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1.
Cell Metab ; 27(2): 450-460.e6, 2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29275960

RESUMO

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr-/- mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr-/- mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.

2.
Diabetes ; 66(7): 2007-2018, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28408435

RESUMO

Neurturin (NRTN), a member of the glial-derived neurotrophic factor family, was identified from an embryonic chicken pancreatic cDNA library in a screen for secreted factors. In this study, we assessed the potential antidiabetic activities of NRTN relative to liraglutide, a glucagon-like peptide 1 receptor agonist, in Zucker diabetic fatty (ZDF) rats. Subcutaneous administration of NRTN to 8-week-old male ZDF rats prevented the development of hyperglycemia and improved metabolic parameters similar to liraglutide. NRTN treatment increased pancreatic insulin content and ß-cell mass and prevented deterioration of islet organization. However, unlike liraglutide-treated rats, NRTN-mediated improvements were not associated with reduced body weight or food intake. Acute NRTN treatment did not activate c-Fos expression in key feeding behavior and metabolic centers in ZDF rat brain or directly enhance glucose-stimulated insulin secretion from pancreatic ß-cells. Treating 10-week-old ZDF rats with sustained hyperglycemia with liraglutide resulted in some alleviation of hyperglycemia, whereas NRTN was not as effective despite improving plasma lipids and fasting glucose levels. Interestingly, coadministration of NRTN and liraglutide normalized hyperglycemia and other metabolic parameters, demonstrating that combining therapies with distinct mechanism(s) can alleviate advanced diabetes. This emphasizes that therapeutic combinations can be more effective to manage diabetes in individuals with uncontrolled hyperglycemia.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Liraglutida/farmacologia , Neurturina/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Tamanho do Órgão , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Zucker
3.
Laryngoscope ; 127(10): 2265-2269, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28322454

RESUMO

OBJECTIVES: To report long-term local control in patients with adenoid cystic cancer (ACC) of the head and neck managed by surgery and identify factors predictive for local failure. STUDY DESIGN: Single-institution retrospective cohort study. METHODS: Eighty-seven patients who had surgery for ACC between 1985 and 2009 were identified. Patient, tumor, and treatment characteristics were recorded. Local recurrence-free survival (LRFS) was recorded by the Kaplan-Meier method. Predictors of local control were identified. RESULTS: The median age was 54 years. Seventy-two (83%) patients had perineural invasion, 61 (70%) had close/positive margins, and 58 (67%) had pT 1T2. Fifty-nine (68%) patients had postoperative radiation therapy (PORT). With a median follow-up of 85 months, the 10-year LRFS was 78.7%. There were 14 local recurrences. On multivariable analysis, pathological tumor (T)3T4 stage and no PORT were independent predictors for local failure. Patients with no PORT had a 13-fold increased risk of local failure compared to patients treated with PORT (P = 0.003) after adjusting for stage. CONCLUSION: After adjusting for T stage, patients who do not get PORT are more likely to have local recurrence. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2265-2269, 2017.


Assuntos
Carcinoma Adenoide Cístico/radioterapia , Carcinoma Adenoide Cístico/cirurgia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Carcinoma Adenoide Cístico/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Período Pós-Operatório , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Resultado do Tratamento
4.
Eur J Cancer ; 51(18): 2768-76, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26602017

RESUMO

BACKGROUND: Due to the rarity of adenoid cystic carcinoma (ACC), information on outcome is based upon small retrospective case series. The aim of our study was to create a large multiinstitutional international dataset of patients with ACC in order to design predictive nomograms for outcome. METHODS: ACC patients managed at 10 international centers were identified. Patient, tumor, and treatment characteristics were recorded and an international collaborative dataset created. Multivariable competing risk models were then built to predict the 10 year recurrence free probability (RFP), distant recurrence free probability (DRFP), overall survival (OS) and cancer specific mortality (CSM). All predictors of interest were added in the starting full models before selection, including age, gender, tumor site, clinical T stage, perineural invasion, margin status, pathologic N-status, and M-status. Stepdown method was used in model selection to choose predictive variables. An external dataset of 99 patients from 2 other institutions was used to validate the nomograms. FINDINGS: Of 438 ACC patients, 27.2% (119/438) died from ACC and 38.8% (170/438) died of other causes. Median follow-up was 56 months (range 1-306). The nomogram for OS had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N-status and M-status) with a concordance index (CI) of 0.71. The nomogram for CSM had the same variables, except margin status, with a concordance index (CI) of 0.70. The nomogram for RFP had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N status and perineural invasion) (CI 0.66). The nomogram for DRFP had 6 variables (gender, clinical T stage, tumor site, pathologic N-status, perineural invasion and margin status) (CI 0.64). Concordance index for the external validation set were 0.76, 0.72, 0.67 and 0.70 respectively. INTERPRETATION: Using an international collaborative database we have created the first nomograms which estimate outcome in individual patients with ACC. These predictive nomograms will facilitate patient counseling in terms of prognosis and subsequent clinical follow-up. They will also identify high risk patients who may benefit from clinical trials on new targeted therapies for patients with ACC. FUNDING: None.


