tbuckley/cabot-search huggingface dataset:
Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI extension
Authors: Samantha Cruz Rivera, Xiaoxuan Liu, An-Wen Chan, Alastair K. Denniston, Melanie J. Calvert, Ara Darzi, Christopher Holmes, Christopher Yau, David Moher, Hutan Ashrafian, Jonathan J. Deeks, Lavinia Ferrante di Ruffano, Livia Faes, Pearse A. Keane, Sebastian J. Vollmer, Aaron Y. Lee, Adrian Jonas, Andre Esteva, Andrew L. Beam, Maria Beatrice Panico, Cecilia S. Lee, Charlotte Haug, Christophe J. Kelly, Christopher Yau, Cynthia Mulrow, Cyrus Espinoza, John Fletcher, David Moher, Dina Paltoo, Elaine Manna, Gary Price, Gary S. Collins, Hugh Harvey, James Matcham, Joao Monteiro, M. Khair ElZarrad, Lavinia Ferrante di Ruffano, Luke Oakden-Rayner, Melissa McCradden, Pearse A. Keane, Richard Savage, Robert Golub, Rupa Sarkar, Samuel Rowley
Journal: Nature Medicine (2020)

The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes. The SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trial protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 26 candidate items, which were consulted upon by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The SPIRIT-AI extension includes 15 new items that were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations for the handling of input and output data, the human-AI interaction and analysis of error cases. SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial.
P68.01 Qualitative Computed Tomographic Features Predict Epidermal Growth Factor Receptor Mutations in Advanced Lung Adenocarcinoma
Authors: C.K. Liam, C.S. Chai, M.T. Ramli Hamid, N.F. Muhammad Gowdh, W.Y. Chan, K.H. Ng
Journal: Journal of Thoracic Oncology (2021)
A Budget Impact Analysis of Gene Therapy for Sickle Cell Disease
Authors: Patrick DeMartino, Meredith B. Haag, Alyssa R. Hersh, Aaron B. Caughey, Joshua A. Roth
Journal: JAMA Pediatrics (2021)

<h3>Importance</h3> Hundreds of gene therapies are undergoing clinical testing and are likely to be priced more than $1 million per course of treatment. The association that high prices will have with insurance coverage of gene therapy remains unclear. Gene therapy for sickle cell disease has shown early success and would be one of the first gene therapies available for a relatively large population. <h3>Objectives</h3> To estimate the budget impact and affordability of a gene therapy for severe sickle cell disease from the perspective of US Medicaid programs with the highest prevalence of sickle cell disease while exploring the impact of an annuity payment model. <h3>Design, Setting, and Participants</h3> A budget impact analysis was performed from January 1 to May 31, 2020, for a sickle cell disease gene therapy from the perspective of 10 state Medicaid plans with a 5-year time horizon, using state-level disease prevalence data from 2012. Disease prevalence, Medicaid enrollment, and expenditures were derived from the available literature. The eligible population was based on modified clinical trial inclusion criteria including individuals aged 13 to 45 years with severe disease. <h3>Exposures</h3> The gene therapy was assumed to be administered to 7% of the eligible population annually and was curative (no subsequent disease-related expenditures). The gene therapy price was $1.85 million in the base case, and baseline disease-related expenditures were $42 200 per year. <h3>Main Outcomes and Measures</h3> The main outcomes were total budget impact and budget impact per member per month in years 1 through 5. One-way sensitivity analysis was used to evaluate uncertainty of market diffusion, size of eligible population, price of therapy, and cost of routine care. <h3>Results</h3> An estimated 5464 Medicaid enrollees would be eligible for the gene therapy nationally, with 2315 individuals in the 10 Medicaid programs of interest (16 per 100 000 enrollees). The model projected a mean 1-year budget impact of $29.96 million per state Medicaid program in the sample ($1.91 per member per month). A 5-year annuity payment reduced the short-term budget impact. <h3>Conclusions and Relevance</h3> This study suggests that a gene therapy for severe sickle cell disease is likely to produce a considerable budget impact for many Medicaid plans while potentially offering substantial benefit to patients. Payers may need to take steps to ensure affordability and access. Gene therapy for sickle cell disease is likely to provide an early demonstration of the unique financial challenges associated with this emerging drug class.
Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies
Authors: Aleix Prat, Anwesha Chaudhury, Nadia Solovieff, Laia Paré, Débora Martinez, Nuria Chic, Olga Martínez-Sáez, Fara Brasó-Maristany, Agnes Lteif, Tetiana Taran, Naveen Babbar, Fei Su
Journal: Journal of Clinical Oncology (2021)

