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In the United States, colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer. For this guideline update, the American Cancer Society (ACS) used an existing systematic evidence review of the CRC screening literature and microsimulation modeling analyses, including a new evaluation of the age to begin screening by race and sex and additional modeling that incorporates changes in US CRC incidence. Screening with any one of multiple options is associated with a significant reduction in CRC incidence through the detection and removal of adenomatous polyps and other precancerous lesions and with a reduction in mortality through incidence reduction and early detection of CRC. Results from modeling analyses identified efficient and model-recommendable strategies that started screening at age 45 years. The ACS Guideline Development Group applied the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria in developing and rating the recommendations. The ACS recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy. The recommendation to begin screening at age 45 years is a qualified recommendation. The recommendation for regular screening in adults aged 50 years and older is a strong recommendation. The ACS recommends (qualified recommendations) that: 1) average-risk adults in good health with a life expectancy of more than 10 years continue CRC screening through the age of 75 years; 2) clinicians individualize CRC screening decisions for individuals aged 76 through 85 years based on patient preferences, life expectancy, health status, and prior screening history; and 3) clinicians discourage individuals older than 85 years from continuing CRC screening. The options for CRC screening are: fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; multitarget stool DNA test every 3 years; colonoscopy every 10 years; computed tomography colonography every 5 years; and flexible sigmoidoscopy every 5 years. CA Cancer J Clin 2018;68:250-281. © 2018 American Cancer Society.
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Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/normas , Programas de Rastreamento/normas , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , American Cancer Society , Detecção Precoce de Câncer/métodos , Humanos , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Risco , Estados UnidosRESUMO
Doxorubicin is a chemotherapy widely used to treat several types of cancer, including triple-negative breast cancer. In this work, we use a Bayesian framework to rigorously assess the ability of ten different mathematical models to describe the dynamics of four TNBC cell lines (SUM-149PT, MDA-MB-231, MDA-MB-453, and MDA-MB-468) in response to treatment with doxorubicin at concentrations ranging from 10 to 2500 nM. Each cell line was plated and serially imaged via fluorescence microscopy for 30 days following 6, 12, or 24 h of in vitro drug exposure. We use the resulting data sets to estimate the parameters of the ten pharmacodynamic models using a Bayesian approach, which accounts for uncertainties in the models, parameters, and observational data. The ten candidate models describe the growth patterns and degree of response to doxorubicin for each cell line by incorporating exponential or logistic tumor growth, and distinct forms of cell death. Cell line and treatment specific model parameters are then estimated from the experimental data for each model. We analyze all competing models using the Bayesian Information Criterion (BIC), and the selection of the best model is made according to the model probabilities (BIC weights). We show that the best model among the candidate set of models depends on the TNBC cell line and the treatment scenario, though, in most cases, there is great uncertainty in choosing the best model. However, we show that the probability of being the best model can be increased by combining treatment data with the same total drug exposure. Our analysis points to the importance of considering multiple models, built on different biological assumptions, to capture the observed variations in tumor growth and treatment response.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Teorema de Bayes , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Proliferação de CélulasRESUMO
BACKGROUND: Since the mid-1980s, the burden of liver cancer in the United States has doubled, with 31,411 new cases and 24,698 deaths occurring in 2014. Foreign-born individuals may be more likely to die of liver cancer than individuals in the general US-born population because of higher rates of hepatitis B infection, a low socioeconomic position, and language barriers that limit the receipt of early cancer detection and effective treatment. METHODS: To determine whether liver cancer mortality rates were higher among foreign-born individuals versus US-born individuals in the United States, population-based cancer mortality data were obtained from the National Center for Health Statistics of the Centers for Disease Control and Prevention. Annual population estimates were obtained from the US Census Bureau's American Community Survey. Age-adjusted mortality rates and rate ratios (RRs) for liver cancer stratified by birth place were calculated, and the average annual percent change (AAPC) was used to evaluate trends. RESULTS: A total of 198,557 deaths from liver and intrahepatic bile duct cancer were recorded during 2005-2014, and 16% occurred among foreign-born individuals. Overall, foreign-born individuals had a 24% higher risk of liver cancer mortality than US-born individuals (RR, 1.24; 95% confidence interval [CI], 1.22-1.25). Foreign-born individuals did not have any significant changes in liver cancer mortality rates overall, but among US-born individuals, liver cancer mortality rates significantly increased (AAPC, 2.7; 95% CI, 2.1-3.3). CONCLUSIONS: Efforts that address the major risk factors for liver cancer are needed to help to alleviate the health disparities observed among foreign-born individuals and reverse the increasing trend observed in the US-born population.
