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Ioka A, Inoue M, Yoneda A, et al.
Effects of the Cessation of Mass Screening for Neuroblastoma at 6 Months of Age: A Population-Based Study in Osaka, Japan.
J Epidemiol. 2016; 26(4):179-84 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: In 2004, the Japanese government halted the 6-month mass screening program for neuroblastoma. We investigated whether its cessation had led to an increase not only in mortality due to this disease but also in the incidence of advanced-stage disease among older children.
METHODS: Study subjects were neuroblastoma patients retrieved from the population-based Osaka Cancer Registry. Trends of incidence and mortality from neuroblastoma were analyzed by calendar year and birth cohort. Prognostic factors, including stage and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) oncogene status, were compared before and after the cessation of mass screening.
RESULTS: Age-standardized incidence rates in 2005-2009 (the cessation period of mass screening; 11.1 per million) were similar to those in 1975-1979 (the pre-screening period; 8.6 per million). Age-standardized mortality rates tended to decrease from 1975-1979 (4.0 per million) to 2005-2009 (2.7 per million) in parallel with the improvement in survival. Analysis by birth cohort indicated that the mortality rates in 2004-2005 (after cessation) for children 0-4 years of age were lower than those in 1975-1979 (O:E ratio 0.25; 95% confidence interval, 0.03-0.90). For children 1-9 years of age, there was a not significant difference in the distribution of stage, MYCN oncogene status, and DNA ploidy between 1991-2003 (the mass screening period) and 2004-2008 (after cessation).
CONCLUSIONS: The cessation of mass screening for neuroblastoma does not appear to have increased mortality due to this disease or incidence of advanced-stage disease among older children.

Arakawa A, Oguma E, Aihara T, et al.
Long-term follow-up results of the observation program for neuroblastoma detected at 6-month mass screening.
J Pediatr. 2014; 165(4):855-7.e1 [PubMed] Related Publications

We conducted an observation program of neuroblastoma in infants, detected by mass screening at 6 months of age; we followed up with them for 15 years. No recurrence was observed after disappearance of tumors, and persistent tumors showed no malignant transformation or metastasis. Histology of the resected tumors showed age-related differentiation.

Sartelet H, Ohta S, Barrette S, et al.
High level of apoptosis and low AKT activation in mass screening as opposed to standard neuroblastoma.
Histopathology. 2010; 56(5):607-16 [PubMed] Related Publications

AIMS: Neuroblastoma is a paediatric solid tumour with a poor outcome except in children <1 year old. Based on catecholamine urinary excretion, mass screening (MS) programmes have been organized but failed to decrease the mortality of this tumour. To test the hypotheses of a spontaneous maturation/differentiation or regression, the levels of poly (ADP-ribose) polymerase (PARP)-1, an early apoptosis marker, of PhosphoAKT, a major apoptosis inhibitor, and of maturation/differentiation were compared in standard and in MS neuroblastomas.
METHODS AND RESULTS: We performed a case-control study of 55 primary tumours and 21 metastases of MS neuroblastomas. Matched controls were standard unscreened neuroblastomas and were paired according to age, stage, and MYCN amplification. The tumours were included in tissue microarrays. Immunohistochemical staining was performed using antibodies against, AKT, phosphoAKT, TRKB and PARP-1. The expression of PARP-1 and that of phosphoAKT were significantly higher in standard than in MS neuroblastomas independently of age and stage of the tumour. PhosphoAKT and PARP-1 expression was significantly correlated in both tumours.
CONCLUSIONS: These data suggest that the better prognosis of patients with MS neuroblastomas compared with classical neuroblastomas was secondary to spontaneous tumour regression mediated by higher levels of apoptosis associated with low activation of AKT.

Related: Apoptosis Canada Kidney Cancer AKT1 PARP1

Tanaka M, Kigasawa H, Kato K, et al.
A prospective study of a long-term follow-up of an observation program for neuroblastoma detected by mass screening.
Pediatr Blood Cancer. 2010; 54(4):573-8 [PubMed] Related Publications

BACKGROUND: A nationwide mass screening for neuroblastoma (NBL) in 6-month-old infants (MS6M) was performed in Japan from 1985 to 2003. Favorable biological features were identified for most of the detected tumors; consequently, we began an observation program for selected screened patients in 1993. Here, we report the clinicopathological findings and present status of patients enrolled in our observation program, with the goal of evaluating its usefulness.
PROCEDURE: Between 1993 and 2003, 53 of 101 patients with NBL detected by MS6M were enrolled. The patients were divided into four groups according to changes in urinary VMA and HVA levels and tumor size.
RESULTS: Urinary VMA and HVA levels decreased in 39 of 53 patients. In 17 of these 39 patients, the tumor became undetectable (Group A); in 22 patients the tumor was detectable (Group B). In seven patients, tumor marker levels varied, and tumor volume gradually increased (Group C). In six patients, tumor marker levels and tumor volume increased in the short term (Group D). One patient had multiple tumors (1M according to International Neuroblastoma Staging System). All tumors in Groups C and D, four tumors in Group B, and one tumor in the 1M patient were removed. No unfavorable biologic factors were noted in any excised tumor.
CONCLUSIONS: The observation program of the present study, one of the largest series for MS6M, confirmed that over 70% of patients who fulfilled the criteria could be observed without surgery.