The prognostic and predictive value of intrinsic subtypes in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with endocrine therapy and ribociclib (RIB) is currently unknown. We evaluated the association of intrinsic subtypes with progression-free survival (PFS) in the MONALEESA trials.A retrospective and exploratory PAM50-based analysis of tumor samples from the phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials was undertaken. The prognostic relationship of PAM50-based subtypes with PFS and risk of disease progression by subtype and treatment were evaluated using a multivariable Cox proportional hazards model, adjusting for age, prior chemotherapy, performance status, visceral disease, bone-only metastases, histological grade, number of metastatic sites, prior endocrine therapy, and de novo metastatic disease.Overall, 1,160 tumors from the RIB (n = 672) and placebo (n = 488) cohorts were robustly profiled. Subtype distribution was luminal A (LumA), 46.7%; luminal B (LumB), 24.0%; normal-like, 14.0%; HER2-enriched (HER2E), 12.7%; and basal-like, 2.6% and was generally consistent across treatment arms and trials. The associations between subtypes and PFS were statistically significant in both arms (P < .001). The risks of disease progression for LumB, HER2E, and basal-like subtypes were 1.44, 2.31, and 3.96 times higher compared with those for LumA, respectively. All subtypes except basal-like demonstrated significant PFS benefit with RIB. HER2E (hazard ratio [HR], 0.39; P < .0001), LumB (HR, 0.52; P < .0001), LumA (HR, 0.63; P = .0007), and normal-like (HR, 0.47; P = .0005) subtypes derived benefit from RIB. Patients with basal-like subtype (n = 30) did not derive benefit from RIB (HR, 1.15; P = .77).In this retrospective exploratory analysis of hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer, each intrinsic subtype exhibited a consistent PFS benefit with RIB, except for basal-like.
P76.30 The Neutrophil-to-Lymphocyte Ratio is a Prognostic Biomarker in Patients with EGFR Mutated Advanced NSCLC
Authors: S. Rouhani, N. Yun, C. Bestvina, B. Gilmore, E. Ritz, I. Tarhoni, M. Batus, J. Borgia, P. Bonomi, M.J. Fidler
Journal: Journal of Thoracic Oncology (2021)
61 Prevalence of RAS/RAF mutations in pancreatic cystic lesions and correlation with malignant potential
Authors: K Taylor, A Begley, MA Catherwood, A Patterson, L Venkatraman, TF Lioe, I Mainie, M Love, M Mitchell, RH Wilson, VM Coyle, P Kelly
Journal: Gut (2017)

Background  Incidence of pancreatic cystic lesions (PCL) is increasing due to ageing populations and increasing cross-sectional imaging. PCL are often benign but have potential for malignant transformation, particularly mucinous cysts. Surveillance strategies and surgical intervention have implications for health economics and patient morbidity/mortality. Despite multimodality investigation, establishing that a PCL is mucinous and its potential for malignant transformation is frequently inaccurate. Molecular characterisation of these lesions may improve classification.  Aim  This exploratory study aims to: determine the prevalence of BRAF, KRAS and NRAS mutations in a cohort of PCL and to correlate these mutations with standard clinicopathological features and patient outcomes.  Method  PCR and Sanger sequencing were used to determine KRAS, NRAS and BRAF mutational status of 20 patients with PCL. Patients were identified sequentially from MDM meetings as having PCL and undergoing diagnostic work-up including imaging, cytology and tumour marker measurement.  Results  The majority of PCL were incidental findings; 10% (n=2) underwent malignant transformation during the follow-up period. Mutations in BRAF and NRAS were not identified. KRAS mutations were found in 10%. No clear association could be found between mutational status, biochemical markers and clinicopathological characteristics or patient outcome at this stage.  Conclusions  There is potential to use mutational status to determine if PCLs are mucinous and likelihood of malignant transformation, however further investigation in a larger sample set with mature outcome data is required. It is likely that mutational status will be helpful as part of a multimodality classification process that also incorporates radiological, cytological and biochemical assessments.
Fibroblast Activation Protein α-Targeted CD40 Agonism Abrogates Systemic Toxicity and Enables Administration of High Doses to Induce Effective Antitumor Immunity
Authors: Eva Sum, Moritz Rapp, Philipp Fröbel, Marine Le Clech, Harald Dürr, Anna Maria Giusti, Mario Perro, Dario Speziale, Leo Kunz, Elena Menietti, Peter Brünker, Ulrike Hopfer, Martin Lechmann, Andrzej Sobieniecki, Birte Appelt, Roberto Adelfio, Valeria Nicolini, Anne Freimoser-Grundschober, Whitney Jordaan, Sara Labiano, Felix Weber, Thomas Emrich, François Christen, Birgit Essig, Pedro Romero, Christine Trumpfheller, Pablo Umaña
Journal: Clinical Cancer Research (2021)

