Toxic cardiomyopathy leading to fatal acute cardiac failure related to vandetanib: a case report with histopathological analysis.

CONTEXT: Medullary thyroid carcinoma (MTC) accounts for 3-4% of all malignant thyroid neoplasias. Vandetanib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor 2, epidermal growth factor receptor, and RET, has been approved by the FDA for the treatment of locally advanced or metastatic MTC. The heart seems to be particularly susceptible to adverse effects associated with TKI therapy, and virtually all TKIs have been associated with cardiovascular events. CLINICAL PRESENTATION: We report the case of a patient with metastatic MTC who was enrolled in the Phase III clinical study (NCT00410761) and presented a favorable response to vandetanib therapy, displaying marked decrease in the level of serologic tumor markers and shrinkage of metastatic lesions. After 14 months of therapy, the patient developed a fatal cardiac failure. Myocardial infarction was excluded by serial measurements of specific cardiac markers (serial troponin-T measurements varied from 0.037 to 0.042 ng/ml) and serologic tests for Chaga's disease were negative. Postmortem examination of the heart revealed cardiomyocyte hypertrophy and marked myocyte degeneration in the subendocardial zones and papillary muscles of the myocardium. These pathological changes are similar to those observed in TKI-treated rats and are suggestive of drug-induced cardiotoxicity. CONCLUSION: This case illustrates a previously unreported serious vandetanib-related adverse effect and highlights the need for close monitoring of patients under TKI therapy in order to identify early signs of congestive heart failure or myocardium damage.

Exon 11 mutations, Ki67, and p16(INK4A) as predictors of prognosis in patients with GIST.

Prognostic biomarkers for GIST are under investigation. The aim of this study was to assess whether exon 11 mutations, Ki67, and p16(INK4A) are predictors of prognosis in GIST. Consecutive GIST cases (n=84) had their specimens evaluated for exon 11 mutations and expression of Ki67 and p16(INK4A). Surgical cases were categorized according to NIH and Miettinen's classification, and survival was analyzed from hospital database. GISTs were predominately gastric (45%) and with spindle cell morphology (74%). The risk category was very low or low in 28%, intermediate in 23%, and high in 49%. Exon 11 mutation was identified in 29 (48%) out of 60 cases studied. There were 12 point mutations, 10 deletions, 4 duplications, and 3 double mutations. A third of GISTs had either high Ki67 index (>3%) or negativity for p16(INK4A). In multivariate analysis, independent predictors of mortality were Ki67>3% (HR=7.3; P=0.036) and high mitotic index (HR=10.4; P=0.043). There was no association between exon 11 mutations and survival. This study suggests that Ki67>3% is an independent predictor of poor prognosis in patients with GIST. Exon 11 mutations and negativity for p16(INK4A) need further studies to address the prognostic value.

Mulher branca, 45 anos, consulta por diarréia crônica, emagrecimento e anemia ferropênica / 45-year-old, white woman presents with chronic diarrhea, weight loss and iron deficiency anemia

Em novembro de 1996, uma mulher branca de 45 anos veio à consulta por diarréia aquosa e emagrecimento acentuado. Negava tabagismo e alcoolismo. Ao exame físico, apresentava mucosas hipocoradas e emagrecimento. Trazia consigo o laudo de uma endoscopia digestiva alta considerada normal e de uma colonoscopia com descrição de cólon espástico. Os exames mostraram, no soro: glicose, 74 mg/dL; uréia, 13 mg/dL; creatinina, 0,4 mg/dL; sódio, 137 mEq/L; e potássio, 4,3 mEq/L. A pesquisa de leucócitos fecais e o parasitológico de fezes foram negativos (três amostras). Foi iniciado sulfato ferroso via oral. A reavaliação, em fevereiro de 1997, mostrou os exames contidos na tabela 1, além de: alanina aminotransferase (ALT), 57 UI/L (3-17); aspartato aminotransferase (AST), 62 UI/L (9-36); bilirrubinas e provas de coagulação normais. Foi iniciada a suplementação de ácido fólico. Como havia queixa de menorragia, a paciente foi avaliada por ginecologista, que indicou reposição hormonal. Em abril de 1998, a paciente persistia com queixa de menorragia e emagrecimento. Foi submetida a nova endoscopia digestiva alta, que evidenciou algumas erosões com fibrina, no antro, e mucosa de bulbo duodenal com aspecto ladrilhado

Perfil da mortalidade neonatal em Porto Alegre: revisäo de 715 casos de necrópsias / Profile of the neonatal mortality in Porto Alegre: review of 715 cases of necropsy

Para a programaçäo da assistência e educaçäo médica é fundamental o conhecimento dos tipos e freqüências de patologias que acometem a populaçäo neonatal da nossa regiäo. Com essa finalidade, os autores, revisaram 715 casos de necrópsias realizadas no HCPA, num período de dez anos, 75,2% dos casos eram provenientes de outros hospitais de Porto Alegre e o restante do próprio HCPA. Os resultados obtidos em relaçäo à mortalidade neonatal correspondem aos descritos na literatura, sendo que nos casos provenientes de outros hospitais de Porto Alegre predominaram: prematuridade (48,3%), doenças hematológicas (46,6%), membrana hialina (33,0%), doenças infecciosas (21,9%), sofrimento fetal (21,2%), mal formaçöes (16,2%), outras (9,4%); e no HCPA: prematuridade (62,7%), membrana hialina (38,4%), doenças hematológicas (36,2%), malformaçöes (24,3%), sofrimento fetal (15,9%),doenças infecciosas (13,6%), e outras (11,9%). Tais dados salietam as características terciárias do HCPA. Esses dados podem contribuir para o conhecimento das condiçöes de saúde de recém-nascidos em nosso meio