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PubMed1995

The cellular and molecular biology of medulloblastoma.

Medulloblastomas are prototypical of primitive neuroectodermal tumors which are some of the most frequent malignant brain tumors of childhood. The cell biology of medulloblastomas is still poorly understood, but recent studies of the expression of trophic factors and their receptors in medulloblastomas and the development of animal models of primitive neuroectodermal tumors may provide clues as to the induction or progression of these tumors. For example, they could clarify mechanisms that regulate cell death, proliferation and differentiation in these tumors.

Brain Neoplasms↗
PubMed1993

Small cell osteosarcoma of bone: an immunohistochemical study with differential diagnostic considerations.

Seventy-nine cases of small round cell tumors involving bone were studied in an attempt to learn whether the immunohistochemical features of the lesions might allow distinction of small cell osteosarcoma from other potential differential diagnostic considerations, including Ewing's sarcoma, atypical Ewing's sarcoma, primitive neuroectodermal tumor, mesenchymal chondrosarcoma, lymphoma, and the Askin tumor. The tissues studied were all formalin-fixed, decalcified, paraffin sections from patients between the ages of 16 and 48 years. With one exception (a small cell osteosarcoma), none of the lesions was cytokeratin positive. Moreover, none of the lesions was epithelial membrane antigen, desmin, factor VIII-related antigen, synaptophysin, or Leu-M1 positive. Accordingly, strong positivity for these antibodies in a majority of tumor cells should prompt inclusion of tumor types other than those listed above in the differential diagnosis. Vimentin positivity was seen in a majority of the tumors studied irrespective of histologic type. Scattered tumor cells (< 25%) showed positivity with antibodies to muscle-specific actin and smooth muscle actin in several of the different tumor types studied. No lesions other than lymphoma were leukocyte-common antigen (LCA) positive; all but two lymphomas were LCA positive, while all but one lymphoma were L26 positive. One (lymphoblastic) lymphoma was LCA and L26 negative. S-100, neuron-specific enolase, and Leu-7 did not prove to be specific for "neural-associated" tumors, but rather appeared in some small cell osteosarcomas, Ewing's sarcomas, atypical Ewing's sarcomas, primitive neuroectodermal tumors, mesenchymal chondrosarcomas, lymphomas, and Askin tumors. Antibody to cell surface antigen HBA71 was positive in three Ewing's sarcomas (two typical and one atypical) and negative in small cell osteosarcoma (three cases), mesenchymal chondrosarcoma (two cases), and lymphoma (one case). While some guidance may be derived from analysis of immunohistochemical staining patterns in a given lesion, the results reported in the present study do not suggest that routine immunohistochemistry alone will permit distinction of these small cell tumors of bone from one another. The value of immunohistochemical studies appears to lie particularly in the use of antibodies to LCA and S-100 protein to distinguish lymphoma and mesenchymal chondrosarcoma, and perhaps antibody to HBA71 to distinguish neural family lesions (such as Ewing's sarcoma), from other small cell tumors, such as small cell osteosarcoma.

Adolescent↗
PubMed1991

Brain tumors occurring before 1 year of age: a retrospective reviews of 22 cases in an 11-year period (1977-1987).

Congenital brain tumors have been reported infrequently and their management remains ill defined. An 11-year review (1977-1987) of all children with brain tumors with the onset of symptoms before 1 year of age was completed. Twenty-two children with the following histological diagnoses were treated: astrocytoma (7 patients), primitive neuroectodermal tumor (6 patients), papilloma or carcinoma of the choroid plexus (3 patients), malignant teratoma (2 patients), dermoid tumor (2 patients), embryonal rhabdomyosarcoma (1 patient), and chloroma (1 patient). Fifteen tumors were supratentorial in location, and 7 were infratentorial. Initial symptoms were hydrocephalus (32%), focal neurological deficit (23%), asymptomatic increase in head circumference (18%), failure to thrive (14%), and seizures (4.5%). The goal of treatment was a radical excision when possible, with primary chemotherapy in the last 6 years of the review period. Radiation therapy was the adjunct to surgery in the initial 5-year period. All patients with papillomas of the choroid plexus and dermoid lesions underwent a total resection with no recurrence. All 7 astrocytomas were supratentorial, with 6 occurring in the diencephalon. Five of the seven patients with astrocytomas survived more than 5 years. The 6 primitive neuroectodermal tumors were located equally between the supra- and infratentorial spaces. Four of the 6 infants with these tumors received chemotherapy (2 received chemotherapy alone; 2 received chemotherapy and radiation therapy) and are tumor free 2 to 9 years later. A fifth child received radiation therapy alone early in the series and survived only 4 months. The family of the other child refused adjunctive treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Astrocytoma↗
PubMed1991