Onitake Y, Hiyama E, Kamei N, et al.
Telomere biology in neuroblastoma: telomere binding proteins and alternative strengthening of telomeres.
J Pediatr Surg. 2009; 44(12):2258-66 [PubMed] Related Publications

PURPOSE: Neuroblastoma (NBL) shows remarkable biologic heterogeneity, resulting in favorable or unfavorable prognoses. Previously, we reported that most unfavorable NBLs express high telomerase activity to maintain telomere length. Recently, telomere binding proteins (TBPs) and alternative lengthening of telomeres (ALTs) have been identified as key factors of telomere maintenance.
METHODS: To evaluate the correlation between telomerase activity, telomere length, and the expression levels of TBPs in NBL, we analyzed and quantified these factors in 121 untreated NBLs.
RESULTS: Shortened and elongated telomeres were detected in 21 (17.3%) and 11 cases (9.0%), respectively, and there was a significant correlation between telomere length and the length of the 3'-overhang. The tumors with shortened or elongated telomeres showed significant lower expression of TBPs, except for RAP1. Although telomerase activity did not correlate with telomere length, 16 of 22 cases with high telomerase activity and 5 of 9 cases (ALT tumors) that showed long telomeres without high telomerase activity resulted in death. High-dose chemotherapy did not have much effect on these deceased ALT cases, but their survival periods were more than 2 years and relatively long compared with the deceased cases with nonelongated telomeres, suggesting that chemoresistance in ALT tumors may be related to slow growth rates.
CONCLUSIONS: High telomerase activity is a poor prognostic factor in NBL. In the cases without high telomerase activity, those with elongated telomere also showed poor outcomes because of chemoresistance. Therefore, ALT and TBPs may be biomarkers for chemosensitivity in NBL. Thus, a better understanding of telomere biology may help define the characteristics of individual NBLs.

Tajiri T, Souzaki R, Kinoshita Y, et al.
Risks and benefits of ending of mass screening for neuroblastoma at 6 months of age in Japan.
J Pediatr Surg. 2009; 44(12):2253-7 [PubMed] Related Publications

PURPOSE: The mass screening (MS) for neuroblastoma (NB) at 6 months of age in Japan was discontinued in 2004. This study assessed the risks and benefits of MS based on an analysis of NB detected before or after discontinuation of MS in Japan.
METHODS: The clinical features and Brodeur's genetic type based on MYCN, DNA ploidy, and other genetic aberrations were assessed in 113 NB patients (20 cases after and 93 cases [55 MS cases] before the discontinuation of MS) older than 6 months treated at one institution since 1985.
RESULTS: The 20 patients with NBs detected after MS was discontinued ranged in age from 7 to 67 months, 12 patients were stage 4, and 11 patients would have been detected at 6 months of age if they had undergone MS. The Brodeur's genetic type of these 20 patients showed that 30% (6/20) were type 1 (low risk), 55% (11/20) were type 2A (intermediate risk), and 15% (3/20) were type 2B (high risk). Of 93 patients with NB detected before MS was discontinued, 60% (56/93) were type 1, 18% (17/93) were type 2A, and 22% (20/93) were type 2B. Among the type 2A patients, 82% (9/11) of the patients detected after MS was discontinued showed stage 4, whereas only 50% (9/18) of those diagnosed before MS was discontinued were stage 4. The genetic analysis using single nucleotide polymorphism (SNP) array for type 2A showed that the pattern of genetic aberration was equivalent in those detected either before or after MS was discontinued.
CONCLUSIONS: There was a decrease of type 1 and an increase of type 2A NB in patients after MS was discontinued in Japan. These results suggest that most of the type 1 detected by MS has regressed, and most of the type 2A detected by MS has appeared sporadically as advanced NB in patients older than 1 year.

Related: MYCN (n-myc)

Katanoda K, Hayashi K, Yamamoto K, Sobue T
Secular trends in neuroblastoma mortality before and after the cessation of national mass screening in Japan.
J Epidemiol. 2009; 19(5):266-70 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: In 2003, the Japanese government halted the national mass screening program for neuroblastoma (NB), which had been running since the mid-1980s. It is not known whether the NB mortality rate subsequently increased or decreased.
METHODS: Utilizing vital statistics data from 1980 through 2006, we analyzed the secular trends in NB mortality by using cancer of the adrenal gland as a surrogate. We examined the validity of this substitution by comparing the results with data from death certificates. Using a joinpoint regression model, we examined the trends in age-specific mortality rates by calendar year and cumulative mortality rates by birth year. The cumulative mortality rate was analyzed for age under 1 or 2 years for infants born after the cessation of the mass screening program.
RESULTS: The number of deaths from cancer of the adrenal gland was closely correlated with the number of deaths from NB. Significant decreases in the mortality rate were observed from 1980 through 2006 by calendar year for those aged under 1 year, 1 to 4 years, and 5 to 9 years. The cumulative mortality rates by birth year also significantly decreased from the 1980 birth cohort. Although the cumulative mortality rates under the age of 2 appear to have increased after the 2003 birth cohort, the change was not statistically significant.
CONCLUSIONS: No significant increase in the NB mortality rate was detected after the cessation of the mass screening program in Japan. However, continuous monitoring is still needed to fully evaluate this health policy decision.

Hiyama E
Neuroblastoma screening in Japan: population-based cohort study and future aspects of screening.
Ann Acad Med Singapore. 2008; 37(12 Suppl):88-4 [PubMed] Related Publications

INTRODUCTION: It is unknown whether screening for neuroblastoma has the benefit of reducing the incidence of advanced diseaseor mortality due to neuroblastoma.Japanese nationwide massscreening for 6 month old infants was launched in 1985 and was performed using quantitative high-performance liquid chromatography (HPLC) between years 1990 to 2003.
MATERIALS AND METHODS: We compared the incidence rates (IR) and the mortality rates (MR) per 100,000 births of neuroblastomas diagnosed before 6 years of age between 2 cohorts: children born during the years 1980 to1984 (Pre-screen cohort, n = 7,620,203) and 1990 to1998 (Screen cohort, n = 10,878,918). We then proposed the optimal timing and procedures for future screening.
RESULTS: Cumulative IR in the Screen cohortwas significantly higher than the Pre-screen cohort (29.80 vs. 11.96, P <0.0001). On the other hand, IR of neuroblastoma diagnosed after 24 months old in the Screen cohort was significantly lower than in the Pre-screen cohort (P <0.0001). The cumulative MR of the Pre-screen cohort was 5.35, whereas that of the Screen cohort was 2.82 (P <0.0001).
CONCLUSIONS: HPLC mass-screening for neuroblastoma at 6 months of age found a marked increase in incidence in younger children (less than 12 month old) and a significant decrease in mortality rates overall. To reduce overdiagnosis of regressing cases and to identify preclinical stages of unfavourable cases, we propose using HPLC-screening at 18 months of age.

