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Introduction: Glycogenic hepatopathy (GH) is a rare complication of type I diabetes mellitus (DM1), resulting in abnormal deposition of glycogen in the liver due to poor glycemic control. Clinical characteristics and natural history of GH are not completely understood in children. In this study, we investigated clinical, biochemical, histologic parameters and outcomes in children with GH. Method: This was a retrospective review of patients less than 18 years old diagnosed with GH and DM. GH was confirmed on liver biopsy. Medical records were reviewed for clinical presentation, laboratory tests, and clinical outcomes. Liver biopsy findings were reviewed by a pediatric pathologist (I. A. G.). Results: Nine children were diagnosed with GH and type 1 DM. The median age at diagnosis of GH was 16 (IQR 14.5-17) years. Duration of diagnosis of DM until GH diagnosis was 7 (IQR 5-11) years. The median frequency of diabetic ketoacidosis before GH diagnosis was three times (IQR 2-5.25). Peak Aspartate transaminase (AST) and Alanine transaminase (ALT) ranged from 115 to 797, and 83-389 units/L, respectively. Only two children had mild fibrosis. Seven of nine had steatosis without steatohepatitis. There was no correlation between glycosylated hemoglobin (HbA1c), or other laboratory tests and liver fibrosis on biopsy. HbA1c was 11.2 (IQR 10.2-12.8) at GH diagnosis and 9.8 (IQR 9.5-10.8) with normalization of liver enzymes. Conclusion: GH appears to be related to poor glycemic control in teenagers with long-term diabetes. GH presents with high to very high aminotransferase especially AST > ALT and resolves with modestly improved glycemic control. Diffuse hepatocyte swelling, steatosis, minimal fibrosis without hepatocyte ballooning or lobular inflammation are most common histological features.
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PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%. RESULTS: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib. CONCLUSIONS: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.
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Aminopiridinas , Benzimidazóis , Neoplasias de Próstata Resistentes à Castração , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do TratamentoRESUMO
In Lebanon, the nationwide vaccination against COVID-19 was launched in February 2021 using the Pfizer-BioNTech vaccine and prioritizing elderly people, persons with comorbidities, and healthcare workers. Our study aims to estimate the post-introduction vaccine effectiveness (VE) of the Pfizer-BioNTech vaccine in preventing COVID-19 hospitalizations among elderly people ≥75 years old in Lebanon. A case-control study design was used. Case patients were Lebanese, ≥75 years old, and hospitalized with positive PCR results during April-May 2021, and randomly selected from the database of the Epidemiological Surveillance Unit at the Ministry of Public Health (MOPH). Each case patient was matched by age and locality to two controls. The controls were hospitalized, non-COVID-19 patients, randomly selected from the MOPH hospital admission database. VE was calculated for fully (2 doses ≥14 days) and partially vaccinated (≥14 days of the first or within 14 days of the second dose) participants using multivariate logistic regression. A total of 345 case patients and 814 controls were recruited. Half were females, with a mean age of 83 years. A total of 14 case patients (5%) and 143 controls (22%) were fully vaccinated. A bivariate analysis showed a significant association with gender, month of confirmation/hospital admission, general health, chronic medical conditions, main income source, and living arrangement. After adjusting for a month of hospital admission and gender, the multivariate analysis yielded a VE of 82% (95% CI = 69-90%) against COVID-19-associated hospitalizations for those fully vaccinated and 53% (95% CI = 23-71%) for those partially vaccinated. Our study shows that the Pfizer-BioNTech vaccine is effective in reducing the risk for COVID-19-associated hospitalizations of Lebanese elderly people (≥75 years old). Additional studies are warranted to explore VE in reducing hospitalizations for younger age groups, as well as reducing COVID-19 infections.
