For which cancer types can neuron-specific enolase be clinically helpful in Turkish patients?

BACKGROUND: The aim of the present study was to evaluate the serum neuron-specific enolase (NSE) levels in patients with prostate cancer, Hodgkin lymphoma, lung cancer and peripheral nerve tumors. MATERIALS AND METHODS: NSE levels were determined by ELISA in the sera of 100 prostate cancer, 47 Hodgkin lymphoma, 35 lung cancer and 35 peripheral nerve tumor patients and also in 132 healthy controls. RESULTS: The median levels of serum NSE were elevated in patients with lung cancer (p=0.018) and peripheral nerve tumors (p=0.008). NSE levels in prostate cancer and Hodgkin lymphoma patients were higher than the controls but there was no statistically significant difference (p>0.05). CONCLUSIONS: We conclude that NSE may be applied in routine to gain insight about the clinical statuses of various cancer patients, but more studies are needed to determine the organ specificity.

Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblastoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-ß pathway in various tumor models. Cytokine TGF-ß can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model.

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.

Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1(fl/fl);Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.

Ultrastructural study of a perineurioma.

A case of soft tissue tumor in the left brachialis muscle of a 49-year-old Japanese female patient was studied by electron microscopy. The tumor was diagnosed as intramuscular myxoma by light microscopy, but electron microscopic observation revealed that the tumor almost entirely consisted of cells similar to normal perineurial cells. The tumor cells possessed long, slender cytoplasmic processes covered by well-developed but discontinuous basal laminae, clusters of pinocytotic vesicles, and infrequent intercellular junctions. Perineurial cells have also been observed in other peripheral nerve lesions: neurofibromas, nerve sheath myxomas, and localized hypertrophic neuropathies. However, the term "perineurioma" or "perineurial cell tumor" should be reserved for discrete tumorous masses that are almost entirely composed of perineurial cells without evidence of residual axons, Schwann cells, fibroblasts, or tactile corpusclelike structures. Perineurioma may represent a third category of peripheral nerve sheath tumors, ultrastructurally distinct from schwannomas and neurofibromas.

Differential protooncogene expression characterizes histopathologically indistinguishable tumors of the peripheral nervous system.

We have found highly predictable patterns of protooncogene expression in cell lines and tumor tissue of neuroblastoma (NB), a tumor of the peripheral nervous system (PNS). These patterns make it possible to recognize two different genetically definable subgroups among histopathologically indistinguishable tumors. Additionally, we have identified a difference in neurotransmitter biosynthetic enzyme activity in these two subgroups of NB. The patterns of protooncogene expression and neurotransmitter biosynthetic enzymes suggests that these tumors arise in different cells of the PNS.

Paraganglioma of the cauda equina: a histological, ultrastructural and immunocytochemical study of two cases with a review of the literature.

The clinical and pathological features of two paragangliomas arising in the cauda equina are described and compared with 14 previous reports. The light microscopic features were similar to those of paragangliomas from other sites, with a 'Zellballen' pattern of cells containing argyrophil granules. Electron microscopy showed densely staining membrane-bound granules, cilia and fibrous bodies in the cytoplasm. The last two features only occur in paragangliomas from this site. gamma-Enolase was demonstrated by the peroxidase-antiperoxidase technique for the first time in these neoplasms. This technique was also used to demonstrate cytokeratins, which appear to be associated with the presence of fibrous bodies. The pathological findings suggest that paragangliomas in this site arise from pre-existing paraganglia, possibly of the visceral autonomic group. The prognosis in cases treated by complete excision appears to be good.

Immunohistochemical demonstration of neuron-specific enolase in neoplasms of the CNS and other tissues.

In normal conditions, neuron-specific enolase (NSE) is histochemically demonstrable only in neurons and cells of the amine precursor uptake and decarboxylation (APUD) system. This has been found not to be true for neoplastic cells. Several types of CNS tumors, including glioblastoma, astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, pineocytoma , meningioma, and choroid plexus papilloma, focally stained positively for NSE. Reactive astrocytes were also frequently positive. In the peripheral nervous system, neuroblastoma, ganglioneuroma, and paraganglioma stained positively for NSE. A number of non-APUD tumors were focally positive. These included schwannoma, carcinoma and fibroadenoma of the breast, renal cell carcinoma, giant cell tumor of the tendon sheath, and chordoma. Caution should be exercised in relying on the immunohistochemical demonstration of NSE as a diagnostic marker in those tumors that do not belong to the APUD cell system. It seems of little value as evidence of differentiation in CNS tumors.

