tbuckley/cabot-search huggingface dataset:
Survival results of phase I dose escalation of stereotactic body radiation therapy and concurrent cisplatin for re-irradiation of unresectable, recurrent head and neck squamous cell carcinoma.
Authors: Michelle Echevarria, Christine H. Chung, Kedar Kirtane, Jameel Muzaffar, Julie Ann Kish, John Arrington, Joaquim Farinhas, Jimmy J. Caudell
Journal: Journal of Clinical Oncology (2021)

e18020 Background: Stereotactic body radiation therapy (SBRT) is a standard option for re-irradiation of recurrent or second primary cancers of the head and neck. We conducted performed a phase I clinical trial to establish a maximum tolerated dose of SBRT with concurrent cisplatin. We previously reported our safety data, and now present our secondary disease control endpoints. Methods: Major inclusion criteria were recurrence of previous squamous cell carcinoma of the head and neck in patients who had previously undergone radiotherapy to doses ≥ 45 Gy to the area of recurrence, ≥ 6 months prior to enrollment, and who were medically unfit for surgery, deemed unresectable, or refused surgery. Patients were treated with radiation therapy every other day for five fractions at three dose levels: 30 Gy, 35 Gy, and 40 Gy. Cisplatin was given prior to every SBRT fraction at a dose of 15 mg/m 2 . Secondary end points reported herein are locoregional control (LRC), freedom from distant metastasis (FFDM), and overall survival (OS). Results: Twenty patients were enrolled and of those 18 patients were evaluable for secondary endpoints. Nine patients had a primary tumor in the oropharynx, four patients in the oral cavity, three in the neck, one in the larynx, and one simultaneously in the larynx and neck. All patients received the planned dose of Cisplatin. Five patients received a radiation dose of 30 Gy, three patients received a dose of 35 Gy, and 9 patients received a dose of 40 Gy. Median gross tumor volume (GTV) was 11.725 cm 3 . With a median follow up of 9 months the 1-year OS was 38.9%. LRC at 1 year was 45.7% and FFDM at 1 year was 87.8%. There was a trend to improved OS with increasing SBRT dose, 40 Gy vs &lt; 40 Gy (p = 0.08). There was an improved 1-year OS with a GTV ≤11.725 cm 3 of 77.8% vs 0% for tumors &gt; 11.725 cm 3 (p &lt; 0.001). For patients with a GTV &lt; 11.725 cm 3 who received 40 Gy the 1 year OS was 100% compared with 0% for tumors larger than 11.725 cm 3 . Conclusions: For patients with previously radiated locally or regionally recurrent head and neck cancer, SBRT up to 40 Gy given concurrently with cisplatin provides reasonable locoregional control and overall survival for patients with smaller tumors. Further evaluation in prospective trials is warranted. Clinical trial information: NCT02158234.
Evaluating the prevalence and nature of sleep disturbances in prostate cancer patients receiving androgen deprivation therapy using a combination of actigraphy and sleep questionnaires.
Authors: Stephen Mangar, Shalini Mondal, Steve Edwards, Hashim Uddin Ahmed, Richard J Wassersug, Alison Falconer, Ray Iles, Dagmara Dimitriou
Journal: Journal of Clinical Oncology (2021)