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Emigrantes e Imigrantes/estatística & dados numéricos , Neoplasias Hepáticas/mortalidade , Mortalidade/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Center for Health Statistics, U.S. , Características de Residência/classificação , Estados Unidos/epidemiologiaRESUMO
From 1970 to 2010 the foreign-born population in the United States has rapidly increased from 9.6 to 40.0 million individuals. Historically, differences in cancer rates have been observed between US-born and foreign-born individuals. However, comprehensive and up-to-date data on US cancer rates by birth place is lacking. To compare cancer mortality rates among foreign and US-born individuals, population-based cancer mortality data were obtained from the CDC's National Center for Health Statistics. Utilizing data recorded on death certificates, individuals were categorized as US-born or foreign-born. Annual population estimates were obtained from the American Community Survey. Age-adjusted mortality rates and rate ratios (RRs) for all cancer sites were calculated using SEER*Stat. A total of 5,670,535 deaths from malignant cancers were recorded in the US from 2005 to 2014 and 9% of deaths occurred among foreign-born individuals. Overall, foreign-born individuals had a 31% lower cancer mortality rate when compared to US-born individuals (Rate Ratio (RR): 0.69 (95% CI: 0.68-0.69)), and similar results were observed when stratifying by sex, race/ethnicity, age, and geographic region. However, foreign-born individuals did have significantly elevated cancer mortality rates for seven cancers sites, of which five were infection-related, including: nasopharynx (RR: 2.01), Kaposi Sarcoma (RR: 1.94), stomach (RR: 1.82), gallbladder (RR: 1.47), acute lymphocytic leukemia (RR: 1.27), liver and intrahepatic bile duct (RR: 1.24), and thyroid (RR: 1.22) cancers. Many of these deaths could be avoided through improved access to prevention, screening, and treatment services for immigrant populations in the US or in their country of origin.
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Emigrantes e Imigrantes/estatística & dados numéricos , Neoplasias/mortalidade , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Atestado de Óbito , Humanos , Pessoa de Meia-Idade , Neoplasias/etnologia , Características de Residência/estatística & dados numéricos , Programa de SEER , Distribuição por Sexo , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Historically, foreign-born individuals in the US have had an elevated risk of dying from gastric cancer when compared to US-born individuals. This is primarily due to factors that occur prior to their immigration to the US, including diet and underlying risk of H. pylori infection. METHODS: National mortality data from 2005 to 2014 were obtained from the CDC's National Center for Health Statistics. Annual population estimates were obtained from the US Census Bureau's American Community Survey for foreign-born and US-born persons. Age-adjusted gastric cancer mortality rates and rate ratios (RR) were calculated stratified by birth place, age, race/ethnicity, and geographic location. RESULTS: From 2005 to 2014, 111,718 deaths from malignant gastric cancer occurred in the US, of which 24,583 (22%) occurred among foreign-born individuals. Overall, foreign-born individuals had higher mortality rates compared with US-born individuals (RR 1.82; 95% CI 1.80, 1.85) and this difference remained after stratifying by sex, age, and geographic location. However, this finding was primarily driven by the low rate of gastric cancer mortality among US-born whites, with similar mortality rates observed among all other foreign-born and US-born groups. Gastric cancer mortality rates significantly decreased during the study period overall (AAPC - 2.50; 95% CI - 3.21, - 1.79) with significant declines observed among US-born (AAPC - 2.81; 95% CI - 3.55, - 2.07) and the foreign-born (AAPC - 2.53; 95% CI - 3.20, - 1.86) population. CONCLUSIONS: Efforts directed at reducing the prevalence of gastric cancer risk factors could help reduce the elevated burden observed among foreign-born individuals and US-born minority groups.