Synovial sarcoma enzyme histochemistry of a typical case.

A typical case of biphasic synovial sarcoma was studied using enzyme histochemistry. A marked difference between the staining characteristics of the spindle cells and the epithelial-like cells was demonstrated by reactions for various hydrolytic enzymes. The epithelial-like cells exhibited a strong reactivity for alkaline phosphatase, acid phosphatase, adenosine triphosphatase and nonspecific esterase, whereas spindle-cells were completely unreactive when tested for these enzymes. This is, to our knowledge, the first report demonstrating differences in the enzymatic pattern of the two cell populations which compose synovial sarcoma.

Creatine kinase isoenzyme patterns in neoplasms of peripheral nerve.

Normal peripheral nerve and neoplastic lesions of peripheral nerve varied in their creatine kinase (CK; EC 2.7.3.2) isoenzyme pattern, as assessed both with electrophoresis and with column chromatography. All three isoenzymes were seen in normal peripheral nerve, but the peripheral nerve tumors, neurofibroma and neurilemmoma, demonstrated predominantly CK-1 isoenzyme activity, with a trace amount of CK-3. No CK-2 activity was demonstrated in these tumors. In contrast, malignant schwannoma tissue contained all three isoenzymes, but in a different proportion than in normal peripheral nerve.

Cerebrospinal fluid lysozyme activity in patients with central nervous system tumours.

The presence of lysozyme in the CSF is considered with regard to its value in the early diagnosis of primary or secondary CNS Tumours. Since the appearance of this enzyme in the CSF is secondary to the increase of protein in the fluid, the search for lysozyme in the CSF is of no practical help in the diagnosis of CNS tumours.

[Ezymohistochemical study of the early stages of carcinogenesis in the rat peripheral nervous system]. / Enzimogistokhimicheskoe issledovanie rannikh stadii kantserogeneza v perifericheskoi nervnoi sisteme krys.

Early blastomatous changes in the peripheral nervous system induced by transplacental N-nitroso-N-ethylurea exposure were manifested in lemmoblasts proliferates, observed starting from the 14th day of the postnatal period in rats. The proliferates showed the increased activity of ortho-phosphoric and carbonic esters hydrolysis enzymes pentose cycle, ultimate glycolysis and the reduced citric acid cycle, tissue respiration, the synthesis of aminoacids, folic acid, nucleoproteids precursors, and a sharp suppression of oxidative desamination. Such profile of enzymic provision was retained in neurinomas developed 6 months following the postnatal period. Based on the data obtained, it is concluded that the process of glial cells malignant transformation is terminated long before the appearance of malignant neoplasms detected macroscopically.

[Deoxyribonucleases in spontaneous and experimental tumors of the nervous system]. / Desoxyribonucleasen in spontanen und experimentellen Tumoren des Nervensystems

DNA- and RNA-concentrations, as well as in vitro activities of DNase I (EC 3.1.4.5), DNase II (EC 3.1.4.6), and DNase I inhibitor, have been determined in 63 spontaneous (man) and 22 experimentally induced (rat) nervous system blastomas of various types and of different degrees of malignancy. Generally, a distinct elevation of DNA concentrations and of the ratio (Q) of DNase II- to DNase I-activities has been observed when compared with control values. A statistically significant relationship could be demonstrated between increase of DNA concentrations and Q in experimentally induced neurinomas of rats as well as in human astrocytomas and glioblastomas. Whereas the increase of Q may be a biochemical expression of elevated DNA synthesis of tumour cells, no conclusions can be drawn as to the role of DNases in the process of malignant transformation.

Sequential development of ethylnitrosourea-induced neurinomas: morphology, biochemistry, and transplantability.

Sequential evaluations were made of the morphology and biochemistry of trigeminal nerves from control and ethylnitrosourea (ENU)-exposed rats from 1 day to 6 months of age. Distinct increases in cellularity were evident as early as 20 days after exposure to ENU. Corresponding increases in N-acetyl-beta-glucosaminidase and beta-glucuronidase were detected at the same time. Transplantation studies were performed with grossly normal trigeminal nerves from 32-, 63-, and 91-day-old control and ENU-exposed rats. One of eight nerves from the 32-day-old ENU-exposed donors developed into neurinomas at the site of transplantation. No tumors developed from nerves of controls. These results indicate that the early increases in cellularity and acid hydrolase activities represent neoplastic rather than preneoplastic changes.