Immunohistochemical analysis of Ewing's sarcoma cell surface antigen p30/32MIC2.

Monoclonal antibody (MAb) HBA71, which was raised against Ewing's sarcoma cells, recognizes a cell-surface glycoprotein, p30/32MIC2, that is encoded by the MIC2 gene in the pseudoautosomal region of human chromosomes X and Y. This immunohistochemical study evaluates the specificity and sensitivity of MAb HBA71 for tumor diagnosis. Frozen and paraffin-embedded tissues of more than 300 tumors of diverse histologic type, including more than 100 small round cell tumors of childhood and adolescence, were tested with this MAb by the avidin-biotin immunoperoxidase procedure. The authors found HBA71 immunoreactivity in 61 of 63 Ewing's sarcomas studied and 9 of 11 primitive neuroectodermal tumors and peripheral neuroepitheliomas. HBA71-negative tumors included neuroblastomas (0 of 24), melanomas (0 of 13), an esthesioneuroblastoma, small cell osteosarcomas (0 of 2), a malignant ectomesenchymoma, desmoplastic SRCT (0 of 5), and medulloblastomas (0 of 5). Heterogeneous expression of HBA71 immunostaining was found in some embryonal rhabdomyosarcomas (3 of 14) and astrocytomas (4 of 7), and in a few neuroendocrine tumors (4 of 26), carcinomas (3 of 94), and lymphomas (6 of 30). Because Ewing's sarcomas are consistently HBA71 positive, the authors searched for antigen-positive normal cells that may represent precursors for these tumors; however, no obvious candidate for the elusive cell of origin for Ewing's sarcoma was identified in the normal fetal tissues tested. Their findings indicate that HBA71 is a highly restricted cell-surface antigen of Ewing's sarcomas and primitive neuroectodermal tumors, and immunohistochemistry employing this antibody may be of value in the differential diagnosis of selected small round cell tumors in childhood and adolescence.

12E7 Antigen↗
PubMed1990

S-antigen and rod-opsin immunoreactions in midline brain neoplasms of transgenic mice: similarities to pineal cell tumors and certain medulloblastomas in man.

Transgenic mice expressing the large T-antigen of the simian virus 40 (SV 40) under the control of 1) the enhancer of Moloney murine sarcoma virus (MSV) and 2) the SV 40 promoter develop undifferentiated neuroectodermal tumors located in the midline of the dorsal brain surface, abnormalities in lens fiber differentiation and retinal dysplasia. In this study the brain neoplasms of six adult animals and the brain of one 11-day old mouse were examined by conventional histology and immunocytochemical demonstration of S-antigen, rod-opsin, neuron-specific enolase, neurofilaments (160 and 200 kDa) and glial fibrillary acidic protein. According to histologic criteria the neoplasms were characterized as "primitive" neuroectodermal tumors composed mainly of small cells with scanty and ill-defined cytoplasm. Neoplastic cells displaying immunoreactive S-antigen were found in five brain tumors; three of these tumors also contained a limited number of rod-opsin immunoreactive neoplastic cells. Some tumor cells had neurite-like processes containing immunoreactive neurofilament (200 kDa). No pathologic lesions were found in the brain of the 11-day old animal. Tumors in transgenic mice may resemble pineal cell tumors and a special subtype of medulloblastoma in man. These neoplasms contain S-antigen immunoreactive and also rod-opsin immunoreactive tumors cells in certain cases. The findings suggest that transgenic mice expressing the large T-antigen of SV 40 may become a valuable animal model for analysing the origin, histogenesis and development of primitive neuroectodermal tumors with photoreceptor-like features (pineal cell tumors and certain medulloblastomas).