Ikematsu S, Nakagawara A, Nakamura Y, et al.
Plasma midkine level is a prognostic factor for human neuroblastoma.
Cancer Sci. 2008; 99(10):2070-4 [PubMed] Related Publications

Neuroblastoma is the third-most-common solid tumor of childhood. To date, no reliable blood marker for neuroblastoma has been established. The growth factor midkine is highly expressed in human carcinomas and its knockdown leads to tumor growth suppression in animal models. The present study evaluated the plasma midkine level in human neuroblastoma patients. Plasma samples were obtained from patients found through mass screening, as well as from sporadic neuroblastoma patients. The total number of cases examined was 756. Among them, prognostic information was available for 175 sporadic cases and 287 mass-screening cases. Midkine levels were significantly higher in neuroblastoma patients, including both mass-screening cases and sporadic cases, than in non-tumor controls (P < 0.0001). The midkine level was significantly correlated with the statuses of MYCN amplification, TRKA expression, ploidy, stage and age (P < 0.0001, < 0.0001, = 0.004, < 0.0001 and < 0.0001, respectively), which are known prognostic factors for neuroblastoma. There was a striking correlation between high plasma midkine level and poor prognosis (P < 0.0001). Within sporadic cases, the midkine level was also strikingly higher than in non-tumor controls (P < 0.0001), and correlated with the statuses of MYCN amplification and stage (P = 0.0005 and = 0.003, respectively). There was a significant correlation between high plasma midkine level and poor prognosis (P = 0.04). Taken together, the present data indicate that plasma midkine level is a prognostic factor for human neuroblastoma.

Related: Cytokines

Hiyama E, Iehara T, Sugimoto T, et al.
Effectiveness of screening for neuroblastoma at 6 months of age: a retrospective population-based cohort study.
Lancet. 2008; 371(9619):1173-80 [PubMed] Related Publications

BACKGROUND: In Japan, a nationwide programme between 1984 and 2003 screened all infants for urinary catecholamine metabolites as a marker for neuroblastoma. Before 1989, this was done by qualitative spot tests for vanillylmandelic acid in urine, and subsequently by quantitative assay with high-performance liquid chromatography (HPLC). However, the Japanese government stopped the mass-screening programme in 2003, after reports that it did not reduce mortality due to neuroblastoma. We aimed to assess the effectiveness of the programme, by comparing the rates of incidence and mortality from neuroblastomas diagnosed before 6 years of age in three cohorts.
METHODS: We did a retrospective population-based cohort study on all children born between 1980 and 1998, except for a 2-year period from 1984. We divided these 22,289,695 children into three cohorts: children born before screening in 1980-83 (n=6,130,423); those born during qualitative screening in 1986-89 (n=5,290,412); and those born during quantitative screening 1990-98 (n=10,868,860). We used databases from hospitals, screening centres, and national cancer registries. Cases of neuroblastoma were followed up for a mean of 78.7 months.
FINDINGS: 21.56 cases of neuroblastoma per 100,000 births over 72 months were identified in the qualitatively screened group (relative risk [RR] 1.87, 95% CI 1.66-2.10), and 29.80 cases per 100,000 births over 72 months in the quantitatively screened group (RR 2.58, 2.33-2.86). The cumulative incidence of neuroblastoma in the prescreening cohort (11.56 cases per 100,000 births over 72 months) was lower than that in other cohorts (p<0.0001 for all comparisons), but more neuroblastomas were diagnosed after 24 months of age in this cohort (p=0.0002 for qualitative screening vs prescreening, p<0.0001 for quantitative screening vs prescreening). Cumulative mortality was lower in the qualitative screening (3.90 cases per 100,000 livebirths over 72 months) and quantitative screening cohorts (2.83 cases) than in the prescreening cohort (5.38 cases). Compared with the prescreening cohort, the relative risk of mortality was 0.73 (95% CI 0.58-0.90) for qualitative screening, and 0.53 (0.42-0.63) for quantitative screening. Mortality rates for both the qualitative and quantitative screening groups were lower than were those for the prescreening cohort (p=0.0041 for prescreening vs qualitative screening, p<0.0001 for prescreening vs quantitative screening).
INTERPRETATION: More infantile neuroblastomas were recorded in children who were screened for neuroblastoma at 6 months of age than in those who were not. The mortality rate from neuroblastoma in children who were screened at 6 months was lower than that in the prescreening cohort, especially in children screened by quantitative HPLC. Any new screening programme should aim to decrease mortality, but also to minimise overdiagnosis of tumours with favourable prognoses (eg, by screening children at 18 months).

Nakaoka T, Uemura S, Nakagawa Y, et al.
Retroperitoneal ganglioneuroblastoma resected 8 years after mass screening: a case report.
J Pediatr Surg. 2007; 42(11):E29-32 [PubMed] Related Publications

An 8-year-old girl presented with abdominal tumor that was discovered incidentally. At surgery, the tumor originated from the retroperitoneal sympathetic trunk; and the histologic diagnosis was ganglioneuroblastoma, nodular (GNBn), unfavorable histology on Shimada's classification, International Neuroblastoma Staging System (INSS) stage 1. This patient was found positive for neuroblastoma (NB) by mass screening at 6 months old. There was no tumor detected, and tumor markers decreased to normal range by 18 months of age. We examined her previous computed tomographic films retrospectively and noticed a mass in the same region indicating that the tumor had been there for 8 years without treatment. This is the first report of infantile mass screening-positive NB appearing after long-term follow-up with unfavorable histology. And the follow-up interval was the longest ever reported. This case is suggestive of considering the natural history and treatment strategies for infantile NBs, and the relationship between infantile NB and ganglioneuroblastoma, nodular. It is important to follow mass screening-positive cases of NB over the long term if wait-and-see policy is adopted.

