Stage 4S Research Articles

Neuroblastoma in the newborn. A study of the Italian Neuroblastoma Registry

Aim Presenting features, treatment and outcome of 134 newborns with neuroblastoma diagnosed over a 27-year period are described. Methods Analyses were performed on the entire cohort and on patients distributed over three periods of diagnosis. Results Twenty-seven tumours (20.1%) were detected prenatally. Localised disease prevailed (65.7%) with an increase of stage 1 patients over time from 18.8% to 46.5%. Disseminated disease accounted for 34.3% of tumours with only one stage 4 and 45 stage 4S. Five-year overall survival (OS) of the entire cohort was 88.3%. Five/88 patients with localised disease died, including three who died of complications (OS, 95.3%). The only stage 4 patient survived. Eleven/45 stage 4S patients died, including 7/18 symptomatic and 4/27 asymptomatic (OS, 74.1%). Conclusion The outcome of neuroblastoma in newborns is excellent. In localised tumours, surgery-related deaths outnumbered deaths due to disease. Symptomatic stage 4S patients were at greater risk of dying.

A focal lesion in the falx cerebri: Harbinger of classic stage 4 neuroblastoma in an infant cured despite residual disease after minimal therapy

An asymptomatic 11-week-old male received no treatment after he was classified as having a suspected atypical form of MYCN-nonamplified hyperdiploid stage 4S neuroblastoma (NB), with masses in an adrenal gland, subcutaneous tissues, and the falx cerebri. Within 2 months, however, disease progressed in dura and bone marrow. Two cycles of low-dose chemotherapy achieved a partial response; treatment was discontinued. Complete remission was documented 24 weeks post-cycle 2, and has continued >6 years. The falx cerebri probably does not represent an atypical site for stage 4S NB, but stage 4 NB with favorable biology is sometimes curable with minimal therapy.

Expression and clinical significance of heparanase in neuroblastoma

Previous studies indicate that heparanase (HPA), an endoglycosidase involved in tumor angiogenesis and metastasis, is up-regulated in a variety of malignancies. However, the expression of HPA in neuroblastoma (NB), one of the most common extra cranial solid tumors in children, remains unknown. This study was undertaken to explore the expression and clinical significance of HPA in NB. Immunohistochemical staining was applied to detect the expression of HPA in 42 cases of NB. The relationships among HPA expression, international neuroblastoma staging system (INSS) stages, histopathological classification, and postoperative survival of the NB patients were analyzed. The expression rate of HPA in NB was 61.9% (26/42), mainly in the cytoplasm of neuroblastoma cells. The expression rates of stage 1-2, stage 3-4 and stage 4S were 35.7%, 80.0% and 62.5%, respectively. The differences between stage 1-2 and stage 3-4 were significant (P<0.01). The expression of HPA was significantly higher in the NB cases that had one of the histopathological factors: age more than 1 year (P<0.01), poorer differentiation (P<0.01), and higher mitosis karyorrhexis index (P<0.01). The survival time of HPA-negative patients was significantly longer than that of HPA-positive patients (P<0.05). Although these results indicate that heparanase might be correlated with development and progression of NB, a larger series of patients with a longer follow-up are probably needed to strengthen its role in assessment of NB prognosis.

Significance of tumor biology compared to metastatic pattern (INSS 4 versus 4s) and age for prognosis of neuroblastoma less than 18 months of age

