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The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.
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Carcinoma Pulmonar de Células não Pequenas , Microbioma Gastrointestinal , Imunoterapia , Neoplasias Pulmonares , Neoplasias , Feminino , Humanos , Masculino , Akkermansia , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Disbiose/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/tratamento farmacológico , Metagenômica/métodos , Neoplasias/microbiologia , Resultado do TratamentoRESUMO
BACKGROUND: ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. METHODS: Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association. RESULTS: Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion. CONCLUSION: In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy.Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.
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SETTING: This paper describes an action research project with the Centre universitaire intégré de santé et de services sociaux - Capitale Nationale (CIUSSS-CN) who identified a need to assess vulnerability in their territories in order to ensure equitable distribution of the Integrated Perinatal and Early Childhood Services (SIPPE) program funds. The objective was to design and validate a multicriteria model to provide a more accurate portrait of vulnerability based on recent social realities. INTERVENTION: Our multidisciplinary research team of 7 members included experts in analytics, decision aiding, and community and public health. In collaboration with 6 CIUSSS-CN professionals, we co-constructed, during 9 workshops, a multicriteria model to aggregate the multiple dimensions of vulnerability. We used a value-focused thinking approach and applied the method MACBETH assisted by a geographic information system. OUTCOMES: Criteria, scales, and weights were validated and led to a vulnerability score for each CIUSSS-CN territory. This score provides a more accurate portrait of territorial disparities based on data and the participants' experience. The model was implemented in a dynamic user-friendly tool and serves to support decision-makers in the resource allocation process. Knowledge transfer was conducted during and after the process. IMPLICATIONS: This multidisciplinary research has served to anchor public health funding in local realities, with an emphasis on equity and stakeholder engagement. Our mixed-method approach integrating qualitative and quantitative data is adaptable to other contexts. Our results can enhance intervention effectiveness and allow for a better response to the needs of the population targeted by the SIPPE program.
RéSUMé: LIEU: Cet article décrit un projet de recherche-action avec le Centre Universitaire Intégré de Santé et de Services Sociaux - Capitale Nationale (CIUSSS-CN) qui a identifié un besoin d'évaluer la vulnérabilité sur son territoire afin d'assurer une distribution équitable des fonds du programme des Services Intégrés en Périnatalité et pour la Petite Enfance (SIPPE). L'objectif était de concevoir et de valider un modèle multicritère permettant de dresser un portrait plus précis de la vulnérabilité en fonction des réalités sociales récentes. INTERVENTION: Notre équipe de recherche multidisciplinaire de 7 membres comprenait des experts en analytique, en aide à la décision et en santé publique et communautaire. En collaboration avec 6 professionnelles du CIUSSS-CN, nous avons co-construit, au cours de 9 ateliers, un modèle d'évaluation multicritère pour agréger les multiples dimensions de la vulnérabilité. Nous avons utilisé une approche de modélisation centrée sur les valeurs et appliqué la méthode MACBETH assistée par un système d'information géographique. RéSULTATS: Les critères, les échelles et les pondérations ont été validés et ont conduit à un score de vulnérabilité pour chaque territoire de la CIUSSS-CN. Ce score fournit un portrait plus précis des disparités territoriales basé sur les données et la connaissance qu'ont les participants du terrain. Le modèle a été implémenté dans un outil dynamique et convivial servant à soutenir les décideurs dans le processus d'allocation des ressources. Le transfert de connaissances a été effectué tout au long du et après le processus. IMPLICATIONS: Cette recherche multidisciplinaire a permis d'ancrer le financement de la santé publique dans les réalités locales, en mettant l'accent sur l'équité et l'engagement des parties prenantes. Notre approche mixte intégrant des données qualitatives et quantitatives est adaptable à d'autres contextes. Nos résultats peuvent améliorer l'efficacité des interventions et permettre de mieux répondre aux besoins de la population ciblée par le programme SIPPE.