Animals↗
PubMed2000

Comparative genomic hybridization of medulloblastomas and clinical relevance: eleven new cases and a review of the literature.

Medulloblastomas are highly malignant primitive neuroectodermal tumors of the cerebellum that display a wide variety of histopathological patterns. However, these patterns do not provide an accurate prediction of clinical-biological behavior and no satisfactory morphological grading system has ever been presented. Genetic alterations may provide additional diagnostic information and allow clinically relevant subgrouping of primitive neuroectodermal tumors. We examined 10 medulloblastomas and one medulloblastoma cell line. One amplification site on chromosome 8q24 was detected in the cell line corresponding to the known amplification of the c-myc gene in this cell line. The gain of 2p21-24 in two tumors was shown to represent amplification of the N-myc gene by Southern blot hybridization and fluorescence in situ hybridization. The data show that the isochromosome 17 can be recognized using comparative genomic hybridization (CGH) by the typical combination of loss of 17p combined with gain of 17q. No specific pattern of genetic alterations could be linked to the clinical behavior of the tumors. We have compared our results with previous CGH studies on medulloblastomas.

Adolescent↗
PubMed1986

Renal and extrarenal rhabdoid tumors in children: a clinicopathologic study of 14 patients.

The clinical and pathologic features of 14 children with rhabdoid tumors are presented. Eight patients had primary renal neoplasms and six had extrarenal tumors. The eight renal rhabdoid tumors were identified among 514 primary renal neoplasms collected at four pediatric institutions. Six patients were under 1 year of age; five children died of tumor-related causes, four of them within 4 months of diagnosis and one 17 months postnephrectomy. Another patient died of sepsis 12 days postnephrectomy. One is alive 13 months postnephrectomy, and one was lost to follow-up evaluation. The most common sites of metastasis were the lymph nodes (seven children) and the lungs (three patients). Three infants with renal rhabdoid tumors had, in addition, intracranial masses, two of which manifested clinically before the detection of the renal tumors, in one confirmed to be a primitive neuroectodermal tumor. Five of the 6 extrarenal tumors were identified among 155,926 surgical pathology specimens examined in the same children's hospitals over the same period of time; the remaining extrarenal rhabdoid tumor was received in consultation from a community hospital. The extrarenal rhabdoid tumors occurred in the dorsum of the right foot, liver, soft tissue of the right chest wall, left temporal lobe, left leg, and left thoracic paraspinal region. The ages ranged from 6 weeks to 15 years and two months. Three patients died of tumor-related causes within 4 months of diagnosis; one was a term stillborn. Two are alive, 1 month and 70 months postdiagnosis. Common sites for metastases included the lungs (three patients), and liver and lymph nodes (two children each). Patients with renal and extrarenal rhabdoid tumors are of similar age, have a similar clinical course, with early metastases and poor response to therapy. Primitive neuroectodermal intracranial tumors have been identified in several reported patients with renal rhabdoid tumors; similar brain tumors have not been documented in patients with extrarenal rhabdoid tumors. The histogenesis of this tumor remains unknown.

Brain Neoplasms↗
PubMed1991

Cerebellar medullomyoblastoma with advanced neuronal differentiation and hamartomatous component.

This report describes an unusual medullomyoblastoma which developed in the cerebellar vermis of a 6-year-old girl. Histological investigation showed a highly cellular and predominantly undifferentiated tumor. Myogenic differentiation was prominent in clusters of large tumor cells with eosinophilic cytoplasm and immunoreactivity for desmin and myoglobin. Electron microscopy revealed the presence of immature Z-bands. Immunohistochemically, numerous cells showed incipient expression of myoblastic marker antigens, supporting the view that medulloblastomas and related primitive neuroectodermal tumors possess the potential for non-neural differentiation. In addition, there was evidence of advanced neuronal differentiation, with expression of neuron-specific enolase, synaptophysin, retinal S-antigen, and the formation of ganglioid tumor cells. Occassional neoplastic cells expressed glial fibrillary acidic protein without morphologically detectable astrocytic differentiation. Associated with the neoplasm was brain tissue containing clusters of neuronal cells and focal accumulations of immature oligodendroglia-like cells which expressed neuronal marker antigens. This unusual component resembled a hamartomatous lesion and would support the hypothesis that the cerebellar medullomyoblastoma originated from a teratomatous or malformative lesion. Alternatively, this component may constitute the end stage of advanced neuronal differentiation of a primitive neuroectodermal tumor.