10010 Background: Neuroblastoma is a heterogeneous disease with variability in outcome among different risk groups. Historically, INSS stage 4s neuroblastoma (age less than 12 months, stage 1 or 2 primary tumor with metastases limited to liver, skin and bone marrow) has a more favorable outcome than infant stage 4 disease. The aim was to determine if metastatic pattern (4 vs 4s) predicted favorable prognosis in infants &lt; 12 months or in toddlers aged 12–18 months when stratifying by biology. Methods: Outcome was analyzed by log rank tests and Cox models for 656 infants with stage 4s neuroblastoma and 1,019 stage 4 patients &lt; 18 months of age in the International Neuroblastoma Risk Group database (n=8,800). Prognostic factors (tumor ploidy, histology, grade, MKI, LDH, MYCN, 11q, 1p, primary site) were tested for association with age/stage subgroups (Fisher's exact test) and in Cox models. Results: MYCNamplification, 1p aberration, diploidy, and high MKI and LDH were more frequent in infant stage 4 than infant 4s tumors. The incidence of unfavorable biology was higher in toddlers aged 12–18 months, but did not differ with stage 4 vs. 4s pattern. EFS was significantly better for infants &lt;12 months with stage 4s than stage 4 (p=0.0004). EFS was similar for toddlers 12–18 months for stage 4 vs. 4s pattern (p=0.3893). Within the 717 patients with 4s pattern of metastases, age 12–18 months had worse EFS than &lt;12 months (p&lt;0.0001). After adjustment for age in 6 separate models, MYCN, 11q, 1p, MKI, and LDH were statistically significant prognostic factors. Although treatment regimens differed, EFS was similar for &lt;12 months vs. 12–18 months for MYCN not amplified patients in both 4S pattern (p=0.8469) and stage 4 (p=0.3783). Conclusions: For patients with MYCN not amplified tumors, outcome for patients 12–18 months is similar to those &lt;12 months regardless of the pattern of metastases. Tumor biology is more critical than metastatic pattern for prognosis of patients aged 12–18 months with stage 4 neuroblastoma. [Table: see text] No significant financial relationships to disclose.

Bone marrow infiltration in infants with disseminated neuroblastoma

10056 Background: The INSS definition of stage 4S neuroblastoma allows a bone marrow infiltration (BMI) no greater than 10%. More extensive involvement is to be consider stage 4. However, the degree of BMI may be difficult to establish, since tumor cells in the marrow commonly aggregate in clumps. So far, no studies have specifically investigated this issue. In this study we have reviewed the bone marrow slides of infants with disseminated neuroblastoma enrolled between January 1998 and July 2008 in the Italian Neuroblastoma Registry. Methods: BMI was arbitrarily considered &lt;10% when it consisted of a maximum of 5 tumor cell aggregates/slide in association to normal cellularity. Marrow was aspirated from iliac crests and slides were stained with Wright-Giemsa method. A minimum of 2 slides for aspirate were examined at low magnification. The same 2 hematologists (CR, MP) examined the slides independently along the study period, blind for clinical data. A third hematologist (FS) joined to perform the reviewing process. Results: Of 142 infants enrolled, we retrieved and reviewed bone marrow slides of 73. Before results of bone marrow study, 31 patients were defined as stage 4, and 42 as stage 4S. Following bone marrow study, 2 patients previously defined as stage 4S who had ≥10% BMI were moved to stage 4. The results of the revision are summarized ( Table ). Conclusions: In this study, only 2/42 infants with stage 4S clinical features had BMI ≥ 10% and were eventually labeled as stage 4. Whether chemotherapy for stage 4 is of advantage for these patients remains to be seen. [Table: see text] No significant financial relationships to disclose.

Expression of CD133 and poor outcome in neuroblastoma associated with chemoresistance mediated by AKT pathway