e17046 Background: Sleep disturbances and cancer related fatigue are commonly associated. Prostate cancer patients may suffer from disturbed sleep as a result of their diagnosis and following treatment, especially with androgen deprivation therapy (ADT). Wrist actigraphy is a non-invasive objective method of sleep data collection. This feasibility study compares sleep data obtained by actigraphy with subjective data from sleep questionnaires in order to determine the nature and severity of sleep disturbances in patients with and without ADT use. Methods: A prospective cross-sectional pilot study was conducted on 74 patients with prostate cancer attending a regional oncology clinic. Two validated subjective sleep questionnaires namely the Pittsburgh Sleep Quality Index [PSQI] and the Epworth Sleepiness Scale [ESS] were used. Patients wore actigraphy watches for a minimum of five consecutive days. The parameters of interest included: actual sleep time, sleep efficiency, fragmentation index, daytime napping frequency and duration. The questionnaire and actigraphy data were compared between 20 patients receiving ADT and 41 who were treatment-naive. Results: The compliance rate for completed actigraphy was 85%. Complete data sets with actigraphy and questionnaires were available from 61 patients. Those already receiving ADT were on LHRH analogues for a median duration of 2.35 years. Poor sleep quality as self-identified by patients from the PSQI (cut-off &gt; 5) was 49% in the treatment-naive group which increased to 70% for those on ADT. For daytime sleepiness as assessed by ESS (cut-off &gt; 10) this was 16% and 20% respectively. Actigraphy showed that patients on ADT reported longer sleep duration (7.4 vs 6.5 hours, p = 0.02), higher levels of nocturnal wakings (51.1% vs 36.7%, p = 0.002), with greater daytime napping duration (80.7mins vs 53.0mins, p = 0.04), and frequency (8.6 vs 5.6, p = 0.02) compared to treatment-naive patients. Conclusions: Self-reported poor sleep quality is common in prostate cancer patients, which appears worse for those receiving ADT. In patients receiving ADT, data derived from actigraphy suggests that although they were sleeping for longer at night, the quality of sleep was poor which, in turn, may be responsible for an increase in the frequency and duration of daytime napping. Based on the current findings, we recommend the use of actigraphy to characterise patients’ sleep patterns and to assess if sleep treatment is needed. Actigraphic data may allow for direct comparisons of different hormonal agents on sleep whilst identifying those with specific sleep disorders amenable to therapeutic intervention.
Efficacy of various types of chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 in-frame insertions.
Authors: Haibo Tang, Xiaoning Li, Jianhong Cai, Xiaomin Wu, Yating Zheng, Mengli Huang
Journal: Journal of Clinical Oncology (2021)

e21155 Background: Approximately 4% of epidermal growth factor receptor (EGFR)−mutated non-small cell lung cancer (NSCLC) present EGFR exon 20 in-frame insertions. These mutations confer intrinsic resistance to available EGFR tyrosine kinase inhibitors (TKIs), as they result in steric hindrance of the drug-binding pocket. Studies have shown that chemotherapy is superior to currently approved EGFR TKIs as a first-line or second-line treatment for EGFR exon 20 in-frame insertions. Nevertheless, the difference in the efficacy of different chemotherapy regimens in patients with EGFR exon 20 in-frame insertions remains unclear. Methods: Data from advanced NSCLC patients harboring EGFR exon 20 in-frame insertions from an independent cohort (Jenn-Yu Wu, 2019) was used to analyze the objective response rates (ORRs), disease control rates (DCRs), progression-free survival (PFS), and overall survival (OS) of different chemotherapy regimens. Results: Thirty-five advanced NSCLC patients harboring EGFR exon 20 in-frame insertions treated with chemotherapy were used to analyze, of which 7 received gemcitabine plus cisplatin (GC), 22 received pemetrexed plus cisplatin (PC), and 6 received taxol plus cisplatin (TC). ORRs were 31.82% for the patients received PC, 14.29% for GC, and 16.67% for TC. DCRs were 72.73% for the patients received PC, 42.86% for GC, and 16.67% for TC. Median PFS was numerically longer in patients who received PC chemotherapy (6.10 m; 95 % CI: 3.46–8.75) than GC (4.20 m; 95 %CI: 2.40–6.00; P = 0.14) or TC (3.40 m; 95 %CI: 1.96–4.84; P = 0.06). Median OS was significantly longer in patients who received PC chemotherapy (22.20 m; 95 % CI: 8.87–35.53) than GC (9.00 m; 95 %CI: 7.46–10.54; P = 0.04), and numerically longer than patients who received TC (8.10 m; 95 %CI: 0.00–22.62; P = 0.19). Conclusions: These results suggest that pemetrexed plus cisplatin may be the preferred chemotherapy for patients harboring EGFR exon 20 in-frame insertions, but further validation is needed in large clinical studies.
First-line treatment outcomes of CML patients in a real-world data setting in Lebanon.
Authors: Fadi Nasr, Intissar Yehia, Reem El Khoury, Saada Diab, Ahmad Ghoche, Lewis Nasr
Journal: Journal of Clinical Oncology (2021)

