tbuckley/cabot-search huggingface dataset:
Weight of Evidence for Hazard Identification: A Critical Review of the Literature
Authors: Pierre Martin, Claire Bladier, Bette Meek, Olivier Bruyere, Eve Feinblatt, Mathilde Touvier, Laurence Watier, David Makowski
Journal: Environmental Health Perspectives (2018)

Background: Transparency when documenting and assessing weight of evidence (WOE) has been an area of increasing focus for national and international health agencies. Objective: The objective of this work was to conduct a critical review of WOE analysis methods as a basis for developing a practical framework for considering and assessing WOE in hazard identification in areas of application at the French Agency for Food, Environmental and Occupational Health and Safety (ANSES). Methods: Based on a review of the literature and directed requests to 63 international and national agencies, 116 relevant articles and guidance documents were selected. The WOE approaches were assessed based on three aspects: the extent of their prescriptive nature, their purpose-specific relevance, and their ease of implementation. Results: Twenty-four approaches meeting the specified criteria were identified from selected reviewed documents. Most approaches satisfied one or two of the assessed considerations, but not all three. The approaches were grouped within a practical framework comprising the following four stages: (1) planning the assessment, including scoping, formulating the question, and developing the assessment method; (2) establishing lines of evidence (LOEs), including identifying and selecting studies, assessing their quality, and integrating with studies of similar type; (3) integrating the LOEs to evaluate WOE; and (4) presenting conclusions. Discussion: Based on the review, considerations for selecting methods for a wide range of applications are proposed. Priority areas for further development are identified. https://doi.org/10.1289/EHP3067
Guideline: 11 professional organizations made 106 recommendations for management of high blood pressure in adults
Authors: James Brophy
Journal: Annals of Internal Medicine (2018)

Source Citation Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. 29146535
First update on overall survival, progression-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors.
Authors: Jonathan R. Strosberg, Edward M. Wolin, Beth A. Chasen, Matthew H. Kulke, David L Bushnell, Martyn E. Caplin, Richard P. Baum, Timothy J. Hobday, Andrew Eugene Hendifar, Maribel Lopera Sierra, Kjell E. Oberg, Philippe B. Ruszniewski, Eric Krenning
Journal: Journal of Clinical Oncology (2018)

4099 Background: The final per-protocol statistical analysis (cut–off date 24 July 2015) of PFS, the primary endpoint of the NETTER-1 study, showed a significant difference (p < 0.0001) between the treatment arms. Supplemental updated analysis was requested by regulatory authorities for registration purposes. Quality of life (QoL) was analysed one year later, with a cut-off date of 30 June 2016 for time to clinically relevant deterioration (TTD) in health-related QoL (HRQoL). Methods: Overall survival (OS) and PFS were evaluated using Kaplan Meier methodology. HRQoL analysis was based on EORTC QLQC-30 and G.I.NET-21 questionnaires, completed at baseline and every 12 weeks thereafter. TTD was defined as the time from randomization to the first QoL deterioration ≥10 points for each patient in the corresponding domain scale. First OS regulatory update cut-off date was 30 June 2016. Results: At this first update, median OS was 27.4 months in Oct arm and still not reached in Lu arm. PFS at this date showed 30 events in the Lu arm and 78 in the Oct arm (HR: 0.21 CI: 0.14 0.33; p < 0.0001). HRQoL TTD was significantly longer in the Lu arm vs. the Oct arm for global health status (HR 0.406; p = 0.0006), physical functioning (HR 0.518; p = 0.0147), role functioning (HR 0.580; p = 0.0298), fatigue (HR 0.621; p = 0.0297), pain (HR 0.566; p = 0.0247), diarrhea (HR 0.473; p = 0.0107), disease related worries (HR 0.572; p = 0.0176) and body image (HR 0.425; p = 0.0058). Conclusions: This supplemental analysis from the NETTER-1 Phase III study confirms the clinically and statistically meaningful PFS benefit, and still suggests a survival benefit with 177Lu-dotatate. It also demonstrates that 177Lu-dotatate provides a significant quality of life benefit for patients compared to high-dose octreotide. Clinical trial information: NCT01578239.
The impact of HPV infection on survival of patients with non-oropharyngeal head and neck cancer.
Authors: Samer Alsidawi, Gustavo Figueiredo Marcondes Westin, Ashish V. Chintakuntlawar, Scott H. Okuno, Katharine Andress Rowe Price
Journal: Journal of Clinical Oncology (2017)

