tbuckley/cabot-search huggingface dataset:
Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial
Authors: Bruno François, Xavier Wittebole, Ricard Ferrer, Jean-Paul Mira, Thierry Dugernier, Sébastien Gibot, Marc Derive, Aurélie Olivier, Valérie Cuvier, Stephan Witte, Peter Pickkers, François Vandenhende, Jean-Jacques Garaud, Miguel Sánchez, Margarita Salcedo-Magguilli, Pierre-François Laterre
Journal: Intensive Care Medicine (2020)
Prospective evaluation of current <i>RAS</i> mutation testing practices in newly diagnosed metastatic colorectal cancer: Middle East and North Africa Registry (MORE-RAS) Study.
Authors: Mohammed Oukkal, Bouzid Kamel, Adda Bounedjar, Abdelsalam Alnajjar, Fouad Abu-Taleb, Abdullah Alsharm, Hassen Mahfouf, Larbaoui Blaha, Amr A. Elsaid, Assia Ouamer, Linah Basir
Journal: Journal of Clinical Oncology (2020)

e16141 Background: RAS testing is essential for treatment selection in metastatic colorectal cancer (mCRC), as anti-EGFR treatment is indicated only in patients with wild-type (WT) RAS. MORE-RAS was a multicenter, multicountry, observational, ambispective (retrospective + prospective) study designed to evaluate RAS mutation status among patients with mCRC in the Middle East and North Africa (MENA) region. Results of the retrospective study over a prior 2-year period have been previously presented. Here, we report on the prospective evaluation of testing practices in newly diagnosed patients from the same centers. Methods: Five countries (Algeria, Egypt, KSA, Kuwait, Lebanon) enrolled patients between Dec 2014 and Feb 2019. Patients with a new diagnosis of histologically proven mCRC, at least 1 measurable lesion per RECIST criteria, and tissue availability for biomarker analysis were included; those with co-existing malignancies or life expectancy &lt; 6 months were excluded. The primary endpoint was evaluation of the rate of RAS mutation in newly diagnosed patients. Follow-up was for 2 years. Results: 500 patients (mean age 54.6 years; 58% female) were included; 96.4% had Stage 4 disease. Primary tumor sites were sigmoidal colon: 33.4%; rectum: 29.6%; ascending colon: 18.4%; descending colon: 11.4%; transverse colon: 5.2%; and unknown: 1.4%. Most frequent sites of metastasis were liver: 43.4%, lung: 16.0%, and peritoneum: 10.1%. Overall, 407 pts (81.4%; 95% CI, 78%–85%) received prescription for RAS testing. RAS WT was found in 58.4% and mutant in 41.6%; the test was inconclusive in 1 pt. Non-prescription was attributed to test unavailability and medical or financial reasons. The distribution of mutations was KRAS: 85%, NRAS: 4.9%, and not available: 10.1%. Predictors of RAS testing prescription were older age, primary tumor localization in ascending colon, and high tumor grade. Knowledge of RAS status resulted in the addition of bevacizumab or anti-EGFR therapy in 20.4% and 21.2% of pts, respectively at Visit 1 (baseline). Conclusions: RAS testing is now routinely prescribed for newly diagnosed mCRC in the MENA region and can change therapy patterns. The RAS mutation rate in this region differs from that in Western countries.
Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS
Authors: Marcin Bączyk, Najwa Ouali Alami, Nicolas Delestrée, Clémence Martinot, Linyun Tang, Barbara Commisso, David Bayer, Nicolas Doisne, Wayne Frankel, Marin Manuel, Francesco Roselli, Daniel Zytnicki
Journal: The Journal of Experimental Medicine (2020)

