did.He said this was the first time he had picked mushrooms since arriving in Minnesota in 2015 and that he had selected the mushrooms because they resembled the Ochre mushroom (Amanita hemibapha var.ochracea) from his native Burma.A site visit to the location where the mushrooms were picked identified one remaining mushroom that matched the patient's description (Figure ); an MMS mycologist examined the mushroom and identified it as Amanita muscaria var.guessowii.A. muscaria mushrooms can contain ibotenic acid and muscimol, which are structurally similar to glutamate and * Karen are one of nine ethics groups in Burma.Approximately 17,000 Karen live in Minnesota, the largest Karen community in the United States.
Preventing an Antigenically Disruptive Mutation in Egg-Based H3N2 Seasonal Influenza Vaccines by Mutational Incompatibility
Authors: Nicholas C. Wu, Huibin Lv, Andrew J. Thompson, Douglas C. Wu, Wilson W.S. Ng, Rameshwar U. Kadam, Chih-Wei Lin, Corwin M. Nycholat, Ryan McBride, Weiwen Liang, James C. Paulson, Chris K.P. Mok, Ian A. Wilson
Journal: Cell Host & Microbe (2019)

Egg-based seasonal influenza vaccines are the major preventive countermeasure against influenza virus. However, their effectiveness can be compromised when antigenic changes arise from egg-adaptive mutations on influenza hemagglutinin (HA). The L194P mutation is commonly observed in egg-based H3N2 vaccine seed strains and significantly alters HA antigenicity. An approach to prevent L194P would therefore be beneficial. We show that emergence of L194P during egg passaging can be impeded by preexistence of a G186V mutation, revealing strong incompatibility between these mutations. X-ray structures illustrate that individual G186V and L194P mutations have opposing effects on the HA receptor-binding site (RBS), and when both G186V and L194P are present, the RBS is severely disrupted. Importantly, wild-type HA antigenicity is maintained with G186V, but not L194P. Our results demonstrate that these epistatic interactions can be used to prevent the emergence of mutations that adversely alter antigenicity during egg adaptation.
Clinical outcome of sequential chemotherapy after immune checkpoint inhibitors in advanced ovarian cancer.
Authors: Luisa Bonilla, Amit M. Oza, Stephanie Lheureux, Sam Saibil, Shiyi Chen, Yeh Chen Lee, Diana Gray, Ilaria Colombo, Ainhoa Madariaga, Neesha C. Dhani, Gita Bhat, Valerie Bowering, Swati Garg, Daniel Yokom, Sunu Lazar Cyriac, Marcus O. Butler
Journal: Journal of Clinical Oncology (2019)

5580 Background: Immunomodulation through check point inhibition is an important treatment strategy in many cancers. In ovarian cancer (OC) response rates with immune checkpoint inhibitors (ICI) alone are around 10%. Chemotherapy antitumoural effect is driven by cytotoxicity and immunomodulatory effect. ICI treatment reduces tumour induced immune-tolerance improving immunocompetence, essential for chemotherapy effect. We chose to investigate clinical outcomes of chemotherapy post ICI in women with OC. Methods: The Tumor Immunotherapy Program (TIP) database at the Princess Margaret Cancer Centre identified patients with OC treated with chemotherapy after ICI from 2011 to 2018. Evaluation of clinical outcomes including response rate (RR), progression free survival (PFS) and overall survival (OS) was assessed for pre ICI, ICI and post ICI. Results: 40 women with OC were treated with chemotherapy after ICI. 90% had high grade serous histology, 7.5% carcinosarcoma and 2.5% low grade serous. Median number of pre ICI treatment lines was 3 (1-8) and 2 (1-6) in the post ICI setting. Median time of ICI initiation from diagnosis was 3 years. At ICI all patients had PS 0-1 and treated in clinical trials. 2% of the patients had platinum refractory disease, 88% had platinum resistant disease and 10% platinum sensitive disease. 50% were treated with ICI single agent, 16% were treated with ICI combined with chemotherapy, 14% ICI combo and 17% ICI in combination with other agents. Patients were treated for a median of 3 cycles (1-26). 8% experienced PR, 18% SD, no CR were seen. 67% of the patients discontinued treatment due to PD, 25% due to toxicity. Last treatment in pre ICI RR was 35%. First treatment in post ICI RR was 30%. RR for each treatment used in post ICI was 9% for liposomal doxorubicin, 25% for single agent platinum, 29% for weekly paclitaxel and 67% for chemotherapy with bevacizumab. Median PFS in the last pre ICI treatment was 6.5m and 5m in the first post ICI treatment. Median PFS and OS for all the population was 53m and 54m respectively. Conclusions: ICI are associated with modest activity in OC, planned clinical trials exploring systematic sequential therapy integrating ICI, targeted agents and chemotherapy are needed.
Identify driver mutants in lung cancer by supernatants of pleural effusion and monitor resistance to targeted therapy.
Authors: Yuehong Wang, Tao Wang, Shanshan Xiao, Ruifang Mao, Rui Lin
Journal: Journal of Clinical Oncology (2019)

