Mass Screening For Neuroblastoma Research Articles

Results of mass screening for neuroblastoma in 18-month-old infants in Osaka area, Japan.

In 2004, the Japanese government halted nationwide mass screening for neuroblastoma in 6-month-old infants as it led to overdiagnosis of localized tumors with favorable prognoses and failed to reduce neuroblastoma-related mortality. However, a new mass screening program for neuroblastoma in 18-month-old infants (18MS) was conducted in the Osaka prefecture. We assessed the efficacy of the 18MS in screening unfavorable cases. Public health centers in Osaka prefecture, excluding the Osaka city area, provided test kits to the guardians of infants who received a check-up at 18months of age between 2004 and 2017. For patients whose standardized urinary levels of vanillylmandelic acid or homovanillic acid exceeded the threshold, they were further examined and treated in two specific hospitals Osaka University Hospital and Osaka Women's and Children's Hospital. Screening-positive patients with and without neuroblastoma were retrospectively reviewed. Among 142,423 children screened during the 18MS, 85 tested positive, and 14 were diagnosed with neuroblastoma. Twelve patients were classified as very low risk, while 2 were classified as high risk, based on the International Neuroblastoma Risk Group risk classification. The 18MS did not screen unfavorable cases with neuroblastoma efficiently, although few participants benefited from it.

B-022 宮城県における神経芽腫18ヶ月二次マススクリーニングの報告 : 2006年までの経過観察(腫瘍, 第44回日本小児外科学会学術集会)

B-022 宮城県における神経芽腫18ヶ月二次マススクリーニングの報告 : 2006年までの経過観察(腫瘍, 第44回日本小児外科学会学術集会)

The incidence and mortality rates of neuroblastoma cases before and after the cessation of the mass screening program in Japan: A descriptive study.

In 2003, Japan's Ministry of Health, Labour and Welfare halted the neuroblastoma (NB) mass screening program, running since 1985. This study aimed to examine whether NB incidence and mortality changed before and after the program halted. This is a descriptive population-based study. We used data from the Monitoring of Cancer Incidence in Japan (MCIJ) project, Vital Statistics of Japan, and Japanese CANcer Survival Information for Society (J-CANSIS). Incidence rate, cumulative incidence rate, mortality rate, cumulative mortality rate, and relative 5-year survival for NB were calculated. Children were divided into two birth cohort groups, consisting of children born before, or after the cessation of the NB mass screening program. We compared the two cohorts, with regards to the cumulative incidence and mortality rates at 5 years old. The incidence rate was lower after the cessation of the NB mass screening program. There was no substantial change in the mortality rate, and no significant variation in the relative 5-year survival between groups. The cumulative incidence rate in the latter cohort was significantly lower than that in the former cohort (rate ratio: 0.39, 95% CI: 0.25-0.61, p < 0.001). No significant difference in the cumulative mortality rate between the two cohorts was observed (rate ratio: 0.99, 95% CI: 0.80-1.22, p = 0.93). The NB incidence rate decreased markedly and the mortality rate did not substantially change after the cessation of the NB mass screening program. The NB mass screening program probably caused overdiagnosis, and its effectiveness was not clear.

A prospective study of a long‐term follow‐up of an observation program for neuroblastoma detected by mass screening

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. 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. 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. 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.

Risks and benefits of ending of mass screening for neuroblastoma at 6 months of age in Japan

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.

Heterogeneous subgroups in human neuroblastoma for clinically relevant risk stratification

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.

Insights into Infant Neuroblastomas Based on an Analysis of Neuroblastomas Detected by Mass Screening at 6 Months of Age in Japan

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. 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. 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. 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.

54: Drug-induced hypersensitivity syndrome in Japan — an analysis of 118 cases studied for HHV-6 reactivation

The present status of neuroblastoma mass screening for early detection in Japan, which was the first national screening program for this tumor and is now approaching its 19th year, is presented. This program is conducted in cooperation with the parents, local health centers, screening centers and hospitals.Of the 357 cases detected at early stages by this program that could be analysed, 97% had a good prognosis.Several technical, clinical and social problems are discussed.

Single nucleotide polymorphism array analysis to predict clinical outcome in neuroblastoma patients

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.

Results for 79 patients with neuroblastoma detected through mass screening at 6 months of age in a single institute

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. 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. 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. Non-treated observation and observation of residual tumor after first-line chemotherapy were useful to reduce medical treatment-related complications.