Excessive excitation is hypothesized to cause motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS), but actual proof of hyperexcitation in vivo is missing, and trials based on this concept have failed. We demonstrate, by in vivo single-MN electrophysiology, that, contrary to expectations, excitatory responses evoked by sensory and brainstem inputs are reduced in MNs of presymptomatic mutSOD1 mice. This impairment correlates with disrupted postsynaptic clustering of Homer1b, Shank, and AMPAR subunits. Synaptic restoration can be achieved by activation of the cAMP/PKA pathway, by either intracellular injection of cAMP or DREADD-Gs stimulation. Furthermore, we reveal, through independent control of signaling and excitability allowed by multiplexed DREADD/PSAM chemogenetics, that PKA-induced restoration of synapses triggers an excitation-dependent decrease in misfolded SOD1 burden and autophagy overload. In turn, increased MN excitability contributes to restoring synaptic structures. Thus, the decrease of excitation to MN is an early but reversible event in ALS. Failure of the postsynaptic site, rather than hyperexcitation, drives disease pathobiochemistry.
Stratification of patients by tumor type using molecular profiling in real-world data.
Authors: Alyssa Antonopoulos, Elizabeth Eldridge, George Managadze, Elia Stupka, Hakim Lakhani, Sadiqa Mahmood
Journal: Journal of Clinical Oncology (2020)

e19262 Background: While Next-Generation Sequencing (NGS) tests become increasingly more common for diagnosis, molecular characterization, and treatment, a significant amount of molecular data derives from single-gene or analyte tests. Single gene test information is stored in disparate sources including electronic medical record (EMR) and data access for clinical use remains a challenge. A solution that harmonizes biomarker data beyond standard NGS-centric data and linked to rich clinical data is required for the complete patient picture. Methods: Health Catalyst’s extended real-world database, Touchstone includes a molecular data mart that integrates data from provider and life sciences proprietary NGS panels, Laboratory Information Systems, and other repositories. A portion of the data is derived from single-gene tests documented in the EMR. Biomarker data from EMRs was extracted from six health systems via a proprietary pipeline for extracting biomarker data. The algorithm relies on a curated ontology for molecular terms and publicly available terminologies for human genetics. Minor transformations extract pertinent variant information where available to harmonize with NGS-level data. Results: Over 44 thousand molecular labs from over 24 thousand patients were identified with this method. The oncology classes for which molecular data was identified in the greatest number of patients include skin, hematological, breast, digestive, and lung cancers (Table). PRTN3, EGFR, BRAF, JAK2, ERBB2, and KRAS are among the most commonly tested genes. Conclusions: Integrated real-world clinical and biomarker data from single gene tests can inform clinical decision-making and support clinical trial recruitment across a broader set of patient population. [Table: see text]
Clinical characteristics, genomic features, and recurrence risk of early-stage MET exon 14 mutant non-small cell lung cancer (NSCLC).
Authors: Gonzalo Recondo, Robin Guo, Paola Cravero, Biagio Ricciuti, Christina Falcon, Natalie Vokes, Mark G. Kris, Giulia Costanza Leonardi, Giuseppe Lamberti, Tom Nguyen, Deepti Venkatraman, Lynette Marie Sholl, Alexander E. Drilon, Mark M. Awad
Journal: Journal of Clinical Oncology (2020)

