National Cancer Institute®
Last Modified: March 1, 2002
UI - 11642491
AU - Shields JA; Shields CL; Brotman HK; Carvalho C; Perez N; Eagle RC Jr
TI - Cancer metastatic to the orbit: the 2000 Robert M. Curts Lecture.
SO - Ophthal Plast Reconstr Surg 2001 Sep;17(5):346-54
AD - Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
PURPOSE: To report the demographics and clinical features of a large series of patients with orbital metastasis. METHODS: Retrospective chart review on 100 consecutive patients and a literature review on orbital metastasis. RESULTS: Of 100 patients, the primary tumor site was breast in 53 (53%), prostate gland in 12 (12%), lung in 8 (8%), skin (melanoma) in 6 (6%), kidney in 5 (5%), gastrointestinal tract in 5 (5%), choroid (melanoma) in 2 (2%), parotid gland in 1 (1%), and adrenal gland (neuroblastoma) in 1 (1%). Of patients in whom a detailed history was available, there was no history of cancer at the time of presentation in 19%. In 10%, the primary tumor remained undetected despite systemic evaluation. There were 36 male patients and 64 female patients whose mean age at diagnosis was 62 years (median 60 years, range 5 to 91 years). Both the right and left orbits were affected equally, and 4 cases (4%) were bilateral. The most frequent clinical findings were limited ocular motility (54%), proptosis (50%), and palpable mass (43%). The diagnoses were established by history, systemic survey, imaging studies, and biopsy. Treatment included chemotherapy, hormone therapy, irradiation, surgical excision, or observation, depending on clinical circumstances. Among patients with sufficient follow-up, 95% died of metastasis, with overall mean survival of 15 months (median 15 months; range 3 to 96 months) after orbital diagnosis. CONCLUSIONS: The most common primary cancers that metastasize to the orbit are breast, prostate gland, and lung cancer. In 19%, there is no history of cancer when the patient presents with ophthalmic symptoms and in 10% the primary site remains obscure despite systemic evaluation. The systemic prognosis is generally poor.
UI - 11601682
AU - Bellincampi L; Ballerini S; Bernardini S; Inserra A; Marchetti P;
TI - Boglino C; Donfrancesco A; Federici G Glutathione transferase P1 polymorphism in neuroblastoma studied by endonuclease restriction mapping.
SO - Clin Chem Lab Med 2001 Sep;39(9):830-5
AD - Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Several members of the different glutathione transferase (GST) gene classes are polymorphic. Particular interest has been focused on the GSTP class because this gene class is up-regulated during the early stage of oncogenesis and is significantly overexpressed in many human tumors. It has also been shown that high levels of GSTP1 expression are associated directly with tumor drug resistance and with poor patient survival. Our aim was to understand the possible association between GSTP1 polymorphism and cellular response to chemotherapeutic drugs in neuroblastoma. In fact, several antineoplastic drugs used in the neuroblastoma high-risk chemotherapeutic protocol are potential substrates of GSTP1-1 (etoposide, adriamycin and carboplatin). The GSTP1 genotype homozygote *A/*A was identified in 11 patients independent of their response to the chemotherapeutic treatment. Only four patients had a heterozygote genotype A*/B*. Therefore, based on our preliminary data, we were not able to conclude that GSTP1 polymorphism had an impact on patient response to treatment in neuroblastoma.
UI - 11723749
AU - Yamaguchi S; Wada T; Oba K; Yoshihiro S; Naito K
TI - Oral etoposide following combination chemotherapy and radiation therapy in a patient with advanced adult neuroblastoma led to long survival.
SO - Int J Clin Oncol 2001 Oct;6(5):259-61
AD - Department of Urology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
Although neuroblastoma is a common tumor of early childhood, it is rare in adults. In spite of the poor prognosis of advanced neuroblastoma in adults, there is still no effective treatment for this condition in adults. Here we report that oral etoposide salvage chemotherapy was able to prolong the survival of an adult patient with advanced neuroblastoma. A 26-year-old man had advanced neuroblastoma that was resistant to combination intravenous chemotherapy and radiation therapy. He was then treated with oral etoposide, at a dose of 50 mg daily for 5 days in a 21-day course. Toxicity was very mild and he was followed as an outpatient while he received 76 courses of this oral etoposide salvage chemotherapy. Seventy months after diagnosis, this patient is still alive and has no new distant metastases.
UI - 11750901
AU - Nguyen HN; Wang C; Perry DC
TI - Depletion of intracellular calcium stores is toxic to SH-SY5Y neuronal cells.
