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OBJECTIVE: To investigate associations between genetic mutations and qualitative as well as quantitative features on MRI in rectal adenocarcinoma at primary staging. METHODS: In this retrospective study, patients with rectal adenocarcinoma, genome sequencing, and pretreatment rectal MRI were included. Statistical analysis was performed to evaluate associations between qualitative features obtained from subjective evaluation of rectal MRI and gene mutations as well as between quantitative textural features and gene mutations. For the qualitative evaluation, Fisher's Exact test was used to analyze categorical associations and Wilcoxon Rank Sum test was used for continuous clinical variables. For the quantitative evaluation, we performed manual segmentation of T2-weighted images for radiomics-based quantitative image analysis. Thirty-four texture features consisting of first order intensity histogram-based features (n = 4), second order Haralick textures (n = 5), and Gabor-edge based Haralick textures were computed at two different orientations. Consensus clustering was performed with 34 computed texture features using the K-means algorithm with Euclidean distance between the texture features. The clusters resulting from the algorithm were then used to enumerate the prevalence of gene mutations in those clusters. RESULTS: In 65 patients, 45 genes were mutated in more than 3/65 patients (5%) and were included in the statistical analysis. Regarding qualitative imaging features, on univariate analysis, tumor location was significantly associated with APC (p = 0.032) and RASA1 mutation (p = 0.032); CRM status was significantly associated with ATM mutation (p = 0.021); and lymph node metastasis was significantly associated with BRCA2 (p = 0.046) mutation. However, these associations were not significant after adjusting for multiple comparisons. Regarding quantitative imaging features, Cluster C1 had tumors with higher mean Gabor edge intensity compared with cluster C2 (θ = 0°, p = 0.018; θ = 45°, p = 0.047; θ = 90°, p = 0.037; cluster C3 (θ = 0°, p = 0.18; θ = 45°, p = 0.1; θ = 90°, p = 0.052), and cluster C4 (θ = 0°, p = 0.016; θ = 45°, p = 0.033; θ = 90°, p = 0.014) suggesting that the cluster C1 had tumors with more distinct edges or heterogeneous appearance compared with other clusters. CONCLUSIONS: Although this preliminary study showed promising associations between quantitative features and genetic mutations, it did not show any correlation between qualitative features and genetic mutations. Further studies with larger sample size are warranted to validate our preliminary data.
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Adenocarcinoma/patologia , Mutação/genética , Medicina de Precisão , Neoplasias Retais/patologia , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes Neoplásicos/genética , Genômica/métodos , Humanos , Metástase Linfática , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Neoplasias Retais/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.
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Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Carcinoma Adenoescamoso/patologia , Neoplasias da Vesícula Biliar/patologia , Mutação , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/cirurgia , Chile , Demografia , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Estados UnidosRESUMO
BACKGROUND: Age is a critical factor in outcome for patients with well-differentiated thyroid cancer. Currently, age 45 years is used as a cutoff in staging, although there is increasing evidence to suggest this may be too low. The aim of this study was to assess the potential for changing the cut point for the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system from 45 years to 55 years based on a combined international patient cohort supplied by individual institutions. METHODS: A total of 9484 patients were included from 10 institutions. Tumor (T), nodes (N), and metastasis (M) data and age were provided for each patient. The group was stratified by AJCC/UICC stage using age 45 years and age 55 years as cutoffs. The Kaplan-Meier method was used to calculate outcomes for disease-specific survival (DSS). Concordance probability estimates (CPE) were calculated to compare the degree of concordance for each model. RESULTS: Using age 45 years as a cutoff, 10-year DSS rates for stage I-IV were 99.7%, 97.3%, 96.6%, and 76.3%, respectively. Using age 55 years as a cutoff, 10-year DSS rates for stage I-IV were 99.5%, 94.7%, 94.1%, and 67.6%, respectively. The change resulted in 12% of patients being downstaged, and the downstaged group had a 10-year DSS of 97.6%. The change resulted in an increase in CPE from 0.90 to 0.92. CONCLUSIONS: A change in the cutoff age in the current AJCC/UICC staging system from 45 years to 55 years would lead to a downstaging of 12% of patients, and would improve the statistical validity of the model. Such a change would be clinically relevant for thousands of patients worldwide by preventing overstaging of patients with low-risk disease while providing a more realistic estimate of prognosis for those who remain high risk.
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Diferenciação Celular , Técnicas de Apoio para a Decisão , Estadiamento de Neoplasias/métodos , Neoplasias da Glândula Tireoide/patologia , Fatores Etários , Brasil , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , New South Wales , América do Norte , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/terapia , Resultado do TratamentoRESUMO
PURPOSE: Although 85% of patients with cancer are diagnosed and treated in the community setting, only 3% are enrolled onto clinical trials. Lack of adequate time, infrastructure, resources, incentives, and reimbursement adversely affect clinical trial participation. In July 2007, Saint Francis Cancer Treatment Center (SFCTC) in Grand Island, Nebraska, was selected as one of the initial 16 sites for the National Cancer Institute Community Cancer Centers Program (NCCCP). METHODS: Clinical trial and related activities data at SFCTC 5 years before and 5 years during the NCCCP were gathered and compared. Data included information on patients in clinical trials, number and type of trials, ratio of underserved patients, staffing, collection and storage of tissue samples, availability of new cancer services, and organizational infrastructure and linkage to National Cancer Institute-designated cancer centers. RESULTS: The number and percentage of patients enrolled onto clinical trials increased from 89 (3.2%) to 640 (23%; P<.001). All enrollees were rural Nebraskans, with 70%age > 65 years. Available treatment and nontreatment (eg, prevention, biospecimen,cancer control) trials increased from eight and three per year to 28 and 12 per year (P=.012), respectively. Staffing increased from 1.2 to 3.9 full-time equivalents (P=.012). A genetic counselor, smoking cessation counselor, and outreach project coordinator and two nurse navigators were hired. The number of tissue samples collected and/or stored increased from 26 (19%) to 320 (52%; P<.001). CONCLUSION: NCCCP participation had a direct and positive impact on all activities, with enhanced access to expanded types of trials and cancer care services. Our data demonstrate the feasibility of successful implementation of an expanded spectrum of clinical trials and programs in a rural community.