9042 Background: MET exon 14 alterations occur in ~3% of patients (pts) with NSCLC. Although clinical and genomic features of MET exon 14 mutant (mut) NSCLC are better characterized in the metastatic setting, less is known about early-stage disease for this molecular subtype. Methods: Clinicopathologic and genomic data were collected from patients (pts) with resected stage I-III MET exon 14 mutant NSCLC at the Dana-Farber Cancer Institute (DFCI) and the Memorial Sloan Kettering Cancer Center (MSKCC). We estimated the disease-free survival (DFS) and overall survival (OS) of patients from the date of surgical resection. The prevalence of MET exon 14 mutations in stage I-III NSCLC was assessed using OncoPanel NGS v3.0 at DFCI. Results: The prevalence of MET exon 14 alterations in resected tumors of pts with stage I-III NSCLC at DFCI using Oncopanel v3 was 2.8% (17/613) overall: 2.9% (16/542) in non-squamous and 1.4% (1/71) in squamous histology. We identified 131 pts with resected stage I-III (I = 73, II = 28, III = 30) MET exon 14 mut NSCLC at DFCI (Oncopanel v1-v3) and MSKCC (MSK-IMPACT), with a median age of 71 years (yrs) (range: 43-88). There were no significant differences in sex, smoking status, or type of MET alteration across stages. In stage I resected tumors there was a higher proportion of adenocarcinoma histology compared to stages II and III (p = 0.009). The median harmonized TMB (mTMB) was similar across stages (p = 0.43). Common genomic co-alterations included MET amplification (amp) (5.3%), CDK4/ 6 amp (19.1%), MDM2 amp (35.1%), TP53 mut (17.6%) and CDKN2A/ B loss (9.2%). The median DFS in stage I, II, and III NSCLC was 8.3 yrs (95% CI: 3.1-8.3), 2.6 yrs (95% CI: 1.0-2.6), and 2.1 yrs (95% CI: 0.7-2.7), respectively (p = 0.017). The median OS in stage I, II, and III NSCLC was 9.2 yrs (95% CI: 8.5 -10.5), not reached (NR) (95% CI: NR-NR), and 4.1 yrs (95% CI: 3.6-4.1), respectively (p = 0.052). Concurrent MET amp was independently associated with worse DFS (HR: 4.9, 95% CI: 1.8-13.1; p = 0.002) in multivariate analysis. Conclusions: MET exon 14 mutations are present in 2.8% of resected stage I-III NSCLCs. Given the prevalence of this molecular alteration in early-stage NSCLC, clinical trials exploring the role of adjuvant and neoadjuvant MET targeted therapies in this population may be warranted.
Deep learning-based predictive imaging biomarker model for EGFR mutation status in non-small cell lung cancer from CT imaging.
Authors: Abhishek Mahajan, Vatsal Kania, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Nandini Sharrel Menon, Rajiv Kumar, Swapnil Rane, Anuradha Chougule, Suthirth Vaidya, Kumar Prabhash
Journal: Journal of Clinical Oncology (2020)

3106 Background: Deep learning based radiogenomic (DLR) models present a promising performance in assisting lung cancer care. The purpose of this study was 1) To develop and validate DLR signatures to predict the EGFR mutation, 2) To assess the incremental value of these DLR signatures in comparison to the traditional clinical and semantic features. Methods: 223 patients were selected from two phase III randomized trials in patients with advanced non-squamous NSCLC with EGFR-sensitizing mutation and EGFR wild type who were planned to receive palliative therapy (trial 1: gefitinib or gefitinib plus pemetrexed and carboplatin and trial 2: pemetrexed maintenance and erlotinib maintenance). Our method is an end-to-end pipeline that requires only the manually selected tumour region in a CT image without precise tumour boundary segmentation or human-defined features. Two deep convolutional neural networks with 3D U-Net architectures are trained to segment lung masses and nodules from 3D regions of the CT image. The primary end point was EGFR prediction using Radiomics and DLR pipeline. We also compared the performance of combination of models in predicting the mutational status. Results: A total of 223 patients (mean age, 54.18 years; age range, 28–80 years) were included in this study. There were 121 (54.3%) patients with EGFR mutation and 102 (45.7%) patients who were EGFR wild type. On multivariate logistic regression analysis, Clinical variable and CT semantic features that were found to be significantly associated EGFR mutation were tumor stage, smoking status, pure solid texture, presence of non-tumor lobe nodule, and average enhancement. For predicting EGFR mutation, ROC curve plotted with clinical variables model, CT semantic variables model, Radiomics model, DLR model showed an AUC value of 0.70, 0.73, 0.94, 0.72 respectively. Clinical variables and semantic features were added to the radiomics predictive model and deep learning predictive model independently, showed further improvement in the accuracy for either model from AUC 0.94+/-0.02 to 0.96+/-0.02 and from AUC 0.72+/-0.02 to 0.82+/-0.04 respectively. Conclusions: The radiomics and DLR model by machine-learned information, extracted from CT images without precise manual segmentation, could predict EGFR mutation with very high accuracy. This AI based model can be used as non-invasive and easy-to-use surrogate imaging biomarker for EGFR mutation status prediction. Clinical trial information: CTRI/2018/10/022102 .
重症小儿手足口病合并中枢性呼吸衰竭四例
Authors: 张玉新
Journal: BMJ (2012)