Assuntos
Carcinoma Adenoide Cístico/terapia , Técnicas de Apoio para a Decisão , Recidiva Local de Neoplasia , Nomogramas , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/patologia , Comportamento Cooperativo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Seleção de Pacientes , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
Ann Surg Oncol ; 22(12): 4014-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25743328

RESUMO

BACKGROUND: This study aimed to show the incidence of distant metastases (DM) in salivary gland cancer as well as the types of histology most commonly associated with it and to identify factors predictive of DM. METHODS: The study identified 301 patients who underwent surgery for cancer of the major salivary glands at Memorial Sloan-Kettering Cancer center between 1985 and 2009. Clinical, tumor, and treatment characteristics were recorded. Tumors were categorized as low-, intermediate-, and high-risk pathology based on histologic subtype and grade. Factors predictive of distant recurrence-free probability (DRFP) were determined by uni- and multivariable analyses. RESULTS: The primary tumor was parotid in 266 patients (88 %), and 96 tumors (32 %) were clinical T3/T4. For 57 patients (18.9 %), DM developed with a 5-year DRFP of 72.7 %. The most common site of metastasis was the lung (50 %). The clinical predictors were male gender, cT4 stage, cN+ stage, and clinical overall stage. The multivariable analysis of clinical variables showed male gender (p = 0.018), cT4 stage (p < 0.001), and cN+ stage (p = 0.004) to be significant. The pathologic predictors were high-risk and high-grade pathology, vascular invasion, perineural invasion, positive margins, pT4 stage, pN+ stage, and overall stage. The multivariable analysis of pathologic variables showed high-grade pathology (p < 0.001), perineural invasion (p = 0.005), and pN+ stage (p = 0.002) to be significant. CONCLUSIONS: Distant metastases developed in approximately 20 % of the patients with salivary gland cancer. The most common site of metastases was the lung. The significant predictors of DM were cT4, cN+, male gender, high-grade pathology, perineural invasion, and positive nodal disease.


Assuntos
Carcinoma/secundário , Neoplasias Parotídeas/patologia , Neoplasias da Glândula Sublingual/patologia , Neoplasias da Glândula Submandibular/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/cirurgia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Parotídeas/cirurgia , Probabilidade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Neoplasias da Glândula Sublingual/cirurgia , Neoplasias da Glândula Submandibular/cirurgia , Adulto Jovem
6.
Mol Metab ; 4(2): 132-43, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25685700

RESUMO

OBJECTIVE: Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obesity. However, the cardiovascular consequences of manipulating glucagon action are poorly understood. METHODS: We assessed infarct size and the following outcomes following left anterior descending (LAD) coronary artery ligation; cardiac gene and protein expression, acylcarnitine profiles, and cardiomyocyte survival in normoglycemic non-obese wildtype mice, and in newly generated mice with selective inactivation of the cardiomyocyte Gcgr. Complementary experiments analyzed Gcgr signaling and cell survival in cardiomyocyte cultures and cell lines, in the presence or absence of exogenous glucagon. RESULTS: Exogenous glucagon administration directly impaired recovery of ventricular pressure in ischemic mouse hearts ex vivo, and increased mortality from myocardial infarction after LAD coronary artery ligation in mice in a p38 MAPK-dependent manner. In contrast, cardiomyocyte-specific reduction of glucagon action in adult Gcgr (CM-/-) mice significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction. Metabolic profiling of hearts from Gcgr (CM-/-) mice revealed a marked reduction in long chain acylcarnitines in both aerobic and ischemic hearts, and following high fat feeding, consistent with an essential role for Gcgr signaling in the control of cardiac fatty acid utilization. CONCLUSIONS: Activation or reduction of cardiac Gcgr signaling in the ischemic heart produces substantial cardiac phenotypes, findings with implications for therapeutic strategies designed to augment or inhibit Gcgr signaling for the treatment of metabolic disorders.