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Since July 2017, pembrolizumab has been approved as a first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with a PD-L1 score ≥ 50% in Quebec. Study objectives were to describe and assess the real-world use of pembrolizumab; report progression-free survival (PFS), overall survival (OS), and immune-related adverse events (IRAEs); and compare outcomes between a fixed dose (FD) and a weight-based capped dose (WCD). Medical records of patients treated in one of Quebec's four adult university teaching hospitals who received pembrolizumab between 1 November 2017 and 31 October 2019 were reviewed and followed until 29 February 2020. Two hundred and seventy-nine patients were included. The median real-world PFS and OS were 9.4 (95% CI, 6.6 to 11.2) and 17.3 months (95% CI, 12.9 to not reached), respectively. IRAEs causing delays or treatment interruptions were seen in 34.4% of patients. Initiating treatment with a FD (49 patients) or using a WCD (230 patients) does not appear to affect PFS, OS, or the occurrence of IRAEs. The use of a WCD strategy allowed approximately CAD 5.8 million in savings during the course of our study. These findings support the effectiveness and safety of pembrolizumab in a real-world setting. The use of a WCD does not appear to have a negative impact on patient outcomes.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/patologia , Hospitais de Ensino , Neoplasias Pulmonares/patologia , Quebeque , UniversidadesRESUMO
Background: Recent developments in artificial intelligence suggest that radiomics may represent a promising non-invasive biomarker to predict response to immune checkpoint inhibitors (ICIs). Nevertheless, validation of radiomics algorithms in independent cohorts remains a challenge due to variations in image acquisition and reconstruction. Using radiomics, we investigated the importance of scan normalization as part of a broader machine learning framework to enable model external generalizability to predict ICI response in non-small cell lung cancer (NSCLC) patients across different centers. Methods: Radiomics features were extracted and compared from 642 advanced NSCLC patients on pre-ICI scans using established open-source PyRadiomics and a proprietary DeepRadiomics deep learning technology. The population was separated into two groups: a discovery cohort of 512 NSCLC patients from three academic centers and a validation cohort that included 130 NSCLC patients from a fourth center. We harmonized images to account for variations in reconstruction kernel, slice thicknesses, and device manufacturers. Multivariable models, evaluated using cross-validation, were used to estimate the predictive value of clinical variables, PD-L1 expression, and PyRadiomics or DeepRadiomics for progression-free survival at 6 months (PFS-6). Results: The best prognostic factor for PFS-6, excluding radiomics features, was obtained with the combination of Clinical + PD-L1 expression (AUC = 0.66 in the discovery and 0.62 in the validation cohort). Without image harmonization, combining Clinical + PyRadiomics or DeepRadiomics delivered an AUC = 0.69 and 0.69, respectively, in the discovery cohort, but dropped to 0.57 and 0.52, in the validation cohort. This lack of generalizability was consistent with observations in principal component analysis clustered by CT scan parameters. Subsequently, image harmonization eliminated these clusters. The combination of Clinical + DeepRadiomics reached an AUC = 0.67 and 0.63 in the discovery and validation cohort, respectively. Conversely, the combination of Clinical + PyRadiomics failed generalizability validations, with AUC = 0.66 and 0.59. Conclusion: We demonstrated that a risk prediction model combining Clinical + DeepRadiomics was generalizable following CT scan harmonization and machine learning generalization methods. These results had similar performances to routine oncology practice using Clinical + PD-L1. This study supports the strong potential of radiomics as a future non-invasive strategy to predict ICI response in advanced NSCLC.
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Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Akkermansia , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Microambiente TumoralRESUMO
BACKGROUND: Alcohol withdrawal is common in hospitalized patients and symptom-triggered guidelines have been shown to reduce treatment duration, length of stay, and need for mechanical ventilation. OBJECTIVES: To assess the feasibility of incorporating symptom-triggered alcohol withdrawal guidelines early in the hospital course and to evaluate outcomes of patients before and after implementation of the guidelines. METHODS: This was a retrospective pre-post study of adult patients admitted from the emergency department to an urban, academic, tertiary care center. Subjects in the preguideline (PRE) group were given benzodiazepines in a nonprotocolized manner at the discretion of the treating physician, whereas subjects in the postguideline (POST) group were treated according to the alcohol withdrawal guidelines with treatment beginning in the emergency department. RESULTS: The PRE group involved 113 admissions for severe alcohol withdrawal and the POST group involved 103 admissions for severe alcohol withdrawal. The median benzodiazepine dose per day, in milligrams of chlordiazepoxide, was higher in the POST group (100 mg in the PRE group vs. 141 mg in the POST group; P<0.02). A higher percentage of patients in the POST group were admitted to the intensive care unit (4.4% in the PRE group vs. 12.6% in the POST group; P=0.05); however, more patients in the PRE group than in the POST group received continuous intravenous sedation and mechanical ventilation, although the difference was not statistically significant (P=0.37 for both variables). There was no difference between the 2 groups in length of stay in the intensive care unit or hospital or discharge disposition. CONCLUSIONS: Incorporating symptom-triggered guidelines for alcohol withdrawal early in the hospital course at a large medical center is feasible. This approach may result in increased benzodiazepine use, but it seems that it is safe and does not result in adverse outcomes.