e14554 Background: Malignant pleural effusion (MPE) from lung cancer is an attractive alternative for molecular testing due to advantages of non-invasiveness and less heterogeneity. Previously, cell pellet blocks of MPE are widely used. This study is to further address whether supernatants of MPE is a suitable source to identify key oncogenic mutants in lung cancer and provide more information for clinical molecular testing. Methods: MPE samples from 12 lung cancer patients were centrifuged to obtain supernatants and cell pellets, and DNA were extracted. The DNA samples were analyzed by a targeted next generation sequencing (NGS) panel using Illumina HiSeq platform. Results: In a pilot study, paired cancer tissue and MPE samples were obtained from 3 lung cancer patients and analyzed using a comprehensive 500-gene cancer panel. Nine mutants were identified both in the tissue samples and MPE samples. We then analyzed another 9 lung cancer patient samples to detect oncogenic mutants using an 18-gene panel. In total, 8 mutants including EGFR L858R, exon 19 deletion, or T790M mutants were identified in MPE samples. For the total 17 mutants from the 12 MPE samples, 10 mutants were observed in both matched supernatant and cell pellet of MPE, of which more pairs (6 out of 10) had supernatants with higher abundance of mutants than cell pellets. More importantly, 7 of the 17 mutants were only detected in the supernatants of the matched MPE. Taken together, these results suggest that supernatant of MPE is a more suitable source to detect key driver mutants of lung cancer. Interestingly, 2 patients had both tyrosine kinase inhibitor (TKI) resistant mutant T790M and TKI sensitive mutants detected in supernatants of MPE; both patients had prior treatment of EGFR TKI, consistent with the development of TKI resistant mutant and supporting the utility of supernatants of MPE in monitoring TKI resistance. Conclusions: This study suggest supernatant of MPE is a more suitable source for identifying key driver mutants for lung cancer and can also be used to monitor response to targeted therapy. The study provides evidence of using supernatant of MPE as alternative source for molecular testing and thus direct precise targeted therapy and effect surveillance.
Treatment approaches and survival outcomes of older patients with locally advanced esophageal cancer (LAEC) in Ireland.
Authors: Petra Martin, Eamonn o'Leary, Sandra Deady, Anne M. Horgan
Journal: Journal of Clinical Oncology (2019)

e23034 Background: Neo+/- adjuvant treatment data in older patients with cancer is sparse due to exclusion of this population from clinical trials. We evaluated the management of locally advanced esophagogastric cancer (LAEC) in older Irish patients to determine treatment modalities utilized and identify factors associated with survival. Methods: Patients diagnosed with LAEC (stage II or III) over a 5 year period (2007-2011)were identified from the National Cancer Registry of Ireland. Follow-up was till end 2014.Demographic characteristicswere assessed. Treatment was classified as “best supportive care (BSC)”, “surgery only”, “neo/adjuvant treatment” and “chemo/radiation alone” (ie chemo, radiotherapy or chemoradiotherapy alone in the absence of surgery).Survival was estimated by Kaplan-Meier estimates and Cox models. Clinicopathologic factors and treatment type found to be significant in univariate analysis were included in a multivariate analysis (MVA). Results: 46%(n = 580) of the 1,251 patients were ≥70yrs, 62% had stage III disease and 51% had gastric cancer. 11% (n = 134) received BSC, 23% (n = 288) had surgery only, 31%(n = 390) had chemo/radiation alone, 35% (n = 439) had neo/adjuvant treatment. 20% (n = 39) of patients ≥75yrs had neoadjuvant treatment compared to 46% &lt; 75 yrs. No patient ≥80yrs received neo/adjuvant treatment. With increasing age patients were less likely to receive neo/adjuvant treatment (p &lt; 0.001), less likely to receive surgery (p &lt; 0.001) and less likely to receive any treatment (p &lt; 0.001).Median survival(OS) decreased with age (&lt; 70yrs: 23months; 70-74: 19months; 75-79:13months; ≥80 years:10 months). In MVA, older age, smoking, later stage, higher grade were significantly associated with a higher risk of death.Including an interaction between treatment and age, patients receiving adjuvant or neoadjuvant treatment had lower risk of death than any other treatment group regardless of age. Conclusions: Older patients were less likely to receive any treatment for LAEC than younger patients. Patients ≥70 years benefit from neo/adjuvant treatment, however,these patients are often excluded based on age. Prospective clinical trials focusing on elderly patients and incorporating life expectancy, comorbidities and geriatric assessment are needed to best guide treatment.
Pathologic up-regulation of TNFSF15–TNFRSF25 axis sustains endothelial dysfunction in unprovoked venous thromboembolism
Authors: Silvia Della Bella, Francesca Calcaterra, Monica Bacci, Claudia Carenza, Chiara Pandolfo, Paola Ferrazzi, Paolo Uva, Massimiliano Pagani, Corrado Lodigiani, Domenico Mavilio
Journal: Cardiovascular Research (2019)