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MONARCH 2 is a global, randomized, double-blind, phase 3 study of abemaciclib/placebo + fulvestrant in patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat population in the MONARCH 2 trial. Consistent with the primary analysis, this subpopulation analysis of East Asian patients indicated progression-free survival benefit in the abemaciclib arm. The median overall survival was not reached in the abemaciclib arm and was 48.9 months in the placebo arm (hazard ratio 0.80; 95% confidence interval 0.52-1.24; p = 0.377). In addition, other efficacy endpoints, including time to chemotherapy, chemotherapy free survival, and time to second disease progression, indicated benefit in the abemaciclib arm. This analysis found no new safety concerns with longer follow-up. These findings support the positive benefit-risk balance of the MONARCH 2 regimen in East Asian patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/metabolismo , Fulvestranto , População do Leste Asiático , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Excess weight is a public health challenge affecting millions worldwide, including younger age groups. The human exposome concept presents a novel opportunity to comprehensively characterize all non-genetic disease determinants at susceptible time windows. This study aimed to describe the association between multiple lifestyle and clinical exposures and body mass index (BMI) in adolescents using the exposome framework. We conducted an exposome-wide association (ExWAS) study using U.S. National Health and Nutrition Examination Survey (NHANES) 2003-2004 wave for discovery of associations between study population characteristics and zBMI, and used the 2013-2014 wave to replicate analysis. We included non-diabetic and non-pregnant adolescents aged 12-18 years. We performed univariable and multivariable linear regression analysis adjusted for age, sex, race/ethnicity, household smoking, and income to poverty ratio, and corrected for false-discovery rate (FDR). A total of 1899 and 1224 participants were eligible from 2003-2004 and 2013-2014 survey waves. Weighted proportions of overweight were 18.4% and 18.5% whereas those for obese were 18.1% and 20.6% in 2003-2004 and 2013-2014, respectively. Retained exposure agents included 75 laboratory (clinical and biomarkers of environmental chemical exposures) and 64 lifestyle (63 dietary and 1 physical activity) variables. After FDR correction, univariable regression identified 27 and 12 predictors in discovery and replication datasets, respectively, while multivariable regression identified 22 and 9 predictors in discovery and replication datasets, respectively. Six were significant in both datasets: alanine aminotransferase, gamma glutamyl transferase, segmented neutrophils number, triglycerides; uric acid and white blood cell count. In this ExWAS study using NHANES data, we described associations between zBMI, nutritional, clinical and environmental factors in adolescents. Future studies are warranted to investigate the role of the identified predictors as early-stage biomarkers of increased BMI and associated pathologies among adolescents and to replicate findings to other populations.
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Expossoma , Adolescente , Biomarcadores , Índice de Massa Corporal , Exposição Ambiental/efeitos adversos , Humanos , Inquéritos NutricionaisRESUMO
INTRODUCTION: The first detected case in Lebanon on 21 February 2020 engendered implementation of a nationwide lockdown alongside timely contact-tracing and testing. OBJECTIVES: Our study aims to calculate the serial interval of SARS-CoV-2 using contact tracing data collected 21 February to 30 June 2020 in Lebanon to guide testing strategies. METHODS: rRT-PCR positive COVID-19 cases reported to the Ministry of Public Health Epidemiological Surveillance Program (ESU-MOH) are rapidly investigated and identified contacts tested. Positive cases and contacts assigned into chains of transmission during the study time-period were verified to identify those symptomatic, with non-missing date-of-onset and reported source of exposure. Selected cases were classified in infector-infectee pairs. We calculated mean and standard deviation for the serial interval and best distribution fit using AIC criterion. RESULTS: Of a total 1788 positive cases reported, we included 103 pairs belonging to 24 chains of transmissions. Most cases were Lebanese (98%) and male (63%). All infectees acquired infection locally. Mean serial interval was 5.24 days, with a standard deviation of 3.96 and a range of - 4 to 16 days. Normal distribution was an acceptable fit for our non-truncated data. CONCLUSION: Timely investigation and social restriction measures limited recall and reporting biases. Pre-symptomatic transmission up to 4 days prior to symptoms onset was documented among close contacts. Our SI estimates, in line with international literature, provided crucial information that fed into national contact tracing measures. Our study, demonstrating the value of contact-tracing data for evidence-based response planning, can help inform national responses in other countries.
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COVID-19 , Busca de Comunicante , Controle de Doenças Transmissíveis , Feminino , Humanos , Líbano/epidemiologia , Masculino , SARS-CoV-2RESUMO
PURPOSE: In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HR+), HER2- advanced breast cancer. This exploratory analysis assessed the efficacy of abemaciclib plus fulvestrant across subgroups of patients receiving study therapy as first- or second-line treatment for metastatic disease. PATIENTS AND METHODS: Improvements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed. RESULTS: The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45-0.73; second-line, HR, 0.48; 95% CI, 0.36-0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64-1.14; second-line, HR, 0.66; 95% CI, 0.46-0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm, n = 265; placebo arm, n = 133), the numerically largest effect on PFS and OS was observed in patients with primary resistance to endocrine therapy (ET; PFS, HR, 0.40; 95% CI, 0.26-0.63; OS, HR, 0.58; 95% CI, 0.35-0.97) and visceral disease (PFS, HR, 0.54; 95% CI, 0.39-0.73; OS, HR, 0.82; 95% CI, 0.58-1.20). In second-line patients (abemaciclib arm, n = 170; placebo arm, n = 86), a numerical benefit in PFS and OS was observed across primary and secondary ET resistance, with numerically more pronounced effects observed in patients with visceral disease (PFS, HR, 0.39; 95% CI, 0.27-0.57; OS, HR, 0.51; 95% CI, 0.33-0.81). Prolongation of time to second disease progression, time to chemotherapy, and chemotherapy-free survival was observed in both subgroups. CONCLUSIONS: Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.
