The lifelong impact of fetal growth restriction on cardiac development

Background: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. Methods: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. Results: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR–FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR–FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR–FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. Conclusions: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development

Acute Progression of BCR-FGFR1 Induced Murine B-Lympho/Myeloproliferative Disorder Suggests Involvement of Lineages at the Pro-B Cell Stage

Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19+ IgM− CD43+ immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19+ IgM− CD43+ were also either B220+ or B220−, suggesting a block in differentiation at the pro-B cell stage. The B220− phenotype was retained in one of the cell lines while the other was B220+. When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease

Pediatric primary intramedullary spinal cord glioblastoma

Spinal cord tumors in pediatric patients are rare, representing less than 1% of all central nervous system tumors. Two cases of pediatric primary intramedullary spinal cord glioblastoma at ages 14 and 8 years are reported. Both patients presented with rapid onset paraparesis and quadraparesis. Magnetic resonance imaging in both showed heterogeneously enhancing solitary mass lesions localized to lower cervical and upper thoracic spinal cord parenchyma. Histopathologic diagnosis was glioblastoma. Case #1 had a small cell component (primitive neuroectodermal tumor-like areas), higher Ki67, and p53 labeling indices, and a relatively stable karyotype with only minimal single copy losses involving regions: Chr8;pter-30480019, Chr16;pter-29754532, Chr16;56160245–88668979, and Chr19;32848902-qter on retrospective comparative genomic hybridization using formalin-fixed, paraffin-embedded samples. Case #2 had relatively bland histomorphology and negligible p53 immunoreactivity. Both underwent multimodal therapy including gross total resection, postoperative radiation and chemotherapy. However, there was no significant improvement in neurological deficits, and overall survival in both cases was 14 months.This report highlights the broad histological spectrum and poor overall survival despite multi modality therapy. The finding of relatively unique genotypic abnormalities resembling pediatric embryonal tumors in one case may highlight the value of genome-wide profiling in development of effective therapy. The differences in management with intracranial and low-grade spinal cord gliomas and current management issues are discussed

Intraoperative neurocytology of primary central nervous system neoplasia: A simplified and practical diagnostic approach

Intraoperative consultations may pose considerable diagnostic challenge to the neuropathologist in diagnosing primary and metastatic neoplasms of the central nervous system (CNS). Cytological preparations in the form of squash, touch, imprint or smears are few of the available modalities in addition to the frozen section (FS). Although the latter is superior in providing both histologic patterns and cytomorphologic details yet smears are of vital importance when tissue available is limited (stereotactic biopsy), scrutinisation of intercellular matrix (astrocytoma versus oligodendroglioma) and evaluation of discohesive cells (lymphoma, pituitary adenoma) and in inflammatory lesions. This review is intended to emphasize the value, applicability and limitations of neurocytology aiming to expedite the intraoperative smear-based diagnoses of CNS neoplasia as per the World Health Organization (WHO) classification. We recommend that whenever possible, both smears and FS should be examined concomitantly and in a correlative manner. In the unlikely event of a mismatch between the findings on smear and FS, intraoperative diagnosis is primarily based on FS, if adequate tissue is available. However, each case must be evaluated on its own merit and in difficult cases relevant differential diagnoses should be offered to facilitate surgical decisions and optimally triage patient management

Neurocytoma: a comprehensive review

Central neurocytomas (CN) are uncommon tumors of the central nervous system, most descriptions of which available in the literature are in the form of isolated case reports and small series. Owing to this rare incidence, diagnosis and management of this neoplasm remain controversial. Usually, these tumors affect lateral ventricles of young adults and display characteristic neuroimaging and histomorphologic findings. Neurocytomas often mimic oligodendrogliomas when confirmation of diagnosis rests on immunohistochemistry, ultrastructure, and genetic studies. Extraventricular neurocytomas, situated entirely within the brain parenchyma and spinal cord, have also been reported. Typically, CN are associated with a favorable outcome although cases with more aggressive clinical course with recurrences are not unknown. MIB-1 labeling index (LI) of >2% often heralds poor prognosis and tumour recurrence. Safe maximal resection is presently considered the ideal therapeutic option, with best long-term prognosis in terms of local control and survival. The role of adjuvant radiotherapy apparently seems to benefit patients with incomplete resection and in atypical neurocytoma. Utility of other therapeutic regimen, however, remains shrouded in controversy. Epidemiology, histogenesis, clinical profile, histology, neuroimaging and therapeutic modalities of neurocytomas have been comprehensively reviewed, with special emphasis on CN and extraventricular neurocytomas and their atypical counterparts

