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OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/epidemiologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Biomarcadores , COVID-19/mortalidade , Método Duplo-Cego , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Tempo de Internação , Masculino , Alta do Paciente , Prognóstico , Respiração Artificial , SARS-CoV-2RESUMO
Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.
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Proteína 7 Relacionada à Autofagia , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Proteínas de Ligação a RNA , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/genética , Células Germinativas/metabolismo , Humanos , Proteínas de Ligação a RNA/genéticaRESUMO
Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.
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The clinical use of genomic analysis has expanded rapidly resulting in an increased availability and utility of genomic information in clinical care. We have developed an infrastructure utilizing informatics tools and clinical processes to facilitate the use of whole genome sequencing data for population health management across the healthcare system. Our resulting framework scaled well to multiple clinical domains in both pediatric and adult care, although there were domain specific challenges that arose. Our infrastructure was complementary to existing clinical processes and well-received by care providers and patients. Informatics solutions were critical to the successful deployment and scaling of this program. Implementation of genomics at the scale of population health utilizes complicated technologies and processes that for many health systems are not supported by current information systems or in existing clinical workflows. To scale such a system requires a substantial clinical framework backed by informatics tools to facilitate the flow and management of data. Our work represents an early model that has been successful in scaling to 29 different genes with associated genetic conditions in four clinical domains. Work is ongoing to optimize informatics tools; and to identify best practices for translation to smaller healthcare systems.
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PURPOSE: To accurately ascertain the frequency of pathogenic germline variants (PGVs) in a pan-cancer patient population with universal genetic testing and to assess the economic impact of receiving genetic testing on healthcare costs. METHODS: In this prospective study, germline genetic testing using a 105-gene panel was administered to an unselected pan-cancer patient population irrespective of eligibility by current guidelines. Financial records of subjects were analyzed to assess the effect of PGV detection on cost of care one year from the date of testing. RESULTS: A total of 284 patients participated in this study, of which 44 patients (15%) tested positive for a PGV in 14 different cancer types. Of the patients with PGVs, 23 patients (52%) were ineligible for testing by current guidelines. Identification of a PGV did not increase cost of care. CONCLUSION: Implementation of universal genetic testing for cancer patients in the clinic, beyond that specified by current guidelines, is necessary to accurately assess and treat hereditary cancer syndromes and does not increase healthcare costs.
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PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Sistema de Registros , Carga TumoralRESUMO
PURPOSE: A telehealth oncology practice was created to care for patients in rural communities to improve access to health care, decrease financial burdens, and save time. PATIENTS AND METHODS: Patients with cancer at Sevier Valley Hospital in Richfield, Utah, were treated with a real-time video-based telehealth program under the care of an oncologist at a tertiary medical center. Data on financial savings, travel hours, mileage avoided, carbon emissions reduced, and revenue retained by Sevier Valley Hospital were collected from 2015 to 2018. RESULTS: From 2015 to 2018, 119 patients with cancer in Richfield, Utah, were treated with telehealth for oncology visits, accounting for 1,025 patient encounters. On average, patients saved 4 hours and 40 minutes and 332 miles roundtrip per encounter. In total, patients' savings were estimated to be $333,074. Carbon emissions were reduced by approximately 150,000 kg. Of new patient referrals, 59% were for solid tumors (70 of 119 referrals; 42 metastatic and 28 nonmetastatic cancers), and 41% were hematology consultations (49 of 119 referrals; 28 classical and 21 malignant hematologic conditions). We estimate that Sevier Valley Hospital retained $3,605,500 in revenue over this 4-year period. CONCLUSION: Using a telehealth program in rural Utah, patients with cancer benefited from substantial time and monetary savings. The local medical center was able to retain revenue it would have otherwise lost to outsourcing cancer care. Recent regulatory changes to address the COVID-19 pandemic should increase the number of patients with cancer treated via telehealth nationwide.