e19031 Background: BCR–ABL-targeting tyrosine kinase inhibitors (TKIs) constitute the cornerstone of treatment of CML leading to a life expectancy that is currently very close to that of age matched individuals in the general population. The aim of the current study was to describe aspects of CML in a real world data setting in Lebanon including responses to first lines with a specific focus on the impact of first-line treatment with imatinib compared to that of the second-generation TKI, dasatinib and nilotinib. We also evaluated what proportion of patients become eligible to attempt to stop their TKI treatment. Methods: Chronic myeloid leukemia registry was analyzed to evaluate response rates in the first line and eligibility for a treatment cessation attempt in adults diagnosed between 2003 and 2019. The registry covered 60 patients. 46 eligible patients were included in the study. BCR-ABL1 levels of ≤ 0.1%, ≤0.01% and ≤0.0032% on the international scale were defined as the molecular response end-points major molecular response(MMR), MR4.0 and MR,4.5 respectively. In the case of a switch in TKI therapy, the clinical chart was reviewed for the reason why the treating physician had changed the therapy (‘treatment failure’ or ‘TKI intolerance’). For the determination of eligibility to stop TKI, the inclusion criteria for the EURO-SKI trial were applied. Results: Seventy-two percent of the patients were treated with imatinib, 28% with a second-generation tyrosine kinase inhibitor (nilotinib and dasatinib). 15% of patients had discontinued their first-line treatment, mainly due to intolerance (10%) or treatment failure (5%). At 24 months, deep molecular response (MR 4.0 and MR4.5) were achieved at 16.7% and 38.9% respectively for imatinib, and at 22.2% and 33.3% respectively for second generation (p=1). The 5-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 37%. Conclusions: In the current study we report the experience in CML from two health care institutions in Beirut, Lebanon. Our findings showed no statistically significant difference in response between the first and second generations. The criteria for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.
Metabolome modulation of the host adaptive immunity in human malaria
Authors: Wael Abdrabou, Mame Massar Dieng, Aïssatou Diawara, Samuel Sindié Sermé, Dareen Almojil, Salif Sombié, Noelie Bere Henry, Désiré Kargougou, Vinu Manikandan, Issiaka Soulama, Youssef Idaghdour
Journal: Nature Metabolism (2021)
GeMAC, an HDAC1 binding protein, stabilizes p21 and co-activates p53 in response to DNA damage
Authors: Zheng Li, Wei-Wen Cai
Journal: Cancer Research (2007)

4926   The p53 tumor suppressor and its transcriptional target, p21, are essential for DNA-damage-induced cell-cycle checkpoints which ensure genomic stability and integrity. Through genome-wide assessments of chromosomal imbalances in DNA-damage-induced mouse lymphomas using microarray-based comparative genomic hybridization (CGH), we identified a novel gene named GeMAC that is frequently deleted in tumors. Knockdown of GeMAC increases proliferative capacity, results in defective cell-cycle checkpoints and cytokinesis, and leads to hypersensitivity to irradiation-induced DNA damage. GeMAC is required to maintain basal and DNA-damage-induced p21 protein levels in mouse embryonic fibroblast cells. Expression of GeMAC stabilizes endogenous p21 independently of ubiquitination and facilitates p53-dependent transcription of p21. Furthermore, GeMAC directly binds to histone deacetylase HDAC1 to stabilize both p21 and p53 by enhancing the acetylation of endogenous p21 and p53, and by interfering with the binding of Mdm2 to p21 and p53. These results highlight a unique role of GeMAC in maintaining genomic stability and its potential values in molecualr cancer therapeutics as an endogenous HDAC1 inhibitor.
Abstract 10832: Effects of Perceived Stress on Subjective and Objective Symptoms of Insomnia and Mental Health Among Patients With Heart Failure
Authors: Allison E Gaffey, Sangchoon Jeon, Matthew M Burg, Daniel Jacoby, Samantha Conley, Nancy S Redeker
Journal: Circulation (2019)

Introduction: Stress is a well-known modifiable risk factor for cardiovascular disease including heart failure (HF). Up to 50% of HF patients endorse chronic insomnia (difficulty falling or staying...
Pre-therapeutic dihydropyridimidine dehydrogenase (DPD) deficiency screening: Impact on fluoropyrimidine dose reduction at the second chemotherapy cycle and on early severe toxicity.
Authors: Côme De Metz, Benjamin Hennart, Marie-Cecile Le Deley, Pierre-Yves Cren, Christophe Desauw, Vincent Bourgeois, Fredrik Laestadius, Emilia Rad, Loic Lebellec, Nicolas Penel, Aurelien Carnot
Journal: Journal of Clinical Oncology (2021)