7.
J Pharm Pharm Sci ; 17(3): 393-400, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25224350

RESUMO

PURPOSE: To determine the risk of clinical trial failure for drugs developed for type-2 diabetes. METHODS: Drugs were investigated by reviewing phase I to phase III studies that were conducted between 1998 and February 2013. The clinical trial success rates were calculated and compared to the industry standard. The drugs were classified into GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors and "Other". The exclusion criteria for drugs in this study: Drugs that were started in phase I studies prior to January 1998 for this indication and drugs whose primary indications were not for the control of blood glucose levels. RESULTS: Data was extracted from clinicaltrials.gov; there were a total of 131 drug candidates that fit our specified criteria, of which 8 received FDA approval. The cumulative success rate for molecules developed for type-2 diabetes is 10%. Small molecules were more successful than biologics. A strong disparity was observed in phase III, with studies that utilised treatment naïve patients having a 40% success rate, compared to an 83% success rate in patients who have had previous anti-hyperglycemic exposure. CONCLUSIONS: 1 in 10 drugs that enter clinical testing in this disease will be approved. The DPP-4 inhibitor class of drugs had the highest success rate of all drug classes with a 63% cumulative success rate; while treatment naïve patients carried the greatest clinical trial risk.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/efeitos adversos , Ensaios Clínicos como Assunto , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Fatores de Risco
8.
Histopathology ; 65(6): 793-804, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25040772

RESUMO

AIMS: To compare the different grading systems of mucoepidermoid carcinoma (MEC) and identify the most reliable and objective histopathologic features predictive of outcome. METHODS AND RESULTS: Seventy-two cases diagnosed as MEC were subjected to a meticulous histopathologic re-review. 20 of 72 (28%) cases were originally misdiagnosed as MEC including 16 as high grade (HG). Among the 52 confirmed MEC, median follow up (FU) was 59 months. Mitosis (≥4/10 High Power Fields), necrosis, pleomorphism, focal keratinization, desmoplasia, and lymph node metastasis were associated with adverse disease specific survival (DSS) and recurrence free survival (RFS) (P < 0.002). In all grading systems, low and intermediate grade had similar DSS and RFS but much better outcome than HG (P < 0.007). All patients with tumour harboring low mitotic rate and no necrosis did not recur except for one patient with a positive margin. All cases with high mitotic rate and necrosis died or recurred. CONCLUSIONS: The majority of previously diagnosed HG MEC cases are misclassified. There is no difference in outcome between low and intermediate grade in all grading schemes. Consideration should be given to stratify MEC based on relatively objective criteria such as mitosis and necrosis.


Assuntos
Carcinoma Mucoepidermoide/patologia , Gradação de Tumores/métodos , Neoplasias das Glândulas Salivares/patologia , Adolescente , Adulto , Idoso , Carcinoma Mucoepidermoide/mortalidade , Criança , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias das Glândulas Salivares/mortalidade , Adulto Jovem
9.
Ann Surg Oncol ; 21(9): 3042-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24719019

RESUMO

PURPOSE: To review our experience in the treatment of the neck in patients with carcinoma of the parotid gland. METHODS: A total of 263 patients were stratified into 3 groups: no neck dissection (NoND), elective neck dissection (END), and therapeutic neck dissection (TND). Clinicopathological characteristics of END and TND versus NoND were compared by Chi square test. Pathological positivity of each neck level was quantified. Neck recurrence-free survival was determined by Kaplan-Meier statistics. RESULTS: There were 232 cN0 and 31 cN+ patients. Of the cN0 patients, 74 had END. All cN+ patients had TND. Of the END group, occult neck metastases were detected in 26 (35 %) patients. The percentage of positivity was 6.7, 28.3, 21.3, 10.8, and 6.7 % for levels I to V, respectively. Compared to the NoND group, the END group was more likely to be over 60 years old, to have cT3T4 disease, and to have disease with more aggressive histology. Of the TND group, pathological positivity was found in 87 %. The percentage of positivity was 51.6, 77, 73, 53, and 40 % for levels I to V, respectively. Patients who had disease-positive necks had a poorer neck recurrence-free survival of 84.8 %. CONCLUSIONS: In patients with cN0 disease, observation of the neck is safe in those who are under 60 years of age with clinical T1 or T2 tumors and who have low-grade histology. END should be carried out in patients with cT3T4 disease or high-grade histology and should involve levels II to IV at a minimum. Patients with cN+ disease commonly have all neck levels involved and therefore should be managed with comprehensive neck dissection.