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Transtornos Induzidos por Álcool/tratamento farmacológico , Benzodiazepinas/farmacologia , Hospitalização/estatística & dados numéricos , Avaliação de Processos e Resultados em Cuidados de Saúde/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Adulto , Benzodiazepinas/administração & dosagem , Cuidados Críticos/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Respiração Artificial/estatística & dados numéricos , Estudos Retrospectivos , Centros de Atenção Terciária/estatística & dados numéricosRESUMO
Rearrangements in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALK+ NSCLC and investigate its relationship with response to crizotinib. Using whole-exome sequencing and RNAseq data, we identified four rare ALK fusion partners (HIP1, GCC2, ERC1, and SLC16A7) and one novel partner (CEP55). At the mutation level, TP53 was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of ALK or gain in EGFR was associated with shorter PFS. This study is the first to report a comprehensive view of the ALK+ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of TP53 mutation as a strong prognostic indication of poor clinical response in ALK+ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALK+ NSCLC.
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Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Variações do Número de Cópias de DNA , Genômica/métodos , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/genética , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/genética , Estudos Prospectivos , Proteína Supressora de Tumor p53/genéticaRESUMO
Treatment of hypotension caused by calcium channel blocker overdose (CCB) remains a challenge. We describe the successful use of vasopressin in two patients with massive CCB overdoses in whom hypotension was unresponsive to calcium, glucagon, insulin, and conventional vasopressor therapies. While various modes of treatments have been used to treat the hypotension of CCB overdose, this is the first report to our knowledge of the successful use of vasopressin in this clinical setting.
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Antídotos/uso terapêutico , Bloqueadores dos Canais de Cálcio/efeitos adversos , Hipotensão/induzido quimicamente , Hipotensão/tratamento farmacológico , Vasoconstritores/uso terapêutico , Vasopressinas/uso terapêutico , Adulto , Anlodipino/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Diazepam/farmacologia , Diltiazem/efeitos adversos , Overdose de Drogas , Quimioterapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
In response to concerns regarding the safety of ephedra-containing dietary supplements, manufacturers have marketed "ephedra-free" products. Many of these contain synephrine, a sympathomimetic amine from the plant Citrus aurantium. Synephrine is structurally similar to ephedrine and has vasoconstrictor properties. We describe a 38-year-old patient with ischemic stroke associated with an ephedra-free dietary supplement containing synephrine and caffeine. The patient presented with memory loss and unsteady gait after taking 1 or 2 capsules per day of a dietary supplement (Stacker 2 Ephedra-Free) for 1 week. He had no notable medical history or major atherosclerotic risk factors and took no other medications. Physical examination showed a mildly ataxic gait and substantial Impairment of both concentration and memory. Computed tomography and magnetic resonance Imaging of the brain showed subacute infarctions in the left thalamus and left cerebellum in the distribution of the vertebrobasilar circulation. Other causes of ischemic stroke were evaluated, and findings were unremarkable; a vasospastic origin was considered most likely. The patient was discharged with nearly complete resolution of symptoms. Synephrine, a sympathomimetic amine related to ephedrine, may be associated with Ischemic stroke. Consumers and clinicians need to be Informed about the potential risks of ephedra-free products.
