Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome

PURPOSE: The diagnostic and prognostic significance of well-defined molecular markers was investigated in childhood primitive neuroectodermal tumors (PNET). MATERIALS AND METHODS: Using microsatellite analysis, Southern blot analysis, and fluorescence in situ hybridization (FISH), 30 primary tumors and six CSF metastasis specimens were analyzed for loss of heterozygosity (LOH) of chromosomes 1q31, 6q, 9q22, 10q, 11, 16q22, and 17p13.1 and/or high-level amplification of the c-myc gene. Experimental data were compared with clinical stage and outcome. RESULTS: LOH of chromosome 17p13.1 was found most frequently (14 of 30 tumors, six of six CSF metastasis specimens); LOH of chromosomes 10q, 16q22, 11, 6, 9q22, and 1q31 was observed in 20.6%, 20%, 14.3%, 12%, 10%, and 0%, respectively. Eight of 32 tumors and CSF specimens showed amplification of c-myc. All tumors with amplification of c-myc were resistant to therapy and had a fatal outcome (mean survival time, 9.3 months). Tumors that displayed LOH of chromosome 17p were associated with metastatic disease. The prognosis of these tumors was worse only when associated with amplification of c-myc. Three of three patients with LOH of 9q22 relapsed. CONCLUSION: In our study, amplification of c-myc was a poor-prognosis marker in PNET. LOH of chromosome 17p was associated with metastatic disease. Molecular analysis of primary tumors using these markers may be useful for stratification of children with PNET in future prospective studies. The other aberrations investigated were not of significant prognostic value, but may provide an entry point for future large-scale molecular studies.     

Ewing''s sarcoma and peripheral primitive neuroectodermal tumors after their genetic union

The presence of BRCA1 protein was determined immunohistochemically in normal and benign breast biopsies, non-familial breast carcinomas and breast carcinomas from one or more individuals from 8 BRCA1 families. Strikingly, little staining was detected in breast carcinomas from BRCA1 families, regardless of the position or type of mutation, whereas strong immunostaining was observed in 28/28 of non-malignant breast biopsies. Furthermore, BRCA1 staining was reduced in non-familial breast carcinomas, since loss of nuclear BRCA1 staining was evident in 19% of non-familial breast carcinomas whilst a similar proportion (20%) showed absence of either cytoplasmic or nuclear BRCA1 staining. Statistical analysis indicates that breast cancer is characterised by a reduction in levels of nuclear BRCA1 in familial (p < 0.001) and non-familial breast cancer (p = 0.001). In non-familial breast cancer absence of nuclear BRCA1, but not cytoplasmic BRCA1, is more common in high grade breast carcinomas (p = 0.03) and in patients with evidence of lymph node involvement (p = 0.05). Correlation between the absence of BRCA1 protein with high grade is consistent with previous findings of a correlation between mutations in the BRCA1 gene and high grade. Our findings provide new evidence in support of BRCA1 as a tumour suppressor protein in non-familial breast cancer.     

Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system

Until fairly recently, investigations into the control of cell production (proliferation) have been the mainstay of studies into the maintenance of mucosal homeostasis and general integrity. However, in addition to proliferation, it is now increasingly evident that programmed cell death, specifically that form of programmed cell death known as apoptosis, is an equally, if not more important, mechanism of regulating mucosal cell number. This review will concentrate on the significance of damage (radiation) induced and spontaneous apoptosis in the maintenance of intestinal epithelial stem cell number and integrity, and its probable link to the level of cancer incidence in the small intestine and colon.     

