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1.
JAMA ; 328(16): 1624-1636, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36282253

RESUMO

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.


Assuntos
Hipercalcemia , Hiperparatireoidismo Primário , Hormônio Paratireóideo , Humanos , Cálcio/sangue , Coma/etiologia , COVID-19/complicações , Desidratação/etiologia , Desidratação/terapia , Denosumab/efeitos adversos , Hipercalcemia/sangue , Hipercalcemia/etiologia , Hipercalcemia/terapia , Hiperparatireoidismo Primário/sangue , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Náusea/etiologia , Neoplasias/sangue , Neoplasias/complicações , Pamidronato/uso terapêutico , Hormônio Paratireóideo/sangue , SARS-CoV-2 , Sonolência , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Vitamina A/efeitos adversos , Vitamina D/efeitos adversos , Vômito/etiologia , Ácido Zoledrônico/uso terapêutico
2.
Front Immunol ; 13: 901273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844527

RESUMO

Background: Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients. Methods: A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks. Results: Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density. Conclusions: Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.


Assuntos
Antígenos HLA-DR , Transplante de Rim , Monócitos , Células Supressoras Mieloides , Neoplasias , Estudos de Coortes , Citocinas/imunologia , Antígenos HLA-DR/imunologia , Humanos , Monócitos/imunologia , Monócitos/patologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/patologia , Transplantados
3.
Clin. transl. oncol. (Print) ; 24(3): 393-406, marzo 2022.
Artigo em Inglês | IBECS | ID: ibc-203537

RESUMO

Microribonucleic acids (miRNAs) are small non-coding ribonucleic acids (ncRNAs), which can affect recognition of homologous sequences and interfere with transcription. It plays key roles in the initiation, development, resistance, metastasis or recurrence of cancers. Identifying circulatory indicators will positively improve the prognosis and quality of life of patients with early cancer. Previous studies have shown that miRNA is highly involved in cancer. In addition, miRNA derived from cancers can be encapsulated as exosomes and further extracted into circulatory systems to realize malignant functions. It indicates that circulating exosome-derived miRNAs have the potential to replace conventional biomarkers as cancer derived exosomes carrying miRNAs can be identified by specific markers and might be more stable and accurate for early diagnosis.


Assuntos
Neoplasias/genética , Exossomos/genética , MicroRNAs/sangue , Diagnóstico Precoce , Neoplasias/sangue , Neoplasias/diagnóstico
4.
Small Methods ; 6(2): e2101234, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35174989

RESUMO

Exosomes, ranging from 30-150 nm in diameter, have emerged as promising non-invasive biomarkers for the diagnosis and prognosis of numerous diseases. However, current research on exosomes is largely restricted by the lack of an efficient method to isolate exosomes from real samples. Herein, the first stimuli-mediated enrichment and purification system to selectively and efficiently extract exosomes from clinical plasma for high-throughput profiling of exosomal mRNAs as cancer biomarkers is presented. This novel isolation system relies on specific installation of the stimuli-responsive copolymers onto exosomal phospholipid bilayers, by which the enrichment and purification are exclusively achieved for exosomes rather than the non-vesicle counterparts co-existing in real samples. The stimuli-mediated isolation system outperforms conventional methods such as ultracentrifugation and polyethylene glycol-based precipitation in terms of isolation yield, purity, and retained bioactivity. The high performance of the isolation system is demonstrated by enriching exosomes from 77 blood plasma samples and validated the clinical potentials in profiling exosomal mRNAs for cancer diagnosis and discrimination with high accuracy. This simple isolation system can boost the development of extracellular vesicle research, not limited to exosomes, in both basic and clinical settings.