SO - Brain Res 2002 Jan 11;924(2):159-66
AD - Department of Pharmacology, George Washington University Medical Center, 2300 I St. NW, 20037, Washington, DC, USA
Inhibiting Ca(2+) uptake by the sarcoendoplasmic reticular Ca(2+)-ATPase pump (SERCA) causes release of Ca(2+) from the endoplasmic reticulum (ER), increased cytosolic Ca(2+) ([Ca(2+)](cyt)) and depletion of ER Ca(2+) stores. These studies were designed to test the effects of SERCA inhibition on neuronal viability, using as a model the human neuroblastoma cell line, SH-SY5Y. Continuous exposure to the SERCA inhibitor thapsigargin (TG) decreased SH-SY5Y viability to <30% after 48 h exposure, and produced DNA laddering. Two other SERCA inhibitors, BHQ and cyclopiazonic acid CPA, were similarly toxic, although at 1000-fold higher concentrations. BHQ and CPA toxicity was prevented by removing drug within several hours, whereas TG toxicity was essentially irreversible. All three SERCA inhibitors caused an increase in [Ca(2+)](cyt) that was partially blocked by the ryanodine receptor inhibitors, dantrolene and DHBP. Pretreatment with 40 microM dantrolene gave substantial protection against TG- or BHQ-induced cell death but it did not inhibit death from staurosporine, which does not cause release of ER Ca(2+). DHBP (20-100 microM) also gave partial protection against TG toxicity, as did ruthenium red (2 microM), but not ryanodine (10 microM). Inhibition of capacitative Ca(2+) entry with EGTA or LaCl(3) or low extracellular Ca(2+), or chelation of [Ca(2+)](cyt) with BAPTA-AM, failed to inhibit TG toxicity, although they prevented increases in [Ca(2+)](cyt) caused by TG. Taken together, these data suggest that toxicity caused by SERCA inhibition in SH-SY5Y cells is caused by ER Ca(2+) depletion, which triggers an apparent apoptotic pathway.
UI - 11753194
AU - Swischuk LE
TI - Stomach pain for 3 weeks.
SO - Pediatr Emerg Care 2001 Dec;17(6):449-51
AD - Department of Radiology, The University of Texas Medical Branch, Galveston, Texas 77550-0709, USA.
UI - 11807663
AU - Girgert R; Wittrock J; Schweizer P
TI - Neuroblastoma: inhibition of progression (Part II). Basic science in pediatric surgery.
SO - Eur J Pediatr Surg 2001 Dec;11(6):363-7
AD - Department of Pediatric Surgery, University of Tubingen, Germany. email@example.com
In neuroblastoma, amplification of the protooncogene N-myc is the most important molecular characteristic predicting a bad outcome for the patients. Despite the importance of the N-myc gene, little is known about the mechanisms regulating its expression. We found evidence that insulin-like growth factor II stimulates the growth of neuroblastoma in a paracrine fashion. Two neuroblastoma cell lines predominantly expressed IGF-II whereas two other cell lines expressed the IGF-receptor. In a receptor-positive cell line, N-myc expression was enhanced by stimulation with IGF-II. As the growth-stimulating signals of the IGF receptor are transmitted via Ras proteins, inactivation of Ras is one promising tool to prevent the induction of N-myc expression by IGF-II. Treatment of neuroblastoma cells with an inhibitor of the farnesyl-protein-transferase (FPTase) inactivated H-ras protein completely and N-ras protein by more than 50 %. Cell growth of neuroblastoma cells in serum containing medium was clearly diminished by inhibition of FPTase. The growth-promoting effect of IGF-II was reduced to exactly half the amount observed in non-inhibited cells.
UI - 11807672
AU - Petit T; de Lagausie P; El Ghoneimi A; Garel C; Aigrain Y
TI - Postnatal management of cystic neuroblastoma.
SO - Eur J Pediatr Surg 2001 Dec;11(6):411-4
AD - Department of Paediatric Surgery, Robert Debre University Hospital, Paris, France. firstname.lastname@example.org
Cystic adrenal neuroblastoma (NB) is highly unusual. We report two cases of cystic NB, detected antenatally and emphasize postnatal strategy management. Case 1: a right cystic mass was detected in a foetus in the 34th week of pregnancy, and checked as the same in the 36th week. Postnatal ultrasonography confirmed the presence of a growing adrenal cystic mass. MRI and MIBG scintigraphy suggested an isolated adrenal tumour, without catecholamine secretion. Surgical resection was decided upon and pathological examination confirmed the diagnosis of cystic NB. Follow-up found a recurrence at 10 months and the patient underwent excision after chemotherapy. Histology confirmed the metastatic origin from NB. Case 2: a right adrenal cystic mass was detected during pregnancy, with no regression of tumour size on postnatal US. MRI, MIBG scintigraphy, and catechol plasma and urinalysis led to the conclusion of an isolated non-secreting lesion. A right adrenalectomy was performed at 1 month. Pathologic examination diagnosed a cystic NB. We would suggest serial US examinations and early removal of any cystic mass with characteristic US signs (thick complex wall) or without regression on one month follow-up. Prenatal diagnosis may provide the best chances for neonatal excision and good prognosis.
UI - 11821825
AU - Tajiri T; Shono K; Tanaka S; Suita S
TI - Evaluation of genetic heterogeneity in neuroblastoma.