Abstract Purpose: CD40 agonists hold great promise for cancer immunotherapy (CIT) as they enhance dendritic cell (DC) activation and concomitant tumor-specific T-cell priming. However, the broad expression of CD40 accounts for sink and side effects, hampering the efficacy of anti-CD40 antibodies. We hypothesized that these limitations can be overcome by selectively targeting CD40 agonism to the tumor. Therefore, we developed a bispecific FAP-CD40 antibody, which induces CD40 stimulation solely in presence of fibroblast activation protein α (FAP), a protease specifically expressed in the tumor stroma. Experimental Design: FAP-CD40's in vitro activity and FAP specificity were validated by antigen-presenting cell (APC) activation and T-cell priming assays. In addition, FAP-CD40 was tested in subcutaneous MC38-FAP and KPC-4662-huCEA murine tumor models. Results: FAP-CD40 triggered a potent, strictly FAP-dependent CD40 stimulation in vitro. In vivo, FAP-CD40 strongly enhanced T-cell inflammation and growth inhibition of KPC-4662-huCEA tumors. Unlike nontargeted CD40 agonists, FAP-CD40 mediated complete regression of MC38-FAP tumors, entailing long-term protection. A high dose of FAP-CD40 was indispensable for these effects. While nontargeted CD40 agonists induced substantial side effects, highly dosed FAP-CD40 was well tolerated. FAP-CD40 preferentially accumulated in the tumor, inducing predominantly intratumoral immune activation, whereas nontargeted CD40 agonists displayed strong systemic but limited intratumoral effects. Conclusions: FAP-CD40 abrogates the systemic toxicity associated with nontargeted CD40 agonists. This enables administration of high doses, essential for overcoming CD40 sink effects and inducing antitumor immunity. Consequently, FAP-targeted CD40 agonism represents a promising strategy to exploit the full potential of CD40 signaling for CIT.
<i>Limosilactobacillus fermentum</i> JL-3 isolated from “Jiangshui” ameliorates hyperuricemia by degrading uric acid
Authors: Ying Wu, Ze Ye, Pengya Feng, Rong Li, Xiao Chen, Xiaozhu Tian, Rong Han, Apurva Kakade, Pu Liu, Xiangkai Li
Journal: Gut Microbes (2021)

Recent studies into the beneficial effects of fermented foods have shown that this class of foods are effective in managing hyperuricemia and gout. In this study, the uric acid (UA) degradation ability of Limosilactobacillus fermentum JL-3 strain, isolated from "Jiangshui" (a fermented Chinese food), was investigated. In vitro results showed that JL-3 strain exhibited high degradation capacity and selectivity toward UA. After oral administration to mice for 15 days, JL-3 colonization was continuously detected in the feces of mice. The UA level in urine of mice fed with JL-3 was similar with the control group mice. And the serum UA level of the former was significantly lower (31.3%) than in the control, further confirmed the UA-lowering effect of JL-3 strain. Limosilactobacillus fermentum JL-3 strain also restored some of the inflammatory markers and oxidative stress indicators (IL-1β, MDA, CRE, blood urea nitrogen) related to hyperuricemia, while the gut microbial diversity results showed that JL-3 could regulate gut microbiota dysbiosis caused by hyperuricemia. Therefore, the probiotic Limosilactobacillus fermentum JL-3 strain is effective in lowering UA levels in mice and could be used as a therapeutic adjunct agent in treating hyperuricemia.
A full set of mitotic phases in peripheral blood
Authors: Huifei Liu, Rachel A. Mariani
Journal: American Journal of Hematology (2021)