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Infecções por Coronavirus/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Pandemias/economia , Pneumonia Viral/economia , Saúde da População , Telemedicina/economia , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Qualidade da Assistência à Saúde/economia , População Rural , Telemedicina/tendências , Utah/epidemiologiaRESUMO
As a high-performance solution for longitudinal monitoring of patients being treated for metastatic cancer, a single-color digital PCR (dPCR) assay that detects and quantifies specific cancer mutations present in circulating tumor DNA (ctDNA) was developed. This customizable assay has a high sensitivity of detection. One can detect a mutation allelic fraction of 0.1%, equivalent to three mutation-bearing DNA molecules among 3000 genome equivalents. The objective of this study was to validate the use of personalized dPCR mutation assays to monitor patients with metastatic cancer. The dPCR results were compared with serum biomarkers indicating disease progression or response. Patients had metastatic colorectal, biliary, breast, lung, and melanoma cancers. Mutations occurred in essential cancer drivers such as BRAF, KRAS, and PIK3CA. Patients were monitored over multiple cycles of treatment for up to a year. All patients had detectable ctDNA mutations. The results correlated with serum markers of metastatic cancer burden, including carcinoembryonic antigen, CA-19-9, and CA-15-3, and qualitatively corresponding to imaging studies. Corresponding trends were observed among these patients receiving active treatment with chemotherapy or targeted agents. For example, in one patient under active treatment, increasing quantities of ctDNA molecules were detected over time, indicating recurrence of tumor. This study demonstrates that personalized dPCR enables longitudinal monitoring of patients with metastatic cancer and may be a useful indicator for treatment response.
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Biomarcadores Tumorais , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Mutação , Medicina de Precisão , Alelos , Classe I de Fosfatidilinositol 3-Quinases/genética , Análise Mutacional de DNA/métodos , Feminino , Humanos , Biópsia Líquida/métodos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Medicina de Precisão/métodos , Reação em Cadeia da Polimerase em Tempo Real , Tomografia Computadorizada por Raios XRESUMO
DNA copy number aberrations (CNA) are frequently observed in colorectal cancers (CRC). There is an urgent need for CNA-based biomarkers in clinics,. n For Stage III CRC, if combined with imaging or pathologic evidence, these markers promise more precise care. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocol's accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC >0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P = 0.0139, HR = 1.688, 95% CI = [1.112-2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, this low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.
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Biomarcadores Tumorais , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Variações do Número de Cópias de DNA/genética , Deleção de Genes , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Genoma/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Taxa de Sobrevida , Adulto JovemRESUMO
The impact of precision oncology on guiding treatment decisions of late-stage cancer patients was previously studied in a retrospective analysis. However, the overall survival and costs were not previously evaluated. We report the overall survival and healthcare costs associated with precision oncology in these patients with advanced cancer. Building on a matched cohort study of 44 patients with metastatic cancer who received all of their care within a single institution, we evaluated the overall survival and healthcare costs for each patient. We analyzed the outcomes of 22 patients who received genomic testing and targeted therapy (precision oncology) between July 1, 2013 and January 31, 2015, and compared to 22 historically controlled patients (control) who received standard chemotherapy (N = 17) or best supportive care (N = 5). The median overall survival was 51.7 weeks for the targeted treatment group and 25.8 weeks for the control group (P = 0.008) when matching on age, gender, histological diagnosis and previous treatment lines. Average costs over the entire period were $2,720 per week for the targeted treatment group and $3,453 per week for the control group, (P = 0.036). A separate analysis of 1,814 patients with late-stage cancer diagnoses found that those who received a targeted cancer treatment (N = 93) had 6.9% lower costs in the last 3 months of life compared with those who did not. These findings suggest that precision oncology may improve overall survival for refractory cancer patients while lowering average per-week healthcare costs, resource utilization and end-of-life costs.
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PURPOSE: The advent of genomic diagnostic technologies such as next-generation sequencing has recently enabled the use of genomic information to guide targeted treatment in patients with cancer, an approach known as precision medicine. However, clinical outcomes, including survival and the cost of health care associated with precision cancer medicine, have been challenging to measure and remain largely unreported. PATIENTS AND METHODS: We conducted a matched cohort study of 72 patients with metastatic cancer of diverse subtypes in the setting of a large, integrated health care delivery system. We analyzed the outcomes of 36 patients who received genomic testing and targeted therapy (precision cancer medicine) between July 1, 2013, and January 31, 2015, compared with 36 historical control patients who received standard chemotherapy (n = 29) or best supportive care (n = 7). RESULTS: The average progression-free survival was 22.9 weeks for the precision medicine group and 12.0 weeks for the control group ( P = .002) with a hazard ratio of 0.47 (95% CI, 0.29 to 0.75) when matching on age, sex, histologic diagnosis, and previous lines of treatment. In a subset analysis of patients who received all care within the Intermountain Healthcare system (n = 44), per patient charges per week were $4,665 in the precision treatment group and $5,000 in the control group ( P = .126). CONCLUSION: These findings suggest that precision cancer medicine may improve survival for patients with refractory cancer without increasing health care costs. Although the results of this study warrant further validation, this precision medicine approach may be a viable option for patients with advanced cancer.