Relation between maternal diet and subsequent primitive neuroectodermal brain tumors in young children

BACKGROUND: It has been hypothesized that a high dietary intake of nitrosamines and their precursors, nitrites and nitrates, is a risk factor for brain tumors. Vitamins C and E inhibit the formation of nitrosamines and thus may be protective. METHODS: We conducted a case-control study of maternal diet and the risk of primitive neuroectodermal tumors of the brain in children. The case patients were under the age of six years at diagnosis in 1986 to 1989. The controls were selected by random-digit telephone dialing and were matched for age and race to 166 case patients. Telephone interviews with the mothers included questions on the frequency of consumption of alcohol, vitamin and mineral supplements, and 53 foods during pregnancy. RESULTS: Significant protective trends were observed for vegetables (odds ratio for the highest quartile group for intake relative to the lowest, 0.37; P for trend = 0.005), fruits and fruit juices (odds ratio, 0.28; P = 0.003), vitamin A (odds ratio, 0.59; P = 0.03), vitamin C (odds ratio, 0.42; P = 0.009), nitrate (odds ratio, 0.44; P = 0.002), and folate (odds ratio, 0.38; P = 0.005). A nonsignificant trend of increasing risk was observed for nitrosamine (odds ratio, 1.65; P = 0.15). The use of iron (odds ratio, 0.43; P = 0.004), calcium (odds ratio, 0.42; P = 0.05), and vitamin C (odds ratio, 0.35; P = 0.04) supplements at any time during the pregnancy and the use of multivitamins during the first six weeks (odds ratio, 0.56; P = 0.02) were associated with decreased risk. In multivariate analyses, folate, early multivitamin use, and iron supplements generally remained protective. CONCLUSIONS: These results do not support the hypothesis that nitrosamines have a role in the development of primitive neuroectodermal tumors in young children, but they do suggest that certain other aspects of maternal diet can influence the risk.     

Mapping of chromosomal gains and losses in primitive neuroectodermal tumors by comparative genomic hybridization

Pediatric fungal pulmonary infections are being seen with increasing frequency. The dimorphic fungi Histoplasma capsulatum. Blastomyces dermatitidis, Coccidioides immitis, and Cryptococcus neoformans frequently cause infections that are asymptomatic. However, patients may suffer pneumonia and disseminated disease. Diagnosis can be made definitively by isolation of the causative organism, but serology or skin testing is often necessary when this is not successful. Severe or life threatening infections are treated with amphotericin B. Recently, new oral azole antifungals are being used more frequently for mild to moderate disease with good success.     

Mutation analysis and loss of heterozygosity of PEDF in central nervous system primitive neuroectodermal tumors

CF mice, i.e., mice without functional CFTR (cystic fibrosis transmembrane conductance regulator) exhibit a very low basal Isc in all regions of the intestinal tract. The low basal Isc in the intestinal epithelia of the CF mice appears to be a result of lack of spontaneous Cl- secretion (and possibly HCO3- secretion) mediated by neurotransmitter release from the enteric nervous system. In contrast to intestinal epithelia from normal mice, the intestinal epithelia of CF mice do not secrete Cl- in response to agents that increase cAMP (forskolin). Furthermore, as in human CF patients, agents that increase intracellular Ca2+ (bethanacol, ionomycin) failed to elicit Cl- secretion in the intestinal epithelia of CF mice. There was no difference in the electrogenic Na(+)-coupled glucose absorption in the CF murine jejuna compared to jejuna from normal mice. However, further studies are warranted to determine whether amiloride-sensitive Na+ absorption is upregulated in the murine CF colon. It was concluded that the intestinal epithelium of the CF mouse model exhibits some striking similarities to its human counterpart, and therefore should be very useful in further characterizing the ion transport defects in this disease.     

Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors

Synovial sarcoma is a relatively common sarcoma in adults, which in its classic bimorphic form infrequently poses a diagnostic problem. Monomorphic spindled variants, as well as the less common poorly differentiated variants, may be confused with other soft-tissue sarcomas; the poorly differentiated variant (PDSS), in particular, may be histologically indistinguishable from other small, blue, round cell tumors, including primitive neuroectodermal tumors (PNETs). Detection of the synovial sarcoma-associated t(X;18) by either cytogenetic or molecular genetic approaches may be necessary to confirm the diagnosis of synovial sarcoma in difficult cases. We evaluated 10 cases of PDSS from eight patients using a panel of antibodies (including those to intermediate filament proteins, nerve-sheath associated markers, and neuronal and neuroectodermal associated markers) in order to better establish the immunophenotype of this tumor and to help distinguish it from the tumors with which it may be confused, particularly PNETs and high-grade malignant peripheral nerve sheath tumors (MPNSTs). Our results showed PDSS to have significant immunophenotypic overlap with both PNETs and MPNSTs. In most instances these three entities may be differentiated by a panel of antibodies that should include those to both low and high molecular weight cytokeratins, epithelial membrane antigen, type IV collagen, CD99, CD56, and S-100 protein. Our results also suggest that synovial sarcoma may be a tumor showing combined neuroectodermal and nerve sheath differentiation--perhaps because of translocation-associated expression of specific proteins--rather than a carcinosarcoma of soft tissues or a tumor of specialized arthrogenous mesenchyme.     