Assuntos
Adenocarcinoma/cirurgia , Procedimentos Cirúrgicos Eletivos , Esvaziamento Cervical , Recidiva Local de Neoplasia/cirurgia , Neoplasias Parotídeas/cirurgia , Adenocarcinoma/secundário , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Parotídeas/patologia , Prognóstico
10.
Ann Surg Oncol ; 21(2): 637-42, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24132626

RESUMO

OBJECTIVES: The objective of this study was to create a nomogram predictive of survival in salivary gland cancer. METHODS: Clinical, tumor, and treatment characteristics were collected for 301 patients who underwent surgery for salivary gland cancer between 1985 and 2009 at Memorial Sloan Kettering Cancer Centre. Factors predictive of overall survival (OS) and cancer-specific survival (CSS) were determined by univariate analysis. Cox risk regression was used to model OS data. Competing risks regression was used for cancer-specific death. Deaths from other causes were treated as competing risks for cancer-specific death. Predictive nomograms for OS and CSS were then created using stepdown method to select predictors of outcome. RESULTS: The median age was 62 (range 9-89) years. There were 156 (52%) males and 145 (48%) females. Five variables predictive for OS (age, clinical T4 stage, histological grade, perineural invasion, and tumor dimension) were used to generate a parsimonious model, and a nomogram was created to predict 10-year survival probability. The concordance index (CI) for this nomogram was 0.809. Five variables predictive for CSS (histological grade, perineural invasion, clinical T4 stage, positive nodal status, and status of margins) were used to generate a second nomogram predicting CSS. This nomogram had a CI of 0.856. Both nomograms were validated internally by assessing discrimination and calibration. CONCLUSIONS: We have developed the first nomograms to predict prognosis in an individual patient with salivary gland cancer.


Assuntos
Nomogramas , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/mortalidade , Neoplasias das Glândulas Salivares/mortalidade , Neoplasias das Glândulas Salivares/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias das Glândulas Salivares/patologia , Taxa de Sobrevida , Adulto Jovem
11.
JAMA Otolaryngol Head Neck Surg ; 139(7): 698-705, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23788168

RESUMO

IMPORTANCE: This nomogram quantifies the risk of recurrence in patients with carcinoma of the major salivary glands. It may facilitate patient counseling on prognosis and may help guide management and posttreatment surveillance in these patients. OBJECTIVES: To identify factors predictive of recurrence after primary surgical treatment of carcinoma of the major salivary glands and create a nomogram that could be used to predict the risk of recurrence in an individual patient. DESIGN Retrospective case series. SETTING Single institution tertiary care cancer center. PATIENTS: After institutional review board approval, 301 patients with previously untreated malignant salivary gland tumors treated at our institution between the years 1985 and 2009 were identified. Among the 301 patients, the median age was 62 (range, 9-89) years and 156 (52%) were male. Patient, tumor, and treatment characteristics were recorded from a retrospective analysis of patient medical charts. MAIN OUTCOMES AND MEASURES: Overall mortality was calculated using the Kaplan-Meier method. Disease-specific mortality and recurrence risk were estimated with cumulative incidence rate. Factors predictive of recurrence were identified using univariate analysis. A Cox proportional hazard model was used to select predictors for the predictive nomogram. RESULTS: With a median follow-up of 43 (range, 1-264) months, the 5-year overall mortality, disease-specific mortality, and recurrence rate were 30%, 28%, and 33%, respectively. There were 70 recurrences (18 local, 12 regional, and 56 distant). The 5 variables most predictive for recurrence were age, grade, vascular and perineural invasion, and nodal metastasis. These variables were selected to generate the nomogram, which had a high concordance index of 0.85. CONCLUSIONS AND RELEVANCE: We introduce a clinically useful nomogram that quantifies the risk of recurrence in carcinomas of the major salivary gland. By quantifying risk for an individual patient, this would enable the clinician to give more accurate prognostic information to the patient resulting in better patient counseling.