Assuntos
Biomarcadores Tumorais/genética , Exossomos/genética , Neoplasias/diagnóstico , Acrilamidas/química , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Detecção Precoce de Câncer , Humanos , Células MCF-7 , Neoplasias/sangue , Neoplasias/genética , Termodinâmica
5.
Ren Fail ; 44(1): 184-190, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35166184

RESUMO

OBJECTIVES: This study aimed to explore the relationship between the blood urea nitrogen/creatinine (BUN/Cre) ratio and all-cause or cause-specific mortality in the general population. METHODS: Participants were enrolled from the National Health and Nutrition Examination Survey (NHANES) during 1999 to 2014. Baseline variables were acquired from questionnaires and examinations. Death status were ascertained from National Death Index records. Cox proportional hazards models with cubic spines were used to estimate hazard ratios (HRs) and 95% confidence interval (CI) of all-cause mortality, cardiovascular and cancer mortality. RESULTS: A total of 42038 participants were enrolled in the study with a median 8.13 years of follow-up. Older people and women tend to have a higher BUN/Cre ratio. After multivariable adjustment, BUN/Cre ratio between 11.43 and 14.64 was associated with the lowest all-cause mortality compared with the participants with the lowest quartile (HR 0.83 [0.76, 0.91]; p < 0.001). The highest quartile of BUN/Cre ratio was associated with the lowest risk of cancer mortality (HR 0.64 [0.53, 0.78]; p < 0.001). Restricted cubic splines showed BUN/Cre was nonlinearly associated with all-cause mortality and linearly associated with cancer mortality. CONCLUSIONS: This study confirmed a U-shape relationship between BUN/Cre ratio and all-cause mortality in the general population.


Assuntos
Nitrogênio da Ureia Sanguínea , Doenças Cardiovasculares/mortalidade , Creatinina/sangue , Neoplasias/mortalidade , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Causas de Morte , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Inquéritos Nutricionais , População , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia
6.
J Hematol Oncol ; 15(1): 15, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-35123511

RESUMO

PURPOSE: Patients with cancer have an increased risk of coronavirus disease 2019 (COVID-19) and an attenuated responses to various vaccines. This meta-analysis aims to assess the serologic response to COVID-19 vaccination in patients with cancer. METHODS: Electronic databases were systematically searched on August 1, 2021 for studies that reported the serologic response to COVID-19 vaccine in cancer patients. Random effects models were used to achieve pooled serologic response rates and odds ratios (ORs). RESULTS: We analyzed 16 observational studies with a total of 1453 patients with cancer. A majority of studies used mRNA vaccines (BNT162b2 or mRNA-1273). The proportion of patients achieving a serologic response after a single and two doses of COVID-19 vaccine were 54.2% (95% confidence interval [CI] 41.0-66.9) and 87.7% (95% CI 82.5-91.5), respectively. Patients with hematologic cancers had a lower response rate after the second dose of vaccine compared to those with solid organ cancers (63.7% vs. 94.9%), which was attributable to the low response rates associated with certain conditions (chronic lymphocytic leukemia, lymphoma) and therapies (anti-CD20, kinase inhibitors). A lower proportion of patients with cancer achieved a serologic response compared to control patients after one and two doses of vaccine (OR0.073 [95% CI 0.026-0.20] and 0.10 [95% CI 0.039-0.26], respectively). CONCLUSIONS: Patients with cancer, especially those with hematologic B-cell malignancies, have a lower serologic response to COVID-19 vaccines. The results suggest that cancer patients should continue to follow safety measures including mask-wearing after vaccination and suggest the need for additional strategies for prophylaxis.


Assuntos
Teste Sorológico para COVID-19/métodos , Vacinas contra COVID-19/imunologia , COVID-19/complicações , Neoplasias/imunologia , SARS-CoV-2/patogenicidade , COVID-19/sangue , COVID-19/terapia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Humanos , Neoplasias/sangue , Neoplasias/terapia , Neoplasias/virologia , Prognóstico , SARS-CoV-2/isolamento & purificação , Taxa de Sobrevida
7.
Int J Mol Sci ; 23(2)2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-35054865

RESUMO

The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an 125Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h-6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter Ktrans alone or Ktrans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (σTUV) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of 125Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the Ktrans MRI parameter as a covariate on the PBPK parameters QTU and σTUV decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities.