10007 Background: Neuroblastoma is a frequent childhood cancer with very heterogeneous prognosis. Recent studies showed that CD133 expression is an independent prognostic marker for low survival in several cancers like medulloblastoma. The aim of our study is to determine the prognostic value of CD133 expression in a large population of neuroblastoma and to determine the chemoresistance of neuroblasts expressing CD133. Methods: 280 tumor samples of neuroblastoma were screened for CD133 expression. Patients had a median follow-up of 7.15 years. One hundred eighteen patients were under one year of age with a median age of 27 months. There were 67 stage 1, 46 stage 2, 43 stage 3, 99 stage 4, and 25 stage 4S. The association of CD133 expression with relapse and survival were determined through univariate and multivariate analysis. Sensitivity of purified CD133+ neuroblasts isolated from 2 human neuroblastoma cell lines (SKNSH and NB10) to doxorubicin, vincristine and cisplatin was evaluated in vitro, as single agents or in combination with LY294002, a AKT inhibitor. Results: CD133 was expressed in 95 of 280 tumors (33%). There was a significant association between CD133 expression and the following poor prognosis co-variates: age (p&lt;0.0001), INSS stage (p&lt;0.0001), MYCN amplification (p&lt;0.0001). Patients with a CD133+ tumor had a three year event-free and overall survival of 43±5% and 51±5%, respectively, as compared to patients with a CD133- tumor with 88±2% (P&lt;0.001) and 95±2% (p&lt;0.001). In a multivariate model, CD133 expression was independently associated with a decreased overall survival (p = 0.003) in the entire cohort. In vitro purified CD133+ neuroblasts were significantly resistant to chemotherapy as compared to their CD133- cells counterpart, but not in presence of the AKT inhibitor. In vitro treatment of unsorted neuroblasts with the three anticancer drugs significantly enriched the CD133+ subpopulation but not in presence of the AKT inhibitor. CD133plus; significantly expressed higher levels of activated proteins in the AKT pathway than CD133−. Conclusions: CD133 is independently associated with a worse outcome in patents with neuroblastoma. This prognosis factor is associated with in vitro resistance to chemotherapy involving activation of the AKT pathway. No significant financial relationships to disclose.

Netrin-1 acts as a survival factor for aggressive neuroblastoma

Neuroblastoma (NB), the most frequent solid tumor of early childhood, is diagnosed as a disseminated disease in >60% of cases, and several lines of evidence support the resistance to apoptosis as a prerequisite for NB progression. We show that autocrine production of netrin-1, a multifunctional laminin-related molecule, conveys a selective advantage in tumor growth and dissemination in aggressive NB, as it blocks the proapoptotic activity of the UNC5H netrin-1 dependence receptors. We show that such netrin-1 up-regulation is a potential marker for poor prognosis in stage 4S and, more generally, in NB stage 4 diagnosed infants. Moreover, we propose that interference with the netrin-1 autocrine loop in malignant neuroblasts could represent an alternative therapeutic strategy, as disruption of this loop triggers in vitro NB cell death and inhibits NB metastasis in avian and mouse models.

Co-regulated expression of HAND2 and DEIN by a bidirectional promoter with asymmetrical activity in neuroblastoma

BackgroundHAND2, a key regulator for the development of the sympathetic nervous system, is located on chromosome 4q33 in a head-to-head orientation with DEIN, a recently identified novel gene with stage specific expression in primary neuroblastoma (NB). Both genes are expressed in primary NB as well as most NB cell lines and are separated by a genomic sequence of 228 bp. The similar expression profile of both genes suggests a common transcriptional regulation mediated by a bidirectional promoter.ResultsNorthern Blot analysis of DEIN and HAND2 in 20 primary NBs indicated concurrent expression levels of the two genes, which was confirmed by microarray analysis of 236 primary NBs (Pearson's correlation coefficient r = 0.65). While DEIN expression in the latter cohort was associated with stage 4S (p = 0.02), HAND2 expression was not associated with tumor stage. In contrast, both HAND2 and DEIN transcript levels were highly associated with age at diagnosis <12 months (p = 0.001). The intergenic region shows substantial homology in different species (89%, 72% and 53% identity between human and mouse, chicken and zebrafish, respectively) and contains many highly conserved putative transcription factor binding sites. Using luciferase reporter gene constructs, asymmetrical bidirectional promoter activity was found in four NB cell lines: In DEIN orientation, an average 3.4 fold increase in activity was observed as compared to the promoterless vector, whereas an average 15.4 fold activation was detected in HAND2 orientation. The presence of two highly conserved putative regulatory elements, one of which was shown to enhance HAND2 expression in branchial arches previously, displayed weak repressor activity for both genes.ConclusionHAND2 and DEIN represent a gene pair that is tightly linked by a bidirectional promoter in an evolutionary highly conserved manner. Expression of both genes in NB is co-regulated by asymmetrical activity of this promoter and modulated by the activity of two cis-regulatory elements acting as weak repressors. The concurrent quantitative and tissue specific expression of HAND2 and DEIN suggests a functional link between both genes.