3096 Background: DPD deficiency screening before fluoropyrimidine is a matter of debate. To avoid lethal toxicity, French authorities impose DPD screening before fluoropyrimidine-based chemotherapy by dosing uracilemia since April 2019. Methods: We have included all consecutive adult patients receiving 5-fluorouracil (5-FU) or capecitabin from April 2019 to January 2020 in 6 cancer centers. During the study period, different methods for screening had been applied: DPYD complete sequencing, phenotype (uracilemia and/or dihydrouracilemia/uracilemia ratio - UH2/U -) or both. All sceening tests were conducted in the same laboratory. Association between the method of DPD screening and fluoropyrimidine dose reduction at second chemotherapy cycle or on severe ≥grade 3 early toxicity (between first and second cycle) was evaluated using multivariate logistic regression. Concordance between genotype and phenotype for DPD deficiency was explored using Cohen Kappa test. Results: We included 597 patients, the median age was 63 (range, 55-77). The most prevalent cancers were digestive (68.3%), head and neck (19.4%) and breast (9.2%). 12.3% of patients received capecitabine and 87.3% received polychemotherapy. DPD deficiency screening was done for most of patients (n=519, 86.9%). DPD screening method consisted in full sequencing of DPYP (n=41; 7.9%), phenotype analysis (n=44, 8.5%) or both (n=424, 83.6%). We did not identify any complete DPD deficiency. Uracilemia was dosed for 467 patients, the median was 6.5 ng/mL and for 21 patients (4.5%) uracilemia was &gt; 16 ng/mL and/or UH2/U &lt;6, suggesting DPD deficiency. Severe early toxicities were observed for 82 patients (14%), with two patients presenting grade 5 toxicity. Overall DPD screening and method of DPD screening were not associated with fluoropyrimidine dose reduction at second cycle or early severe toxicity. In multivariate analysis, the only predictor for fluoropyrimidine reduction at second cycle (n = 125 patients) was polychemotherapy (OR=2.8; p=0.012). Kappa between uracilemia and UH2/U was 0.23 (poor concordance). Kappa between DPYP sequencing and uracilemia or UH2/U was 0.09 (very poor concordance). Conclusions: No DPD deficiency screening method was associated with dose adaptation at second cycle or early severe toxicity. The optimal strategy for DPD screening requires further clinical evaluation.
Mindfulness based stress reduction (MBSR) to improve cardiovascular (CV) function and psychosocial outcomes in breast cancer survivors.
Authors: Anne Hudson Blaes, Patricia Jewett, Prabhjot Nijjar, Susan Everson-Rose
Journal: Journal of Clinical Oncology (2021)

e24058 Background: Breast cancer survivors on aromatase inhibitors (AIs) can develop endothelial dysfunction, a measure of increased CV risk. Stress modifying techniques such as MBSR may improve CV function and quality of life (QOL). We present data of a pilot study assessing the impact of MBSR on endothelial dysfunction and psychosocial outcomes. Methods: 31 women with locally advanced breast cancer and taking an AI were randomized 1:1 to 8 weekly MBSR classes or wait-list control. Subjects with tobacco use, known hypertension or hyperlipidemia were excluded. Participants completed surveys and vascular testing at baseline and 10 weeks. With the COVID-19 pandemic, MBSR classes were held on a virtual platform. Endothelial function was measured using the Endo-PAT2000 system; reductions in EndoPAT ratio (&lt;1.6) are indicative of worsening endothelial function and increased CV risk. Questionnaires included the CDC’s 4-item Healthy Days Core Module (HRQOL), Patient Health Questionnaire (PHQ)-8 for depression, the Perceived Stress Scale, and the Generalized Anxiety Disorder Scale (GAD-7). Functional test markers were compared between groups using t-tests. Results: Baseline mean age was 59 years, body mass index was 28.4 kg/m 2 , mean systolic blood pressure was 128.1 mmHg and cholesterol was 226.9 mg/dL. These measures did not differ between groups. Baseline EndoPAT ratio (0.60) and follow up (0.52) were low in all participants. As statewide COVID-19 cases spiked, 3/31 participants did not return for a second assessment, and for another 5 participants, one EndoPAT ratio measurement was not interpretable. Both groups showed a decline in EndoPat ratio pre-to-post, but the decline among MBSR participants (all of whom completed the intervention) was five times less than that observed among controls [Table]. Groups did not differ on QOL or psychosocial outcomes. Conclusions: Breast cancer survivors on AIs have endothelial dysfunction, a measure of increased CV risk. Stress reduction techniques, using virtual platforms, are feasible and acceptable to this patient population, and may help improve endothelial function. Further research and longer follow up is warranted in understanding the long-term impact of these interventions on CV risk and psychosocial well-being. [Table: see text]
Treated dentin matrix induces odontogenic differentiation of dental pulp stem cells via regulation of Wnt/β-catenin signaling
Authors: Sirui Liu, Jingjing Sun, Shuai Yuan, Yanyu Yang, Yuping Gong, Ying Wang, Runying Guo, Xue Zhang, Yiming Liu, Hongyan Mi, Meiyue Wang, Mengzhe Liu, Rui Li
Journal: Bioactive Materials (2021)