手足口病多由柯萨奇A16及肠道病毒71型引起,重症病例多由后者引起,可伴发脑膜炎、脑炎,遗留后遗症,甚至危及生命.合并脑炎导致呼吸中枢损害、出现中枢性呼吸衰竭者少见.现就我院2010年4例重症小儿手足口病合并中枢性呼吸衰竭进行回顾性分析. 关键词：手足口病
KEYLYNK-009: A phase II/III, open-label, randomized study of pembrolizumab (pembro) plus olaparib vs pembro plus chemotherapy after induction with first-line pembro plus chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC).
Authors: Hope S. Rugo, Antonio Llombart-Cussac, Fabrice Andre, Mark E. Robson, Shigehira Saji, Nadia Harbeck, Peter Schmid, David W. Cescon, Jin Seok Ahn, Rita Nanda, Aditya Bardia, Li Fan, Jaime Alberto Mejia, Vassiliki Karantza
Journal: Journal of Clinical Oncology (2020)

TPS596 Background: Combination therapy with immunotherapy + chemotherapy is a promising approach for first-line (1L) treatment of locally recurrent, inoperable TNBC or metastatic TNBC (mTNBC). However, an unmet need exists for effective and tolerable maintenance regimens in mTNBC to sustain clinical benefit after induction therapy and avoid potential toxicity or resistance in response to prolonged chemotherapy. The PARP inhibitor olaparib has demonstrated efficacy in the maintenance setting for multiple platinum-sensitive tumors, and the prevalence of BRCA mutations in TNBC may make these tumors particularly sensitive to DNA-damaging agents. Moreover, previous data suggest that combination therapy with olaparib and the PD-1 inhibitor pembro may have clinical benefits. KEYLYNK-009 (NCT04191135) is a phase II/III, open-label, randomized study of pembro + olaparib or pembro + chemotherapy after induction with 1L pembro + chemotherapy in patients with locally recurrent, inoperable TNBC or mTNBC. Methods: This 2-in-1 study design will enroll ~317 patients in phase II; if a planned efficacy boundary is met, ~615 additional patients will be enrolled in phase III. Patients eligible for induction therapy must have measurable, locally recurrent, inoperable TNBC that cannot be treated with curative intent or mTNBC previously untreated with chemotherapy in the metastatic setting. All patients will receive up to 6 cycles of induction therapy with pembro 200 mg every 3 wk (Q3W) + chemotherapy (carboplatin AUC 2 + gemcitabine 1000 mg/m 2 ). Patients eligible for postinduction treatment must achieve complete or partial response or maintain stable disease during induction after 4-6 treatment cycles, with ECOG PS 0/1 and no grade &gt;1 toxicities related to induction therapy (excluding alopecia, Hb ≥9.0 g/dL, grade 2 hyper-/hypothyroidism, or grade 2 hyperglycemia). These patients will be randomized 1:1 to receive pembro 200 mg Q3W + olaparib 300 mg twice daily or continue pembro + chemotherapy (same as induction regimen). Olaparib and chemotherapy may continue until progression or unacceptable toxicity; pembro may continue for ≤35 cycles (including induction), unacceptable toxicity, or progression. Phase III dual primary endpoints are PFS per RECIST v1.1 by BICR and OS. Secondary endpoints include OS and PFS in patients with BRCAm, health-related quality of life, and safety. Enrollment is ongoing. Clinical trial information: NCT04191135 .
Research progress in erectile dysfunction
Authors: 赵学英, 刘学伟, 李凤鸣, 张喜庄, 杨永军
Journal: BMJ (2006)