Clinical appearance of neuroblastoma 10 years after screening

A follow-up study was performed for children with previous repeated positive results by neuroblastoma mass screening and negative clinical results (30 out of 439,128 children screened in Austria between 1991 and 2003, median follow-up 113 months). Four children had continuously elevated urine catecholamines for more than 6 months. One of these patients was diagnosed with pelvic neuroblastoma and multiple metastases 10 years after the first positive screening result. In the light of a 'wait and see' strategy for localized neuroblastomas, our observation suggests that these patients should be further observed even after normalization of urine catecholamines.

Biology of neuroblastomas that were found by mass screening at 6 months of age in Japan

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. 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. 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. About 12% of tumors found by MS showed unfavorable biological (types 2 and 3) characteristics.

Neuroblastoma mass screening in late infancy: insights into the biology of neuroblastic tumors.

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. 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. 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). 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.

Outcome of infants with neuroblastoma detected by mass screening and surgically treated in shiga prefecture, Japan: what is the role of surgery?

Mass screening for neuroblastoma at the age of 6 months is helpful for early diagnosis and excellent outcome but is judged as overdiagnosis in detecting cases that regress spontaneously. On the other hand, in biologically unfavorable cases of N-myc amplification, early treatment instead of the usual observation in infancy may be of benefit. The authors evaluated, retrospectively, 20 infants with neuroblastoma found by mass screening. In 19 patients, complete tumor resection and lymph-node dissection was achieved 4 of them with nephrectomy. Partial resection was performed in one. Ten infants showed tumor stage I or II, 10 had an advanced stage III or IV. One tumor was N-myc positive and showed chromosome 1p heterozygosity. The serum NSE level was a significant predictor of survival. The 2-year, event-free survival rate was 95%; one child (stage II, complete resection, N-myc positive, 1p heterozygosity, highest NSE serum level, chemotherapy) died 2 years after resection. The screening detected many tumors at advanced stages but only one with N-myc amplification. It, therefore, identified favorable oncogenic characteristics despite an advanced stage. Even this study could not answer the question whether screening can decrease the incidence of neuroblastoma with unfavorable stages in older children. The authors conclude that as long as the prognostic value of screening programs is unclear, extended resection with nephrectomy and lymph-node dissection, as well as aggressive postsurgical chemotherapy are not justifiable in infancy. Chemotherapy may be considered in N-myc applification and a high NSE serum level. Further data are required from bigger multicentric samples with a shorter duration of the study to exclude the influence of changing factors in surgical, medical, and radiologic management.—Peter Schmittenbecher

Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany

Neuroblastoma is the second most frequent malignancy in childhood. We investigated whether screening for neuroblastoma at 1 year of age reduces the incidence of metastatic disease or mortality. Screening was offered in 6 of the 16 German states from 1995 to 2000 with the remaining states serving as controls. We studied 2,581,188 children in the screening area born between 1994 and 1999 and 2,117,600 in the control area. We compared mortality from neuroblastoma and the incidence of disseminated disease in the two groups. The screened group and the control group had similar rates of stage 4 neuroblastoma and mortality due to neuroblastoma. Comparison of the screened group and the control area revealed substantial over diagnosis in the screened participants. The present findings provide no support for mass screening for neuroblastoma at 1 year of age.

Mass screening for neuroblastoma in Japan: Lessons learned and future directions

Background/Purpose: Since 1985, a nationwide mass screening program (MS) for neuroblastoma has been conducted for 6-month-old infants throughout Japan, resulting in the detection of more than 1,900 cases of neuroblastoma. The outcome of these patients has been excellent: more than 97% of them are alive. Yet, several reports suggest that the number of advanced-stage neuroblastoma patients over 1 year of age has not changed substantially. The current report focuses on the 15-year experience with MS of the Kyushu Pediatric Oncology Study Group. Methods: The clinical and biological features of neuroblastoms detected (n = 320) and not detected by MS (n = 245) were compared. Regional and national statistics for neuroblastoma before and after 1985 were analyzed using standard epidemiologic measures for the occurrence of disease. Results: The majority of the MS-positive cases were biologically favorable and had an excellent outcome. In contrast, the majority of non-MS patients in whom neuroblastoma later developed had advanced-stage, unfavorable-prognosis tumors. The overall mortality rate of neuroblastoma in the Kyushu area was not improved by MS. Conclusions: The optimal time for screening is the point at which neuroblastomas regressing spontaneously can no longer be detected, but more aggressive disease can be found. A birth cohort study could determine the optimal timing for a second screening. Identification of other new prognostic factors may be required. J Pediatr Surg 37:949-954. Copyright 2002, Elsevier Science (USA). All rights reserved.