Thyroid cancer in pregnant women: diagnostic and therapeutic management

There is considerable literature on the effect of pregnancy on established thyroid cancer. In contrast, there are only isolated case reports of management of thyroid cancer diagnosed de novo during pregnancy. We describe four such patients. We recommend fine-needle aspiration biopsy (FNA) of solitary thyroid nodules found early in pregnancy. When the cytopathology is diagnostic of thyroid cancer, thyroidectomy under local or general anesthesia is advised. The patient should be given levothyroxine in a dose sufficient to keep serum thyroid-stimulating hormone (TSH) low. Serum thyroglobulin is a valuable noninvasive method of evaluating completeness of this therapy. The work-up of a nodule found late in pregnancy is best deferred until after delivery.     

Current trends in the detection and management of carotid body tumors

PURPOSE: Because the natural history of carotid body tumors is believed to be unpredictable, immediate surgical removal has been recommended. The present study reviews our experience in the diagnosis and treatment of these uncommon lesions. METHODS: The medical records of patients who appeared for treatment with carotid body tumors between 1981 and 1997 were reviewed. Patients demographics, mode of presentation, imaging and treatment modalities, Shamblin classification, and neurologic complications (stroke, cranial nerve injuries) were analyzed. RESULTS: Over the past 16 years, 31 patients with 32 carotid body tumors have been evaluated, with an average follow-up of 3.2 years. The patients were arbitrarily classified into two groups on the basis of the mode of detection. Seventy percent (23 of 32) of the tumors discovered on clinical or self-examination were classified as Group 1; 28% (9 of 32) of the tumors detected during duplex scanning for carotid artery disease (8) or MRI (1) were classified as Group 2. The mean size of chemodectomas found on palpation (4.3 +/- 1.7 cm) was larger than that of those detected by duplex ultrasound (2.7 +/- 1.0 cm; p < 0.05, by paired t test). Preoperative embolization was successfully performed in 5 of 6 instances of large tumors; the remaining patient suffered a procedure-related stroke. Thirty-one carotid body tumors were resected. In one case, the tumor was felt by the primary surgeon to be too small (0.9 x 0.7 cm on duplex scan) to warrant immediate excision; this patient is being followed by periodic duplex scanning. Five neurologic complications were noted in Group 1, one after preoperative embolization and four after surgery. One cranial nerve injury occurred in Group 2. One patient had a large recurrent chemodectoma with clinical evidence of metastatic disease. CONCLUSION: The increasing use of sophisticated imaging modalities may allow earlier discovery of carotid body tumors before they can be clinically detected. Resection of carotid body tumors of all sizes in appropriate surgical candidates remains the standard of care. Unfortunately, resection of even small tumors is associated with a low but constant incidence of neurologic complications.     

Primitive neuroectodermal tumors of the minor pelvis in women--case report]

A primitive neuroectodermal tumour (PNET) of the minor pelvis is a rare malignant small-cell tumour developing from the neural groove. It metastatizes into the lungs, bones, liver and brain. Treatment involves radical surgical extirpation followed by chemotherapy and actinotherapy. The author presents the case-history of PNET of the pelvis minor in a 33-year-old woman.     

