ABSTRACT
Forty percent of renal cell carcinomas (RCCs) in childhood are characterized by translocation involving transcription factor E3 (TFE3) family members. Here, we describe a case of TFE3-positive RCC in which metastatic relapse to the mediastinal lymph nodes and pulmonary nodules was treated with single-agent sunitinib, a multitargeted tyrosine inhibitor. Complete radiologic remission was achieved after only 3 courses of treatment, and surgical exploration of metastases failed to identify any residual viable disease. The published experience of sunitinib in TFE-RCC is limited, and prospective evaluation of its activity in a larger number of patients is warranted.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Pyrroles/therapeutic use , Translocation, Genetic/genetics , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Child , Female , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Lung Neoplasms/genetics , Lung Neoplasms/secondary , Lymphatic Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Remission Induction , Sunitinib , Tomography, X-Ray ComputedABSTRACT
The Ewing sarcoma family of tumors (ESFT) represents an aggressive spectrum of malignant tumour types with common defining histological and cytogenetic features. To evaluate the functional activation of signal transducer and activator of transcription 3 (STAT3) in ESFT, we evaluated its activation in primary tissue sections and observed the functional consequences of its inhibition in ESFT cell lines. STAT3 was activated (tyrosine 705-phosphorylated) in 18 out of 31 primary tumours (58%), either diffusely (35%) or focally (23%). STAT3 was constitutively activated in 3 out of 3 ESFT cell lines tested, and its specific chemical inhibition resulted in complete loss of cell viability. STAT3 inhibition in ESFT cell lines was associated with several consistent changes in chemokine profile suggesting a role of STAT3 in ESFT in both cell survival and modification of the cellular immune environment. Together these data support the investigation of STAT3 inhibitors for the Ewing family of tumors.
ABSTRACT
PURPOSE: Neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN) are neuroblastic tumours (NT) of sympathetic nervous system origin. Brain lipid-binding protein (BLBP) has potential morphogenic activity during nervous system development but has not been studied in these tumours. We analyzed the expression of BLBP in NT according to histological subtypes and extent of differentiation. METHODS: Thirty cases of NT (10 each of NB, intermixed GNB, and GN) were identified from the histopathology archive of a single center. Tissue sections were obtained from representative paraffin blocks and immunohistochemistry for BLBP performed. RESULTS: Brain lipid-binding protein was not expressed in any NB case. In all cases of GN, BLBP was strongly expressed in the cytoplasm of mature ganglion cells but negative in Schwannian stroma. In the intermixed GNB, there was similar strong BLBP immunoreactivity in the cytoplasm of fully differentiated and differentiating ganglion cells but no BLBP expression in immature neuroblasts. CONCLUSION: Brain lipid-binding protein is strongly expressed in mature and maturing ganglion cells in NT (GN and GNB), whereas it is absent in poorly differentiated neuroblasts of GNB and NB. Cytoplasmic expression of BLBP in NT increases as the cells undergo neural differentiation and is therefore associated with the extent of tumour differentiation and favorable histology.
Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/pathology , Carrier Proteins/metabolism , Ganglioneuroma/pathology , Neuroblastoma/pathology , Tumor Suppressor Proteins/metabolism , Biopsy, Needle , Brain Neoplasms/diagnosis , Child , Child, Preschool , Diagnosis, Differential , Fatty Acid-Binding Protein 7 , Female , Ganglioneuroblastoma/diagnosis , Ganglioneuroblastoma/pathology , Ganglioneuroma/diagnosis , Humans , Immunohistochemistry , Male , Neuroblastoma/diagnosis , Sensitivity and SpecificityABSTRACT
Neural stem cells are present in the human post-natal brain and are important in the development of brain tumours. However, their contribution to non-neoplastic human disease is less clear. We have tested the hypothesis that malformations of cortical development contain abnormal (pathological) stem cells. Such malformations are a major cause of epilepsy. Two of the most common malformations [focal cortical dysplasia (FCD) and cortical tubers] are characterised by the presence of a population of abnormal cells known as balloon cells. The identity of these cells is unknown but one hypothesis is that they are an abnormal stem cell that contributes to the pathogenesis of the malformation. We have characterised in tissue, and isolated in culture, an undifferentiated population of balloon cells from surgical resections of FCD and cortical tubers. We show that beta1-integrin labels a sub-population of balloon cells with a stem cell phenotype and show for the first time that these cells can be isolated in vitro. We have characterised the immunohistochemical, morphological and ultrastructural features of these cells. This is the first isolation of an abnormal cell with features of a progenitor/stem cell from a non-neoplastic disease of the brain.