Assuntos
Carcinoma/patologia , Recidiva Local de Neoplasia , Nomogramas , Neoplasias das Glândulas Salivares/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Neoplasias das Glândulas Salivares/mortalidade , Taxa de Sobrevida
12.
Ann Surg Oncol ; 20(7): 2396-404, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23397152

RESUMO

BACKGROUND: The objective of this study was to determine the incidence and cause of disease-specific death in patients with mucoepidermoid carcinoma (MEC) affecting the major salivary glands. METHODS: A total of 94 patients with MEC treated at Memorial Sloan-Kettering Cancer Center between 1985 and 2009 were identified from a preexisting database of 451 patients with major salivary gland cancer. Patient, tumor, and treatment characteristics were recorded from a retrospective analysis of patient charts. There were 49 males (52 %), and the median age was 57 years (range, 9-89 years). Of the 94 patients, 49 % had low, 22 % had intermediate, and 28 % had high-grade carcinoma. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method. Cause of death was determined by chart review. Predictors of DSS were identified by univariate analysis. RESULTS: With a median follow-up of 59 months (range, 1-257), the 5-year OS, DSS, and RFS for all patients were 76 %, 83 %, and 79 %, respectively. DSS was significantly poorer for high-grade MEC compared with low/intermediate-grade MEC (5-year DSS 37 % vs 100 %, P < .001). There were 9 disease-specific deaths. The cause of death in 7 patients was distant metastatic disease with locoregional recurrence accounting for death in only 2 patients. CONCLUSION: Outcome in patients with mucoepidermoid cancers of the major salivary glands is generally good. Mortality occurs almost exclusively in patients with high-grade tumors. The cause of death in the majority of patients is distant metastatic disease rather than locoregional recurrence.


Assuntos
Carcinoma Mucoepidermoide/mortalidade , Carcinoma Mucoepidermoide/secundário , Recidiva Local de Neoplasia/mortalidade , Neoplasias das Glândulas Salivares/mortalidade , Neoplasias das Glândulas Salivares/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Criança , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Taxa de Sobrevida , Adulto Jovem
13.
Diabetes ; 62(4): 1196-205, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23160527

RESUMO

Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and α-cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor. Gcgr(Hep)(-/-) mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr(-/-) mice. Despite preservation of islet Gcgr signaling, Gcgr(Hep)(-/-) mice developed hyperglucagonemia and α-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-cell mass, wild-type islets were transplanted into Gcgr(-/-) or Gcgr(Hep)(-/-) mice. Wild-type islets beneath the renal capsule of Gcgr(-/-) or Gcgr(Hep)(-/-) mice exhibited an increased rate of α-cell proliferation and expansion of α-cell area, consistent with changes exhibited by endogenous α-cells in Gcgr(-/-) and Gcgr(Hep)(-/-) pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating α-cell proliferation and mass may facilitate the generation and expansion of α-cells for transdifferentiation into ß-cells and the treatment of diabetes.


Assuntos
Células Secretoras de Glucagon/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Fígado/metabolismo , Receptores de Glucagon/metabolismo , Animais , Glicemia , Feminino , Glucagon/administração & dosagem , Glucagon/sangue , Células Secretoras de Glucagon/citologia , Células Secretoras de Glucagon/patologia , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hiperplasia , Resistência à Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Fígado/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glucagon/genética , Transdução de Sinais
14.
Diabetes ; 62(2): 510-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23099862

RESUMO

Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and ß-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic ß-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in ß-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.


Assuntos
Polipeptídeo Inibidor Gástrico/biossíntese , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Fragmentos de Peptídeos/metabolismo , Proglucagon/metabolismo , Animais , AMP Cíclico/antagonistas & inibidores , Polipeptídeo Inibidor Gástrico/genética , Deleção de Genes , Técnicas de Introdução de Genes , Receptor do Peptídeo Semelhante ao Glucagon 1 , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase/genética , Homeostase/fisiologia , Imuno-Histoquímica , Incretinas/metabolismo , Células Secretoras de Insulina/citologia , Masculino , Camundongos , Proglucagon/análise , Receptores dos Hormônios Gastrointestinais/genética , Receptores de Glucagon/metabolismo
15.
Arch Otolaryngol Head Neck Surg ; 137(11): 1154-60, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22106243