Treated dentin matrix (TDM) is an ideal scaffold material containing multiple extracellular matrix factors. The canonical Wnt signaling pathway is necessary for tooth regeneration. Thus, this study investigated whether the TDM can promote the odontogenic differentiation of human dental pulp stem cells (hDPSCs) and determined the potential role of Wnt/β-catenin signaling in this process. Different concentrations of TDM promoted the dental differentiation of the hDPSCs and meanwhile, the expression of GSK3β was decreased. Of note, the expression of the Wnt/β-catenin pathway-related genes changed significantly in the context of TDM induction, as per RNA sequencing (RNA seq) data. In addition, the experiment showed that new dentin was visible in rat mandible cultured with TDM, and the thickness was significantly thicker than that of the control group. In addition, immunohistochemical staining showed lower GSK3β expression in new dentin. Consistently, the GSK3β knockdown hDPSCs performed enhanced odotogenesis compared with the control groups. However, GSK3β overexpressing could decrease odotogenesis of TDM-induced hDPSCs. These results were confirmed in immunodeficient mice and Wistar rats. These suggest that TDM promotes odontogenic differentiation of hDPSCs by directly targeting GSK3β and activating the canonical Wnt/β-catenin signaling pathway and provide a theoretical basis for tooth regeneration engineering.
Hepatitis A Virus Infections Among Men Who Have Sex with Men — Eight U.S. States, 2017–2018
Authors: Monique A. Foster, Megan G. Hofmeister, Justin P. Albertson, Kerri B. Brown, Alexis W. Burakoff, Ami P. Gandhi, Rosie E. Glenn-Finer, Prabhu Gounder, Po-Yi Ho, Tracy Kavanaugh, Julia Latash, Rebecca L. Lewis, Atkinson G. Longmire, Angela Myrick-West, Dana M. Perella, Vasudha Reddy, Emma S. Stanislawski, Juliet E. Stoltey, Susan M. Sullivan, Okey F. Utah, Jennifer Zipprich, Eyasu H. Teshale
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

During 1995-2011, the overall incidence of hepatitis A decreased by 95% in the United States from 12 cases per 100,000 population during 1995 to 0.4 cases per 100,000 population during 2011, and then plateaued during 2012-2015.The incidence increased by 294% during 2016-2018 compared with the incidence during 2013-2015, with most cases occurring among populations at high risk for hepatitis A infection, including persons who use illicit drugs (injection and noninjection), persons who experience homelessness, and men who have sex with men (MSM) (1-3).Previous outbreaks among persons who use illicit drugs and MSM led to recommendations issued in 1996 by the Advisory Committee on Immunization Practices (ACIP) for routine hepatitis A vaccination of persons in these populations (4).Despite these longstanding recommendations, vaccination coverage rates among MSM remain low (5).In 2017, the New York City Department of Health and Mental Hygiene contacted CDC after public health officials noted an increase in hepatitis A infections among MSM.Laboratory testing* of clinical specimens identified strains of the hepatitis A virus (HAV) that subsequently matched strains recovered from MSM in other states.During January 1, 2017-October 31, 2018, CDC received reports of 260 cases of hepatitis A among MSM from health departments in eight states, a substantial increase from the 16 cases reported from all 50 states during 2013-2015.Forty-eight percent (124 of 258) of MSM patients were hospitalized for a median of 3 days.No deaths were reported.In response to these cases, CDC supported state and local health departments with public health intervention efforts to decrease HAV transmission among MSM populations.These efforts included organizing multistate calls among health departments to share information, providing guidance on developing targeted outreach and managing supplies for vaccine campaigns, and conducting laboratory testing of clinical specimens.Targeted outreach for MSM to increase awareness about hepatitis A infection and improve access to vaccination services, such as providing convenient locations for vaccination, are needed to prevent outbreaks among MSM.This analysis included confirmed cases of hepatitis A among MSM whose symptoms began during January 1,