Assuntos
Anticorpos Monoclonais/imunologia , Meios de Contraste/química , Imageamento por Ressonância Magnética , Neoplasias/imunologia , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Cetuximab/imunologia , Cetuximab/farmacocinética , Humanos , Masculino , Camundongos , Modelos Biológicos , Neoplasias/sangue , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
8.
Anticancer Res ; 42(2): 1059-1064, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35093907

RESUMO

BACKGROUND: Cytogenetic analysis of chromosomes in blood lymphocytes can be used to reveal biomarkers of tumor risk. The frequency of chromosomal aberrations (CAs) appears to correlate with the later incidence of cancer. PATIENTS AND METHODS: In our work, a total of 515 healthy Hungarian medical workers and 725 controls were enrolled in our investigation. The CAs in peripheral blood lymphocytes were analyzed. RESULTS: The frequency of CAs was significantly higher in the groups working with ionizing radiation and with cytostatic agents compared to unexposed controls and in male smokers rather than non-smokers. The frequency of dicentric chromosomes, however, was not significantly different between control and exposed groups. Among 82 cancer cases (6.6%), the most frequent types were cancer of the breast (20.5%), colon (12.8%), lung and thyroid gland (9-9%). Our analysis showed 8.1% cancer cases in smokers compared to 5.7% in non-smokers. CONCLUSION: The potential exposure to carcinogens did not modify the effect of CAs on cancer risk but tobacco smoking did increase risk.


Assuntos
Aberrações Cromossômicas/estatística & dados numéricos , Linfócitos/metabolismo , Neoplasias/epidemiologia , Recursos Humanos em Hospital/estatística & dados numéricos , Adolescente , Adulto , Idoso , Aneuploidia , Estudos de Casos e Controles , Estudos de Coortes , Análise Citogenética , Feminino , História do Século XX , História do Século XXI , Hospitais/estatística & dados numéricos , Humanos , Hungria/epidemiologia , Incidência , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Exposição Ocupacional/análise , Exposição Ocupacional/estatística & dados numéricos , Medição de Risco , Adulto Jovem
9.
Indian J Pathol Microbiol ; 65(1): 93-99, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35074971

RESUMO

CONTEXT: Circulating free DNA (cfDNA) analysis has emerged as novel noninvasive diagnostic biomarker in several solid tumors. Raised levels have been reported in several malignancies and may correlate with clinicopathological and treatment response. The current study was designed to assess the diagnostics of cfDNA in different tumor types of malignancies correlating with tumor (T), nodes (N), and metastases (M) stage. DESIGN: Serum samples were collected from treatment naïve cases with histologically diagnosed tumors including 23 brain tumors, 48 breasts, 50 gallbladder carcinoma (GBC), 13 lungs, 68 oral squamous cell carcinoma (OSCC), and 25 normal controls. CfDNA was quantified with real-time polymerase chain reaction (PCR), Invasive ductal carcinoma (IDC) using beta-globin gene amplification. Cut off values for diagnostics were calculated using receiver operating curve analysis. RESULTS: Contrary to other cfDNA studies where it was postulated that cfDNA would not cross the blood-brain barrier and reach the systemic circulation, we found detectable cfDNA in glioma with median (Q1-Q3) of 349.22 ng/ml (19.87-1276.58). Median cfDNA concentration in breast, gallbladder, lung, oral and normal controls was 328.72 (128.38-624.44), 778.50 (589.88-1864.35), 348.73 (194.67-483.61), 386.27 (47.88-959.67), and 74.12 (49.66-120.00), respectively. Grades I and II glioma had significantly lower levels compared to Grades III and IV (P = 0.0001). Significant difference in median cfDNA values in IDC and GBC was observed with increasing tumor grades, stage, T stage, nodal stage and metastasis and with stage of OSCC cases. CONCLUSION: CfDNA levels showed good diagnostic discrimination in glioma, GBC, breast, lung carcinoma, and OSCC. Significant increase in titers was evident with increase in cancer stage from I to IV in breast, GBC and OSCC.