Characterisation of stable cell clones derived from an unusual neuroblastoma stage 4S with MYCN amplification

Characterisation of stable cell clones derived from an unusual neuroblastoma stage 4S with MYCN amplification

Specific gene expression profiles and chromosomal abnormalities are associated with infant disseminated neuroblastoma

BackgroundNeuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. Clinical distinction of stage 4s from lethal stage 4 can be difficult, but critical for therapeutic decisions. The aim of this study was to investigate chromosomal alterations and differential gene expression amongst infant disseminated NB subgroups.MethodsThirty-five NB tumours from patients diagnosed at < 18 months (25 stage 4 and 10 stage 4s), were evaluated by allelic and gene expression analyses.ResultsAll stage 4s patients underwent spontaneous remission, only 48% stage 4 patients survived despite combined modality therapy. Stage 4 tumours were 90% near-diploid/tetraploid, 44% MYCN amplified, 77% had 1p LOH (50% 1p36), 23% 11q and/or 14q LOH (27%) and 47% had 17q gain. Stage 4s were 90% near-triploid, none MYCN amplified and LOH was restricted to 11q. Initial comparison analyses between stage 4s and 4 < 12 months tumours revealed distinct gene expression profiles. A significant portion of genes mapped to chromosome 1 (P < 0.0001), 90% with higher expression in stage 4s, and chromosome 11 (P = 0.0054), 91% with higher expression in stage 4. Less definite expression profiles were observed between stage 4s and 4 < 18m, yet, association with chromosomes 1 (P < 0.0001) and 11 (P = 0.005) was maintained. Distinct gene expression profiles but no significant association with specific chromosomal region localization was observed between stage 4s and stage 4 < 18 months without MYCN amplification.ConclusionSpecific chromosomal aberrations are associated with distinct gene expression profiles which characterize spontaneously regressing or aggressive infant NB, providing the biological basis for the distinct clinical behaviour.

Poor Survival for Infants With MYCN-Amplified Metastatic Neuroblastoma Despite Intensified Treatment: The International Society of Paediatric Oncology European Neuroblastoma Experience

To report the results of a prospective, nonrandomized European study on infants with neuroblastoma and MYCN gene amplification. Infants with neuroblastoma (stage 2, 3, 4, and 4s) and MYCN gene amplification who were diagnosed between 1999 and 2004 were eligible for enrollment onto the study. After diagnosis, staging, and mandatory biologic studies, induction chemotherapy (IC) with conventional drugs was administered, followed by delayed surgery, megatherapy (busulfan-melphalan as a conditioning regimen), and local radiotherapy. Of the 46 infants enrolled onto the study, 35 infants were eligible; of these 35 infants, 97% had metastatic spread (24 infants had stage 4, and 10 infants had stage 4s). Two-year overall survival (OS) was 30% (SE, 0.08), with median survival time of 12 months, and 23 deaths due to disease. Two-year, event-free survival (EFS) was 29% (SE, 0.07). The treatment was well tolerated with no deaths as a result of toxicity or severe toxicity. Despite protocol adherence, 30% of the patients who were assessable for response to IC experienced disease progression or did not respond. Stage and high lactate dehydrogenase reached significance in the univariate analysis (P = .028 and .039, respectively for OS; and P = .05 and .031 respectively, for EFS). Ten of 16 patients who received megatherapy are still alive. Although treatment was well tolerated, survival was poor and our IC failed to achieve a satisfactory response in 30% of our patients. New therapeutic approaches and more intense world-wide collaboration are needed to achieve a cure in this population.