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Aminopiridinas/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/administração & dosagem , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Combinação de Medicamentos , Feminino , Humanos , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Receptor ErbB-2/análise , Resultado do TratamentoRESUMO
BACKGROUND: In MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR] 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial. METHODS: The premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n = 72; placebo plus fulvestrant, n = 42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS). RESULTS: At the primary objective cutoff (February 14, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR 0.415; 95% CI 0.246-0.698). At the pre-specified OS interim cutoff (20-June-2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR 0.477; 95% CI 0.302-0.755). A numerical OS benefit was observed with abemaciclib plus fulvestrant compared to fulvestrant alone (HR 0.689; 95% CI 0.379-1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR 0.599), TTC (HR 0.674), and CFS (HR 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously. CONCLUSIONS: Results of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant. CLINICAL TRIAL REGISTRATION: NCT02107703. Registered April 08, 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02107703 .
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Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/uso terapêutico , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de SobrevidaRESUMO
BACKGROUND: Influenza surveillance systems in the Eastern Mediterranean Region have been strengthened in the past few years and 16 of the 19 countries in the Region with functional influenza surveillance systems report their influenza data to the EMFLU Network. This study aimed to investigate the epidemiology of circulating influenza viruses, causing SARI, and reported to the EMFLU during July 2016 to June 2018. METHODS: Data included in this study were collected by 15 countries of the Region from 110 SARI sentinel surveillance sites over two influenza seasons. RESULTS: A total of 40,917 cases of SARI were included in the study. Most cases [20,551 (50.2%)] were less than 5years of age. Influenza virus was detected in 3995 patients, 2849 (11.8%) were influenza A and 1146 (4.8%) were influenza B. Influenza A(H1N1)pdm09 was the predominant circulating subtype with 1666 cases (58.5%). Other than influenza, respiratory syncytial virus was the most common respiratory infection circulating, with 277 cases (35.9%). CONCLUSION: Influenza viruses cause a high number of severe respiratory infections in EMR. It is crucial for the countries to continue improving their influenza surveillance capacity in order detect any unusual influenza activity or new strain that may cause a pandemic.
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Influenza Humana/epidemiologia , Infecções Respiratórias/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Betainfluenzavirus/isolamento & purificação , Masculino , Região do Mediterrâneo/epidemiologia , Pessoa de Meia-Idade , Oriente Médio/epidemiologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sincicial Respiratório Humano/isolamento & purificação , Estações do Ano , Vigilância de Evento Sentinela , Índice de Gravidade de Doença , Adulto JovemRESUMO
Peripheral precocious puberty results from peripheral production of sex steroids independent of activation of the hypothalamic-pituitary gonadal axis. It is much less common than central precocious puberty. Causes are variable and can be congenital or acquired. In this review, we will discuss the diagnosis and management of the most common etiologies including congenital adrenal hyperplasia, McCune Albright syndrome, familial male-limited precocious puberty, and adrenal and gonadal tumors.
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Hiperplasia Suprarrenal Congênita/complicações , Puberdade Precoce/etiologia , Neoplasias das Glândulas Suprarrenais/complicações , Feminino , Displasia Fibrosa Poliostótica/complicações , Humanos , Masculino , Puberdade Precoce/complicações , Puberdade Precoce/diagnóstico , Puberdade Precoce/terapiaRESUMO
In 2009, Lebanon hosted the 6th Francophone Games. Pandemic A(H1N1)2009 virus presented significant health threat at the time. A surveillance strategy was implemented for the timely detection and management of epidemiological events and outbreaks, in particular for A(H1N1)2009 virus cases. Data were collected and managed daily and feedback was generated through daily bulletins. A total of 299 medical consultations were reported, 29% of which related to infectious diseases. There were 10 cases reported as acute respiratory infections; all tested negative for A(H1N1)2009 virus within 24 hours. Twenty-three cases of gastroenteritis were reported, for which 11 stool cultures were negative. While pandemic A(H1N1)2009 did not interfere with the Games, it was essential to strengthen surveillance and to have timely epidemiological information. This was achieved through preparedness, a multi-disciplinary approach, timely management and coordination.