RESUMO

OBJECTIVE: To develop statistical prediction tools to select patients for short-stay thyroidectomy based on dynamic quantification of individual risk for postoperative hypocalcemia. DESIGN: Clinical and biochemical factors that could influence postoperative calcium levels were analyzed. A multivariable logistic regression model was used to study the predictive ability of each variable for hypocalcemia. A step-down model reduction selection method was used to rank the predictors according to their predictive accuracy. SETTING: Memorial Sloan Kettering Cancer Center. PATIENTS: A test population of 393 patients who met our inclusion criteria and who underwent total thyroidectomy at Memorial Sloan Kettering Cancer Center in the year 2008 made up the modeling data set, 116 of whom developed biochemical hypocalcemia postoperatively (29.5%). The nomograms were validated on an independent data set consisting of 296 selected patients who underwent total thyroidectomy during the year 2005, using the same selection criteria for inclusion as those for the modeling data set. MAIN OUTCOME MEASURES: The 8 predictors with the highest predictive accuracy were selected to generate a nomogram, which was validated both internally and externally using an independent data set. A second nomogram was developed for assessing the probability of a patient stay of 24 hours or shorter, based on preoperative and intraoperative factors. RESULTS: The 8 variables of highest predictive value were age, sex, medications, history of cancer, preoperative serum calcium level, creatinine concentration, central neck dissection, and alkaline phosphatase levels. A nomogram was created based on the final parsimonious model. The nomogram had excellent accuracy (concordance index of 74.6%) and scored high on internal validation tests. The concordance index of the second nomogram for predicting the likelihood of discharge from the hospital within 24 hours was 70%. CONCLUSION: We have produced a set of nomograms that can dynamically quantify the risk of postthyroidectomy hypocalcemia and prolonged hospital stay based on preoperative clinical and biochemical variables and intraoperative surgical variables.


Assuntos
Cálcio/sangue , Hipocalcemia/classificação , Seleção de Pacientes , Doenças da Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Hipocalcemia/sangue , Hipocalcemia/etiologia , Masculino , Pessoa de Meia-Idade , Nomogramas , Período Pós-Operatório , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Doenças da Glândula Tireoide/sangue , Adulto Jovem
16.
J Clin Invest ; 121(5): 1917-29, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21540554

RESUMO

Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr-/- mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr-/- mice by generating Gcgr-/-Glp1r-/- mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr-/-Glp1r-/- mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr-/- mice. Unexpectedly, deletion of Glp1r in Gcgr-/- mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr-/-Glp1r-/- islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor (Gipr) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr-/-Glp1r-/- islets expressed increased levels of the cholecystokinin A receptor (Cckar) and G protein-coupled receptor 119 (Gpr119) mRNA transcripts, and Gcgr-/-Glp1r-/- mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion.


Assuntos
Glucagon/metabolismo , Incretinas/metabolismo , Receptores de Glucagon/genética , Animais , Colecistocinina/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Teste de Tolerância a Glucose , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Consumo de Oxigênio , Pâncreas/metabolismo , Fenótipo , Ratos
17.
Diabetes ; 58(9): 2148-61, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19509017

RESUMO

OBJECTIVE: Clinical reports link use of the glucagon-like peptide-1 receptor (GLP-1R) agonists exenatide and liraglutide to pancreatitis. However, whether these agents act on the exocrine pancreas is poorly understood. RESEARCH DESIGN AND METHODS: We assessed whether the antidiabetic agents exendin (Ex)-4, liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or the biguanide metformin were associated with changes in expression of genes associated with the development of experimental pancreatitis. The effects of Ex-4 when administered before or after the initiation of caerulein-induced experimental pancreatitis were determined. The importance of endogenous GLP-1R signaling for gene expression in the exocrine pancreas and the severity of pancreatitis was assessed in Glp1r(-/-) mice. RESULTS: Acute administration of Ex-4 increased expression of egr-1 and c-fos in the exocrine pancreas. Administration of Ex-4 or liraglutide for 1 week increased pancreas weight and induced expression of mRNA transcripts encoding the anti-inflammatory proteins pancreatitis-associated protein (PAP) (RegIIIbeta) and RegIIIalpha. Chronic Ex-4 treatment of high-fat-fed mice increased expression of PAP and reduced pancreatic expression of mRNA transcripts encoding for the proinflammatory monocyte chemotactic protein-1, tumor necrosis factor-alpha, and signal transducer and activator of transcription-3. Sitagliptin and metformin did not significantly change pancreatic gene expression profiles. Ex-4 administered before or after caerulein did not modify the severity of experimental pancreatitis, and levels of pancreatic edema and serum amylase were comparable in caerulein-treated Glp1r(-/-) versus Glp1r(+/+) mice. CONCLUSIONS: These findings demonstrate that GLP-1 receptor activation increases pancreatic mass and selectively modulates the expression of genes associated with pancreatitis. However, activation or genetic elimination of GLP-1R signaling does not modify the severity of experimental pancreatitis in mice.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Pancreatite/metabolismo , Pancreatite/fisiopatologia , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Animais , Ceruletídeo/toxicidade , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/genética , Exenatida , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Genes fos/fisiologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/toxicidade , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/toxicidade , Liraglutida , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Pâncreas Exócrino/efeitos dos fármacos , Pâncreas Exócrino/fisiologia , Pancreatite/induzido quimicamente , Proteínas Associadas a Pancreatite , Peptídeos/toxicidade , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Peçonhas/toxicidade
18.
Int J Pediatr Otorhinolaryngol ; 73(8): 1076-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19473711