Assuntos
Ácidos Nucleicos Livres/sangue , Neoplasias/diagnóstico , Neoplasias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Feminino , Neoplasias da Vesícula Biliar/sangue , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/classificação , Adulto Jovem
10.
Bull Cancer ; 109(2): 151-169, 2022 Feb.
Artigo em Francês | MEDLINE | ID: mdl-35012767

RESUMO

In oncology, the identification of targets that correlate with a type of cancer has led to a profound change in the notion of "tumor markers". Technological advances, in particular the development of high-throughput sequencing, have led to the emergence of a new generation of molecular biomarkers for tumors. Despite their limited utility for screening and diagnosis, conventional tumor markers remain interesting for evaluation of prognoses, the choice and optimization of treatments, as well as for monitoring the effectiveness of those treatments. In this article, we revisit the conventional serum markers that are enjoying a 'come back' thanks to the development of high-performance scores based on biological, cytological, clinical, or radiological criteria.


Assuntos
Biomarcadores Tumorais/sangue , Oncologia/métodos , Proteínas de Neoplasias/sangue , Neoplasias/sangue , Medicina de Precisão/métodos , França , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/terapia , Especificidade de Órgãos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Resultado do Tratamento
11.
JAMA Netw Open ; 5(1): e2141633, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-35015064

RESUMO

Importance: Individuals with cancer often have an elevated platelet count at the time of diagnosis. The extent to which an elevated platelet count is an indicator of cancer is unclear. Objective: To evaluate the association of an elevated platelet count with a cancer diagnosis. Design, Setting, and Participants: This nested case-control study included Ontario residents enrolled in the provincial health insurance plan who had 1 or more routine complete blood count (CBC) tests performed between January 1, 2007, and December 31, 2017, with follow-up through December 31, 2018. Case patients were individuals with a new cancer diagnosis during the observation period. Eligible control individuals were cancer free before the date of diagnosis for a case patient to whom they were matched. One case patient was matched to 3 controls based on sex, age, and health care use patterns. Data were analyzed from September 24, 2020, to July 13, 2021. Exposures: Case patients and controls were assigned to 1 of 5 exposure groups based on age- and sex-specific platelet count distributions in the control population: very low (≤10th percentile), low (>10th to 25th percentile), medium (>25th to <75th percentile), high (75th to <90th percentile), and very high (≥90th percentile). Main Outcomes and Measures: Odds ratios (ORs) were estimated for specific cancer sites for each category of platelet count at intervals up to 10 years after a blood test. Results: Of the 8 917 187 eligible Ontario residents with a routine CBC record available, 4 971 578 (55.8%) were women; the median age at the first CBC was 46.4 years (IQR, 32.5-59.5 years). Among individuals with a routine CBC record available, 495 341 (5.6%) received a diagnosis of first primary cancer during the 10-year observation period. The OR for a solid tumor diagnosis associated with a very high platelet count vs a medium platelet count in the 6-month period before the diagnosis was 2.32 (95% CI, 2.28-2.35). A very high platelet count was associated with colon (OR, 4.38; 95% CI, 4.22-4.54), lung (OR, 4.37; 95% CI, 4.22-4.53), ovarian (OR, 4.62; 95% CI, 4.19-5.09), and stomach (OR, 4.27; 95% CI, 3.91-4.66) cancers. Odds ratios attenuated with increasing time from CBC test to cancer diagnosis. Conclusions and Relevance: In this nested case-control study, an elevated platelet count was associated with increased risk of cancer at several sites. Our findings suggest that an elevated platelet count could potentially serve as a marker for the presence of some cancer types.