6048 Background: The role of Human Papilloma Virus (HPV) infection in non-oropharyngeal squamous cell carcinoma (non-OPSCC) of the head and neck is unknown. Current available studies have yielded conflicting results due to limited number of patients. We present a large analysis from the National Cancer Database (NCDB) evaluating HPV-positive non-OPSCC. Methods: Using the NCDB registry, we included adults diagnosed with non-OPSCC from 2004-2012 with available HPV status. A cohort of patients with OPSCC was analyzed for HPV prevalence comparison. Survival analysis was performed using Kaplan-Meier method and stratified using HPV-status. The prognostic effect of variables was studied using Cox proportional hazards models. The JMP software was used for statistical analysis. Results: A total of 8726 non-OPSCC patients were identified and primary sites included the oral cavity (50%), larynx (41%) and hypopharynx (9%). 11% of non-OPSCC patients had evidence of infection with high-risk HPV strains compared to 61% of OPSCC patients. HPV-positive non-OPSCC patients presented at slightly younger age, had more advanced stage and higher tumor grade compared to HPV-negative patients (P &lt; 0.01). HPV-positive non-OPSCC patients had better survival than HPV-negative patients (HR 0.82, 95% CI 0.72-0.93, P &lt; 0.01) and this was most pronounced in patients with locally advanced disease (5-year survival 50% versus 40%, HR 0.69, 95% CI 0.6-0.8, P &lt; 0.01). A univariate and multivariate analysis were performed adjusting for age, sex, race, stage, primary site, Charlson/Deyo comorbidity score, financial income, tumor grade, surgery, radiation and chemotherapy administration. Smoking history was unavailable. HPV positivity was an independent predictor of better survival in non-OPSCC in multivariate analysis (HR 0.69, 95% CI 0.59-0.8, P &lt; 0.01). Conclusions: HPV infection is seen in a subset of patients with non-OPSCC head and neck cancer and these present with more advanced tumors. The survival of patients with HPV-positive non-OPSCC is significantly better than HPV-negative tumors. Routine HPV testing and enrollment in treatment de-intensification clinical trials similar to OPSCC might be appropriate for this patient population.
Training and validation cohort analysis for predicting radiation therapy response in human glioblastoma.
Authors: David Corwin, Russell Rockne, Maciej M. Mrugala, Jason K. Rockhill, Kristin Swanson
Journal: Journal of Clinical Oncology (2013)

e13018 Background: Glioblastomas comprise 50% of primary brain tumors and are the most fatal, with a median survival time of 14 months despite aggressive treatment. Due to disease heterogeneity and the presence of subclinical disease, there is a large variability in treatment response among patients, making it difficult to assess treatment efficacy and confounding clinical decision making. Methods: A patient-specific, mathematical model of glioblastoma has been shown to predict untreated growth as well as the effect of radiation therapy. We expand on the technique presented in Rockne 2010 to determine patient-specific radiosensitivity and post therapy radial growth using only pretreatment data. From a potential cohort of 44 patients we randomly chose a training set of 30 to compute the relationship for the radiosensitivity parameter (alpha) versus the net proliferation rate. We then used that relationship to compute an individualized alpha for the remaining 14 test patients based only on pretreatment information. For each of the test patients we compared the observed T1Gd visible radius at the first post radiotherapy timepoint with the simulated prediction. Results: Half of the patients demonstrated average absolute differences between the observed and simulated post radiotherapy T1Gd radii of less than 5 mm, within the measurement error associated with contouring the tumor on MRI, with a maximum difference of 2.5 cm. The largest errors were observed in patients with significant resection. Conclusions: This patient-specific, mathematical model of glioma growth and response to radiotherapy can potentially predict radioresponse in vivo, prior to the commencement of therapy. As a clinical tool, this can have prognostic applications and separate responders from non-responders before deciding to treat with radiotherapy. The larger error for patients with more extensive resections is not unexpected given the difficulties in contouring and assessing tumor burden post surgery. This can be improved by including other imaging modalities such as pre-gadolinium T1 and improving the quantification of extent of resection.
Genomic profiling of non-small cell lung cancer in the community setting.
Authors: Martin Gutierrez, Kelly Choi, Richard Burnham Lanman, Stan M Skrzypczak, Ruth Pe Benito, Victoria DeVincenzo, Yvonne Owusu-Sarpong, Courtney Anderson, Dhakshila Paramanathan, Kathyrn Tanenbaum, Matthew Love, Eric V Schultz, Andrew Pecora, Stuart L. Goldberg
Journal: Journal of Clinical Oncology (2016)