Cell Differentiation↗
PubMed1983

Preradiation chemotherapy for newly diagnosed childhood brain tumors. A modified Phase II trial.

A poor-risk population of children with primary malignant central nervous system (CNS) tumors, other than gliomas, can be identified by their young age, by the presence of disease dissemination at diagnosis, and possibly by subtotal resection of the primary tumor. These children require at least neuraxis radiation therapy and possibly chemotherapy for disease control. Unfortunately, once neuraxis radiation is administered, tolerance of subsequent chemotherapy is limited. The authors have explored a multimodal treatment approach in 14 poor-risk patients initially consisting of a modified Phase II chemotherapy trial followed by neuraxis radiation. The diagnoses were medulloblastoma (5), pineoblastoma (3), cerebral primitive neuroectodermal tumor (3), germinoma (2), and choroid plexus carcinoma (1). Eleven patients had disseminated CNS disease, and two had bone marrow involvement at diagnosis. Nine patients received 2 courses of intravenous cyclophosphamide (80 mg/kg) alone over 8 weeks, and five others received three daily doses of intrathecal Ara-C (50 mg/m2) and oral hydroxyurea (40 mg/kg) with each course of cyclophosphamide. There were four complete responses (two dysgerminomas, one pineoblastoma, and one primitive neuroectodermal tumor), one partial response (medulloblastoma), and three mixed responses (two medulloblastomas, one pineoblastoma) to chemotherapy alone, for a response rate of 57%. Twelve patients subsequently tolerated the planned dose of neuraxis radiation. The median survival of all patients was 11 months, and seven of eight deaths were related to recurrent disease. The hematologic toxicity was appreciable, and one death resulted from gram-negative septicemia. Through the use of this type of Phase II trial, valuable information can be obtained on the response rates to specific chemotherapy agents administered prior to radiation. Although cyclophosphamide alone was an active agent in this context, these treatment regimens did not have an important affect on survival.

Age Factors↗
PubMed2002

Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance Epidemiology and End Results.

BACKGROUND: It has been suggested that cerebellar medulloblastoma (M) and primitive neuroectodermal tumors (PNET) arising elsewhere in the nervous system, represent a single entity (M/PNET), although this concept is controversial. Cancer registries permit population-based description of cases reported as medulloblastoma, those reported as PNET and description of the aggregate, M/PNET. PROCEDURE: We reviewed the 768 cases of M/PNET (633 diagnosed medulloblastoma and 135 diagnosed PNET) among persons under 20 years of age in the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database. RESULTS: The incidence of M/PNET rose 23%, from 4 per 10(6) person-years in 1973-77 to 4.9 per 10(6) person-years in 1993-98. Cases reported as PNET were more likely than those reported as medulloblastoma to be supratentorial (30.4% vs. 1.9%, P < 0.001) and to be female (42.2% vs. 35.4%, P = 0.13). The difference in 5-year survival between the 600 children with infratentorial medulloblastoma vs. the 49 children with infratentorial PNET was not statistically significant (55% vs. 43%). Regardless of reporting diagnosis, survival was poorer among children age 0-3 years and those with supratentorial tumors. Children diagnosed in the more recent period from 1985-1998 had a longer median survival than children diagnosed in 1973-84 (4.9 years vs. 10 years, P < 0.05). Rates were 42% higher among Whites compared to Blacks (4.5/10(6) person-years vs. 3.1/10(6) person-years, P < 0.01). CONCLUSIONS: We found M/PNET is increasing in incidence and more frequent among Whites. Given that medulloblastoma and PNET are histologically identical and have similar epidemiologic profiles, future studies should provide analyses that combine these entities.

Adolescent↗
PubMed2004

Karyotypic evolution pathways in medulloblastoma/primitive neuroectodermal tumor determined with a combination of spectral karyotyping, G-banding, and fluorescence in situ hybridization.