Assuntos
Neoplasias/sangue , Neoplasias/epidemiologia , Contagem de Plaquetas/estatística & dados numéricos , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ontário
12.
Bull Cancer ; 109(2): 170-184, 2022 Feb.
Artigo em Francês | MEDLINE | ID: mdl-35034786

RESUMO

Technological advances, in particular the development of high-throughput sequencing, have led to the emergence of a new generation of molecular biomarkers for tumors. These new tools have profoundly changed therapeutic management in oncology, with increasingly precise molecular characterization of tumors leading to increasingly personalized therapeutic targeting. Detection of circulating tumor cells and/or circulating tumor DNA in blood samples -so-called 'liquid biopsies'- can now provide a genetic snapshot of the patient's tumor through an alternative and less invasive procedure than biopsy of the tumor tissue itself. This procedure for characterizing and monitoring the disease in real time facilitates the search for possible relapses, the emergence of resistance, or emergence of a new therapeutic target. In the long term, it might also provide a means of early detection of cancer. These new approaches require the treatment of ever-increasing amounts of clinical data, notably, with the goal of calculating composite clinical-biological predictive scores. The use of artificial intelligence will be unavoidable in this domain, but it raises ethical questions and implications for the health-care system that will have to be addressed.


Assuntos
Inteligência Artificial/tendências , Biomarcadores Tumorais/sangue , Biópsia Líquida , Oncologia/tendências , Neoplasias/sangue , Medicina de Precisão/tendências , Inteligência Artificial/ética , DNA Tumoral Circulante/sangue , Gerenciamento de Dados , Detecção Precoce de Câncer/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Imunoterapia , Biópsia Líquida/métodos , Oncologia/métodos , MicroRNAs/sangue , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Células Neoplásicas Circulantes
13.
Biochem Pharmacol ; 196: 114654, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34129857

RESUMO

Cholesterol is an amphipathic sterol molecule that is vital for maintaining normal physiological homeostasis. It is a relatively complicated molecule with 27 carbons whose synthesis starts with 2-carbon units. This in itself signifies the importance of this molecule. Cholesterol serves as a precursor for vitamin D, bile acids, and hormones, including estrogens, androgens, progestogens, and corticosteroids. Although essential, high cholesterol levels are associated with cardiovascular and kidney diseases and cancer initiation, progression, and metastasis. Although there are some contrary reports, current literature suggests a positive association between serum cholesterol levels and the risk and extent of cancer development. In this review, we first present a brief overview of cholesterol biosynthesis and its transport, then elucidate the role of cholesterol in the progression of some cancers. Suggested mechanisms for cholesterol-mediated cancer progression are plentiful and include the activation of oncogenic signaling pathways and the induction of oxidative stress, among others. The specific roles of the lipoprotein molecules, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), in this pathogenesis, are also reviewed. Finally, we hone on the potential role of some cholesterol-lowering medications in cancer.


Assuntos
Anticolesterolemiantes/uso terapêutico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Lipoproteínas/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Animais , Anticolesterolemiantes/farmacologia , HDL-Colesterol/antagonistas & inibidores , LDL-Colesterol/antagonistas & inibidores , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Lipoproteínas/antagonistas & inibidores
14.
J Pediatr Hematol Oncol ; 44(1): e194-e198, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001793

RESUMO

Fever in a neutropenic pediatric oncology patient requires prompt assessment due to the risk of infectious complications. The appropriate management of fever in non-neutropenic patients, however, is not well-established. We describe the rate of bacteremia in a cohort of non-neutropenic pediatric oncology patients with fever at a large institution. Patients were included if they presented to the emergency department or outpatient clinic between 2009 and 2014 with fever, had a central venous catheter (CVC), and were not neutropenic. Three hundred eighty-six episodes of fever occurring in 159 patients were included in the data analysis. Fifty-nine percent of patients were male, 41% had a diagnosis of acute lymphoblastic leukemia, and 90% had a port-a-cath as CVC. The rate of bacteremia was 3.4%; presence of a port-a-cath was protective against bacteremia whereas a white blood cell count >20,000/mm3 was associated with a higher likelihood of bacteremia. Gram-positive microorganisms were most commonly isolated (64.3%) and frequently resistant to cephalosporins. In summary, in our study, the rate of bacteremia was low among non-neutropenic, well-appearing pediatric cancer patients with a CVC and was not associated with any serious medical complications. Prospective research is needed to determine the most appropriate management of these patients.