Excellent Outcome With Reduced Treatment for Infants With Disseminated Neuroblastoma Without MYCN Gene Amplification

On the assumption that most infants with disseminated neuroblastoma without MYCN amplification (MYCNA) have a favorable prognosis, two concomitant prospective trials were started in which chemotherapy was limited to patients presenting life- or organ-threatening symptoms or overt metastases to skeleton, lung, or CNS. Surgery was to be performed only in the absence of surgical risk factors. One hundred seventy infants with disseminated neuroblastoma without MYCNA, diagnosed between June 1999 and June 2004 in nine European countries were eligible for either of the two studies. Trial 99.2 included all stage 4S infants and those with stage 4 with a primary tumor infiltrating across the midline or positive skeletal scintigraphy who were to be observed in absence of symptoms. Trial 99.3 included infants with overt metastases to the skeleton, lung, and CNS to be treated with a minimum of four chemotherapy courses. The 125 infants treated on trial 99.2 had a 2-year overall survival (OS) of 97.6% with no difference between asymptomatic and symptomatic patients (97.7% v 97.3%), patients without or with unresectable primary tumors (96.8% v 100%), and patients without or with positive skeletal scintigraphy without radiologic abnormalities (97.2% v 100%). The 45 infants treated on trial 99.3 had a 2-year OS of 95.6%. No patients died of surgery- or chemotherapy-related complications. Infants with disseminated disease without MYCNA have excellent survival with minimal or no treatment. Asymptomatic infants with an unresectable primary tumor or positive skeletal scintigraphy without radiologic abnormalities may undergo observation alone.

Congenital Stage 1 Neuroblastoma Evolved Into Stage 4s

A newborn with a prenatally detected adrenal mass underwent complete resection of a stage 1 favorable histology neuroblastoma (NB) without MYC-N amplification. Two months later, the infant presented with a local recurrence and multiple hepatic metastases. Close follow-up without therapy was adopted for stage 4s NB. Enlarging tumor lesions were seen until the child was 8 months old, followed by later decrease in size. At 36 months of follow-up, the child is alive and disease-free. We describe this case of NB and its abnormally short evolution from stage 1 to stage 4s, despite initial surgery. Its spontaneous regression may help us understand the natural history of congenital NB.

Histone Deacetylase 8 in Neuroblastoma Tumorigenesis

The effects of pan-histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression. The purpose of this study was to evaluate the role of individual HDACs in neuroblastoma tumorigenesis. We have investigated the mRNA expression of all HDAC1-11 family members in a large cohort of primary neuroblastoma samples covering the full spectrum of the disease. HDACs associated with disease stage and survival were subsequently functionally evaluated in cell culture models. Only HDAC8 expression was significantly correlated with advanced disease and metastasis and down-regulated in stage 4S neuroblastoma associated with spontaneous regression. High HDAC8 expression was associated with poor prognostic markers and poor overall and event-free survival. The knockdown of HDAC8 resulted in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest, and differentiation in cultured neuroblastoma cells. The treatment of neuroblastoma cell lines as well as short-term-culture neuroblastoma cells with an HDAC8-selective small-molecule inhibitor inhibited cell proliferation and clone formation, induced differentiation, and thus reproduced the HDAC8 knockdown phenotype. Global histone 4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment. Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis and identify this HDAC family member as a specific drug target for the differentiation therapy of neuroblastoma.