A 14-year-old male with Li-Fraumeni syndrome was diagnosed as pleomorphic anaplastic xanthoastrocytoma 9 years ago. In the 3 years following his initial diagnosis, he experienced three episodes of intracranial relapse. He then had five episodes of recurrent extra-cranial metastatic diseases over the past 6 years, which was controlled by resection and chemo-radiation therapies until 2 years ago. Despite multi-modal treatment, his disease progressed with extensive multiple organ involvement by radiology studies. He was found to have sudden markedly decreased platelet count during a two-week period (platelet count: 89 000/μl to 48 000/μl to 10 000/μl). He had severe anemia (hemoglobin 5.3 g/dl) and a normal stable white blood cell count (average 4 700/μL). Blood smear revealed erythroid precursors at different stages. Remarkably, many normal or abnormal mitotic figures (about 5% of erythroblasts) in prophase, metaphase, anaphase, telophase and cytokinesis, were identified (aqueous Romanowsky stain, 1000x). Flow cytometry detected 14.6% aberrant proerythroblasts expressing CD7, CD13, CD33, CD36, CD45 (dim), CD71 (bright), CD117, glycophorin-A, without CD34, myeloperoxidase, or other myelomonocytic and lymphoid markers. Cytogenetic analysis showed a complex karyotype (45,XY,inv(2)(q11.2q31),dic(5;7)(q11.2;p12),+8,-11,add(12)(q13),add(13)(q14),-16,add(18)(p11.1),der(?)t(?;11)(?;q23)[7]/44,sl,+dic(11;12)(p11.2;p11.2),-add(13),+13,-der(?)[6]/44,sl,+add(11)(p11.2),-add(13),+13,inv(15)(q15q24),-18[5]/nonclonal[2].ish der(?)t(?;11)(KMT2A+). Fluorescence in situ hybridization confirmed 5q deletion, three copies of chromosome 8 centromere and RUNX1T1, and 16q deletion by loss of one CBFB signal. A diagnosis of therapy related myeloid neoplasm, pure erythroid leukemia was made upon bone marrow examination. The patient succumbed to disease approximately 2 months later despite chemotherapy for AML. Pure erythroid leukemia (PEL) is the rarest subtype of acute myeloid leukemia.1 Secondary PEL mostly occurs in older patients with only two reported cases in children.2 The germline p53 mutation in our patient, likely contributes to the development and refractory nature of the pleomorphic anaplastic xanthoastrocytoma, and subsequent development of therapy related PEL. The authors declare no conflict of interest. Dr. Huifei Liu made the diagnosis. Dr. Huifei Liu wrote the manuscript and prepared the photos. Dr. Mariani edited the manuscript. This case report did not require IRB approval by Nationwide Children's Hospital. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
OA11.06 IMpower133: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage Small-Cell Lung Cancer
Authors: M. Reck, L. Horn, T.S.K. Mok, A. Mansfield, R. De Boer, G. Losonczy, S. Sugawara, R. Dziadziuszko, M. Krzakowski, A. Smolin, M. Hochmair, M. Garassino, G. Castro, H. Bischoff, A. Cardona, S. Morris, S. Liu
Journal: Journal of Thoracic Oncology (2021)
Insulin Pump Treatment for the Hospitalized Patient
Authors: Samantha Coffer, Lindsay Schlichting, John M. Cunningham
Journal: JAMA Internal Medicine (2021)

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MA06.03 Phosphorylated Ribosomal Protein S6, Correlation With Characteristics and Clinical Outcome in Patients With MPM: Results from ETOP Mesoscape
Authors: I. Opitz, J.H. Rüschoff, M. Haberecker, Z. Tsourti, K. Nackaerts, L. Ampollini, M. De Perrot, L. Brcic, E. Nadal, S. Gray, J. Aerts, E. Verbeken, E. Silini, F. Zaeimi, M. Samarzija, R. Llatjos, S. Tsimpoukis, J. Von Der Thüsen, S. Finn, K. Monkhorst, N. Marti, G. Dimopoulou, R. Kammler, S. Peters, P. Baas, R. Stahel, F. Mesoscape Consortium
Journal: Journal of Thoracic Oncology (2021)
The clear and persistent impact of air pollution on chronic respiratory diseases: a call for interventions
Authors: Isabella Annesi-Maesano, Francesco Forastiere, John Balmes, Erika Garcia, Jack Harkema, Stephen Holgate, Frank Kelly, Haneen Khreis, Barbara Hoffmann, Cara Nichole Maesano, Rob McConnell, David Peden, Kent Pinkerton, Tamara Schikowski, George Thurston, Laura S. Van Winkle, Christopher Carlsten
Journal: European Respiratory Journal (2021)