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Surtos de Doenças/prevenção & controle , Influenza Humana/epidemiologia , Vigilância da População , Esportes , Controle de Doenças Transmissíveis , Aglomeração , Humanos , Vírus da Influenza A Subtipo H1N1 , Líbano/epidemiologia , Medição de RiscoRESUMO
In 2009, Lebanon hosted the 6th Francophone Games. Pandemic A[H1N1]2009 virus presented significant health threat at the time. A surveillance strategy was implemented for the timely detection and management of epidemiological events and outbreaks, in particular for A[H1N1]2009 virus cases. Data were collected and managed daily and feedback was generated through daily bulletins. A total of 299 medical consultations were reported, 29% of which related to infectious diseases. There were 10 cases reported as acute respiratory infections; all tested negative for A[H1N1]2009 virus within 24 hours. Twenty-three cases of gastroenteritis were reported, for which 11 stool cultures were negative. While pandemic A[H1N1]2009 did not interfere with the Games, it was essential to strengthen surveillance and to have timely epidemiological information. This was achieved through preparedness, a multi-disciplinary approach, timely management and coordination
En 2009, le Liban a accueilli la sixième édition des Jeux de la Francophonie. Le virus pandémique A[H1N1] 2009 représentait une menace sanitaire majeure à l'époque. Une stratégie de surveillance a été mise en place en vue d'une détection et d'une prise en charge rapides des événements épidémiologiques et des flambées, notamment de cas de virus A[H1N1]2009. Les données ont été collectées et gérées sur une base journalière, et une rétroinformation était générée au moyen de bulletins quotidiens. Un total de 299 consultations médicales a été rapporté, dont 29% en rapport avec des maladies infectieuses. Dix cas d'infections respiratoires aiguës ont été notifiés. Tous se sont révélés négatifs au test de recherche du virus A[H1N1] 2009 réalisé sous 24h. Vingt-trois cas de gastroentérite ont été signalés, pour lesquels 11 coprocultures se sont révélées négatives. Si la pandémie A[H1N1] 2009 n'a pas impacté les Jeux, il était essentiel de renforcer la surveillance et de mettre en place un système d'information épidémiologique rapide. Ces objectifs ont été atteints au moyen d'une préparation, d'une approche multidisciplinaire, ainsi que d'une prise en charge et d'une coordination rapides
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Doenças Transmissíveis , Vigilância em Saúde Pública , Surtos de DoençasRESUMO
OBJECTIVE: Polydipsia and polyuria are common reasons for referral to the Pediatric Endocrine clinic. In the absence of hyperglycemia, diabetes insipidus (DI) should be considered. The objectives of the study were to determine the prevalence of central DI (CDI) in a group of children presenting for evaluation of polydipsia and polyuria, and to determine if predictive features were present in patients in whom the diagnosis of DI was made. METHODS: The study was a retrospective chart review of children presenting to the endocrine clinic with complaints of polydipsia and polyuria over a 5-year period. RESULTS: The charts of 41 patients (mean age 4.9 ± 3.7 years, 28 males) were reviewed. CDI was diagnosed in 8 (20%) children based on abnormal water deprivation test (WDT) results. All but one patient had abnormal magnetic resonance imaging (MRI) findings, the most common being pituitary stalk thickening. Children with DI were older (7.86 ± 4.40 vs. 4.18 ± 3.20 years, P = .01) and had a higher propensity for cold beverages intake and unusual water-seeking behaviors compared to those without DI. Baseline WDT also revealed higher serum sodium (Na) and osmolality. CONCLUSION: The incidence of CDI in children presenting with polydipsia and polyuria is low. Factors associated with higher likelihood of pathology include older age, propensity for cold beverage intake, and higher baseline serum Na and osmolality on a WDT. ABBREVIATIONS: BMI = body mass index CDI = central diabetes insipidus DI = diabetes insipidus Na = sodium WDT = water deprivation test.