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Emigração e Imigração/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Mortalidade/tendências , Neoplasias Gástricas/mortalidade , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Características de Residência , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
PURPOSE: To develop and validate a mechanism-based, mathematical model that characterizes 9L and C6 glioma cells' temporal response to single-dose radiation therapy in vitro by explicitly incorporating time-dependent biological interactions with radiation. METHODS: We employed time-resolved microscopy to track the confluence of 9L and C6 glioma cells receiving radiation doses of 0, 2, 4, 6, 8, 10, 12, 14 or 16 Gy. DNA repair kinetics are measured by γH2AX expression via flow cytometry. The microscopy data (814 replicates for 9L, 540 replicates for C6 at various seeding densities receiving doses above) were divided into training (75%) and validation (25%) sets. A mechanistic model was developed, and model parameters were calibrated to the training data. The model was then used to predict the temporal dynamics of the validation set given the known initial confluences and doses. The predictions were compared to the corresponding dynamic microscopy data. RESULTS: For 9L, we obtained an average (± standard deviation, SD) Pearson correlation coefficient between the predicted and measured confluence of 0.87 ± 0.16, and an average (±SD) concordance correlation coefficient of 0.72 ± 0.28. For C6, we obtained an average (±SD) Pearson correlation coefficient of 0.90 ± 0.17, and an average (±SD) concordance correlation coefficient of 0.71 ± 0.24. CONCLUSION: The proposed model can effectively predict the temporal development of 9L and C6 glioma cells in response to a range of single-fraction radiation doses. By developing a mechanism-based, mathematical model that can be populated with time-resolved data, we provide an experimental-mathematical framework that allows for quantitative investigation of cells' temporal response to radiation. Our approach provides two key advances: (i) a time-resolved, dynamic death rate with a clear biological interpretation, and (ii) accurate predictions over a wide range of cell seeding densities and radiation doses.
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Glioma , Glioma/radioterapia , Humanos , Modelos TeóricosRESUMO
Purpose: Deep learning is a promising technique for spleen segmentation. Our study aims to validate the reproducibility of deep learning-based spleen volume estimation by performing spleen segmentation on clinically acquired computed tomography (CT) scans from patients with myeloproliferative neoplasms. Approach: As approved by the institutional review board, we obtained 138 de-identified abdominal CT scans. A sum of voxel volume on an expert annotator's segmentations establishes the ground truth (estimation 1). We used our deep convolutional neural network (estimation 2) alongside traditional linear estimations (estimation 3 and 4) to estimate spleen volumes independently. Dice coefficient, Hausdorff distance, R 2 coefficient, Pearson R coefficient, the absolute difference in volume, and the relative difference in volume were calculated for 2 to 4 against the ground truth to compare and assess methods' performances. We re-labeled on scan-rescan on a subset of 40 studies to evaluate method reproducibility. Results: Calculated against the ground truth, the R 2 coefficients for our method (estimation 2) and linear method (estimation 3 and 4) are 0.998, 0.954, and 0.973, respectively. The Pearson R coefficients for the estimations against the ground truth are 0.999, 0.963, and 0.978, respectively (paired t -tests produced p < 0.05 between 2 and 3, and 2 and 4). Conclusion: The deep convolutional neural network algorithm shows excellent potential in rendering more precise spleen volume estimations. Our computer-aided segmentation exhibits reasonable improvements in splenic volume estimation accuracy.
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For adults and adolescents (i.e., persons aged >/=13 years), the human immunodeficiency virus (HIV) infection classification system and the surveillance case definitions for HIV infection and acquired immunodeficiency syndrome (AIDS) have been revised and combined into a single case definition for HIV infection. In addition, the HIV infection case definition for children aged <13 years and the AIDS case definition for children aged 18 months to <13 years have been revised. No changes have been made to the HIV infection classification system, the 24 AIDS-defining conditions for children aged <13 years, or the AIDS case definition for children aged <18 months. These case definitions are intended for public health surveillance only and not as a guide for clinical diagnosis. Public health surveillance data are used primarily for monitoring the HIV epidemic and for planning on a population level, not for making clinical decisions for individual patients. CDC and the Council of State and Territorial Epidemiologists recommend that all states and territories conduct case surveillance of HIV infection and AIDS using the 2008 surveillance case definitions, effective immediately.