Barrette S, Bernstein ML, Robison LL, et al.
Incidence of neuroblastoma after a screening program.
J Clin Oncol. 2007; 25(31):4929-32 [PubMed] Related Publications

PURPOSE: A significant increase in the incidence of neuroblastoma occurred among a 5-year birth cohort (May 1989 to April 1994) during an active urinary screening program for its early detection. We examined the postscreening incidence of neuroblastoma in the subsequent 5-year birth cohort (May 1994 to April 1999), with follow-up to 2002, to determine whether the incidence remained increased.
PATIENTS AND METHODS: We reviewed institutional records of patients diagnosed with neuroblastoma during the period from 1994 to 2002 who were born in 1994 to 1999 in the province of Quebec, as well as in the state of Minnesota and the province of Ontario, regions that had served as controls during the screening interval. We calculated and compared incidence rates during the 1994 to 2002 time period.
RESULTS: For the 5-year birth cohort as a whole, the rate of newly diagnosed neuroblastoma was higher in Quebec than in the control populations of Minnesota and Ontario (standardized incidence ratio, 1.34; 95% CI, 1.03 to 1.70). However, in years 4 and 5 of the interval, population-based incidence declined to the same levels as those seen in the control areas.
CONCLUSION: The institution of a urinary screening program for neuroblastoma led to increased awareness of the diagnosis and an elevated rate of diagnosis even after the completion of the screening evaluation. However, this halo effect was transient, with diagnostic rates subsequently decreasing within the range seen in control populations.

Hiyama E, Yamaoka H, Kondo S, et al.
Heterogeneous subgroups in human neuroblastoma for clinically relevant risk stratification.
Pediatr Surg Int. 2007; 23(11):1051-8 [PubMed] Related Publications

Neuroblastoma is a heterogeneous tumor and that may have a favorable or unfavorable prognosis. In Japan, a nation-wide neuroblastoma mass-screening (MS) project assessed 6-month-old infants between 1985 and 2003, and almost all neuroblastomas, including regressing or maturing tumors were thought to be detected in this period. To evaluate the heterogeneity of neuroblastoma subgroups, we analyzed patients with neuroblastoma who had been diagnosed during this period. The clinical courses of 4,209 patients with neuroblastoma, including 1,560 MS detected patients, whose tumors had been diagnosed between 1971 and 1995 were registered. The 2,520 cases registered between 1985 and 1995 were compared to 1,050 cases registered between 1971 and 1980 and analyzed by a multi-gene target model to determine the age distribution of neuroblastoma incidence. We hypothesized that three target genes were responsible for the progression of neuroblastoma: one pair of tumor suppressor gene alleles, one oncogene, and one gene controlling regression/differentiation. This simulation study revealed that the age distribution at initial diagnosis of neuroblastoma was divided into four groups based on post-fertilization age: 20-40, 40-50, 60-90, and 160-200 weeks. Since neuroblatoma in the first group occurred prenatal, post-natal clinical neuroblastoma can be classified into three age groups: 0-6 months, 1-2 years, and 3-4 years. The 0- to 6-month group consisted of mostly benign tumors, and the two older groups had predominantly malignant phenotypes. Our proposed model could explain qualitatively the distribution of neuroblastoma consisting of one subgroup with a favorable prognosis and two subgroups with unfavorable prognosis. For clinically relevant risk stratification, an age cutoff should be considered by the age distribution of these heterogeneous subgroups.

Suita S, Tajiri T, Higashi M, et al.
Insights into infant neuroblastomas based on an analysis of neuroblastomas detected by mass screening at 6 months of age in Japan.
Eur J Pediatr Surg. 2007; 17(1):23-8 [PubMed] Related Publications

BACKGROUND/PURPOSE: Mass screening (MS) for neuroblastoma (NB) at 6 months of age in Japan was discontinued in 2004. We have previously reported that the majority of NB detected by MS showed a good prognosis, with only a few cases demonstrating an unfavorable outcome (J Pediatr Surg 2002, Cancer 2001). This study aims to provide insights into infant NB by assessing the details of the clinical courses in patients treated with a standard regimen and the biological features of such cases using highly sensitive methods at one institution in Japan.
METHODS: In 76 NB detected through MS treated at Kyushu University Hospital, the clinical features and MYCN amplification, 1p deletion, 17q gain, the expression level of TRKA using FISH and the quantitative PCR were analyzed.
RESULTS: Of these 76 persons with NB treated at one institution, 97 % are still alive, while 2 cases died from other diseases. Three patients experienced a recurrence after complete remission (CR), and 2 patients demonstrated refractory disease since the initial diagnosis. Two of the 3 NB patients with recurrence have demonstrated a 2nd CR, while one case still has multiple active diseases. Regarding the findings of highly sensitive biological analyses, 5/74 (7 %) showed MYCN amplification, 2/24 (8 %) cases had a 1p deletion, 3/33 (9 %) cases had a 17q gain, 5/50 (10 %) cases had diploidy, 1/25 (4 %) cases had a low expression of TRKA, and 2/76 (3 %) cases had an unfavorable histology. Of the 76 NB, 13 tumors (17 %) had one or more unfavorable factors (UF). Of the 5 refractory NB, 1 case had 3 UF, 1 case had 2 UF, 1 case had 1 UF, and 2 cases had no UF. As a result, 60 % of the refractory NB had one or more UF.
CONCLUSIONS: Of the NB detected by MS at one institution in Japan, 17 % had one or more unfavorable factors (UF) and might have a higher risk of recurrence than the patients with no UF, although the unfavorable biology of several refractory cases is still unclear even after highly sensitive analyses. At least one-fifth of the NB cases detected by MS are anticipated cases. In infantile neuroblastomas, it may therefore be most important to analyze biologically prognostic factors using highly sensitive methods followed by immediate surgical intervention. Since the MS program has been discontinued in Japan, it will be necessary in future to assess the mortality and characteristics of NB detected clinically.