SO - Surgery 2002 Jan;131(1 Suppl):S283-7
AD - Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
BACKGROUND AND METHODS: The prognosis in neuroblastoma, which is the most common solid tumor in children, tends to vary greatly, and many studies have demonstrated both clinical and biological factors to be closely correlated with the outcome. In order to select the optimal treatment according to the degree of malignancy of neuroblastoma, it is essential to accurately and rapidly identify any genetic heterogeneity associated with the prognosis. We assessed the status of some genetic abnormalities (MYCN amplification, deletion of the short arm of chromosome 1, DNA ploidy, and a gain of the chromosome 17q region) associated with the prognosis using several molecular biological methods. RESULTS AND CONCLUSIONS: The combination of several molecular biological techniques is thus considered to be useful for elucidating the degree of malignancy of neuroblastoma. In particular, diagnostic analyses based on a combination of the fluorescence in situ hybridization (FISH) method and the quantitative polymerase chain reaction (PCR) method may be considered to be the most effective methods for quickly and accurately evaluating any aberrations in the gene dosages associated with the patients' outcomes.
UI - 11685689
AU - Iwanaka T; Yamamoto K; Ogawa Y; Arai M; Ito M; Kishimoto H; Hanada R;
TI - Imaizumi S Maturation of mass-screened localized adrenal neuroblastoma.
SO - J Pediatr Surg 2001 Nov;36(11):1633-6
AD - Department of Surgery, Saitama Children's Medical Center, 2100 Magome, Iwatsuki, Saitama 339-8551, Japan.
BACKGROUND/PURPOSE: In infants, neuroblastoma has been known to spontaneously differentiate into a benign ganglioneuroma. Although several investigators have compared mass-screened with unscreened, disseminated with localized, and adrenal with retroperitoneal neuroblastoma, there are very few cross-comparisons of the above parameters. Herein, the authors report the maturation of mass-screened, localized adrenal neuroblastoma. METHODS: Fifty-one mass-screened adrenal neuroblastomas were divided into 2 groups. In infants less than 1 year of age (Group A), 45 neuroblastomas were resected, whereas 6 neuroblastomas were resected after observation in 1- to 4-year-old children (group B). Histopathology of the tumors in the 2 groups was compared. Data were analyzed by X(2) test, and P <.05 was considered significant. RESULTS: According to the International Neuroblastoma Pathological Classification, 41 of 45 tumors of group A were "differentiating neuroblastoma" and 4 of 6 tumors of group B were "maturing ganglioneuroma." Maturation toward ganglioneuroblastoma was observed in 16 neuroblastomas of group A (36%) and 6 neuroblastomas of group B (100%). In group A, 58% had low mitosis karyorrhexis index (MKI); all patients in group B had low MKI. CONCLUSIONS: If left untreated, maturation of mass-screened, localized adrenal neuroblastomas is a common phenomenon. These children do not need to undergo early operation. Copyright 2001 by W.B. Saunders Company.
UI - 11750845
AU - Eggert A; Grotzer MA; Zuzak TJ; Ikegaki N; Zhao H; Brodeur GM
TI - Expression of Apo-3 and Apo-3L in primitive neuroectodermal tumours of the central and peripheral nervous system.
SO - Eur J Cancer 2002 Jan;38(1):92-8
AD - Division of Oncology and Biostatistics, The Children's Hospital of Philadelphia, PA 19104, USA.
Deregulation of apoptosis has been implicated in the pathogenesis, spontaneous regression and treatment resistance of neuroblastoma. A newly recognised member of the tumour necrosis factor (TNF)-family of death receptors known as Apo-3 has been mapped to human chromosome 1p36.3, a region commonly deleted in aggressive neuroblastoma. Based on its localisation and function, Apo-3 is a candidate for the putative neuroblastoma tumour suppressor gene. Therefore we analysed mRNA expression of the Apo-3 receptor/ligand (Apo-3/Apo-3L) system in a representative panel of 18 neuroblastoma cell lines, 41 primary neuroblastoma and 13 ganglioneuromas/ganglioneuroblastomas by semi-quantitative RT-PCR. We compared the level of expression with the well-established prognostic factors age, stage, histology, MYCN-amplification and TrkA expression, as well as outcome. For comparison, we studied Apo-3/Apo-3L expression in 27 central nervous system (CNS) primitive neuroectodermal tumours/medulloblastomas (PNET/medulloblastoma) and in six normal brain samples. Neuroblastoma cell lines with 1p deletion and MYCN-amplification expressed significantly lower levels of Apo-3 (P=0.009 and P=0.03, respectively) compared with neuroblastoma cell lines without 1p deletion or MYCN-amplification. The mean expression level of Apo-3L was significantly higher in ganglioneuromas/ganglioneuroblastomas compared with neuroblastomas (P=0.001) and in normal brain compared with PNET/medulloblastoma (P<0.0001). Expression of Apo-3L was significantly associated with survival in neuroblastomas (P<0.049) and in PNET/medulloblastomas (P=0.01). Expression of Apo-3 was significantly associated with survival in PNET/medulloblastomas (P=0.03). Thus, the Apo-3 receptor/ligand system might be involved in the regulation of apoptosis in neuroblastomas and PNET.
UI - 11857022
AU - Perel Y; Amrein L; Dobremez E; Rivel J; Daniel JY; Landry M
TI - Galanin and galanin receptor expression in neuroblastic tumours: correlation with their differentiation status.