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Síndrome da Imunodeficiência Adquirida/classificação , Síndrome da Imunodeficiência Adquirida/epidemiologia , Infecções por HIV/classificação , Infecções por HIV/epidemiologia , Vigilância da População/métodos , Síndrome da Imunodeficiência Adquirida/diagnóstico , Adolescente , Adulto , Linfócitos T CD4-Positivos , Criança , Pré-Escolar , DNA Viral/análise , Anticorpos Anti-HIV/análise , Infecções por HIV/diagnóstico , Humanos , Lactente , Recém-Nascido , RNA Viral/análise , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Implementation of sensitive screening methods for human immunodeficiency virus (HIV) and hepatitis viruses prompts the question of what quantitative risks may result from altered deferral strategies for donation of blood by men who have had sex with men (MSM). STUDY DESIGN AND METHODS: Quantitative probabilistic models were developed to assess changes in the residual risk of transfusion-transmitted HIV and hepatitis B virus (HBV) associated with blood testing and quarantine release errors (QREs) in the initial year of two hypothetical policy scenarios that would allow donations from donors who have abstained from MSM behavior for at least 5 years (MSM5) or at least 1 year (MSM1). RESULTS: The MSM5 and MSM1 models, respectively, predicted annual increases in units of HIV-infected blood of 0.5% (0.03 mean additional units; 95% confidence interval [CI], 0-1) and 3.0% (0.18 mean additional units; 95% CI, 0-1) over current estimated HIV residual risk using recent, nationwide biologic product deviation reports to estimate QRE rates. These estimates are approximately 10-fold lower than estimates based on New York State QRE data from the previous decade. The models predicted smaller increases in infectious HBV donations. CONCLUSIONS: QREs remain the most significant preventable source of risk. More accurate inputs, including the percentage of MSM in the population, the percentage of MSM who have abstained from MSM activity for 1 or 5 years, the prevalence of HIV and HBV in MSM who have abstained from MSM activity for 1 or 5 years, the rate of self-deferral, and QRE rates, are required before making more precise predictions.
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Doadores de Sangue , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Comportamento Sexual , Adolescente , Adulto , Idoso , Infecções por HIV/transmissão , Hepatite B/prevenção & controle , Hepatite B/transmissão , Humanos , Masculino , Pessoa de Meia-Idade , QuarentenaRESUMO
Treatment response assays are often summarized by sigmoidal functions comparing cell survival at a single timepoint to applied drug concentration. This approach has a limited biophysical basis, thereby reducing the biological insight gained from such analysis. In particular, drug pharmacokinetic and pharmacodynamic (PK/PD) properties are overlooked in developing treatment response assays, and the accompanying summary statistics conflate these processes. Here, we utilize mathematical modeling to decouple and quantify PK/PD pathways. We experimentally modulate specific pathways with small molecule inhibitors and filter the results with mechanistic mathematical models to obtain quantitative measures of those pathways. Specifically, we investigate the response of cells to time-varying doxorubicin treatments, modulating doxorubicin pharmacology with small molecules that inhibit doxorubicin efflux from cells and DNA repair pathways. We highlight the practical utility of this approach through proposal of the "equivalent dose metric." This metric, derived from a mechanistic PK/PD model, provides a biophysically-based measure of drug effect. We define equivalent dose as the functional concentration of drug that is bound to the nucleus following therapy. This metric can be used to quantify drivers of treatment response and potentially guide dosing of combination therapies. We leverage the equivalent dose metric to quantify the specific intracellular effects of these small molecule inhibitors using population-scale measurements, and to compare treatment response in cell lines differing in expression of drug efflux pumps. More generally, this approach can be leveraged to quantify the effects of various pharmaceutical and biologic perturbations on treatment response.