Related: Chromosome 1 Chromosome 17 NTRK1 MYCN (n-myc)

Nishio N, Mimaya J, Nara T, et al.
Results for 79 patients with neuroblastoma detected through mass screening at 6 months of age in a single institute.
Pediatr Int. 2006; 48(6):531-5 [PubMed] Related Publications

BACKGROUND: In Japan, mass screening for neuroblastoma has been performed at 6 months of age to improve the prognosis of this condition for more than 20 years. In recent years, most neuroblastomas detected by mass screening were considered to have favorable biological features and sometimes tend to regress spontaneously.
METHODS: The authors established non-treated observation criteria in 1997 and criteria for observation of residual tumor after first-line chemotherapy in 1999, and have made an effort to reduce the intensity of medical treatment for neuroblastoma. The authors examined outcomes of 79 patients who were found in the Shizuoka neuroblastoma mass screening at 6 months of age and who received medical treatment or underwent observation in Shizuoka Children's Hospital, Shizuoka, Japan, between December 1981 and December 2004.
RESULTS: A total of 77 patients survived but the remaining two patients died from complications of medical treatment. None of the patients died due to progression of neuroblastoma. In the cases, non-treated observation was performed in 17. Of those, 12 patients are now under non-treated observation. Of their tumors, two have disappeared, nine have become smaller and another one has not change in size. Observation of residual tumor after first-line chemotherapy was performed in 15 cases, and three disappeared and the other 12 cases became smaller. Medical treatment-related complications were observed in 20 of 67 patients who received medical treatment, and 18 of the 20 patients were seen before establishing non-treated observation criteria.
CONCLUSION: Non-treated observation and observation of residual tumor after first-line chemotherapy were useful to reduce medical treatment-related complications.

Hiyama E, Yamaoka H, Kamimatsuse A, et al.
Single nucleotide polymorphism array analysis to predict clinical outcome in neuroblastoma patients.
J Pediatr Surg. 2006; 41(12):2032-6 [PubMed] Related Publications

PURPOSE: Neuroblastoma (NB) is a heterogeneous tumor and demonstrates favorable or unfavorable outcomes. In Japan, a nationwide NB mass screening (MS) had been performed on 6-month-old infants for approximately 20 years, which might have detected almost all NB including regressing/maturing tumors. To clarify the heterogeneity of this tumor, we examined genetic alterations in the representative cases using genomewide microarrays.
METHODS: Genomic DNA was extracted from 198 NB tissue samples and paired blood samples including 76 MS-detected cases and analyzed by single nucleotide polymorphism arrays.
RESULTS: The single nucleotide polymorphism array classified the genetic aberrations into 4 types: whole gain/loss type, partial gain/loss type, MYCN-amplified type, and silent type. Most MS-detecting cases belonged to the whole gain/loss type, whereas unfavorable cases who died of disease showed partial gain/loss, MYCN-amplified, or silent types.
CONCLUSIONS: Genomewide genetic analysis is useful to predict the outcome of patients. Although the cases whose tumors showed whole gain/loss may respond well to contemporary therapy, sparing intensive surgery, current therapeutic strategy may be insufficient for the subgroups with partial gain/loss, MYCN-amplified, or silent type. Validation of these results would provide new tools to predict clinical outcome of children with NB.

Iehara T, Hosoi H, Akazawa K, et al.
MYCN gene amplification is a powerful prognostic factor even in infantile neuroblastoma detected by mass screening.
Br J Cancer. 2006; 94(10):1510-5 [PubMed] Free Access to Full Article Related Publications

MYCN is the most powerful prognostic factor in cases of older children. However, how MYCN is related to the prognosis of infantile cases is not clear. A mass screening program was carried out by measuring urinary catecholamine metabolites (VMA and HVA) from 6-month-old infants. Of 2084 cases detected by the screening program, MYCN amplification (MNA) was examined by Southern blot analyses in 1533 cases from 1987 to 2000. Of the 1533 cases examined, 1500 (97.8%) showed no MNA, 20 cases (1.3%) showed MNA from three to nine copies, and 13 (0.8%) cases showed more than 10 copies. The 4-year overall survival rates of these three groups (99, 89 and 53%, respectively) were significantly different (P<0.001), indicating that MYCN copy number correlates with the prognosis. Cases with MNA more than 10 copies were more advanced than those without amplification (stage III, IV vs I, II, IVs; P<0.001). Patients with MNA more than 10 copies had significantly higher serum levels of neuron-specific-enolase (NSE) and ferritin than non-amplified patients (P=0.049, P=0.025, respectively). MYCN amplification was strongly correlated with a poor prognosis in infantile neuroblastoma cases. Therefore, for the selection of appropriate treatment, an accurate determination of MNA is indispensable.

Barrette S, Bernstein ML, Leclerc JM, et al.
Treatment complications in children diagnosed with neuroblastoma during a screening program.
J Clin Oncol. 2006; 24(10):1542-5 [PubMed] Related Publications

PURPOSE: The Québec Neuroblastoma Screening Program was put in place to investigate the possibility of decreasing mortality from high-risk neuroblastoma through early screening. We assess treatment complications in the patients diagnosed during this screening program.
PATIENTS AND METHODS: A total of 476,603 patients born during the screening period were eligible. Parents of 425,838 children (89%) agreed to participate in the 3-week screening, and 73% agreed to participate in the 6-month screening. Forty-five patients had neuroblastoma. We reviewed the medical and research charts for all patients diagnosed by screening. Follow-up was available from 8 to 13 years after screening.
RESULTS: Forty-five patients were diagnosed by screening. All patients were treated according to the Pediatric Oncology Group recommendations of the time. All patients had surgery, and 29 patients received chemotherapy. No patient died from neuroblastoma. Eleven patients suffered complications from treatment. Two patients had life-threatening complications.
CONCLUSION: In view of the lack of impact of screening programs on neuroblastoma mortality, evidence that many of the tumors detected through screening can be observed without treatment and the serious complications that may arise from therapy, we do not support neuroblastoma screening programs for children.