SO - Br J Cancer 2002 Jan 7;86(1):117-22
AD - Laboratory of Differentiation and Development Biology, EA DRED 483, University of Bordeaux 2, 146, rue Leo Saignat, 33076 Bordeaux Cedex, France. email@example.com
Neuroblastoma and its benign differentiated counterpart, ganglioneuroma, are paediatric neuroblastic tumours arising in the sympathetic nervous system. Their broad spectrum of clinical virulence is mainly related to heterogeneous biologic background and tumour differentiation. Neuroblastic tumours synthesize various neuropeptides acting as neuromodulators. Previous studies suggested that galanin plays a role in sympathetic tissue where it could be involved in differentiation and development. We investigated the expression and distribution of galanin and its three known receptors (Gal-R1, Gal-R2, Gal-R3) in 19 samples of neuroblastic tumours tissue by immunohistochemistry, in situ hybridization and fluorescent-ligand binding. This study provides clear evidence for galanin and galanin receptor expression in human neuroblastic tumours. The messengers coding for galanin, Gal-R1 and -R3 were highly expressed in neuroblastoma and their amount dramatically decreased in ganglioneuroma. In contrast, Gal-R2 levels remained unchanged. Double labelling studies showed that galanin was mainly co-expressed with its receptors whatever the differentiation stage. In neuroblastic tumours, galanin might promote cell-survival or counteract neuronal differentiation through the different signalling pathways mediated by galanin receptors. Finally, our results suggest that galanin influences neuroblastoma growth and development as an autocrine/paracrine modulator. These findings suggest potential critical implications for galanin in neuroblastic tumours development.
UI - 11857322
AU - Krams M; Hero B; Berthold F; Parwaresch R; Harms D; Rudolph P
TI - Proliferation marker KI-S5 discriminates between favorable and adverse prognosis in advanced stages of neuroblastoma with and without MYCN amplification.
SO - Cancer 2002 Feb 1;94(3):854-61
AD - Department of Pathology, University of Kiel, Kiel, Germany. firstname.lastname@example.org
BACKGROUND: The biologic behavior of neuroblastoma is notoriously variable, and even carefully elaborated prognostic models fail to predict the clinical course in a portion of cases. Because the proliferative activity is determined by the sum of all molecular imbalances that influence cell cycling, the authors investigated the potential prognostic relevance of the tumor growth fraction in neuroblastoma. METHODS: A retrospective analysis was conducted on a cohort of 161 neuroblastoma patients with a median follow-up period of 72.8 months. Tumors were classified according to Hughes typing and grading criteria. The proliferative index (PI) was assessed immunohistochemically on archival biopsy specimens using monoclonal antibody Ki-S5 (Ki-67), and the MYCN status was determined by means of Southern blot analysis. RESULTS: The PI, MYCN status, International Neuroblastoma Staging System (INSS) stage, International Neuroblastoma Pathology Classification grade, Hughes grade, and the patients' age at diagnosis were all found to be significant predictors of event free survival by univariate Kaplan-Meier analysis. However, the PI identified prognostically distinct subsets in higher tumor stages and Grade 2 and 3 neuroblastomas as well as tumors with unfavorable histology, and enabled risk stratification in tumors with and without MYCN amplification (P = 0.034 and 0.002, respectively). Multivariate Cox regression analysis selected INSS stage (relative risk [RR], 4.05; P < 0.0001) and the PI (RR, 2.49; P = 0.007) as the sole independent prognostic indicators, whereas MYCN entered the selection only after exclusion of the PI. CONCLUSIONS: It emerges that the PI as a single factor has greater predictive power than the MYCN status. Proliferation measurements therefore might significantly improve the accuracy of current prognostic models for neuroblastoma. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10256
UI - 11565832
AU - Sarkar AK; Burlingame SM; Zang YQ; Dulai V; Hicks MJ; Strother DR;
TI - Nuchtern JG Major histocompatibility complex-restricted lysis of neuroblastoma cells by autologous cytotoxic T lymphocytes.
SO - J Immunother 2001 Jul-Aug;24(4):305-11
AD - DeBakey Department of Surgery, Baylor College of Medicine, and The Texas Children's Cancer Center, Texas Children's Hospital, Houston, USA.
Vigorous host immune reactivity to neuroblastoma may correlate with better prognosis, but identification of human cytotoxic T-lymphocyte (CTL) responses has been relatively unsuccessful. We generated neuroblastoma-reactive CTL lines from two human leukocyte antigen (HLA) A2+ neuroblastoma patients by stimulation of peripheral blood lymphocytes (PBLs) with irradiated autologous tumor cells pretreated with interferon-gamma in the presence of low concentrations of interleukin-2 (5 U/mL). These lines lyse autologous tumor cells but do not kill HLA mismatched allogeneic tumor cells, Epstein-Barr virus-transformed autologous B cells, or standard natural killer cell targets. Cytotoxic T lymphocytes generated from one patient recognize tumor cells from several HLA-A2 matched children, although the other patient's CTLs do not kill tumor cells from other HLA-A2+ individuals. Pretreatment of CTLs or target cells with appropriate standard monoclonal antibodies demonstrates that these CTLs are major histocompatibility complex class I (HLA-A2) restricted and that the effector cell population is CD8+. Our findings suggest that these tumor cells express at least one common HLA-A2 restricted antigen and at least one unique private epitope. Autologous tumor-specific CTLs can be readily generated from patients' PBLs and maintained in long-term culture using standard techniques.