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INTRODUCTION: Historically, foreign-born women in the U.S. are less likely to be screened and are more likely to die from cervical cancer when compared with their U.S.-born counterparts. In order to inform prevention efforts and reduce this health disparity, mortality data were obtained from the National Center for Health Statistics to describe cervical cancer mortality among U.S.- and foreign-born women. METHODS: Annual population estimates were obtained from the U.S. Census Bureau's American Community Survey from 2005 to 2014. From 2017 to 2018, age-adjusted mortality rates and rate ratios were calculated by nativity status, race/ethnicity, age, geographic region, and country of birth. RESULTS: From 2005 to 2014, a total of 5,924 deaths from cervical cancer were recorded among the foreign-born population, compared with 33,893 deaths among U.S.-born women. Overall, foreign-born women had a lower cervical cancer mortality rate when compared with the U.S.-born women (rate ratio=0.95, 95% CI=0.92, 0.97). However, older foreign-born women had significantly higher mortality rates compared with U.S.-born women: aged 65-79 years (rate ratio=1.15, 95% CI=1.09, 1.22) and ≥80 years (rate ratio=1.43, 95% CI=1.32, 1.55). Women born in Mexico had significantly elevated rates of cervical cancer mortality (rate ratio=1.35, 95% CI=1.27, 1.42) when compared with U.S.-born women. CONCLUSIONS: Efforts that work to increase cervical cancer screening access and guideline compliance might further reduce the cervical cancer deaths in the U.S., and the excess burden observed among older foreign-born women.
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Emigrantes e Imigrantes/estatística & dados numéricos , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/mortalidade , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Características de Residência , Fatores Socioeconômicos , Estados Unidos/epidemiologiaRESUMO
The goal of this study is to experimentally and computationally investigate combination trastuzumab-paclitaxel therapies and identify potential synergistic effects due to sequencing of the therapies with in vitro imaging and mathematical modeling. Longitudinal alterations in cell confluence are reported for an in vitro model of BT474 HER2+ breast cancer cells following various dosages and timings of paclitaxel and trastuzumab combination regimens. Results of combination drug regimens are evaluated for drug interaction relationships based on order, timing, and quantity of dose of the drugs. Altering the order of treatments, with the same total therapeutic dose, provided significant changes in overall cell confluence (p < 0.001). Two mathematical models are introduced that are constrained by the in vitro data to simulate the tumor cell response to the individual therapies. A collective model merging the two individual drug response models was designed to investigate the potential mechanisms of synergy for paclitaxel-trastuzumab combinations. This collective model shows increased synergy for regimens where trastuzumab is administered prior to paclitaxel and suggests trastuzumab accelerates the cytotoxic effects of paclitaxel. The synergy derived from the model is found to be in agreement with the combination index, where both indicate a spectrum of additive and synergistic interactions between the two drugs dependent on their dose order. The combined in vitro results and development of a mathematical model of drug synergy has potential to evaluate and improve standard-of-care combination therapies in cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Modelos Biológicos , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Calibragem , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação por Computador , Feminino , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do TratamentoRESUMO
Multiparametric imaging is a critical tool in the noninvasive study and assessment of cancer. Imaging methods have evolved over the past several decades to provide quantitative measures of tumor and healthy tissue characteristics related to, for example, cell number, blood volume fraction, blood flow, hypoxia, and metabolism. Mechanistic models of tumor growth also have matured to a point where the incorporation of patient-specific measures could provide clinically relevant predictions of tumor growth and response. In this review, we identify and discuss approaches that use multiparametric imaging data, including diffusion-weighted magnetic resonance imaging, dynamic contrast-enhanced magnetic resonance imaging, diffusion tensor imaging, contrast-enhanced computed tomography, [18F]fluorodeoxyglucose positron emission tomography, and [18F]fluoromisonidazole positron emission tomography to initialize and calibrate mechanistic models of tumor growth and response. We focus the discussion on brain and breast cancers; however, we also identify three emerging areas of application in kidney, pancreatic, and lung cancers. We conclude with a discussion of the future directions for incorporating multiparametric imaging data and mechanistic modeling into clinical decision making for patients with cancer.