RESUMO

OBJECTIVE: The bone-anchored hearing aid (BAHA) is an essential part of the armamentarium of the modern otolaryngologist dealing with ear disorders. A two-stage approach for implantation in children is recommended by the manufacturers. In our practice we implant BAHA in children as a single procedure. We describe our technique and results. METHOD: We performed a review of all children having a BAHA between 1997 and 2005. Surgery was performed by taking a post-auricular split skin graft and excising the underlying soft tissues. Drilling, tapping and fixture placement were performed as per the manufacturer's instructions. The skin graft was then sutured in place and perforated in its centre and the abutment placed. Ten to twelve weeks were allowed for osseointegration before the hearing aid attachment. RESULTS: Thirty children were implanted. Age at implantation ranged from 3 to 15 years (mean 9.1 and median 8.1 years). Main indications included recurrent otorrhoea, conductive hearing loss and aural atresia. Follow-up was at 4-6 weeks review initially, curtailing to 6 monthly reviews and then annual review. Early complications of skin infection occurred in two patients. Late complications such as skin hypertrophy and chronic infection occurred in two patients. Two patients lost the fixture due to trauma, both were subsequently reimplanted. There was no incidence of implant failure to osseointegrate. Twenty-eight children (93%) implanted wear their BAHAs. CONCLUSION: Our results show that a single-stage technique is associated with a low rate of early complications, with no reports of fixture loss due to osseointegration failure.


Assuntos
Auxiliares de Audição , Adolescente , Criança , Pré-Escolar , Pavilhão Auricular/anormalidades , Otopatias/terapia , Perda Auditiva Condutiva/cirurgia , Humanos , Complicações Pós-Operatórias , Implantação de Prótese/métodos
19.
Am J Physiol Endocrinol Metab ; 296(3): E415-21, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19116373

RESUMO

Glucagon is secreted from the alpha-cells of the pancreatic islets and regulates glucose homeostasis through modulation of hepatic glucose production. As elevated glucagon levels contribute to the pathophysiology of hyperglycemia in subjects with type 2 diabetes, reduction of glucagon receptor gene (Gcgr) activity represents a potential target for the treatment of T2DM. Herein, we review current concepts of glucagon action in hepatic and extrahepatic tissues and evaluate the therapeutic potential, mechanisms of action, and safety of reducing Gcgr signaling for the treatment of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Glucagon/metabolismo , Receptores de Glucagon/metabolismo , Animais , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/terapia , Receptores de Glucagon/genética
20.
J R Soc Med ; 98(9): 415, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16140853

RESUMO

To investigate a suspicion that many ear, nose and throat patients have unfounded concerns about cancer, we questioned 50 patients who had attended a routine clinic after screening-out of those with possibly cancer-related features. None of the 50 proved to have cancer. 15 (30%) had been worried about cancer and 7 of these were still worried despite the consultation. Unwarranted fears about cancer are best dealt with by the referring clinician, especially when the wait for an appointment will be long. Such fears also need to be recognized and addressed by the specialist.


Assuntos
Ansiedade , Medo , Neoplasias de Cabeça e Pescoço/psicologia , Otorrinolaringopatias/psicologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Otolaringologia , Otorrinolaringopatias/diagnóstico , Ambulatório Hospitalar , Pacientes Ambulatoriais , Projetos Piloto , Inquéritos e Questionários , Listas de Espera
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