UI - 11681538
AU - Eldrup E; Clausen N; Scherling B; Schmiegelow K
TI - Evaluation of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma 3,4-dihydroxyphenylalanine (DOPA) as tumor markers in children with neuroblastoma.
SO - Scand J Clin Lab Invest 2001;61(6):479-90
AD - Department of Internal Medicine E. Herlev Hospital, University of Copenhagen, Denmark. email@example.com
Catecholamines and their metabolites are important in the diagnosis of neuroblastoma (NB). Plasma (p-) levels of 3,4-dihydroxyphenylalanine (DOPA) are increased in most NB, probably reflecting decreased DOPA decarboxylase activity. Urine (u-) homovanillic acid (HVA), a DOPA and dopamine (DA) metabolite. is also increased in most NB. DOPAC (3,4-dihydroxyphenylacetic acid) is an important metabolite of DA in tissues with monoamine oxidase (MAO) activity. Because MAO is expressed in NB tumor cells, we studied the importance of measuring p-DOPAC and p-DOPA as compared to u-HVA and u-vanillylmandelic acid (VMA) in the diagnosis and follow-up of NB. DOPAC, DOPA, dopamine, noradrenaline, adrenaline, VMA and HVA were measured by reverse-phase HPLC with electrochemical detection in 106 children (28 with NB (13 newly diagnosed), 25 with other solid tumors, 28 hospitalized for nonneoplastic diseases, and 25 healthy children). P-DOPAC or p-DOPA concentrations were above the upper normal range in 92% of untreated NB patients, as were u-HVA or u-VMA levels. None of these tumor markers was correlated to tumor stage or survival. P-DOPA but not p-DOPAC was correlated to age in NB children. Increased values of p-DOPAC and p-DOPA were found in one patient surviving NB for 10 years. Plasma DOPAC concentrations were decreased in children hospitalized for non-NB diseases, probably reflecting reduced food intake. Plasma analyses of DOPA and DOPAC seem to be useful alternatives in the diagnosis and follow-up of NB if urine sampling is to be avoided. Plasma DOPAC may be an index of nutritional status in various diseases.
UI - 11757502
AU - Simpson PB; Bacha JI; Palfreyman EL; Woollacott AJ; McKernan RM; Kerby J
TI - Retinoic acid evoked-differentiation of neuroblastoma cells predominates over growth factor stimulation: an automated image capture and quantitation approach to neuritogenesis.
SO - Anal Biochem 2001 Nov 15;298(2):163-9
AD - Department of Biochemistry and Molecular Biology, Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, United Kingdom. Peter_Simpsom@merck.com
To facilitate the characterization of compounds that have positive growth factor mimetic effects on neuritogenesis, we have implemented a high-throughput functional assay which measures, in a multiparametric manner, the proliferation and differentiation characteristics of cells in a microtiter plate. Conditions were established using chronic incubation of SH-SY5Y human neuroblastoma cells with retinoic acid (RA) and/or nerve growth factor (NGF) in which discernible alterations in proliferation, growth, and differentiation of cells were induced. SH-SY5Y cells were fixed and labeled by immunocytochemistry, and an automated image acquisition and analysis package on Cellomics ArrayScanII was utilized to quantify the effects of these treatments on cell characteristics. NGF and retinoic acid were found to increase multiple parameters of SH-SY5Y differentiation, including an increased proportion of cells having neurites and increased extent of branching. However, marked differences in the effects of these compounds on SH-SY5Y growth and differentiation were also detected: whereas NGF increased cell number, RA treatment decreased cell number, and RA but not NGF caused significant elongation of neurites. This study quantifies and characterizes the effects of differentiating and proliferating agents on a human-derived neuroblastoma cell line. The high-content, rapid-throughput nature of this assay makes it ideal for functional identification and characterization of compounds regulating cell behavior.
UI - 11738505
AU - Mack TG; Dayanandan R; Van Slegtenhorst M; Whone A; Hutton M; Lovestone
TI - S; Anderton BH Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells.
SO - Neuroscience 2001;108(4):701-12
AD - Department of Neuroscience and Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, London, UK. firstname.lastname@example.org
The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss. Interaction of tau with microtubules is thought to be regulated by phosphorylation. Investigating FTDP-17 mutations transiently expressed as enhanced green fluorescent protein (EGFP)-tagged proteins for the first time in differentiated neuronal cells, we found that two out of three missense mutations showed surprisingly decreased phosphorylation at the pathologically relevant S202/T205 site, mutant EGFP-tau being completely dephosphorylated in most cells. Moreover, phosphorylation at the S396/S404 site was moderately decreased for all mutant isoforms. Although microtubule integrity was not affected, with all mutants tested we demonstrated an increase in cellular tau protein level, some of which is microtubule-bound. Further enhancing this EGFP-tau accumulation by inhibition of tau degradation resulted in the previously less phosphorylated mutant EGFP-tau becoming highly phosphorylated.We conclude that the missense tau mutations primarily result in an excess of neuronal tau, which may interfere with important cellular functions such as axonal transport.
UI - 11857353
AU - Castino R; Pace D; Demoz M; Gargiulo M; Ariatta C; Raiteri E; Isidoro C
TI - Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas.