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Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Terapia Combinada , Simulação por Computador , Fluordesoxiglucose F18 , Humanos , Neoplasias/patologia , Compostos Radiofarmacêuticos , Resultado do Tratamento , Carga TumoralRESUMO
CONTEXT: Incidence of human immunodeficiency virus (HIV) in the United States has not been directly measured. New assays that differentiate recent vs long-standing HIV infections allow improved estimation of HIV incidence. OBJECTIVE: To estimate HIV incidence in the United States. DESIGN, SETTING, AND PATIENTS: Remnant diagnostic serum specimens from patients 13 years or older and newly diagnosed with HIV during 2006 in 22 states were tested with the BED HIV-1 capture enzyme immunoassay to classify infections as recent or long-standing. Information on HIV cases was reported to the Centers for Disease Control and Prevention through June 2007. Incidence of HIV in the 22 states during 2006 was estimated using a statistical approach with adjustment for testing frequency and extrapolated to the United States. Results were corroborated with back-calculation of HIV incidence for 1977-2006 based on HIV diagnoses from 40 states and AIDS incidence from 50 states and the District of Columbia. MAIN OUTCOME MEASURE: Estimated HIV incidence. RESULTS: An estimated 39,400 persons were diagnosed with HIV in 2006 in the 22 states. Of 6864 diagnostic specimens tested using the BED assay, 2133 (31%) were classified as recent infections. Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56,300 (95% confidence interval [CI], 48,200-64,500); the estimated incidence rate was 22.8 per 100,000 population (95% CI, 19.5-26.1). Forty-five percent of infections were among black individuals and 53% among men who have sex with men. The back-calculation (n = 1.230 million HIV/AIDS cases reported by the end of 2006) yielded an estimate of 55,400 (95% CI, 50,000-60,800) new infections per year for 2003-2006 and indicated that HIV incidence increased in the mid-1990s, then slightly declined after 1999 and has been stable thereafter. CONCLUSIONS: This study provides the first direct estimates of HIV incidence in the United States using laboratory technologies previously implemented only in clinic-based settings. New HIV infections in the United States remain concentrated among men who have sex with men and among black individuals.
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Infecções por HIV/epidemiologia , Soroprevalência de HIV , Vigilância da População , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Infecções por HIV/transmissão , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
We develop a combined experimental-mathematical framework to investigate heterogeneity in the context of breast cancer treated with doxorubicin. We engineer a cell line to over-express the multi-drug resistance 1 protein (MDR1), an ATP-dependent pump that effluxes intracellular drug. Co-culture experiments mixing the MDR1-overexpressing line with its parental line are evaluated via fluorescence microscopy. To quantify the impact of population heterogeneity on therapy response, these data are analyzed with a coupled pharmacokinetics/pharmacodynamics model. The proliferation and death rates of each line vary with co-culture condition (the relative fraction of each cell line at the time of seeding). For example, the death rate in the parental line under low-dose doxorubicin treatment is increased from 0.64 (± 0.22) × 10-2 to 1.46 (± 0.58) × 10-2 h-1 with increasing fractions of MDR1-overexpressing cells. The growth rate of the MDR1-overexpressing line increases 29% as its relative fraction is decreased. Simulations of the pharmacokinetics/pharmacodynamics model suggest increased efflux from MDR1-overexpressing cells contributes to the increased death rate in the parental cells. Experimentally, the death rate of parental cells is constant across co-culture conditions under co-treatment with an MDR1 inhibitor. These data indicate that intercellular pharmacokinetic variability should be considered in analyzing treatment response in heterogeneous populations.
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Antineoplásicos , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Microscopia de Fluorescência , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Medical oncology is in need of a mathematical modeling toolkit that can leverage clinically-available measurements to optimize treatment selection and schedules for patients. Just as the therapeutic choice has been optimized to match tumor genetics, the delivery of those therapeutics should be optimized based on patient-specific pharmacokinetic/pharmacodynamic properties. Under the current approach to treatment response planning and assessment, there does not exist an efficient method to consolidate biomarker changes into a holistic understanding of treatment response. While the majority of research on chemotherapies focus on cellular and genetic mechanisms of resistance, there are numerous patient-specific and tumor-specific measures that contribute to treatment response. New approaches that consolidate multimodal information into actionable data are needed. Mathematical modeling offers a solution to this problem. In this perspective, we first focus on the particular case of breast cancer to highlight how mathematical models have shaped the current approaches to treatment. Then we compare chemotherapy to radiation therapy. Finally, we identify opportunities to improve chemotherapy treatments using the model of radiation therapy. We posit that mathematical models can improve the application of anticancer therapeutics in the era of precision medicine. By highlighting a number of historical examples of the contributions of mathematical models to cancer therapy, we hope that this contribution serves to engage investigators who may not have previously considered how mathematical modeling can provide real insights into breast cancer therapy.