Kaneko Y, Kobayashi H, Watanabe N, et al.
Biology of neuroblastomas that were found by mass screening at 6 months of age in Japan.
Pediatr Blood Cancer. 2006; 46(3):285-91 [PubMed] Related Publications

BACKGROUND: Mass screening (MS) of neuroblastoma has been carried out by measuring the urinary catecholamine metabolites in infants at the age of 6 months in Japan. We assessed the incidence of neuroblastoma that may be a target for MS by studying tumor biology.
PROCEDURE: FISH on chromosome 1 and MYCN analysis was performed on 453 patients that were classified into three clinical groups (287 infants found by MS, 51 infants < 12 months diagnosed clinically, and 115 children >or=12 months diagnosed clinically). The relationship between the biological types of tumors and the clinical outcome was examined.
RESULTS: Type 1 (trisomy 1 and normal MYCN), type 2 (disomy 1/tetrasomy 1 and normal MYCN), and type 3 (disomy 1/tetrasomy 1 and amplified MYCN) tumors were found in 88.2%, 10.5%, and 1.4% of infants found by MS, in 68.0%, 24.0%, and 8.0% of infants diagnosed clinically, and in 23.4%, 42.3%, and 34.2% of children diagnosed clinically (P < 0.001). Infants with type 1 tumors found by MS or diagnosed clinically had earlier stages of the disease (P < 0.0001 and P = 0.0005) and better overall survival (P < 0.001 and P = 0.005) than children with type 1 tumors diagnosed clinically. Infants with type 2 tumors found by MS, had earlier stages (P = 0.06 and P < 0.0001) and better overall survival (P = 0.014 and P < 0.001) than infants or children with type 2 tumors diagnosed clinically. All three clinical groups of patients with type 3 tumors had advanced stages and dismal prognoses.
CONCLUSIONS: About 12% of tumors found by MS showed unfavorable biological (types 2 and 3) characteristics.

Related: Chromosome 1 FISH MYCN (n-myc)

Soderstrom L, Woods WG, Bernstein M, et al.
Health and economic benefits of well-designed evaluations: some lessons from evaluating neuroblastoma screening.
J Natl Cancer Inst. 2005; 97(15):1118-24 [PubMed] Related Publications

BACKGROUND: Well-designed evaluations of health services are frequently made today. However, the extent of the evaluations' benefits and costs is not well documented, creating uncertainty whether their use is optimal from society's perspective. We examined these costs and benefits using data from one well-designed evaluation, the Quebec Neuroblastoma Screening Project (QNSP). It screened most Quebec newborns between 1989 and 1994 for neuroblastoma. As previously reported, the screening did not reduce neuroblastoma mortality and caused adverse health effects.
METHODS: We compared the cost of doing the QNSP with its benefits. Had the QNSP not been undertaken, neuroblastoma screening would have been implemented throughout North America. We assume that screening would have started in 1989 and ended in 2002. The QNSP's benefits include the health costs and adverse health effects averted by not using ineffective screening during those 14 years. In our calculations we used neuroblastoma incidence data for the QNSP and for Ontario where there was no screening, detailed data describing the health services used by the patients, and Quebec cost data for those services.
RESULTS: The QNSP cost 8.77 million dollars (2002 US dollars). By not implementing similar screening programs between 1989 and 2002, the United States and Canada avoided 574.1 million dollars in health costs, the unnecessary treatment of 9223 children, and false-positive findings for 5003 children screened.
CONCLUSIONS: The health care costs and adverse health effects averted by the QNSP justify its costs. These results show that well-designed evaluations can yield--at least sometimes--benefits substantially greater than their high costs. This raises an important policy issue: are these evaluations now being under- or over used?

Related: Canada USA

Krause A, Combaret V, Iacono I, et al.
Genome-wide analysis of gene expression in neuroblastomas detected by mass screening.
Cancer Lett. 2005; 225(1):111-20 [PubMed] Related Publications

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and the third most common pediatric cancer. Although numerous factors including patient age, disease stage and genetic abnormalities have been shown to be predictive of outcome, the mechanisms responsible for the highly variable clinical behavior of this tumor remain largely unknown. In order to gain new insights into the biology of this tumor, we performed microarray analysis and compared the gene expression patterns of NB detected by mass screening, characterized by highly probable spontaneous regression, versus stage 4 NB with poor prognosis. The bioinformatics analysis revealed a set of 19 discriminatory genes that may play a significant role in the natural progression of the disease. Validation of these results and further mechanistic studies would shed new light on the biology of tumor progression, and provide new tools to predict clinical outcome in children with NB.

Tanaka T, Iehara T, Sugimoto T, et al.
Diversity in neuroblastomas and discrimination of the risk to progress.
Cancer Lett. 2005; 228(1-2):267-70 [PubMed] Related Publications

The clinical diversity of Neuroblastomas (NBs) was discriminated into three groups with high sensitivity and specificity to patient's outcome. The 'high risk' NB is defined with any of following conditions, MYCN amplification or unfavorable histology of International Neuroblastoma Pathological Classification (INPC) or low Ha-ras/trk A expression. The 'low risk' NB is defined with all following conditions, single copy of MYCN and INPC favorable histology and high Ha-ras/trk A expression and localized tumor. The remaining NBs were classified into 'intermediate risk' ones. According to these criteria, the diversity of the 248 mass-screening NBs was shown with variety progressive risk; 40% were classified in low risk group, 25% were in high risk group and 35% were in intermediate risk group.