Assuntos
Antibacterianos/administração & dosagem , Bacteriemia , Febre , Neoplasias , Bacteriemia/sangue , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Cateterismo Venoso Central , Cateteres Venosos Centrais , Criança , Pré-Escolar , Feminino , Febre/sangue , Febre/tratamento farmacológico , Febre/epidemiologia , Febre/metabolismo , Humanos , Masculino , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/microbiologia , Estudos Retrospectivos
15.
Clin Transl Oncol ; 24(3): 393-406, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34524618

RESUMO

Microribonucleic acids (miRNAs) are small non-coding ribonucleic acids (ncRNAs), which can affect recognition of homologous sequences and interfere with transcription. It plays key roles in the initiation, development, resistance, metastasis or recurrence of cancers. Identifying circulatory indicators will positively improve the prognosis and quality of life of patients with early cancer. Previous studies have shown that miRNA is highly involved in cancer. In addition, miRNA derived from cancers can be encapsulated as exosomes and further extracted into circulatory systems to realize malignant functions. It indicates that circulating exosome-derived miRNAs have the potential to replace conventional biomarkers as cancer derived exosomes carrying miRNAs can be identified by specific markers and might be more stable and accurate for early diagnosis.


Assuntos
Detecção Precoce de Câncer/métodos , MicroRNAs/sangue , Neoplasias/sangue , Neoplasias/diagnóstico , Exossomos/genética , Humanos
16.
Clin Pharmacol Ther ; 111(2): 455-460, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34656072

RESUMO

Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf ) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) -10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI -16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Esomeprazol/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Disponibilidade Biológica , Capecitabina/administração & dosagem , Capecitabina/sangue , Bebidas Gaseificadas , Estudos Cross-Over , Interações Medicamentosas , Monitoramento de Medicamentos , Esomeprazol/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/diagnóstico , Países Baixos , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Resultado do Tratamento
17.
Cancer Invest ; 40(2): 115-123, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34699294

RESUMO

Patients with cancer are at significantly greater risk of COVID-19 and its complications than the general population. Since IgG antibodies remain detectable well after infection with the SARS-CoV-2 virus, seroprevalence can be used to estimate the proportion of the cancer population previously infected and potentially immune to SARS-CoV-2. The current study is a multi-center, prospective observational study to assess the seroprevalence of SARS-CoV-2 IgG antibody in a cancer population referred for vaccination between April and June 2021. Of a total of 270 adult patients with cancer accrued, 16% reported a history of COVID-19 more than four weeks previously confirmed by PCR. At the same time, serologic positivity for SARSCoV2 IgG was found in 29% of patients prior to vaccination including nearly 20% of patients without a history of confirmed COVID-19. Seropositivity was significantly greater in females consistent with higher rates in patients with breast cancer and gynecologic cancers. A seroconversion rate of 79.5% was observed in cancer patients with a history of PCR confirmed COVID-19, less than observed in the general population. In multivariable analysis, gender and prior history of COVID-19 were both independently associated with seropositivity prior to vaccination. Follow-up is continuing of this cohort of patients with cancer following vaccination to assess antibody and clinical outcomes.


Assuntos
COVID-19/epidemiologia , Imunoglobulina G/sangue , Neoplasias/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/imunologia , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Estudos Prospectivos , Estudos Soroepidemiológicos , Caracteres Sexuais , Adulto Jovem
18.
Br J Cancer ; 126(3): 514-520, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34480094

RESUMO

BACKGROUND: Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored. METHODS: We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions. RESULTS: NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value. CONCLUSION: Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.


Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/patologia , Proteínas de Fusão Oncogênica , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptor trkA/genética , Benzamidas/uso terapêutico , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Indazóis/uso terapêutico , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico
19.
J Pediatr Hematol Oncol ; 44(1): e138-e143, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34486540

RESUMO

Children with cancer require central venous access which carries risk for line-related infections. The necessity of peripheral and central blood cultures is debated for those with fevers. We evaluated and described results for first episode of paired blood cultures from children with cancer who have a central venous line using retrospective database. Blood culture results, laboratory data, and medical outcomes were included. Descriptive analyses of blood culture results and clinical data were performed. There were 190 episodes of paired positive blood cultures with 167 true positive episodes. Of the true positive episodes, 104 (62.3%) were positive in both central and peripheral cultures, 42 (25.1%) were positive in central only cultures, and 21 (12.6%) were positive in peripheral cultures only. Intensive care unit admission within 48 hours after blood cultures (n=33) differed significantly: 28.7% for both central and peripheral, 10% for central only, and 0% for peripheral only (P=0.009). Central line removal (n=34) differed by type of positivity but was not significant: 22.1% for both central and peripheral, 23.8% for central only, and 4.8% for peripheral only (P=0.15). Peripheral blood cultures provided important medical information yet had differences in short-term clinical outcomes. Further evaluation of medical decision making is warranted.


Assuntos
Hemocultura , Infecções Relacionadas a Cateter , Febre , Unidades de Terapia Intensiva , Neoplasias , Adolescente , Infecções Relacionadas a Cateter/sangue , Infecções Relacionadas a Cateter/microbiologia , Criança , Pré-Escolar , Feminino , Febre/sangue , Febre/microbiologia , Febre/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/sangue , Neoplasias/microbiologia , Neoplasias/terapia , Estudos Retrospectivos
20.
J Pediatr Hematol Oncol ; 44(1): e160-e167, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34310474

RESUMO

Bloodstream infections (BSIs) adversely affect clinical outcome in children with cancer. Over 1 decade, this retrospective cohort study describes pathogen distribution in BSIs and antimicrobial susceptibility against empirical antibiotics frequently prescribed in children with cancer. The antibiotic efficacy was evaluated through the determination of minimal inhibitory concentrations for piperacillin-tazobactam and meropenem and by disk diffusion for remaining antibiotics. From 2004 to 2013, 398 BSIs occurred in 196 children with cancer (median age: 5.4 y), resulting in 457 bacteria. Overall, 266 (58.2%) were Gram-positive, and 191 (41.8%) were Gram-negative with a significant Gram-positive increase over time (P=0.032). Coagulase-negative staphylococci (74, 16.2%), viridans group streptococci (67, 14.7%), Escherichia coli (52, 11.4%), and Staphylococcus aureus (39, 8.5%) were the most common pathogens. Susceptibility to piperacillin-tazobactam (95.9%, P=0.419) and meropenem (98.9%, P=0.752) was stable over time, and resistance was observed among viridans group streptococci against piperacillin-tazobactam (18%) and meropenem (7%) and among Enterobacterales against piperacillin-tazobactam (3%). Vancomycin showed 98% Gram-positive activity, gentamicin 82% Gram-negative activity and ampicillin, cefotaxime, and cefuroxime were active in 50%, 72%, and 69% of pathogens, respectively, and BSI-related mortality was 0%. In conclusion, over 1 decade, we report an increase in Gram-positive BSIs, and stable, low-resistance rates against currently recommended empirical antibiotics, piperacillin-tazobactam and meropenem.


Assuntos
Antibacterianos/administração & dosagem , Bactérias , Infecções Bacterianas , Meropeném/administração & dosagem , Neoplasias , Combinação Piperacilina e Tazobactam/administração & dosagem , Sepse , Adolescente , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/microbiologia , Estudos Prospectivos , Sepse/tratamento farmacológico , Sepse/microbiologia
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