Medulloblastomas (MBs) or primitive neuroectodermal tumors (PNETs) represent 15%-30% of pediatric brain tumors and are the most common brain tumors in children; they are rare in adults. Classification of these tumors is based on tissue morphology and is often controversial and problematic. Karyotypic analysis of these tumors using conventional cytogenetic methods is often a difficult process that may be hindered by a limited number of metaphase cells and poor chromosome morphology, often leading to only partial characterization of the chromosomal abnormalities. We investigated three primary human tumors and four cell lines (CHO-707, DAOY, D-341, and PFSK) utilizing a combination of conventional G-banding, spectral karyotyping (SKY), and fluorescence in situ hybridization (FISH) techniques. A high level of intratumoral heterogeneity was seen, with multiple numerical and structural chromosomal aberrations. The chromosomes most frequently involved in structural aberrations were chromosomes 1 (14 rearrangements), 7 (9 rearrangements), and 21 (9 rearrangements). The chromosomes most frequently involved in numerical aberrations were chromosomes 1, 12, and 13 (four cases) and chromosomes 14, 17, 19, 21, 22, and X (three cases). Numerous aberrant chromosomes were characterized only with the SKY analysis, and based on these findings multiple clones were identified, facilitating analysis of karyotypic evolution. The most frequent evolution mechanism was via polyploidization, followed by acquisition of additional numerical or structural aberrations (or both); however, the results showed that the karyotypic evolution process in these tumors is typically divergent and complex.

Adult↗
PubMed1999

[High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for refractory bone and soft tissue sarcomas].

High-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to 10 patients with refractory bone and soft tissue sarcoma (2 patients with primitive neuroectodermal tumor, 4 patients with Ewing's sarcoma, 3 patients with synovial sarcoma and one patient with osteosarcoma). Busulfan 4 mg/kg x 4, melphalan 140 mg/m2 and thiotepa 200 mg/m2 x 3 were used in the high-dose chemotherapy. Complications related to the treatment were limited to one patient who developed hepatic veno-occlusive disease, no serious complications were seen in the other patients. Four patients died of their disease, one patient was alive with the disease and 5 patients were alive with no evidence of disease. The prognosis for non-resectable primitive neuroectodermal tumor and Ewing's sarcoma is said to be very poor. However, there are some patients in whom the disease is kept in remission by high-dose chemotherapy with autologous peripheral blood stem cell transplantation, so this therapy may be a possible substitute for radical operation. With spindle cell sarcomas, the efficacy of this treatment was temporary, so it will be necessary to investigate frequent high-dose chemotherapy and to change the high-dose chemotherapy regimen.

Adolescent↗
PubMed1999

Increased oncogenicity of subclones of SV40 large T-induced neuroectodermal tumor cell lines after loss of large T expression and concomitant mutation in p53.

A model for medulloblastoma-like primitive neuroectodermal tumors was established in rat using retrovirally transduced SV40 large T antigen (LT) as an inducing agent (O. D. Wiestler et al., Brain Pathol., 2: 47-59, 1992). A cell line isolated from such a tumor and clonal derivatives thereof were biologically and molecularly characterized. In the parental tumor cell line, TZ870, which had been selected for G418 resistance, virtually all cells expressed LT and wild-type p53, which were complexed to each other. When plated in soft agar, these cells grew relatively slowly and formed disperse colonies. However, when grown without selection pressure, these cells reproducibly gave rise to LT-negative and G418-sensitive derivatives, LT-0 cells. Surprisingly, these latter cells exhibited a higher degree of malignancy both in vitro, growing readily to large colonies in soft agar, and in vivo, where they gave rise to a rapidly growing malignant tumor. Clonal selection from TZ870 cells revealed two types of clones: in one type, LT expression was stably maintained, even without selection pressure, whereas the other type lost the LT coding sequences. All LT-negative clones exhibited the same phenotype as the LT-0 cells. Reexpression of LT had no effect. However, LT no longer formed complexes with p53, and p53 was metabolically stable, suggesting that it had been mutated. Sequence analyses and diagnostic restriction digests of the p53 gene revealed that (a) both the parental LT-transformed cells and their derivatives contained only one complete p53 allele and (b) all LT-positive clones expressed wild-type p53, whereas all LT-negative clones expressed a mutant allele with a common mutation at Cys-174-->Tyr, indicating their clonal origin. We assume that the loss of LT coding sequences is the consequence of the p53 mutation, perhaps by inducing genomic instability, and that both the p53 mutation and additional genetic alterations that accompany the loss of LT coding sequences might contribute to enhanced malignancy.