Oue T, Inoue M, Yoneda A, et al.
Profile of neuroblastoma detected by mass screening, resected after observation without treatment: results of the Wait and See pilot study.
J Pediatr Surg. 2005; 40(2):359-63 [PubMed] Related Publications

BACKGROUND/PURPOSE: Neuroblastoma (NB) detected by mass screening (MS) usually shows favorable prognosis and sometimes regresses spontaneously. Therefore, the authors started an observation program for these patients to avoid overtreatment. In this study, the authors analyzed the profile of NB resected after observation to elucidate the nature of NB detected by MS.
METHODS: Between 1994 and 2004, 22 NB patients matched the following criteria and entered the observation program after obtaining informed consent: stage I or II, less than 5 cm in diameter, and without involvement of large vessels or organs. If increase in size, elevation of tumor markers, or evidence of metastasis was observed, the tumor was immediately resected.
RESULTS: Thirteen (59%) of 22 cases showed spontaneous regression. In the remaining 9 cases, tumors were resected because of parents' request, increase in size, and/or elevation of tumor markers. Four tumors had at least one unfavorable biologic feature, and 3 of them had more than 2. According to Shimada's system, 2 had unfavorable histology. One was diploid tumor, 3 had 1p deletion, and Trk-A expression was low in 4 tumors. All patients survived without evidence of recurrence.
CONCLUSIONS: The observation program has shown that at least one third of the NB detected by MS regressed spontaneously. On the other hand, MS may detect some cases with unfavorable tumor in early stage, which benefit from screening.

Related: NTRK1

Fritsch P, Kerbl R, Lackner H, Urban C
"Wait and see" strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening.
Pediatr Blood Cancer. 2004; 43(6):679-82 [PubMed] Related Publications

Neuroblastomas in infants may regress or mature spontaneously. Consequently, some authors have applied a "wait and see" strategy for tumors found by urinary mass screening. Recently, improved technique and increasing frequency of ultrasound examinations have led to an increase of neuroblastoma cases in pre- and post-natal period. We describe five cases, four diagnosed by routine ultrasound examination and one detected by urinary mass screening, who were monitored with a "wait and see" strategy in order to spare surgery. Median age at diagnosis was 4 months (range 2-10 months). All tumors were adrenal neuroblastomas. All patients met the following criteria: localized tumors, tumor size less than 5 cm in diameter, absence of invasive growth, vanillylmandelic acid (VMA) and homovanillic acid (HVA) less than 50 microg/mg creatinine, and informed consent of parents. Monitoring was performed by monthly ultrasound examinations and urine catecholamine analysis. Median follow-up is 14 months (5-28 months). Three tumors showed spontaneous regression, one is still under observation. In one patient the tumor increased in size and was resected after 14 months of observation displaying favorable histology, but chromosome 1p imbalance. Previous reports describe the adoption of a "wait and see" strategy in selected cases of localized neuroblastoma detected by mass screening. Our study confirms that this strategy may be similarly applied in incidentally or clinically detected cases. However, possible benefit has to be carefully balanced against possible risks.

Nishi M, Hanai J, Fujita K, et al.
Is the mass screening for neuroblastoma ineffective?
J Exp Clin Cancer Res. 2003; 22(4):673-6 [PubMed] Related Publications

Though a recent study (Schilling et al. 2002) concluded that the mass screening for neuroblastoma targeting children age 12 months was ineffective, we pointed out several serious problems and reestimated its effectiveness using their data. They employed the subjects in the "control area" as controls, not the "non-participants" whose biases are fewer because their area is the same as that of the participants. The incidence of neuroblastoma among the subjects in the "control area" was about 25% smaller than that of the "non-participants". This leads to underestimation of the effectiveness of the mass screening. They combined false negatives with true positives to calculate the incidence of the "screened group". But since many spontaneous regression cases are included in the true positives, this method inflates the incidence of the "screened group", leading to underestimation of the effectiveness of the mass screening. When the false negatives are compared with the non-participants, the incidence of the cases in stage 4 among the latter is about 40% of that of the former, and the mortality is less than two-thirds. The percentage of spontaneous regression cases among the true positives is estimated to be about 40%. These results are better than those of the Japanese screening programs (targeting infants age 6 months), supporting the effectiveness of mass screening for neuroblastoma.

Hashimoto T, Koizumi K, Nishina T, Abe K
Clinical usefulness of iodine-123-MIBG scintigraphy for patients with neuroblastoma detected by a mass screening survey.
Ann Nucl Med. 2003; 17(8):633-40 [PubMed] Related Publications

UNLABELLED: The purpose of this study was to evaluate the usefulness in a clinical setting of iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy, planar and single photon emission computed tomography (SPECT) images, in patients with neuroblastoma as detected by a mass screening survey.
METHODS: 123I-MIBG planar whole body images, and regional SPECT images of patients with neuroblastoma in 51 studies were reviewed. They were all detected by a mass screening survey performed in the 6th month after birth using vanil mandelic acid (VMA), and homovanillic acid (HVA) and the neuroblastoma had been confirmed by surgery. Scintigraphy was performed 24 hours after injection of 111 MBq of 123I-MIBG. We assessed the accuracy of the planar whole body images in order to demonstrate the extent of the lesion and the correlation between the degree and extent of the lesions of 123I-MIBG accumulation and clinical staging with tumor markers, such as urinary VMA, urinary HVA, serum neuron specific enolase (NSE) and serum lactate dehydrogenase (LDH). Additionally, we evaluated SPECT how useful supplemental SPECT might be in a clinical setting as compared with planar whole body images.
RESULTS: 123I-MIBG planar whole body images revealed all 33 (100%) primary lesions, 4 of the 5 cases (80%) with liver metastasis, 3 of the 13 (23%) with lymph nodes metastasis and 1 of 3 (33%) with bone marrow infiltration. The extent and degree of accumulation correlated with the values of urinary VMA, urinary HVA and serum NSE. SPECT images helped to understand the positional relation in all cases and provided useful additional information for clinical staging in 7 cases.
CONCLUSION: 123I-MIBG scintigraphy with planar and SPECT images is useful for evaluating patients with neuroblastoma, following detection by a mass screening survey.