SO - Int J Cancer 2002 Feb 20;97(6):775-9
AD - Dipartimento di Scienze Mediche, Laboratorio di Patologia Molecolare, Universita A. Avogadro, Novara, Italy.
Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomal-lysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen. Copyright 2001 Wiley-Liss, Inc.
UI - 11839584
AU - Douc-Rasy S; Barrois M; Echeynne M; Kaghad M; Blanc E; Raguenez G;
TI - Goldschneider D; Terrier-Lacombe MJ; Hartmann O; Moll U; Caput D; Benard J DeltaN-p73alpha accumulates in human neuroblastic tumors.
SO - Am J Pathol 2002 Feb;160(2):631-9
AD - Departement de Biologie Clinique, Centre National de Recherche Scientifique-Unite Mixte de Recherche 1598, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Neuroblastic tumors (NTs), occurring in early childhood, display a wide spectrum of differentiation. Recurrent deletions involving the p73 locus are frequently observed in undifferentiated NTs. To address the question of the possible implication of p73 in neuroblastic differentiation, we investigated the status of the expression of this gene in a panel of differentiated and undifferentiated tumors. Although mutations were not found, p73 transcript profiles differed between undifferentiated and differentiated tumors. The frequency of the transcripts lacking exon 2 (species 1-3) appeared to be higher in undifferentiated than in differentiating and differentiated NTs. In contrast, products from using an alternate promoter (DeltaN-p73) were present in all NTs. In addition, only DeltaN-p73, but not full-length proteins, were detected by immunoblotting, suggesting a greater stability of N-truncated isoforms. Importantly, as in the adrenal medulla, most NTs showed p73-positive immunohistological staining with a cellular distribution and intensity varying according to the neuronal differentiation. Surprisingly, we observed redistribution of p73 from the nucleus to the cytoplasm during neuroblastic differentiation. Our data suggest that, in undifferentiated NTs, a link may exist between the accumulation of DeltaN-p73alpha variants and the "nuclear exclusion" of p53.
UI - 11594709
AU - Kounami S; Douno S; Matsubara H; Takayama J; Ohira M
TI - Olfactory neuroblastoma as a second malignant neoplasm in a patient previously treated for childhood acute leukemia.
SO - Pediatr Hematol Oncol 2001 Oct-Nov;18(7):459-63
AD - Department of Pediatrics, National Cancer Center Hospital, Tokyo, Japan.
Various kinds of second malignant neoplasms after sucessful treatment for childhood acute leukemia have been reported. The authors describe an unusual case of an olfactory neuroblastoma in a patient previously treated for childhood acute leukemia including autologous bone marrow transplantation. The prophylactic cranial irradiation and the total body irradiation during autologous bone marrow transplantation may have induced the development of their patient's olfactory neuroblastoma. Although a second primary olfactory olfactory neuroblastoma is rare is rare, it should be added to the list of second malignant neoplasms in the sinonasal region.
UI - 11594710
AU - Iwata A; Hirota T; Konno K; Fujimoto T; Sumida S; Sato K; Hara K
TI - Osteosarcoma as a second malignancy after treatment for neuroblastoma.
SO - Pediatr Hematol Oncol 2001 Oct-Nov;18(7):465-9
AD - Department of Pediatrics, Aichi Medical University, Japan.
A 4-month old girl was diagnosed as having stage IV neuroblastoma of the right adrenal gland. Preoperative chemotherapy was given, followed by local surgical excision. Postoperatively, irradiation of the tumor bed and adjuvant chemotherapy was given for 11 months. Nine years after cessation of chemotherapy, the patient developed left hip-joint pain. Biopsy of the ischium showed chondroblastic osteosarcoma. Limb salvage surgery was performed after preoperative chemotherapy. Postoperatively, adjuvant chemotherapy was given for 14 months. Twenty-two months after treatment for the secondary osteosarcoma, the patient has been remained in disease-free condition without any evidence of relapse. A second osteosarcoma occurring outside the radiation field after treatment for neuroblastoma is quite rare. This unusual case emphasized the need for close monitoring for development of second malignant neoplasms in survivors of neuroblastoma even in the absence of a known predisposing factor, such as radiation therapy.
UI - 11878578
AU - Reuland P; Geiger L; Thelen M H; Handgretinger R; Haase B;
TI - Muller-Schauenburg W; Niethammer D; Bares R Follow-up in neuroblastoma: comparison of metaiodobenzylguanidine and a chimeric anti-GD2 antibody for detection of tumor relapse and therapy response.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):437-42
AD - Department of Nuclear Medicine, University of Tubingen, FRG, Germany.