勃起功能障碍(erectile dysfunction,ED)是指男性持续或反复的阴茎勃起功能不良,出现不能获得或维持充分勃起而无法完成满意性行为的情况[1],是一种常见的男性性功能障碍,严重影响患者的生活质量以及人际、婚姻关系。
Oral DNA vaccination targeting VEGFR2 combined with anti-PDL1 avelumab in patients with progressive glioblastoma: Safety run-in results—NCT03750071.
Authors: Wolfgang Wick, Antje Wick, Olivier L. Chinot, Martin J. Van Den Bent, Filip Yves Francine Leon De Vos, Marc Mansour, Lilli Podola, Heinz Lubenau, Michael Platten
Journal: Journal of Clinical Oncology (2020)

3001 Background: VEGFR2 overexpression in glioblastoma serves as a target for VEGFR2 primed T cells using VXM01 DNA vaccine encoding for VEGFR2. VXM01 is delivered in a bacterial Ty21a carrier suitable for oral administration. A previous phase I/II study in 14 patients with progressive glioblastoma showed that detection of VEGFR2 specific T cells as well as altered intra-tumoral immunity is correlated with prolonged overall survival, one partial response was reported with VXM01 alone. Three patients received nivolumab in addition to VXM01, which resulted in one complete and one partial clinical response. Based on these findings, a trial combining VXM01 and avelumab was designed. Methods: A multicentre, open-label phase I/II study ( EudraCT 2017-003076-31) in progressive glioblastoma includes 30 patients (24 non-resectable, 6 resectable) previously treated with temozolomide/radiotherapy. VXM01 is administered on day 1, 3, 5, 7 followed by boostings q4w. Avelumab 800mg is given intravenously q2w. Treatment continues up to week 48 followed by a 2 year observation period. The safety run-in phase of dose groups treated with VXM01 10 6 or 10 7 CFU plus avelumab was completed with 9 patients. Safety evaluation by the Data Safety Monitoring Board was performed after 3 and 9 patients treated for at least 5 weeks. Endpoints include safety and tolerability, objective response rate (ORR), clinical response using immune-response assessment in Neurooncology criteria (iRANO), and immunological assays like ELISpot, FACS, TCR-sequencing and tumor stainings. Results: No treatment-related toxicities were observed. Three partial responses with tumor reductions of 58, 81 and 95% to baseline were reported in 9 patients according to iRANO. Two of these patients are progression-free &gt; 6 months. Significant VEGFR2 specific T cell responses were measured in several patients, and pre-existing intra-tumoral T cells are positively associated with the effectiveness of the immunotherapy combination. Conclusions: VXM01 in combination with avelumab was safe and produces detectable peripheral VEGFR-2 specific immune responses. Three patients had an objective response. Clinical trial information: NCT03750071 .
Prediction of the molecular status in non-small cell lung cancer based on metastatic pattern: A free webtool powered by artificial intelligence.
Authors: Benjamin Besse, Alison Dormieux, Laura Mezquita, Renaud Monnet, Melodie Tazdait, Ludovic Lacroix, Etienne Rouleau, Julien Adam, Jordi Remon Masip, María Bluthgen, Francesco Facchinetti, Lambros Tzelikas, Pernelle Lavaud, Charles Naltet, Cecile Le Pechoux, Corinne Balleyguier, David Planchard, Nathalie Lassau, Paul-Henri Cournede, Caroline Caramella
Journal: Journal of Clinical Oncology (2020)