Okazaki T, Kohno S, Mimaya J, et al.
Neuroblastoma detected by mass screening: the Tumor Board's role in its treatment.
Pediatr Surg Int. 2004; 20(1):27-32 [PubMed] Related Publications

Japan has a nationwide mass-screening program for neuroblastoma in 6-month-old infants. Neuroblastoma can regress spontaneously, and some institutions observe selected cases. We evaluated the management of screened neuroblastoma at our hospital since 1997 when an observation program was introduced. Criteria for the observation program were stage-I, stage-II, or stage-IVs tumors, urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels <40 microg/mg creatinine, tumor <5 cm in diameter, no invasion to the intraspinal canal or great vessels, and parental consent to participate. Patients who did not meet observation criteria underwent surgery or mild chemotherapy according to the location of the tumor. If patients met observation criteria after chemotherapy, surgical intervention was no longer performed. Thirty-six patients attended our hospital for screened neuroblastoma from 1997 to 2002. Thirty-three patients who were managed at our hospital participated in this study. Ten subjects met observation criteria. Tumors regressed in 7 patients (mean follow-up period 36.3 months) with corresponding decreases in VMA and HVA levels (group A). Three underwent surgery (group B) because of increasing VMA and HVA levels, increase in tumor size, or guardian's request. Twenty-three subjects did not meet observation criteria. Four patients underwent primary surgery (group C), and 19 patients had chemotherapy initially. Fourteen patients met observation criteria after chemotherapy and two are still having chemotherapy (group D). Three patients required surgery due to insufficient regression of their tumors (group E). Fourteen subjects in group D had marked decreases in VMA and HVA levels and tumor size (mean follow-up period 29.1 months), and tumors were not detected using imaging techniques in 8 patients. Histological examination of all resected specimens during the study period showed favorable histology and no N-myc amplification. There was no evidence of unfavorable prognosis in any of the 33 subjects, although 1 patient who underwent primary surgery had a vanishing kidney 1 year later and 1 patient had multiple bony metastases after complete resection of tumor, which was treated by chemotherapy. Until the real significance of mass screening for neuroblastoma as a public health measure is confirmed, observation with careful follow-up should be adopted more extensively because it has a favorable outcome in many cases, and is associated with minimal therapeutic complications.

Kerbl R, Urban CE, Ambros IM, et al.
Neuroblastoma mass screening in late infancy: insights into the biology of neuroblastic tumors.
J Clin Oncol. 2003; 21(22):4228-34 [PubMed] Related Publications

PURPOSE: Neuroblastoma screening in early infancy has detected predominantly "favorable" tumors. We postponed screening to an age between 7 and 12 months to test whether this shift of screening age might influence the detection rate of genetically/clinically unfavorable tumors.
PATIENTS AND METHODS: In a 10-year period, 313,860 infants were screened by analysis of urine catecholamines. When a neuroblastoma was diagnosed, at least two different areas from every tumor were analyzed for genetic features (MYCN amplification, 1p status, ploidy). Furthermore, neuroblastoma incidence and mortality of the screened group and the cohort of 572,483 children not participating in the screening program were compared.
RESULTS: Forty-six neuroblastomas were detected by mass screening. In 17 tumors (37%) at least one of the biologic features was "unfavorable." In 10 of 17 patients, one or more of these alterations were only focally present (tumor heterogeneity). In the screened cohort, neuroblastoma incidence was significantly higher when compared with unscreened children (18.2 v 11.2/100,000 births), while there was a trend towards lower incidence of stage 4 over 1 year (2.2 v 3.8). Mortality was not significantly different (0.96 v 1.57).
CONCLUSION: In contrast to other neuroblastoma screening programs, more than one-third of patients were found with unfavorable genetic markers in our study. The high proportion of focal alterations suggests that biologically young neuroblastomas may consist of genetically favorable and unfavorable parts/areas/clones. We conclude that at least one-third of neuroblastomas detected by screening in late infancy are anticipated cases. This, however, does not result in significantly reduced mortality.

Related: Chromosome 1 MYCN (n-myc)

Spix C, Michaelis J, Berthold F, et al.
Lead-time and overdiagnosis estimation in neuroblastoma screening.
Stat Med. 2003; 22(18):2877-92 [PubMed] Related Publications

In Germany, neuroblastoma is the most frequent extracranial solid childhood tumour. Its properties made it seem an ideal candidate for screening. A German trial assessed the effect of screening at one year of age from 1995-2001 in a nationwide project. We present here the methods developed for the estimation of lead-time and overdiagnosis in this project. Follow up on 1.5 million screened children and 2.1 million control children is currently available until June 2002. Ascertainment of control cohort cases and false negative cases is complete up to this date. A method for determining an empirical lead-time distribution and overdiagnosis estimate from comparing the age specific incidences in the control group and the study group is presented. Lead-time leads to an excess of cases in the screening group at the screening age and cases missing at higher age. If more cases are observed at the screening age than can be explained by lead-time, the difference is attributed to overdiagnosis. The width of the screening age window and the empirical maximum lead-time have to be chosen from graphs. About 1.0/100000 cases (20 per cent of the possible cases) experienced lead-time while 6.8/100000 cases were overdiagnosed. The mean lead-time was estimated to be about 15 months. The number of cases who might benefit is much smaller than was expected before the study while the overdiagnosed group is much larger. The method is robust against the choices that have to be made in the estimation process.

Ohira M, Morohashi A, Nakamura Y, et al.
Neuroblastoma oligo-capping cDNA project: toward the understanding of the genesis and biology of neuroblastoma.
Cancer Lett. 2003; 197(1-2):63-8 [PubMed] Related Publications

Neuroblastoma (NBL) is a common pediatric cancer originated from the neuronal precursor cells of sympathoadrenal lineage. NBLs show a variety of clinical phenotypes from spontaneous regression to malignant progression with acquirement of resistance to therapy. To understand the molecular mechanism of the genesis, progression, and regression of NBL, we need to identify key molecules determining the neuronal development of sympathoadrenal lineage. To this end, we have performed the NBL cDNA project. It includes (1) mass-cloning of the expressed genes from oligo-capping cDNA libraries derived from primary NBLs with different clinical and biological features; (2) mass-identification of differentially expressed genes between favorable and unfavorable subsets; and (3) molecular and functional analyses of the novel genes, which could be useful prognostic indicators. To date, 10,000 cDNA clones in total, approximately 40% of which contained novel sequences, were randomly picked up and DNA sequenced. We have identified approximately 500 differentially expressed genes between favorable and unfavorable subsets of NBL, among which more than 250 were the genes with unknown function.

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