Early and correct diagnosis of local tumor recurrence, occurrence of metastases, and therapy response are essential in patients with neuroblastoma stage IV. The aim of the study was to evaluate the diagnostic value of metaiodobenzylguanidine (mIBG) and a chimeric GD2 antibody in the follow-up of patients with neuroblastoma. In a prospective study, mIBG (N = 31 scans) and immunoscintigraphy were compared with a chimeric antiganglioside antibody, ch14.18 (MAb) (N = 31 scans), labeled with technetium Tc 99m in the follow-up of 18 patients with stage IV neuroblastoma. The findings were compared with histologic findings, other imaging examinations, and clinical changes over the course of 4 to 6 years. For the diagnosis of local tumor recurrences, sensitivity was 80% for MAb and 70% for mIBG. Specificity was 93% for MAb and 72% for mIBG. The MAb was superior for the detection of skeletal metastases, with a sensitivity of 82% compared with 72% for mIBG. Specificity was 100% for both techniques. Also, for soft tissue/lymph node metastases, sensitivity for MAb was higher (50%) than for mIBG (31%). Specificity was 100% for each technique. In sequential studies, metastases were detected earlier with MAb (mean: 2.3 m for skeletal metastases, 3.6 m for soft tissue metastases) than with mIBG. After therapy, tumor uptake was visualized longer with mIBG (mean 6.3 m) than with MAb. The chimeric antibody ch14.18 is likely to be valuable for follow-up examinations and for assessment of therapy response because of earlier detection of new metastases.
UI - 11740055
AU - Candanedo-Gonzalez FA; Alvarado-Cabrero I; Gamboa-Dominguez A;
TI - Cerbulo-Vazquez A; Lopez-Romero R; Bornstein-Quevedo L; Salcedo-Vargas M Sporadic type composite pheochromocytoma with neuroblastoma: clinicomorphologic, DNA content and ret gene analysis.
SO - Endocr Pathol 2001 Fall;12(3):343-50
AD - Department of Pathology, Oncology Hospital, Centro Medico Nacional Siglo XXI, IMSS. Mexico, D.F. Mexico. email@example.com
Composite pheochromocytomas (CP) account for only 3% of all pheochromocytomas. We analyzed the clinical, immunohistochemical, ultrastructural, DNA content, and 634 ret mutation features in a 56-year-old Mexican woman with CP localized in the right adrenal gland and associated to a blood pressure of 140/90 mmHg. Clinical symptoms were absent after surgery. The tumor showed pheochromocytoma and neuroblastoma components. This dual phenotype was supported by light microscopy and corroborated by immunohistochemistry and ultrastructural findings. Flow cytometric analysis showed that both components were diploid. A genetic mutational analysis of the ret oncogene in exon 11 showed no 634 mutation. This case demonstrates the indolent behavior of neuroblastoma associated to a sporadic-type CP in an adult patient.
UI - 11880474
AU - Kitanaka C; Kato K; Ijiri R; Sakurada K; Tomiyama A; Noguchi K;
TI - Nagashima Y; Nakagawara A; Momoi T; Toyoda Y; Kigasawa H; Nishi T; Shirouzu M; Yokoyama S; Tanaka Y; Kuchino Y Increased Ras expression and caspase-independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression.
SO - J Natl Cancer Inst 2002 Mar 6;94(5):358-68
AD - Biophysics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. firstname.lastname@example.org
BACKGROUND: Neuroblastoma undergoes spontaneous regression frequently during its natural course. Although programmed cell death (PCD) has been implicated in this process, accumulating evidence suggests that apoptosis, a form of PCD that is regulated by caspases, may not play a major role. We examined the mechanism(s) of spontaneous regression of neuroblastoma, focusing on the role of Ras, a favorable prognostic marker of neuroblastoma. METHODS: Tumor tissues were analyzed by light microscopy, electron microscopy, and immunohistochemistry to examine cell degeneration and expression of Ras and several indicators of PCD. Cell degeneration was also studied in vitro in neuroblastoma cells transfected with the H-ras gene. All statistical tests were two-sided. RESULTS: Immunohistochemical analyses revealed that Ras expression was increased in areas of cellular degeneration lacking apoptotic characteristics. The degenerating cells were fragmented without nuclear condensation and, essentially, lacked caspase-3 activation and apoptotic DNA fragmentation. These cells had ultrastructural features of autophagic degeneration, another form of PCD that is distinct from apoptosis. Focal areas of degeneration associated with Ras expression were seen more frequently in tumors from patients detected in a mass-screening program (53 [60.9%] of 87) than in tumors from clinically detected, advanced-stage patients over 1 year of age (7 [29.2%] of 24) (P =.006; chi-square test), suggesting a positive relationship between Ras-associated degeneration and probability of spontaneous regression/favorable prognosis. The characteristic features of Ras-associated nonapoptotic degeneration observed in tumor samples were recapitulated in vitro by transfection-mediated Ras expression, and Ras-mediated degeneration was augmented by TrkA, another favorable prognostic marker. CONCLUSIONS: High-level expression of H-Ras in neuroblastoma cells is associated with caspase cascade-independent, nonapoptotic PCD. This Ras-mediated nonapoptotic tumor cell death may play a key role in spontaneous regression of neuroblastoma.
UI - 11737230
AU - Huang S; Lichtenauer UD; Pack S; Wang C; Kim AC; Lutchman M; Koch CA;
TI - Torres-Cruz J; Huang SC; Benz EJ Jr; Christiansen H; Dockhorn-Dworniczak B; Poremba C; Vortmeyer AO; Chishti AH; Zhuang Z Reassignment of the EPB4.1 gene to 1p36 and assessment of its involvement in neuroblastomas.