Animals↗
PubMed2001

[Primary neuroectodermal tumor (PNET) of the kidney: 26 cases. Current status of its diagnosis and treatment].

OBJECTIVE: To report a case of primitive neuroectodermal tumor (PNET) of the kidney and review the literature and the 25 cases previously reported as PNET. METHODS: A 39-year-old man who consulted for nephric colic is described. Ultrasound evaluation disclosed a mass arising from the left kidney. The clinical, radiological and pathologic features, treatment and differential diagnosis of small cell tumors are discussed, as well as the important role of immunohistochemical techniques (positive staining with O13 or 12E7 antibodies) and cytogenetic analysis [a characteristic chromosomal translocation t(11;22) (q24;q12) or variant translocation, such as t(21;22) (q22;q12), may be detected by fluorescence in situ hybridization (FISH) or polymerase chain reaction-reverse transcriptase (PCR-RT)]. RESULTS: Survival of our patient was 20 months. Only three of the 25 previously reported cases had a longer survival: 60, 48 and 24 months. Mean survival was 10 months. 95.24% of the cases were positive for NSE. Immunostaining (CD99) was performed in 16 patients and was found to be positive in all cases. Cytogenetic and molecular analyses were performed in 11 cases; PCR-RT was negative in two, as well as in the case described herein. CONCLUSIONS: PNET is a highly aggressive neoplasm that tends to recur locally and to metastasize. Despite the poor response to standard therapy combining surgical resection, postoperative irradiation and chemotherapy, the results might change due to current research on genetic therapy based on creating antisense oligonucleotides against the EWS-FLI 1 fusion gene.

Adult↗
PubMed1997

Neurogenic potential of Ewing's sarcoma cells.

We investigated the capacity of eight well-characterized Ewing's sarcoma cell lines to differentiate towards a neural phenotype. Ewing's sarcoma cells expressed the neuroectoderm-associated antigens such as nerve growth factor (NGF) receptor, N-CAM (6H7 and Leu-19) and Leu-7. Ewing's sarcoma cells also exhibited the potential for neural differentiation at the mRNA level; neuron-specific medium- and low-sized filament (NF-M and NF-L) expression was induced by dibutyryladenosine cyclic monophosphate. The pattern of expression of NF-L obtained by using alternative polyadenylation sites in Ewing's sarcoma cells differed from that in peripheral primitive neuroectodermal tumour (PNET) cells, and was similar to that in undifferentiated neural tissues. Furthermore, the NGF receptors detected by immunohistochemistry were found to be non-functional as assayed by c-fos induction with NGF treatment. The results indicate that Ewing's sarcoma cells maintain a primitive phenotype and have the potential to differentiate into a neural phenotype, indicating that Ewing's sarcoma is distinct from PNET.

Bone Neoplasms↗
PubMedDate not supplied

In vitro antiproliferative effects of albumin-doxorubicin conjugates against Ewing's sarcoma and peripheral neuroectodermal tumor cells.