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INTRODUCTION: A defining hallmark of cancer is aberrant cell proliferation. Efforts to understand the generative properties of cancer cells span all biological scales: from genetic deviations and alterations of metabolic pathways to physical stresses due to overcrowding, as well as the effects of therapeutics and the immune system. While these factors have long been studied in the laboratory, mathematical and computational techniques are being increasingly applied to help understand and forecast tumor growth and treatment response. Advantages of mathematical modeling of proliferation include the ability to simulate and predict the spatiotemporal development of tumors across multiple experimental scales. Central to proliferation modeling is the incorporation of available biological data and validation with experimental data. Areas covered: We present an overview of past and current mathematical strategies directed at understanding tumor cell proliferation. We identify areas for mathematical development as motivated by available experimental and clinical evidence, with a particular emphasis on emerging, non-invasive imaging technologies. Expert commentary: The data required to legitimize mathematical models are often difficult or (currently) impossible to obtain. We suggest areas for further investigation to establish mathematical models that more effectively utilize available data to make informed predictions on tumor cell proliferation.
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Proliferação de Células/fisiologia , Modelos Teóricos , Neoplasias/patologia , Diagnóstico por Imagem/métodos , Humanos , Modelos BiológicosRESUMO
We analyzed national surveillance data that had been reported to the Centers for Disease Control and Prevention to elucidate the impact of recent clinical and public health efforts to further decrease the number of human immunodeficiency virus (HIV) infections and resulting morbidity caused by perinatal transmission. Long-term trends in pediatric (ages, 0-13 years), perinatal acquired immune deficiency syndrome (AIDS) cases were analyzed by log-linear Poisson regression for the period 1992-2004. Estimates for the number of perinatal HIV infections that occurred during the more recent period of 2001-2004 were developed by extrapolation from the 33 states with ongoing HIV (non-AIDS) reporting to the entire United States with the use of a probabilistic model. The number of pediatric perinatal AIDS cases that were identified decreased from 858 in 1992 to only 41 in 2004. These declines were consistent across demographic and regional subgroups. Data on the number of perinatal HIV infections suggests ongoing declines throughout the early years of the 21st century from 277 (95% CI, 224-346) in 2001 to 138 (95% CI, 96-186) in 2004. The incidence and morbidity associated with perinatal HIV infection continue to decline. To ensure that existing prevention efforts continue to achieve control of these infections, consistent methods of public health surveillance must be instituted throughout the entire United States.
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Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas , Centers for Disease Control and Prevention, U.S. , Notificação de Doenças , Humanos , Incidência , Recém-Nascido , Modelos Estatísticos , Morbidade , National Center for Health Statistics, U.S. , Vigilância da População , Estados Unidos/epidemiologiaRESUMO
The Centers for Disease Control and Prevention maintains a national surveillance system that provides data about the HIV/AIDS epidemic for program planning and resource allocation. Until recently, incidence of HIV infection (i.e., the number of individuals recently infected with HIV) has not been directly measured. New serologic testing methods make it possible to distinguish between recent and long-standing HIV-1 infection on a population level. This article describes the new National HIV Incidence Surveillance System.
Assuntos
Soropositividade para HIV/epidemiologia , HIV-1/imunologia , Vigilância da População , Centers for Disease Control and Prevention, U.S. , Notificação de Doenças , Humanos , Técnicas Imunoenzimáticas , Incidência , Desenvolvimento de Programas , Administração em Saúde Pública , Porto Rico/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Since the height of HIV incidence in the mid-1980s, advances in treatment have delayed progression of HIV infection. As a result, surveillance of AIDS cases alone is no longer sufficient to monitor the current status of the HIV epidemic. At the national level, new HIV diagnoses and progression of these cases to AIDS are used to describe the epidemic. The capacity to monitor the national HIV epidemic has consistently improved over the last several years. An increasing number of states report diagnosed HIV cases to the national surveillance system, allowing data from this system to better represent the national picture. Monitoring the national HIV epidemic depends on a nationwide system using standardized methods of data collection, and establishing such a comprehensive system remains one of the highest priorities for national HIV case surveillance.