SO - Eur J Clin Invest 2001 Oct;31(10):907-14
AD - Molecular Pathogenesis Unit, Surgical Neurology Branch, NINDS/NIH, Building 10/Room 5D32, 9000 Rockville Pike, Bethesda, MD 20892, USA.
OBJECTIVES: EPB4.1 has been previously mapped to human chromosome 1p33-p34.2. In contradiction to this chromosomal location, we have mapped EPB4.1-1p36 by using fluorescence in situ hybridization and radiation hybrid mapping. In neuroblastomas, deletions of the telomeric end of chromosome 1 (1p36) are the most common genetic aberration. METHODS: We investigated whether genetic aberrations of EPB4.1 can be detected in some neuroblastomas by analyzing 72 tumours for EPB4.1 mutation, expression, and alternative splicing pattern. Furthermore, EPB4.1 protein from a neuroblastoma cell line was studied for its subcellular localization. RESULTS: Sequence changes could be detected in 14 out of 72 neuroblastomas, including missense, silent, and intronic changes. Duplex RT-PCR analysis revealed a subset of 11 tumours expressing significantly low levels of EPB4.1. Significant EPB4.1 sequence changes that were detected included an exon 4 G/A missense mutation (amino acid: V/I) that was shown to be associated with absence of wild-type EPB4.1 expression (3 tumours), an exon 8 G/A missense mutation (V/M) (1 tumour), and an intronic sequence change that was shown to be associated with the presence of an aberrant transcript (1 tumour). Splicing pattern analysis revealed that all EPB4.1 transcripts from tumours exclude exon 3, a splicing pattern for generating the 135 kDa isoform. EPB4.1 cDNA cloned from a neuroblastoma cell line produced a 135-kDa protein with a cytoplasm/membrane localization. CONCLUSIONS: Out of 72 neuroblastomas we have identified 11 tumours with impaired EPB4.1 expression and 5 tumours with significant sequence changes. We also found that the 135 kDa isoform is the main EPB4.1 product in neuroblastoma. EPB4.1 cDNA from a neuroblastoma cell line produced a 135-kDa protein and displayed a cytoplasm/membrane localization in transfected cells.
UI - 11847429
AU - Truckenmiller ME; Vawter MP; Cheadle C; Coggiano M; Donovan DM; Freed
TI - WJ; Becker KG Gene expression profile in early stage of retinoic acid-induced differentiation of human SH-SY5Y neuroblastoma cells.
SO - Restor Neurol Neurosci 2001;18(2-3):67-80
AD - Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. email@example.com
PURPOSE: The human SH-SY5Y cell line is an established model for retinoic acid (RA)-induced neural differentiation. We employed a broad human 15K microarray (15,000 genes) and focused Neuroarray (1152 genes) to examine changes in gene expression early in the process of differentiation (6 hr), before morphology or growth changes are observed. METHODS: 33 P-labeled CDNA probes prepared from RNA extracts of RA-treated and control cultures were hybridized to array membranes, and levels of expression were quantified and compared. RESULTS: In the 15K array, 19 % of the genes were decreased (0.4 % were named genes and the remainder were expressed sequence tags (ESTs) or unknowns), and 9 % were increased (4.2 % named genes). In the Neuroarray, 3 % were decreased and 8 % were increased. CONCLUSIONS: Summary gene profiles are presented, which include transcription factors, genes associated with cell cycle, cell shape, neurotransmission, intermediary filaments, and others. The prevalence of down-regulated genes in the broad 15K array and up-regulated genes in the neuro-focused array suggests a pattern shift in gene expression associated with differentiation. The predominance of ESTs among the down-regulated genes indicates a great number of as-yet-unidentified genes are repressed in early stage neural differentiation.
UI - 11878777
AU - Anderson C P; Seeger R C; Satake N; Monforte-Munoz H L; Keshelava N;
TI - Bailey H H; Reynolds C P Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line.
SO - J Pediatr Hematol Oncol 2001 Nov;23(8):500-5
AD - Division of Hematology-Oncology, Children's Hospital Los Angeles, California 90027, USA.
BACKGROUND: Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable. PATIENTS AND METHODS: The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM. RESULTS: CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 micromol/L) maximally depleted CHLA-171 glutathione to 36% of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 micromol/L; peak plasma concentration in the patient equals 3.9 micromol/L) and moderately resistant to BSO (LD90 = 509 micromol/L; steady-state concentration in the patient equals 397 micromol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 micromol/L) and levels of L-PAM (10-40 micromol/L) clinically achievable only with hematopoietic stem cell support. CONCLUSIONS: The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM.
UI - 11836721
AU - Yoon G; Graham G; Weksberg R; Gaul HP; DeBaun MR; Coppes MJ
TI - Neuroblastoma in a patient with the Beckwith-Wiedemann syndrome (BWS).
SO - Med Pediatr Oncol 2002 Mar;38(3):193-9
AD - Alberta Children's Hospital, Calgary, Alberta, Canada.
UI - 11836726
AU - Pumberger W; Pomberger G; Wiesbauer P
TI - Postoperative intussusception: an overlooked complication in pediatric surgical oncology.
SO - Med Pediatr Oncol 2002 Mar;38(3):208-10
AD - Division of Pediatric Surgery, University of Vienna, Vienna / Wien,