e20616 Background: Genotyping in patients (pts) with advanced NSCLC may identify mutations (mut) amenable to targeted therapy (TT). We identified in a 2010-2014 community series a 60% testing rate for EGFR/ALK among stage IV pts (Gutierrez ASCO 2015; e19113). 2014 guidelines added 5 additional targets for testing. Methods: Retrospective review advanced non-squamous NSCLC treated by 89 community oncologists (16 sites) throughout NJ and MD (Jan 2013 – Dec 2015). Results: 634 pts with NSCLC (566 stage IV and 68 stage IIIB) in the COTA database (89% adenocarcinoma, 7% NOS, 3% large cell, 1% sarcomatoid); median age 68 yrs; 52% female. 477 pts (75%) underwent any genotyping. Testing rates for EGFR were 67% in 2013, 80% 2014 and 69% 2015 (similar pattern with other mut). In never/passive smokers EGFR testing rate was 84% (47% pos for mut); 70% former smokers tested (13% pos); current 64% tested (5% pos) (p < 0.001 testing by smoking). KRAS testing performed in 32% with 31% pos, but did not triage genotyping (97% KRAS pos pts were tested for EGFR). Comprehensive NGS testing was performed in 15%, with additional 18% undergoing limited genotyping beyond EGFR/ALK. Rates of comprehensive NGS increased (2013: 10%, 2015: 23%; p < 0.001). Similar rates of NGS testing were observed among oncologists caring for > 10 pts or < 10 pts (15% vs 16%). 31 pts (5%) underwent second biopsy to obtain tissue for genotyping. Insufficient tissue was cited by 8%, with other documentation for non-testing lacking. Actionable EGFR/ALK findings were identified in 107 pts (22% tested); 73% of these received TT; 6% started chemo prior to test results (median 26 days vs 22 days who received TT; p = 0.36); 10% no treatment (7% early deaths). Genotyping identified actionable mut in 17 pts (2.6% overall population); (9 MET Amp/ 88 tested, 2 BRAF/98 tested, 2 ERBB2/ 52 tested, 2 RET/ 82 tested, 1 ROS1/ 85 tested, 1 MET Exon 14/ 46 tested). Among these 17 pts only 1 received TT (herceptin). Conclusions: Genotyping for EGFR/ALK remain below guidelines; most patients are undergenotyped for all 7 treatable mut. NGS testing rates are slowly increasing, which may reduce insufficient tissue exclusions. We plan to explore whether non-invasive comprehensive genotyping with cell-free DNA NGS may increase utilization of TT.
Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation
Authors: Julián Albarrán-Juárez, Andras Iring, ShengPeng Wang, Sayali Joseph, Myriam Grimm, Boris Strilic, Nina Wettschureck, Till F. Althoff, Stefan Offermanns
Journal: The Journal of Experimental Medicine (2018)