Bilateral adrenal neuroblastoma

Bilateral adrenal neuroblastoma is extremely rare. To date, 45 cases have been reported in the literature. We retrospectively identified and reviewed 15 cases of bilateral adrenal neuroblastoma, treated between 1988 and 2004, by the French Society of Pediatric Oncology. We then compared our cohort to the 45 cases reported in literature. Median age at diagnosis was 4 months in our cohort whereas it was 3 months in the literature. The same percentage of infants was found in both series (86.6%). Disease had generally been detected due to metastasis-related symptoms. Ten out of 15 patients in our cohort and 18/39 cases in the literature were classified as stage 4S according to the International Neuroblastoma Staging System (INSS). The incidence of stage 4S was significantly higher than that described in other neuroblastoma cohorts (P = 10(-4)). Five-year overall survival was 90% for stage 4S. In our series, bilateral neuroblastoma was neither associated with familial cases nor with any risk factors. The majority of bilateral neuroblastoma carry a favorable prognosis. Exceptional cases exhibiting risk factors, such as amplified MYCN, are comparable to high-risk unilateral neuroblastoma cases with the same poor prognostic features. The therapeutic strategy could be similar to that used against unilateral neuroblastoma, except for surgery. However, the low incidence of relapse and the risk of adrenal failure if radical surgery is performed, argue against an aggressive surgical approach.

Is aggressive local treatment necessary for diffuse liver involvement in patients with progression of stage 4s neuroblastoma to stage 4?

Three patients with stage 4S neuroblastoma without MYC-N amplification who progressed to stage 4 with persistent liver involvement, were treated with iodine 131–meta-iodobenzylguanidine therapy, chemotherapy, and surgery. Successive histologic examination of the liver showed differentiation of the tumor in 2 patients and fibrosis in the third. One patient died of brain metastases at the age of 30 months. The other 2 patients are alive at 50 and 44 months. Diffuse liver involvement in patients with stage 4 progression of previous stage 4S without MYC-N amplification may differentiate after treatment. The aim of this report is to draw attention to major liver surgery that it may not be necessary in tumors without MYC-N amplification, despite the persistence of lesions in the liver.

MYCN-non-amplified metastatic neuroblastoma with good prognosis and spontaneous regression: A molecular portrait of stage 4S

Stage 4 neuroblastoma (NB) are heterogeneous regarding their clinical presentations and behavior. Indeed infants (stage 4S and non-stage 4S of age <365 days at diagnosis) show regression contrasting with progression in children (>365 days). Our study aimed at: (i) identifying age-based genomic and gene expression profiles of stage 4 NB supporting this clinical stratification; and (ii) finding a stage 4S NB signature. Differential genome and transcriptome analyses of a learning set of MYCN-non amplified stage 4 NB tumors at diagnosis ( n = 29 tumors including 12 stage 4S) were performed using 1Mb BAC microarrays and Agilent 22K probes oligo-microarrays. mRNA chips data following filtering yielded informative genes before supervised hierarchical clustering to identify relationship among tumor samples. After confirmation by quantitative RT-PCR, a stage 4S NB's gene cluster was obtained and submitted to a validation set ( n = 22 tumors). Genomic abnormalities of infant's tumors (whole chromosomes gains or loss) differ radically from that of children (intra-chromosomal rearrangements) but could not discriminate infants with 4S from those without this presentation. In contrast, differential gene expression by looking at both individual genes and whole biological pathways leads to a molecular stage 4S NB portrait which provides new biological clues about this fascinating entity.

Localized Infant Neuroblastomas Often Show Spontaneous Regression: Results of the Prospective Trials NB95-S and NB97