Angiogenic patterns and their quantitation in high grade astrocytic tumors

Background: The objectives of this study on high grade astrocytic tumors were (i) to establish differences, if any, between grades III & IV tumors among angiogenic parameters, both qualitative and quantitative, and (ii) to correlate angiogenic parameters with proliferation indices, namely T2a and MIB1 labeling indices. Design: Twenty nine consecutive cases of WHO grades III (11) and IV (18) astrocytic tumors diagnosed in the year-2004 were studied, using H&E and CD34, MIB1 and T2a immunostaining by streptavidin biotin technique. Angiogenic patterns were studied and parameters quantitated using Image Pro Plus software (four hotspots) on CD34 immunostained sections to determine intratumoral microvessel density (iMVD), microvascular area (MVA), aspect, mean diameter (MD) and fractal dimension (FD). Results: Main angiogenic patterns of capillary (18) and glomeruloid (9) types were best developed in glioblastomas. Statistically significant differences (P<0.05) were seen between grades III and IV in iMVD, aspect, MD and FD, but not in angiogenic patterns or MVA (P=0.27). Statistically significant differences (P<0.05) were seen between glioblastomas with glomeruloid vs. capillary types in iMVD and FD, but not in MVA, aspect and mean vessel diameter. T2a values correlated with MIB1 labeling indices (R=0.965, P<0.001). Intratumoral endothelial MIB1 LI was significantly higher in grade IV as compared to grade III, but did not correlate with angiogenic parameters. No correlation of angiogenic patterns and proliferation indices was noted (R=−0.221, P=0.26). Limited follow up data showed all recurrent grade IV tumors to be of glomeruloid type. Conclusion: Increased angiogenesis in grade IV, as compared to grade III, astrocytic tumors is characterized by an increased number/density of vessels: an increase in vessels characterized by disproportionate lengthening and likely associated with the infiltrative properties of the tumors; and an increase in pliable, irregularly shaped or structured vessels. In addition, there is a greater frequency of glomeruloid structures indicating inadequate directional migration of the newly formed vessels. The lack of correlation of these angiogenesis parameters with the MIB1 and T2a proliferation indices reflects the complexity of angiogenesis parameters in high grade gliomas. Further studies are needed to determine the usefulness of the angiogenic parameters in the improved diagnosis (grading) and prognosis of astrocytic tumors

Extra gonadal germ cell tumours: report of two cases

Extra gonadal germ cell tumours (EGGCT) in women are rare. We report here two such patients. The clinical and laboratory features were - young age, 25 and 22 years, midline location (mediastinum, scalp), elevated tumour marker and normal ovaries on CAT scan. The histological subtype was embryonal carcinoma in both cases. Complete response (CR) was achieved with cisplatin based chemotherapy (CT). Both patients had return of normal ovarian functions and have delivered normal babies (1st patient one, 2nd patient 2 babies). Both remain asymptomatic and disease-free at 30 + and 55 + months follow-up. We conclude that patients with EGGCT after treatment with cisplatin based CT achieve CR with return of normal ovarian functions and prolonged survival

Granular cell astrocytoma: Case report

Granular Cell Astrocytoma (GCA) is a rare astrocytic brain tumor histologically composed of plump astrocytic cells with abundant eosinophilic granular cytoplasm that exhibits immunoreactivity for GFAP and S100 proteins. It is associated with poor outcome often akin to glioblastoma despite its bland histologic appearance. We report a case of GCA in which neoplastic cells resembled macrophages on intra-operative frozen section and smear. Paraffin sections showed features of a granular cell astrocytoma, WHO grade IV, with diffuse immunohistochemical coexpression of GFAP and S100. No mutation of IDH1 or P53 was identified by immunohistochemistry; however, ATRX loss indicating mutation supported an astrocytic lineage. Additionally, sporadic weak cytoplasmic staining for CD68 and EMA and negative staining for CD163 is likely non-specific due to increased lysosomal activity and does not indicate true histiocytic or epithelial differentiation. We recommend that in the absence of overt high-grade features or admixture with conventional diffuse astrocytoma on intra-operative smear and frozen section, it may be advisable to wait to confirm the diagnosis on paraffin section histology and immunohistochemical stains before proceeding with definitive tumor resection. This diagnostic approach will prevent over-treatment by resection of non-neoplastic mimics of GCA