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Diabetes Insípido Neurogênico/epidemiologia , Polidipsia/epidemiologia , Poliúria/epidemiologia , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Incidência , Masculino , Estudos RetrospectivosRESUMO
Varicoceles are the most common cause of infertility in men. Despite the high prevalence of varicoceles, only a small percentage of men with varicoceles have subfertility or infertility. In adolescents, the prevalence of varicoceles increases dramatically during puberty to reach adult prevalence rates. The development of varicoceles during puberty can impair testicular growth and function. Data on hormonal and semen parameters in adolescents with varicoceles are limited, making it harder to determine which varicoceles are associated with infertility and which may benefit from surgery. The main indications for varicocelectomy in adolescents with varicoceles include a volume differential between unaffected and affected testes or abnormality in semen analysis.
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Infertilidade Masculina , Varicocele , Procedimentos Cirúrgicos Vasculares , Adolescente , Humanos , Infertilidade Masculina/epidemiologia , Infertilidade Masculina/patologia , Infertilidade Masculina/cirurgia , Masculino , Prevalência , Espermatogênese/fisiologia , Varicocele/epidemiologia , Varicocele/patologia , Varicocele/cirurgiaRESUMO
The Her2 oncogene is expressed in â¼25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here, we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR(+/+)) mice were crossed with doxycycline-inducible Neu-NT (MTB/TAN) mice to produce the MTB/TAN/MKR(+/+) mouse model. Both MTB/TAN and MTB/TAN/MKR(+/+) mice were administered doxycycline in drinking water to induce Neu-NT mammary tumor formation. In tumor tissues removed at 2, 4, and 6 weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor/IGF1 receptor, suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no further increase in tumor weight was observed in MTB/TAN/MKR(+/+) compared with MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR(+/+) mice compared with controls (MTB/TAN/MKR(+/+) 16.41±4.18 vs MTB/TAN 5.36±2.72). In tumors at the 6-week time point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer-associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR(+/+) mice resulted in larger primary tumors, with more mesenchymal cells and therefore more aggressive tumors with more numerous pulmonary metastases.
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Hiperinsulinismo/complicações , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/patologia , Animais , Humanos , Hiperinsulinismo/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Receptor ErbB-2RESUMO
Hypothalamic obesity syndrome can affect brain tumor patients following surgical intervention and irradiation. This syndrome is rare at diagnosis in childhood cancer, but has been reported with relapse of acute lymphoblastic leukemia. Here we present a case of hypothalamic obesity syndrome as the primary presentation of a toddler found to have CNS+ B-cell lymphoblastic lymphoma. Cytogenetic studies on diagnostic cerebrospinal fluid revealed MLL gene rearrangement (11q23). Hyperphagia and obesity dramatically improved following induction and consolidation chemotherapy. We describe a novel presentation of hypothalamic obesity syndrome in CNS B-cell lymphoblastic lymphoma, responsive to chemotherapy.
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Cromossomos Humanos Par 11/genética , Rearranjo Gênico , Neoplasias Hipotalâmicas , Proteína de Leucina Linfoide-Mieloide/genética , Obesidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Pré-Escolar , Histona-Lisina N-Metiltransferase , Humanos , Hiperfagia/diagnóstico por imagem , Hiperfagia/tratamento farmacológico , Hiperfagia/genética , Neoplasias Hipotalâmicas/diagnóstico por imagem , Neoplasias Hipotalâmicas/tratamento farmacológico , Neoplasias Hipotalâmicas/genética , Masculino , Obesidade/diagnóstico por imagem , Obesidade/tratamento farmacológico , Obesidade/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , RadiografiaRESUMO
UNLABELLED: We assessed the efficacy and safety of a liposomal cisplatin (lipoplatin) and vinorelbine combination in metastatic breast cancer (MBC). Thirty-five patients were treated. The objective response rate was 53.1% and the median survival time was 22 months. Grade 3/4 neutropenia was observed in 44% of cycles, and febrile neutropenia was seen in 4 patients (11.4%). No grade 3/4 nephrotoxicity or neuropathy was noted. This combination is effective and well tolerated in patients with MBC and it warrants investigation as first-line treatment. BACKGROUND: Liposomal cisplatin (lipoplatin) has a mechanism of action similar to that of cisplatin, with reduced toxicities and enhanced or similar efficacy. We wanted to assess the efficacy and safety of a lipoplatin/vinorelbine combination in a phase II clinical trial in metastatic breast cancer (MBC). METHODS: Thirty-five patients with HER-2/neu-negative (HER-2/neu(-)) MBC were enrolled. Lipoplatin 120 