The excellent prognosis of localized neuroblastoma in infants, the overdiagnosis observed in neuroblastoma screening studies, and several case reports of regression of localized neuroblastoma prompted us to initiate a prospective cooperative trial on observation of localized neuroblastoma without cytotoxic treatment. For infants with localized neuroblastoma without MYCN amplification, chemotherapy was scheduled only in cases with threatening symptoms; otherwise, the tumor was either resected or observed by ultrasound and magnetic resonance imaging (MRI). Of 340 eligible participants, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor. Of those 93 patients with unresected tumors, spontaneous regression was seen in 44, local progression in 28, progression to stage 4S in seven, and progression to stage 4 in four. Time to regression was quite variable, with first signs of regression noted 1 to 18 months after diagnosis and in 15 of 44 patients even after the first year of life. So far, complete regression was observed in 17 of 44 patients 4 to 20 months after diagnosis. Known clinical risk factors were not able to differentiate between patients with regression and regional or metastatic progression. Overall survival (OS; 3-year OS, 0.99 +/- 0.01) and metastases-free survival (rate at 3 years, 0.94 +/- 0.03) for patients with unresected tumors was excellent and was not different from patients treated with surgery or chemotherapy. Spontaneous regression is regularly seen in infants with localized neuroblastoma and is not limited to the first year of life. A wait-and-see strategy is justified in those patients.

Expression and clinical significance of stem cell marker CD133 in human neuroblastoma

Recent evidences indicate that CD133, a kind of transmembrane protein, can be used as a marker to isolate stem cells from tumors originating from neural crest. This study was undertaken to explore the expression and clinical significance of stem cell marker CD133 in neuroblastoma (NB). Immunohistochemical staining was used to detect the expression of CD133 in 32 patients with NB and 8 patients with ganglioneuroblastoma (GNB). The relationships were analyzed among CD133 expression, international neuroblastoma staging system (INSS) stages, pathological classification, and postoperative survival time of NB patients. The expression rates of CD133 in NB and GNB were 46.9% (15/32) and 37.5% (3/8) respectively, mainly in cytoplasm of neuroblastoma cells. The expression rates of stage 1-2, stage 3-4 and stage 4S were 30.7%, 57.9% and 37.5%, respectively. The differences in various stages were significant (P<0.05). The positive rate of CD133 in patients with unfavorable histology (52.4%) was significantly higher than that in patients with favorable histology (36.8%) (P=0.007). The survival time of CD133 negative patients was significantly longer than that of CD133 positive patients (P=0.026). CD133 which might be correlated with the development and progression of NB can serve as one of the important indicators for prognosis of NB.

Neuroblastoma;Variable Symptoms of A Neurogenic Tumor; A Report From Iran

Objective to current data available, neuroblastoma is the most frequent extracranial solid tumor in infants and children; because of its relationship to the primitive sympathetic ganglia, it may progress or regress spontaneously to more malignant or benign forms of tumors, respectively. It is also an important cause of the Opsoclonus Myoclonus Ataxia Syndrome (OMAS), or the “dancing eyes” syndrome. The risk factor of neuroblastoma includes patient’s age at diagnosis; degree of tumor spread, and selected biologic variables such as serum LDH, urinary and serum catecholamines such as VMA and HVA, ploidy and MYCN copy numbers. So, detection of risk factors and risk directed therapy are the mainstay of patient management. Materials & Methods For this study the records of 43 out of 46 patients, aged less than 14 years, admitted over 8 years (1996-2004), with the confirmed diagnosis of neuroblastoma or ganglioneuroblastoma were evaluated for full course of therapy and follow up. Results patient group, 60% were male and 40% female. The most frequent clinical stage was stage 3 (34.7%), followed with stage 4 (32.6%) and 2 (26%). Less than 2% of patients presented with pure neurologic symptoms and these responded well to treatment. Relapse was seen more frequently in stage 4 patients and less in stage 4S. The OPEC protocol, started in 81% of patients, achieved a 54% response; on the other hand, in 15%, N6 was used, with the response rate of 40%. Patient data was analyzed and interpreted using SPSS software to reveal which clinical and biologic factors improve neuroblastoma outcome. Conclusion and patients’ age at the time of diagnosis are the most important clinical factors to predict outcome, while primary tumor site and some biologic findings such as urinary VMA and serum LDH levels have a less important value