<b>Air pollution is responsible for chronic respiratory symptoms and diseases. Efforts to reduce air pollution exposure to protect public health, especially from emissions from both fossil fuel combustion and biomass combustion, are needed urgently.</b>https://bit.ly/3hJtCze
On the Origin of Sensitivity and Specificity
Authors: Nicholas Binney, Christopher Hyde, Patrick M. Bossuyt
Journal: Annals of Internal Medicine (2021)

Although it is commonly said that the notions of sensitivity and specificity were first defined by Jacob Yerushalmy in 1947, the sensitivity and specificity of diagnostic tests have been assessed as far back as the early 1900s. These notions share a common origin with the development of serology. They were originally immunologic concepts, closely associated with the development of complement fixation reactions for syphilis. Here, the authors trace how immunologic sensitivity and specificity were transformed into diagnostic sensitivity and specificity. By relocating the origins of these concepts to the early 20th century, they highlight how these origins were bound to then-commonplace assumptions about specific infectious disease entities.
P76.24 A Randomized Phase 2 Trial of Anlotinib Plus Docetaxel vs Docetaxel as 2nd-Line Therapy for EGFR-Negative NSCLC (ALTER-L018)
Authors: L. Wu, Z. Wu, Z. Xiao, J. Weng, M. Xiao, Z. Ma, Y. Chen, H. Zhang, Y. Cao, H. Duan, P. Cao, Q. Wang, J. Li, Y. Xu, X. Pu, K. Li
Journal: Journal of Thoracic Oncology (2021)
P76.68 The Impact of Eligibility for Anti-Angiogenic Treatment to the Prognosis of Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutations
Authors: H. Kodama, H. Kenmotsu, M. Yabe, N. Nishioka, E. Miyawaki, T. Miyawaki, N. Mamesaya, H. Kobayashi, S. Omori, K. Wakuda, A. Ono, T. Naito, H. Murakami, T. Takahashi
Journal: Journal of Thoracic Oncology (2021)
P21.11 Durvalumab after Concurrent cChemotherapy and High-Dose Radiotherapy in Locally Advanced Non-Small Cell Lung Cancer
Authors: Y. Landman, N. Kurman, O. Jacobi, O. Yariv, I. Peretz, O. Rotem, E. Dudnik, A. Zer, A. Allen
Journal: Journal of Thoracic Oncology (2021)
Nivolumab maintenance in high-risk acute myeloid leukemia patients: a single-arm, open-label, phase II study
Authors: Patrick K. Reville, Hagop M. Kantarjian, Farhad Ravandi, Elias Jabbour, Courtney D. DiNardo, Naval Daver, Naveen Pemmaraju, Maro Ohanian, Yesid Alvarado, Lianchun Xiao, Gheath Alatrash, Sanam Loghavi, Caitlin R. Rausch, Gautam Borthakur, Marina Konopleva, Jorge Cortes, Tapan M. Kadia
Journal: Blood Cancer Journal (2021)
Signaling, Deconstructed: Using Optogenetics to Dissect and Direct Information Flow in Biological Systems
Authors: Payam E. Farahani, Ellen H. Reed, Evan J. Underhill, Kazuhiro Aoki, Jared E. Toettcher
Journal: Annual Review of Biomedical Engineering (2021)

Cells receive enormous amounts of information from their environment. How they act on this information-by migrating, expressing genes, or relaying signals to other cells-comprises much of the regulatory and self-organizational complexity found across biology. The "parts list" involved in cell signaling is generally well established, but how do these parts work together to decode signals and produce appropriate responses? This fundamental question is increasingly being addressed with optogenetic tools: light-sensitive proteins that enable biologists to manipulate the interaction, localization, and activity state of proteins with high spatial and temporal precision. In this review, we summarize how optogenetics is being used in the pursuit of an answer to this question, outlining the current suite of optogenetic tools available to the researcher and calling attention to studies that increase our understanding of and improve our ability to engineer biology.