The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 receptor, and Gq/G11-mediated signaling. However, only disturbed flow leads to Piezo1- and Gq/G11-mediated integrin activation resulting in focal adhesion kinase-dependent NF-κB activation. Mice with induced endothelium-specific deficiency of Piezo1 or Gαq/Gα11 show reduced integrin activation, inflammatory signaling, and progression of atherosclerosis in atheroprone areas. Our data identify critical steps in endothelial mechanotransduction, which distinguish flow pattern-dependent activation of atheroprotective and atherogenic endothelial signaling and suggest novel therapeutic strategies to treat inflammatory vascular disorders such as atherosclerosis.
Correlation of MLLT3 deletion mutation with response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients identified by whole-exome sequencing.
Authors: Rong-xin Zhang, Wen-juan Ma, Gong Chen, Xiao Jun Wu, Zhen-hai LU, Yang-kui Gu
Journal: Journal of Clinical Oncology (2018)

e15549 Background: Not all locally advanced rectal cancer patients respond to neoadjuvant chemoradiotherapy, however, there is still no clear maker to predict the respond to neoadjuvant chemotherapy. In this study, we used the tissue samples obtained before clinical treatment to detect the genetic causes to the differences in the response to chemoradiotherapy. Methods: We performed whole-exome sequencing of DNA from ten locally advanced rectal cancer patients. All patients received 50Gy radiotherapy combined with two cycles of CapOX (Capecitabine with Oxaliplatin) followed by radical surgery resection. The respond to chemoradiotherapy was determined by TRG (tumor regression grading) system. The nucleotide variants identified from the peripheral blood leucocyte were compared with those from the tumor sample to find the specific genetic variants for each patient. The group of patients with good respond group were compared with the low response to find the variants that had significant different distribution. Results: We identified 147 genetic variants (distributed in 113 genes) significantly associated with treatment outcome in the comparison of good respond and bad respond groups. The most significant loci was novel deleteion mutation (MLLT3: NM_004529: exon5: c.498_500del: p.166_167del). By performing pathway enrichment analysis with these genes using the public database, we found that the associated mutated genes were significantly enriched in the transcriptional misregulation in cancer pathway (p-value < 0.01). The gene MLLT3 was a member of them. Using the co-expression and co-localization analysis we found that several other genes can interact with each other and the MLLT3 was in the interaction network. Conclusions: To the best of our knowledge, this is the first report identifying MLLT3 deletion mutation as the a predict maker for the respond of chemoradiotherapy in rectal cancer. The gene MLLT3 and several other genes in the cancer misregulation pathways play an important role in the control of the treatment response.
Assessment of efficacy and safety of bevacizumab in the treatment of brain metastases radionecrosis: A retrospective cohort analysis.
Authors: Aurelien Gobert, Roger Sun, Lizza Hendriks, Sylvain Reuzé, Samy Ammari, Jean-Philippe Spano, Benjamin Besse
Journal: Journal of Clinical Oncology (2018)

e14014 Background: The incidence of brain metastases (BM) increases with frequent use of stereotactic radiotherapy. The main complication is radionecrosis (RN), without any validated treatment. Retrospective data from a small number of patients suggest that bevacizumab (Bev) is an effective treatment in this critical clinical issue. Our study was conducted to evaluate the efficacy and safety of Bev in the treatment of BM RN. Methods: Demographic data were retrospectively collected from patients treated with Bev for a BM RN at Gustave Roussy center. The clinical benefit was assessed by a symptomatic improvement, a decrease or a complete stop of daily corticosteroid use. Progression-free survival, overall survival, radiological response and safety were also reported. Results: From October 2011 and September 2017, 20 patients were treated with Bev for 29 RN lesions (Table 1). The main regiment use for Bev was 4 injections at 7,5mg/kg/Q3W. Ten patients had an extra-cerebral disease and 9 were treated with chemotherapy or targeted therapy in association with Bev. After a median follow-up of 9.9 months (1,3 – 21,1 months), a clinical improvement was early observed in 13/20 patients (65%) and an average dose reduction of 58 mg (0-220) of corticosteroids in 16/20 patients. The median progression-free survival and overall survival were 7.8 months (0.6-21.1) and 13.9 months (1.3-21.1), respectively. No brain hemorrhage was reported even when hemorrhagic stigmatism was noted at diagnosis. Conclusions: Bev use is associated with clinical, radiological and survival benefit in patients treated for a metastatic disease, with a favorable safety profile. To our knowledge, this is the largest study evaluating the efficacy and safety profile of Bev specifically in BM RN. Patient characteristics Patients (N = 20) Age Médian (min - max) 63 (46-78) Sexe Female (n, %) 12 (60%) Male (n, %) 8 (40%) Primitive Lung (n, %) 11 (55%) Non-squamous cell (n, %) 8 (40%) Squamous cell (n, %) 2 (10%) Small-cell lung cancer (n, %) 1 (5%) Breast (n, %) 4 (20%) Melanoma (n, %) 2 (10%) Ovarian (n, %) 1 (5%) Renal (n, %) 1 (5%) PEComa (n, %) 1 (5%) Time for RN diagnosis after radiotherapy (months) Median (min - max) 8,6 (2,2-33,8)
Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset
Authors: Byoung Chul Cho, Busayamas Chewaskulyong, Ki Hyeong Lee, Arunee Dechaphunkul, Virote Sriuranpong, Fumio Imamura, Naoyuki Nogami, Takayasu Kurata, Isamu Okamoto, Caicun Zhou, Ying Cheng, Eun Kyung Cho, Pei Jye Voon, Jong-Seok Lee, Helen Mann, Matilde Saggese, Thanyanan Reungwetwattana, Suresh S. Ramalingam, Yuichiro Ohe
Journal: Journal of Thoracic Oncology (2018)
Oral Contraceptive Progestin and Estrogen Use and Increases in Breast, Ovarian, and Endometrial Cancers
Authors: Ellen C. Grant
Journal: JAMA Oncology (2018)