The 3-5 year survival rates of patients with disseminated Ewing's sarcoma (ES) or the closely related peripheral primitive neuroectodermal tumors (PNET) remain low, even under aggressive treatment involving highly toxic multidrug chemotherapeutic regimens. ES and PNET are sensitive to doxorubicin, but may escape treatment by expression of the multidrug-resistant phenotype and/or other mechanisms. In this study, we have identified albumin as growth supporting factor for ES and PNET cells in IGF-I-supplemented serum-free tissue culture medium. To investigate the specificity and toxicity of albumin-based drug conjugates, doxorubicin was coupled to bovine serum albumin (BSA) by either a two step glutaraldehyde or carbodiimide-C4-spacer technique, yielding monomeric DOX-albumin conjugates with conjugation numbers ranging from 3-20 moles DOX/mole BSA. Cellular uptake of fluorescein-isothiocyanate-(FITC)-labeled albumin and DOX-albumin conjugates could be demonstrated by flow cytometric measurements of cell-associated fluorescence and confocal microscopy. The cytostatic activity of these conjugates against ES/PNET cell lines, a neuroblastoma (LAN-1) and prostate cancer carcinoma cell line (PC-3) and normal lymphoblasts was tested in short-term proliferation assays (48 h). The results show a high selectivity of the DOX-albumin conjugates for ES/PNET cell lines, with highest growth inhibition by conjugates with low DOX conjugation numbers (n = 3) in serum-supplemented medium (17-32 fold loss of activity compared to free DOX), followed by 20-DOX-C4-albumin in serum-free medium and low activity of the other conjugates. In conclusion, DOX-albumin conjugates inhibit the growth of ES/PNET cell lines selectively, showing low activity against the unrelated carcinoma line PC-3 and sparing normal lymphoblasts. The inverse correlation of activity and conjugation number demonstrates a low cytotoxic activity of DOX in acid-stable binding to monomeric albumin, pointing to a selective cytostatic activity of the modified albumin against ES and PNET cells, even in the presence of a 100 fold excess of unmodified serum albumin.

Carbodiimides↗
PubMed2004

Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.

We investigated a family with an autosomal recessive syndrome of cafe-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previously unrecognized PMS2 pseudogene, corresponding to exons 9-15, within a 100-kb inverted duplication situated 600 kb centromeric from PMS2 itself. This information allowed a redesigned sequence analysis, identifying a homozygous mutation (R802X) in PMS2 exon 14. Furthermore, in the family with Turcot syndrome, in which the first inherited PMS2 mutation (R134X) was described, a further truncating mutation was identified on the other allele, in exon 13. Further whole-genome analysis shows that the complexity of PMS2 pseudogenes is greater than appreciated and may have hindered previous mutation studies. Several previously reported PMS2 polymorphisms are, in fact, pseudogene sequence variants. Although PMS2 mutations may be rare in colorectal cancer, they appear, for the most part, to behave as recessive traits. For technical reasons, their involvement in childhood cancer, particularly in primitive neuroectodermal tumor, may have been underestimated.

Adenosine Triphosphatases↗
PubMed1994

MIC2 analysis in pediatric lymphomas and leukemias.

Monoclonal antibodies to the glycoprotein product of the MIC2 gene strongly and reliably stain primitive neuroectodermal tumors and Ewing's sarcomas, and are negative in neuroblastomas and most rhabdomyosarcomas. Therefore, these antibodies are helpful in the diagnosis of small round cell tumors of childhood (SRCT). Lymphomas also are in the differential diagnosis of SRCT, but few have been studied with respect to MIC2 protein expression. In the present study we used the 12E7 antibody to assess MIC2 expression in 82 pediatric non-Hodgkin's lymphomas. Forty lymphoblastic, 22 small noncleaved, and 20 large cell lymphomas were studied. Strong immunoreactivity was found in 37 of the 40 (93%) lymphoblastic lymphomas, whereas only one of the 22 (5%) small noncleaved lymphomas was 12E7 positive. Four of the 20 (20%) large cell lymphomas also were immunoreactive. Three 12E7+ lymphoblastic lymphomas were primary in bone and were of B-progenitor lineage; Ewing's sarcoma was included in the initial differential diagnosis of these cases. Evaluation of 125 pediatric acute lymphocytic leukemia (ALL) cases for MIC2 expression showed similar results, with all 36 T-cell ALLs showing strong expression, one of eight B-cell (Burkitt-like) ALLs showing 12E7 expression, and 62 of 81 B-progenitor ALLs showing 12E7 positivity. We conclude that among the SRCTs, MIC2 expression is not limited to Ewing's sarcoma and primitive neuroectodermal tumors, but also shows strong and reliable expression in lymphoblastic lymphomas and related leukemias. MIC2 analysis continues to be helpful in the diagnosis of SRCT, provided that a panel of antibodies is used. In addition, the possibility that MIC2 analysis may aid in the distinction of lymphoblastic lymphomas from small noncleaved lymphomas needs to be further addressed.

12E7 Antigen↗