Clinical and biologic characteristics for recurring neuroblastoma at mass screening cases in Japan.

It is said that most cases detected by neuroblastoma mass screening at 6 months of age tend to have a favorable clinical course after a surgical resection either with or without mild chemotherapy. However, a few cases have an unfavorable outcome. In the current study, the authors analyzed the clinical and biologic characteristics for recurring neuroblastoma in mass screening cases. In 245 cases detected through mass screening in the Kyushu area in Japan, the clinical data and biologic features (N-myc status, DNA ploidy, Shimada histology, neuron-specific enolase (NSE), ferritin) were investigated, whereas, in particular, the data for recurring cases also were analyzed. Of 245 cases, 28 tumors had one or more biologically unfavorable prognostic factors, and 6 patients experienced recurrence. Three of the six patients with recurring disease underwent a complete resection of the primary tumor, whereas three cases had undergone an incomplete resection of the tumor. Regarding the initial chemotherapy, three cases received mild chemotherapy, two cases received no chemotherapy, and one case had high-dose multidrug chemotherapy. Regarding biologic prognostic factors, four of six cases with recurring disease had one or more unfavorable factors, whereas two cases had no unfavorable factors. Regarding the outcome after recurrence, four cases are CR, one case has a stable residual tumor, and one case died of disease with N-myc amplification. Most neuroblastomas detected by mass screening at 6 months of age have biologically favorable factors. However, approximately 10% of the cases had one or more unfavorable factors and thus might have a higher risk of recurrence than the patients with no unfavorable factors. Conversely, some cases with recurring disease had no unfavorable factors; however, the reason for this is still unclear. A long-term follow-up for mass screening cases is important, and it also might be necessary to research the established biologic factors and identify other new prognostic factors.

Observation of untreated patients with neuroblastoma detected by mass screening: a "wait and see" pilot study.

Recent studies have indicated that mass screening for neuroblastoma detects tumors that otherwise would have regressed spontaneously without recognition. Therefore, we started an observation program for these patients to determine how frequently spontaneous regression occurs. Eighteen patients were detected by mass screening between June 1994 and December 1996. Eight of these cases matched the following criteria and entered the observation program: Stage I or II, less than 5 cm in diameter; no involvement of large vessels or organs; not difficult to resect; informed consent. If there were an increase in tumor size, an elevation of tumor markers, or evidence of metastasis, the tumor would be immediately resected. Five of the eight cases showed spontaneous regression. Although the remaining three tumors were resected 6-10 months after diagnosis, all patients survived without evidence of recurrence. At least 60% of neuroblastoma cases who entered our observation program regressed spontaneously.

Population-based and controlled study to evaluate neuroblastoma screening at one year of age in Germany: interim results.

The German Neuroblastoma Screening Project is the first controlled and population-based screening study to evaluate the presumed benefit of neuroblastoma mass screening at 1 year of age (10-18 months). Screening takes place in 6 of the 16 German states; children from the remainder serve as controls. The German Childhood Cancer Registry enables a mostly complete follow-up and detection of false-negative patients. Up to December, 1999, 1,199,165 children were examined for urinary catecholamine metabolites and 124 cases of neuroblastoma were detected preclinically, giving a detection rate of 10.3/100,000. Within this cohort, 33 false-negative cases were found. The results of this screening program will be crucial for further implementation of neuroblastoma screening.

Comparison of the incidences of neuroblastoma for screened and unscreened cohorts

The incidences of neuroblastoma in screened cohorts and unscreened cohorts were compared to evaluate the usefulness of neuroblastoma mass screening. Data for screened and unscreened populations were collected from annual reports from the Neuroblastoma Committee and the number of cases of neuroblastoma with information on the screening history was provided by the Japan Children's Cancer Registry, whose registration rate has been estimated to be 0.71. In the age category of 6–11 months, the ratios of incidences per 106 person‐years for unscreened to screened cohorts were 6.58 [95% confidence intervals (CI) 4.51‐9.60] during the early period, 1985–1989, and 11.15 (95% CI 7.65‐16.25) during the later period, 1990–1994. However, they were 0.67 (95% CI 0.31‐1.44) and 0.81 (95% CI 0.33‐2.03) for the age categories of 1–4 y and 2–4 y during the early period and 1.32 (95% CI 0.63‐2.76) and 1.17 (95% CI 0.48‐2.89) for the age categories of 1–4 y and 2–4 y, respectively. The incidences of neuroblastoma per 10 person‐years were not different among screened and unscreened cohorts. Neuroblastoma mass screening has not contributed to any decrease in the incidence of neuroblastoma in children over 1 y of age.