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Lack of micro-RNA 128A expression as a novel prognostic marker in neuroblastoma patients and combination with TERT hyperexpression to define patient outcomes.
Authors: Alexander Druy, Grigory Tsaur, Egor Shorikov, Artem Zaychikov, Yulia Olshanskaya, Leonid Saveliev, Larisa Fechina
Journal: Journal of Clinical Oncology (2017)

e22014 Background: Rearrangements of TERT gene with its correspondent hyperexpression were identified as adverse prognostic markers in neuroblastoma (NB) patients, while significance of microRNAs expression is undiscovered. Methods: RNA from 103 fresh-frozen NB tissues was subjected to reverse transcription qPCR for miR128A and TERT expression evaluation. Copy number variations were determined by MLPA and FISH. Correspondence of miR128A and TERT expression levels to event-free survival (EFS) was proved by ROC-analysis and established threshold levels (TL) were utilized for group separation in subsequent survival analysis. Median of follow-up time achieved 5.8 years. Results: Abundant TERT expression and lack of miR128A expression resulted in superior frequency of adverse events (p = 0.027, TL = 4,7E-3 and p = 0.004, TL = 4.6E-2 respectively). EFS in group of patients with TERT expression above 4,7E-3 (group TERT) was 0.66SE0.07, in patients with miR128A expression below 4.6E-2 (group miR128A) was 0.64SE0.15, patients harboring both TERT overexpression and lack of miR128A expression (group miR128/TERT) had dismal outcome: EFS 0.29SE0.11, comparing to patients without these abnormalities (group "neither"): EFS 0.92SE0.06, p &lt; 0.001. Analogously, cumulative incidence of progression differed significantly between all these groups, p &lt; 0.001. MYCN amplified (MNA) samples were accumulated in the groups TERT and miR128/TERT (p = 0.061), while chromosome 17 gain, 9p and 14q deletions prevailed in the group "neither" (p = 0.014, 0.043 and 0.017 accordingly). MNA and 14q deletion had prognostic significance in the correspondent groups (p &lt; 0.001, p = 0.022). The classifier was proposed for distinguishing patients with unequal outcome: MNA EFS = 0.25SE0.11, MYCN single copy patients divided into groups miR128A/TERT (0.40SE0.15), miR128A (0.60SE0.15) and TERT (0.74SE0.08). Group "neither" was separated basing on presence (0.71SE0.17) and absence (EFS = 1.00) of 14q deletion, p &lt; 0.001. Conclusions: Levels of miR128A and TERT expression together with cytogenetic data allow discriminating patients into groups with significantly different outcome.