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Custos de Cuidados de Saúde , Neoplasias/mortalidade , Neoplasias/terapia , Medicina de Precisão/economia , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Análise Custo-Benefício , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular/economia , Mutação , Neoplasias/economia , Neoplasias/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Direct percutaneous endoscopic jejunostomy (DPEJ) is increasingly used as a method for obtaining jejunal enteral access. The most cited reason of unsuccessful placement is poor transillumination, which may be related to obesity. Whether obesity affects failure and complication rates has not been previously described. OBJECTIVE: To compare the success rate and adverse events (AEs) associated with DPEJ placement in patients who were overweight and patients who were obese compared with patients who were normal or underweight defined by body mass index (BMI). DESIGN: Retrospective database review. SETTING: A tertiary-referral center. PATIENTS: Eighty DPEJ placements between February 2000 and September 2005. MAIN OUTCOME MEASUREMENTS: DPEJ placement success in patients who were overweight/obese (BMI >or= 25) versus patients who were normal or underweight (BMI <25). Secondary end points included procedure time and AEs. RESULTS: Eighty DPEJs were placed in 75 patients. Of these DPEJs, 65 (81%) succeeded and 15 (19%) failed. Success rates were 23 of 24 for patients who were underweight (96%), 25 of 31 for patients with normal BMI (81%), 8 of 11 for patients who were overweight (73%), and 6 of 10 for persons who were obese (60%) (odds ratio 3.43, 95% CI 1.03-11.44; P< .05 for BMI >or= 25 vs BMI<25). Overall, AEs were not significantly different for patients with BMI <25 versus BMI >or=25 (24/55 vs 9/21, respectively; P= .64). However, 4 of the 5 severe AEs occurred in patients with a BMI >or= 25 (P= .07). LIMITATIONS: Retrospective single center. CONCLUSIONS: DPEJ placement in patients who were overweight or obese was feasible, but procedural success was less frequent, and a trend toward more frequent major AEs was seen than in persons with normal or decreased BMI. BMI was an easily assessed preprocedural factor for DPEJ success and complication rates.
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Endoscopia Gastrointestinal/métodos , Nutrição Enteral/métodos , Gastroparesia/terapia , Jejunostomia/métodos , Obesidade/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Contraindicações , Endoscopia Gastrointestinal/efeitos adversos , Feminino , Gastroparesia/epidemiologia , Humanos , Jejunostomia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pancreatite/epidemiologia , Pancreatite/terapia , Seleção de Pacientes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Video capsule endoscopy (VCE) may be useful for surveillance of small-bowel polyps in patients with familial adenomatous polyposis (FAP). OBJECTIVE: To compare VCE to standard endoscopy for diagnosing small-bowel polyps in a defined segment of small bowel (proximal to a tattoo) and the entire examined small bowel. DESIGN: Prospective. SETTING: Single tertiary referral center. PATIENTS: Participants with FAP (n = 32). The majority were selected for their high number of proximal small-bowel polyps and prior endoscopic tattoo placement in the proximal small bowel. INTERVENTIONS: VCE (interpreted by 2 readers), push enteroscopy (PE), and lower endoscopy (LE) to count and measure small-bowel polyps. RESULTS: In the defined segment, VCE detected a median of 10.0 (interquartile range [IQR], 5.0-19.0) and 9.0 (IQR, 6.0-16.0) polyps for each reader compared with a median of 41.0 (IQR, 19.0-64.0) polyps on PE (P = .002). Agreement between the 2 methods was fair (kappa = 0.34, 0.36). Agreement between VCE and PE was poor to fair (kappa = 0.10, 0.22) for estimating the size of the largest polyp and poor (kappa = -0.20, -0.27) for detecting large polyps (> or =1 cm). In the entire examined small bowel, VCE diagnosed a median of 38.0 (IQR, 10.5-71.5) and 54.0 (IQR, 13.0-100.0) polyps for each reader compared with a median of 123.0 (IQR, 38.5-183.0) for combination endoscopy (PE and LE) (P < .001). Agreement between the 2 methods was fair to moderate (kappa = 0.21, 0.56). LIMITATIONS: Participants selected for high polyp burden, and results may not be applicable to all patients with FAP. CONCLUSIONS: VCE underestimates the number of small-bowel polyps in persons with FAP and does not reliably detect large polyps.