mg/m(2) (days 1, 8, and 15) and vinorelbine 30 mg/m(2) (days 1 and 8) were administered in a 21-day cycle. RESULTS: Thirty-five patients were included in the intent-to-treat (ITT) analysis; 32 patients were evaluable for response. The objective response rate was 53.1%. Complete response (CR) was achieved in 3 patients (9.4%), partial response (PR) was seen in 14 patients (43.8%), stable disease (SD) was obtained in 12 patients (37.5%), and progressive disease (PD) was seen in 3 patients (9.4%). Median time to disease progression was 8 months (range 6-10 months). After a median follow-up of 15.5 months, 18 patients were still alive; the median survival time was 22 months (95% confidence interval [CI], 14-30). A total of 174 cycles were administered. Neutropenia was the most frequent hematologic toxicity, with grade 3/4 neutropenia observed in 44% of cycles. Febrile neutropenia was observed in 4 patients (11.4%). No grade 3/4 nephrotoxicity or neuropathy was noted. Grade 1/2 nephrotoxicity occurred in 8 patients (22.9%) and grade 3 vomiting was seen in 3 patients (8.6%). CONCLUSIONS: The results of this trial reveal that vinorelbine/lipoplatin is effective in treating patients with MBC. This regimen is well tolerated with no grade 3/4 nephrotoxicity or neuropathy. The investigation of this regimen as first-line treatment in MBC is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Adolescente , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/metabolismo , Células Receptoras Sensoriais/metabolismo , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , Vinorelbina , Adulto JovemRESUMO
PURPOSE: Iron dysregulation can cause retinal disease, yet retinal iron regulatory mechanisms are incompletely understood. The peptide hormone hepcidin (Hepc) limits iron uptake from the intestine by triggering degradation of the iron transporter ferroportin (Fpn). Given that Hepc is expressed in the retina and Fpn is expressed in cells constituting the blood-retinal barrier, the authors tested whether the retina may produce Hepc to limit retinal iron import. METHODS: Retinas of Hepc(-/-) mice were analyzed by histology, autofluorescence spectral analysis, atomic absorption spectrophotometry, Perls' iron stain, and immunofluorescence to assess iron-handling proteins. Retinal Hepc mRNA was evaluated through qPCR after intravitreal iron injection. Mechanisms of retinal Hepc upregulation were tested by Western blot analysis. A retinal capillary endothelial cell culture system was used to assess the effect of exogenous Hepc on Fpn. RESULTS: Hepc(-/-) mice experienced age-dependent increases in retinal iron followed by retinal degeneration with autofluorescent RPE, photoreceptor death, and subretinal neovascularization. Hepc(-/-) mice had increased Fpn immunoreactivity in vascular endothelial cells. Conversely, in cultured retinal capillary endothelial cells, exogenous Hepc decreased both Fpn levels and iron transport. The retina can sense increased iron levels, upregulating Hepc after phosphorylation of extracellular signal regulated kinases. CONCLUSIONS: These findings indicate that Hepc is essential for retinal iron regulation. In the absence of Hepc, retinal degeneration occurs. Increases in Hepc mRNA levels after intravitreal iron injection combined with Hepc-mediated decreases in iron export from cultured retinal capillary endothelial cells suggest that the retina may use Hepc for its tissue-specific iron regulation.
Assuntos
Envelhecimento/fisiologia , Peptídeos Catiônicos Antimicrobianos/fisiologia , Apoferritinas/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Receptores da Transferrina/metabolismo , Retina/metabolismo , Degeneração Retiniana/metabolismo , Animais , Apoferritinas/genética , Apoptose , Western Blotting , Proteínas de Transporte de Cátions/genética , Bovinos , Células Cultivadas , Endotélio Vascular/metabolismo , Fluorescência , Técnica Indireta de Fluorescência para Anticorpo , Hepcidinas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Receptores da Transferrina/genética , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Espectrofotometria AtômicaRESUMO
Polycythemia vera (PV) is a common cause of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). The postpartum period is a precipitating cofactor. An additional heparin-induced thrombocytopenia/thrombosis (HIT/T) leads to a life-threatening condition in which transjugular intrahepatic portosystemic shunting (TIPS) seems to be the only life-saving procedure. We describe the case of a subacute BCS and PVT in the late postpartum period. The diagnosis was established using CT scan, MRI, and Doppler ultrasonography of abdominal vessels and the laboratory findings were compatible with PV. After a successful creation of TIPS, a HIT/T worsened the hemorrhagic and thrombotic picture. TIPS procedure was successfully repeated and heparin was replaced with Fondaparinux and then vitamin K antagonist. The treatment with interferon alpha-2A, started after the normalization of liver functions, resulted in a complete remission within 6 months. The JAK2 V617F mutation clone remained undetectable after 2 years' follow-up.