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Infarto Encefálico/induzido quimicamente , Suplementos Nutricionais/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Sinefrina/efeitos adversos , Adulto , Humanos , MasculinoRESUMO
OBJECTIVES: Oximes such as pralidoxime (2-PAM) are essential antidotes for life-threatening organophosphate poisoning. Unfortunately, oximes are expensive, have limited use, and have short shelf lives. As such, maintaining large stockpiles in preparation for terrorist activity is not always possible. We have demonstrated that atropine is stable well beyond its labeled shelf life and that recently expired 2-PAM was clinically efficacious in a series of poisoned patients. Because 2-PAM is often dosed empirically, clinical improvement does not guarantee pharmacological stability. We therefore chose to analyze the chemical stability of expired 2-PAM. METHODS: Samples of lyophylized 2-PAM were maintained according to the manufacturer's recommendations for 20 years beyond the published shelf life. We studied 2-PAM contained in a MARK I autoinjector that was stored properly for 3 years beyond its expiration date. An Agilent LC/MSD 1100 with diode-array detector and an Agilent Sorbax SB-C-18, 4.6 × 150-mm, 5-µm column were used with the following solvent systems: water with 0.01% trifluoroacetic acid and methanol with 0.01% trifluoroacetic acid. Fresh reagent grade 2-PAM was used as a standard. Results were repeated for consistency. RESULTS: Lyophylized 2-PAM was a white powder that was clear and colorless in solution. Liquid chromatography was identical to the standard and resulted in 2 isolated peaks with identical mass spectra, suggesting that they are stereoisomers. The autoinjector discharged a clear, yellowish solution. In addition to the 2 peaks identified for lyophylized 2-PAM, a small third peak was identified with a mass spectra corresponding to the reported N -methyl pyridinium carboxaldehyde degradation product. CONCLUSIONS: When properly stored, lyophylized 2-PAM appears to be chemically stable well beyond its expiration date. Although the relative amount of degradation product found in solubilized (autoinjector) 2-PAM was small, it is unclear whether this may be toxic and therefore is of concern. Further studies performed with lots of drug stored under varied conditions would be required to fully determine the stability of expired 2-PAM.
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Antídotos/química , Terrorismo Químico/prevenção & controle , Planejamento em Desastres , Compostos de Pralidoxima/química , Cromatografia Líquida , Estabilidade de Medicamentos , Armazenamento de Medicamentos/métodos , Humanos , Espectrometria de Massas , Fatores de Tempo , Estados UnidosRESUMO
Esophageal dilation is a rare complication of scleroderma and CREST syndrome. A case of atelectasis secondary to right inferior bronchus compression by a massively dilated esophagus is described. The authors are unaware of any previous cases of atelectasis secondary to esophageal dilation in scleroderma.
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Doenças do Esôfago/complicações , Atelectasia Pulmonar/etiologia , Escleroderma Sistêmico/complicações , Idoso , Dilatação Patológica/complicações , Doenças do Esôfago/diagnóstico por imagem , Esôfago/diagnóstico por imagem , Humanos , Masculino , RadiografiaAssuntos
Suplementos Nutricionais/efeitos adversos , Fenilefrina/química , Síncope/induzido quimicamente , Sinefrina/efeitos adversos , Sinefrina/química , Agonistas alfa-Adrenérgicos/efeitos adversos , Agonistas alfa-Adrenérgicos/química , Humanos , Fenilefrina/efeitos adversos , Fatores de Risco , Sensibilidade e Especificidade , Sinefrina/administração & dosagemRESUMO
Carvedilol is a non-selective beta-adrenoreceptor antagonist that is also an antagonist at the alpha(1)-adrenoreceptor. This unique pharmacological effect may produce a different toxicodynamic profile compared to other beta-adrenoreceptor antagonists. Only one previous case of carvedilol overdose has been reported. Here, we report massive carvedilol ingestion confirmed by quantitative analysis. The case report deals with an 84-year-old man who chewed a total of 60 (6.25 mg) tablets and rapidly developed symptoms. Vital signs on presentation were systolic blood pressure 70 mmHg; heart rate 45 beats/min.; respirations 18 breaths/min.; temperature 37 degrees . The electrocardiogram showed a junctional rhythm at 49 beats/min. The patient was treated with normal saline boluses, repeated glucagon boluses (2-3 mg each) and a dopamine infusion. At 14 hr after ingestion, he was weaned off vasopressors and was in a normal sinus rhythm. Quantitative confirmation showed a carvedilol serum concentration of 472 ng/ml (steady-state concentration 8.5 ng/ml during 6.25 mg twice daily dosing). Despite its unique pharmacological properties, the clinical manifestations of carvedilol overdose appear similar to other beta-adrenoreceptor antagonists.