9535 Background: Molecular characterization of metastatic lung adenocarcinomas is mandatory but might be hampered by the quantity of tissue, restricted access to molecular platforms or limited economical resources. Our aim was to develop a tool supported by the hypothesis that radiological patterns of pts could help predict the rate of positivity of the most common oncogenic drivers. Methods: We defined an algorithm based on a molecularly defined cohort of 656 pts with stage IV lung adenocarcinoma. Two radiologists centrally reviewed the baseline imaging. Clinical data were retrospectively collected. There were 135 EGFR mutations, 81 ALK fusions, 47 BRAF mutations, 141 KRAS mutations, and 146 pan-negative tumors for these 4 oncogenic drivers. Univariate correlation analyses were performed to define an algorithm predicting the molecular testing positivity based on the metastatic pattern. Subsequently, an online tool was developed. This study was approved by our institutional review board. Results: Metastatic patterns correlated with the genomic drivers when compared to the pan-negative group. In the EGFR group, pleural metastases were more frequent (32% vs. 20%; p = 0.021), whereas adrenal and node metastases less frequent (6% vs.23%; p &lt; 0.001 and 11% vs. 23% respectively; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% vs. 29%; p = 0.043 and 37% vs. 24% respectively; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (47% vs. 20%; p &lt; 0.001 and 11% vs. 3% respectively; p = 0.04) and bone metastases less common (21% vs. 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK and BRAF groups (6%, 7% and 15% vs. 1%; p = 0,016, p = 0,009 and p &lt; 0,001 respectively). A free online access to the algorithm is now available after registration at http//tactic-ct.fr. Physicians enter age, sex, smoking status and the sites of metastases at diagnosis (present/absent/unknown). A mutation score is calculated, reflecting the % of chance to find an oncogenic driver. On the website, contributors can also enter new cases and an artificial intelligence will refine the algorithm and expand the number of oncogenic drivers. Conclusions: Our free access tool allows establishing a hierarchy in the molecular testing based on simple clinical and radiological information. Continual learning from new cases entered in the database will increase the sensitivity of the tool. This tool might save time, tumor tissue, economical resources and accelerate access to personalized treatment.
Impact of advance care planning on the place of death for cancer patients: A retrospective cohort study.
Authors: Martina Orlovic, Julia Riley, Joanne Droney
Journal: Journal of Clinical Oncology (2020)

e24007 Background: Place of death is an important indicator of quality of end-of-life care (EOLC). Most patients do not want to die in hospital and hospital deaths are costly to healthcare organisations. Advance care planning (ACP) includes discussions about where patients want to die. Cancer patients often have a distinct illness trajectory with a clear terminal phase, enabling opportunities for EOLC planning. This work aims to explore the impact of ACP on the outcomes and place of death for cancer patients. Methods: A retrospective decedent cohort study of 10,727 cancer patients with a Coordinate My Care (CMC) record created 2011-2019. CMC is a digital platform that enables patients to record, revise and share their ACP and EOLC preferences with primary, secondary and urgent healthcare providers in London. Logistic regression analysis was applied to examine the relationship between in-hospital death and a range of individual characteristics and EOLC preferences. Results: Only 1% chose hospital as their preferred place of death. Overall, 71% died in their place of preference. Home (42%) was the most common place of death, while 20% died in hospital. The likelihood in-hospital death is positively associated with being older (OR = 1.12, p &lt; 0.1), hospital being the preferred place of care (OR = 2.56, p &lt; 0.001), hospital being the preferred place of death (OR = 2.85, p &lt; 0.001) and if the preferred place of death is not recorded (OR = 1.32, p &lt; 0.001). By contrast, patients who are severely frail (OR = 0.61, p &lt; 0.001), who chose not to be resuscitated (OR = 0.56, p &lt; 0.001) and who have a ceiling of treatment for symptomatic rather than intensive hospital based treatments (OR = 0.40, p &lt; 0.001) are less likely to die in hospital. Conclusions: Most cancer patients prefer out-of-hospital death. Discussing, recording and sharing individual’s EOL preferences leads to better quality EOLC. Patient characteristics influence in-hospital deaths, but EOLC preferences exert stronger impact. Enabling cancer patients to die outside of hospital has positive implications for patients and their families and supports cost-effective use of healthcare resources.