Endogenous ornithine in search for CNS functions and therapeutic applications

The vertebrate brain has the machinery to transport arginine and ornithine, and to form within nerve endings from these amino acids glutamate and GABA, the major excitatory and inhibitory neurotransmitters. Ornithine aminotransferase is a key enzyme of the Arg-->Orn-->Glu-->GABA pathway; the physiological significance of this pathway is still unclear. With 5-fluoromethylornithine, a selective inactivator of ornithine aminotransferase, a tool is in our hands that allows us to study biochemical and behavioral consequences of elevated tissue ornithine concentrations. Increase of the rate of hepatic urea formation, and of ornithine decarboxylation are the most important changes in vertebrates following inactivation of ornithine aminotransferase. Administration of 5-fluoromethylornithine prevented the accumulation of lethal concentrations of ammonia in brain, and ameliorated pathological consequences of thioacetamide intoxication. Inhibition of ornithine catabolism has, therefore, potentials in the therapy of those hyperammonemic states which are characterized by a conditional deficiency of ornithine. The enhancement of polyamine formation due to elevated ornithine concentrations may allow us to favorably affect tissue regeneration following injury.     

Narcolepsy in children--a diagnostic and therapeutic challenge

Narcolepsy is a socially and psychologically disabling disease that most often develops in adolescence or early adulthood. In a number of studies about one-third of the patients had experienced the first symptoms before the age of 15. The diagnosis and subsequent treatment is usually not established until several years later, often ten to fifteen years after the appearance of the first symptoms. If unrecognized and untreated, narcolepsy may lead to serious psychological and social problems during childhood and early adulthood, which may in turn cause difficulties in social adjustment later in life. This stresses the importance of early diagnosis. The diagnosis is based on clinical and polysomnographic criteria. In children, however, the clinical symptoms and polysomnographic findings may be atypical, making it difficult to establish a definite diagnosis. Three patients, two five-year olds and one four and a half-year old, are presented to illustrate the problems and considerations which must be taken into account in the diagnosis and treatment of children with narcolepsy.     

New diagnostic and therapeutic aspects of lymphogranulomatosis

The prognosis of lymphogranulomatosis has improved by the considerably improved diagnostics as well as the modern radiological and polychemo-therapeutical methods. Today the average survival time is between 4 and 5 years. But survival times up to 15 years and more are described. Apart from the early diagnosis, into which according to the opinion of many internal specialists the otorhinolaryngologists must be included more than it was hitherto the case, nowadays the modern radiotherapy with explorative laparotomy and splenectomy and the perhaps following combination chemotherapy might bring a further improvement. Growing age, histological types with a small number of lymphocytes, too late diagnosis and deficient control decrease, however, signigicantly the chances of surviving. Certainly, in future more modern methods of chemotherapy must be used. The same applies to the treatment of the developing immunoinsufficiency and the eventual further performance of the cytostatic treatment in the sense of a maintenance therapy. From the modern point of view the way taken might lead to still higher survival times. In as far immunotherapy will be of greater importance already in the next years is not yet to be decided at present.     

Primary testicular and paratesticular tumors of childhood

Testicular and paratesticular neoplasms are uncommon tumors of childhood. Consequently, the experience gained with regard to their optimal management is limited in any given children's cancer centre. Here we review the classification, diagnosis, and staging of testicular and paratesticular neoplasms and subsequently discuss the more frequently occurring ones: germ cell tumors, gonadal stromal tumors, gonadoblastoma, tumors of the supporting tissue, lymphomas and leukemias, tumor-like lesions, secondary tumors, and tumors of the adnexa.     

New diagnostic and therapeutic possibilities in neonatal sepsis

Neonatal sepsis remains a major clinical problem in neonatology, with high morbidity and mortality rates. The host defence against infections is immature in the newborn infant, and this makes the child more susceptible to invasive infection. The neutrophil storage pool and various granulocyte functions are impaired. In addition, the levels of immunoglobulins and complement are low. The detection of raised levels of complement activation products and cytokines may be of diagnostic help at an early stage of neonatal infection. Rapid treatment with antibiotics is essential for a favourable outcome. Possible adjuvant treatment may be to reduce the relative immunodeficiency by giving immunoglobulins or colony-stimulating factors which increase the production of leukocytes. Further, the potent inflammatory reaction initiated by the microorganisms may be suppressed by various therapies. In spite of much research in this field, no such adjuvant treatment has so far been shown to improve the outcome of neonatal sepsis.