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Institutos de Câncer , Ensaios Clínicos como Assunto/estatística & dados numéricos , Centros Comunitários de Saúde , Serviços de Saúde Comunitária , Programas Governamentais , National Cancer Institute (U.S.) , Serviços de Saúde Rural , Feminino , Humanos , Masculino , Nebraska , Estados UnidosRESUMO
Two main classes of methodology have been developed for addressing the analytical intractability of generalized linear mixed models: likelihood-based methods and Bayesian methods. Likelihood-based methods such as the penalized quasi-likelihood approach have been shown to produce biased estimates especially for binary clustered data with small clusters sizes. More recent methods using adaptive Gaussian quadrature perform well but can be overwhelmed by problems with large numbers of random effects, and efficient algorithms to better handle these situations have not yet been integrated in standard statistical packages. Bayesian methods, although they have good frequentist properties when the model is correct, are known to be computationally intensive and also require specialized code, limiting their use in practice. In this article, we introduce a modification of the hybrid approach of Capanu and Begg, 2011, Biometrics 67, 371-380, as a bridge between the likelihood-based and Bayesian approaches by employing Bayesian estimation for the variance components followed by Laplacian estimation for the regression coefficients. We investigate its performance as well as that of several likelihood-based methods in the setting of generalized linear mixed models with binary outcomes. We apply the methods to three datasets and conduct simulations to illustrate their properties. Simulation results indicate that for moderate to large numbers of observations per random effect, adaptive Gaussian quadrature and the Laplacian approximation are very accurate, with adaptive Gaussian quadrature preferable as the number of observations per random effect increases. The hybrid approach is overall similar to the Laplace method, and it can be superior for data with very sparse random effects.
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Teorema de Bayes , Funções Verossimilhança , Modelos Lineares , Adolescente , Adulto , Animais , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/cirurgia , Simulação por Computador , Feminino , Guatemala , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/epidemiologia , Gravidez , Radiografia , População Rural , Comportamento Sexual Animal , Carcinoma de Células Escamosas de Cabeça e Pescoço , Urodelos , Adulto JovemRESUMO
BACKGROUND: The variable incidence of gallbladder cancer (GBCA) suggests regional pathogenetic differences. This study compares cell cycle-regulatory, angiogenesis-related, and PI3K pathway protein expression in GBCAs from three continents. METHODS: Immunohistochemical expression of several proteins was assessed, correlated with clinicopathologic variables, and compared among centers from Chile (Fundación Arturo López Pérez [FALP]), Japan (Yokohama City University [YCU]), and the United States (Memorial Sloan-Kettering Cancer Center [MSKCC]). Hierarchical clustering was used to partition the data based on protein-expression and treatment center. RESULTS: Tissue from 117 patients (MSKCC = 76; FALP = 22; YCU = 19) was analyzed. Mdm2 overexpression was seen only at MSKCC (p < 0.0001). Absence of p21 (p = 0.03) and VEGFR2 (p = 0.018) were more common and p27 expression was less frequent (p = 0.047) in tumors from YCU. Ki-67 labeling index in YCU tumors (median = 10) was two-thirds lower than at other centers. On hierarchical clustering analysis, all YCU patients (p = 0.017) and those with early tumors (p = 0.017) clustered separately from MSKCC. Median disease-specific survival after curative intent (R0) resection was 27 months and was similar among centers (p = 0.9). Median disease-specific survival of patients with early tumors was 28.4 months and was higher at YCU (not reached, p = 0.06). CONCLUSIONS: Cell cycle-regulatory protein expression patterns of YCU tumors differed from those treated at FALP and MSKCC. The differential clustering of protein expression and survival in patients with early tumors suggest regional differences in pathogenesis and disease biology.
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Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Chile , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Japão , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estados Unidos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: Vascular 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) uptake has been suggested as a means of identifying metabolically active atheroma, whereas vascular calcification is accepted as an indicator of atherosclerosis. This investigation describes the frequency and stability of 18F-FDG uptake and vascular calcification in the thoracic aorta on serial 18F-FDG positron emission tomography/computed tomography (PET/CT) studies and correlates the findings with clinical data and risk factors for cardiovascular disease (CVD). MATERIALS AND METHODS: Serial 18F-FDG-PET/CT scans of 100 cancer patients who had at least 2 PET/CT studies were reviewed. Sites of aortic 18F-FDG uptake and calcifications were identified. Results were compared to assess the frequency and stability of the vascular findings and their correlation with clinical data. RESULTS: 18F-FDG aortic uptake was seen in 70% of the patients on the initial scan and changed on the second scan in 55% of the patients. Calcifications were often seen in patients with 18F-FDG uptake, but calcification and 18F-FDG uptake were present at the same site in only 2 cases. Both calcification and 18F-FDG uptake correlated with age. Patients with diabetes, hypertension, hyperlipidemia, or a history of CVD had significantly more calcifications. No correlation was seen between 18F-FDG uptake and calcification stability and the interval between scans, age, risk factors, or history of CVD. CONCLUSIONS: 18F-FDG vascular uptake was common on PET/CT and correlated with vascular calcifications, although the specific sites rarely overlapped. Calcifications were stable over time, but 18F-FDG uptake changed in more than half of the patients, supporting the postulate that inflammation in atheroma is a waxing and waning inflammatory process.