Abstract Aims The pathogenetic mechanisms underlying unprovoked venous thromboembolism (uVTE) are largely unknown. In this study, we investigated the molecular mechanisms involved in uVTE pathogenesis by using ex vivo expanded endothelial colony-forming cells (ECFCs), which represent a valuable non-invasive tool for the assessment of endothelial function. Methods and results We isolated and expanded ECFCs from the peripheral blood of uVTE patients and observed that these cells underwent earlier senescence and showed lower growth rate compared with ECFCs obtained from healthy donors. Through microarray expression profiling, we demonstrated that 2905 genes were differentially expressed between patients and controls. Among them, the anti-angiogenic cytokine TNF superfamily member 15 (TNFSF15) and its death-receptor TNFRSF25 were up-regulated in uVTE ECFCs, and this finding was validated by RT-qPCR. TNFSF15 up-regulation was confirmed at the protein level in ECFC supernatants, and the in vivo relevance of these findings was further corroborated by demonstrating that also the plasmatic levels of TNFSF15 are increased in uVTE patients. After proving that exogenous TNFSF15 exerts pro-apoptotic and anti-proliferative activity on control ECFCs, we demonstrated through blocking experiments that TNFSF15 up-regulation contributes to impaired survival and proliferation of uVTE ECFCs. Conclusion By providing evidence that TNFSF15 impairs ECFC functions crucial to endothelial repair, and that uVTE patients have increased TNFSF15 levels both ex vivo and in vivo, the results of this study suggest that pathologic up-regulation of TNFSF15–TNFRSF25 axis may contribute to uVTE pathogenesis, and may represent the target for novel therapeutic strategies aimed at preventing recurrences in uVTE patients.
Abstract 12449: The Electrocardiogram Left Ventricular Hypertrophy With Strain Pattern Predicts Recurrence in Paroxysmal Atrial Fibrillation Patients After Radiofrequency Catheter Ablation
Authors: Lu Wang, Song-Nan Li, Mohamed Salim, Zhe Wang, Wang-Yang Yang, Man Ning, Ri-Bo Tang, Cai-Hua Sang, Chen-Xi Jiang, Rong-Hui Yu, De-Yong Long, Nian Liu, Rong Bai, Xin Du, Jian-Zeng Dong, Chang-Sheng Ma
Journal: Circulation (2015)

Introduction: The present of left ventricular hypertrophy (LVH) or LVH with strain pattern on electrocardiogram (ECG) are independently predictors of new-onset atrial fibrillation (AF). Hypothesis: We assessed the hypothesis that LVH with or without strain can predict recurrence after radiofrequency catheter ablation (RFCA) of AF in paroxysmal atrial fibrillation (PAF) patients. Methods: 436 PAF patients undergoing RFCA were enrolled and clustered into 3 subgroups: Non-LVH (218 patients), LVH (182 patients), LVH with strain (36 patients). LVH was characterized by the Romhilt-Estes point system and ECG strain was defined as ST-segment depression≥1-mm and T-wave inversion≥1 mm in the lateral leads. Results: After 42 (interquartile range, 18.0 to 60.0 months) months follow-up period with a median of 1 (1 to 3) RFCA procedure, sinus rhythm was maintained in 248 patients (60.2%) without antiarrhythmic drugs. Patients with LVH (79, 43.6%) and LVH with strain (22, 62.9%) tended to experience much higher AF episodes recurrence ratio compared to those with non-LVH (71, 33.3%; P=0.000). In multivariate analysis after adjustment for age, sex, CHA2SDVAS score and left atrial diameter (LAD), the present of LVH with strain was the only independent risk factor of AF recurrence (95%CI: 1.242 to 5.808, P=0.012). Conclusions: That present of LVH with strain but not LVH alone is a strong and independent predictor of AF recurrence in PAF patients following RFCA.