Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma

In neuroblastoma, N-myc amplification and loss of heterozygosity for the short arm of chromosome 1 (LOH 1p) are common genetic abnormalities. We have recently shown that the presence of additional material of the long arm of chromosome 17 (add.17q) also occurs relatively frequently. In the present study, we analyzed a series of 55 tumors for LOH 1p, N-myc amplification and add.17q, using Southern blot analysis with polymorphic DNA probes of pairs of tumor and constitutional DNA. We determined the correlation of these parameters with clinical variables, such as age, stage, serum lactate dehydrogenase (LDH) and ferritin and also with outcome. LOH 1p occurred in 20 out of 55 cases (36%) and was found more often in stage III/IV tumors and in the older age group, although both correlations were not statistically significant. N-myc amplification was only demonstrated in 12 tumors with concomitant LOH 1p and was not present in the 35 cases without LOH 1p. Add.17q was found in 20/53 (38%) informative cases. LOH 1p was shown to be the most significant predictor of a poor outcome (P < 0.00001), independent of age and stage. LOH 1p is also of prognostic value in those cases without N-myc amplification, indicating a stronger prognostic value for LOH 1p. Add.17q was also associated with an unfavourable prognosis, although this was less significantly then with LOH 1p (P = 0.00004). © 1995 Wi1ey-Liss Inc.     

Immune evaluation of 50 children with neuroblastoma at onset

Several studies document the importance of immunity in the host-tumor relationship in neuroblastoma patients, evidentiating a correlation between clinical compromission and immune impairment. In this study we evaluated some aspects of cellular and humoral immune capacity in 50 neuroblastoma patients at onset. The aim of this investigation was to define, if any, the common immune pattern of these patients, and to evidentiate a possible correlation with prognosis. Immune tests performed were serum immunoglobulin quantitation, absolute value of total T and B lymphocytes, and lymphocyte reactivity to phytohemagglutinin (PHA), Concanavalin A (ConA), and Pokeweed mitogen (PWM). In patients with localized or regional disease, diminished values of lymphocytes were observed in 4/16 cases, a datum highly correlated to a poor final outcome (P <0.01). Mitogen response and serum immunoglobulin levels were frequently altered, but no prognostic value was evidentiated. Thirty-one children with disseminated disease presented more frequent and extended abnormalities: No parameter was found to correlate with prognosis, except for an impaired PHA response that paradoxically assumed a favourable prognostic meaning. Our results suggest that only the total lymphocyte number can contribute to predict the survival ratio in patients with regional disease.     

Association of N-myc amplification with neuroblastoma: The Australian and New Zealand experience

Tumour samples from 38 patients with neuroblastoma were analysed for the presence of N-myc amplification. N-myc gene copy number in tumour DNA was determined by Southern blotting, and by dilution analysis where appropriate. Available clinical data, obtained at tissue collection and by subsequent questionnaire included patient age at diagnosis, catecholamine, ferritin and neuron-specific enolase levels, treatment and disease status. This study was designed to investigate the use of N-myc amplification data as an additional indicator for determination of prognosis. Patients with amplified N-myc had more rapid disease progression than those without amplification (P less than 0.005). Stratification of Stage III and IV patients using N-myc amplification permitted identification of a subgroup with poorer prognosis. The results demonstrate that determination of N-myc amplification is important in assessment of prognosis and subsequent treatment in patients with neuroblastoma.     

The Role of Surgery in the Management of Stage IV Neuroblastoma: A Single Institution Study

The role of surgery in the management of Stage IV neuroblastoma is still far from clear. Seventy-nine patients with this diagnosis presented to the Children's Hospital of Philadelphia during the 10-year period, 1977 to 1986. Four-year survival was 23%. A major resection of the primary tumor was undertaken in 54 patients. The timing of the procedure (at presentation or delayed) had no effect on survival. The patients were divided into three groups based on the extent of surgical resection: Group 1, no surgery or biopsy only (25); Group 2, complete gross resection (34); Group 3, incomplete resection with residual gross disease (20). Four-year survival was 16, 15, and 45%, respectively. The patients were then classified as favorable or unfavorable, on the basis of biological prognostic factors at presentation. When this analysis was combined with the extent of surgery it was discovered that Group 3 contained a higher proportion of favorable patients, accounting for the better survival. Within each group survival correlated with the expected prognosis. The outcome for a patient with Stage IV neuroblastoma depends on the biological characteristics of the tumor, and there is currently no evidence that these can be favorably altered by the timing or extent of surgical resection. Defining the appropriate role of surgery in the management of these patients will require a prospective randomized study which takes into account the inherent biological variability of the disease. © 1995 Wi1ey-Liss, Inc.     

Treatment of stage III neuroblastoma with emphasis on intensive induction chemotherapy: A report from the neuroblastoma group of the spanish society of pediatric oncology

From October 87 to April 92, 172 children were admitted in the N-I-87 protocol of the Spanish Society of Pediatric Oncology for the diagnosis and treatment of neuroblastoma. Forty-eight were considered Evans stage III, 33 of them being older than 1 year. All children were treated with induction chemotherapy (IC) and surgery. IC consisted of three courses of high-dose cisplatin-VM-26 alternating with three further courses of cyclophosphamide-doxorubicin (CAD). Infants less than 1 year received the same drugs at lower doses. After surgery, maintenance chemotherapy was administered to all children during 14 months. It consisted of four pairs of drugs rotated every 4 weeks. Radiotherapy was administered exclusively to patients older than 1 year with residual tumor after IC and surgery. Response was evaluated after IC and surgery. In children older than 1 year, response was obtained in 28/33 (88%). Fifteen of them (47%) achieved complete remission (CR), seven (22%) good partial response (GPR), six (19%) partial response (PR); and in three patients (9%) there was progressive disease (PD). Actuarial survival at 48 months was 0.60 ± 0.10 and EFS was 0.61 ± 0.12. Audiologic impairment was considered the worst toxicity. In children less than 1 year the response rate to IC and surgery was 93% (14/15); nine infants obtained complete response and four had GPR. Only one patient experienced PD in the first 6 months of therapy and died. The other 14 are alive and well at a mean follow-up time of 48 months. Chemotherapy toxicity was mild and reversible. © 1995 Wiley-Liss, Inc.     

Influence of image‐defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group

Background

The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image‐defined risk factors (IDRF) on operative complications and survival (EFS and OS).

Procedure

534 patients with localised, non‐MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo‐adjuvant chemotherapy.

Results

In L1 patients (Group 1) 5‐year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients.

Conclusions

In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning. Pediatr Blood Cancer 2015;62:1536–1542. © 2015 Wiley Periodicals, Inc.     

Excess of congenital abnormalities in French-Canadian children with neuroblastoma: A case series study from Montreal

Neuroblastoma is one of the most common cancers of childhood. Some studies have shown an excess of congenital abnormalities in children who have been diagnosed with neuroblastoma. In this study we examined the medical records of all children with neuroblastoma seen at St. Justine Children's Hospital between the years 1977 and 1993. A total of 141 children (131 of French-Canadian ancestry) were included in this study. Twelve children (8.5%) had 21 defined congenital abnormalities (1,490 per 10,000 children). This compared with a rate of 444.3 children with abnormalities per 10,000 live births (4.44%) for all congenital abnormalities in the British Columbia Health Surveillance Registry, 1979–1988 (relative risk 1.91, P = 0.03). Six of the 12 children had cardiovascular malformations. These and previous results suggest that there may be a common developmental origin to neuroblastoma and to some congenital malformations. Genes that control development may be worthy of further study in these children. Med. Pediatr. Oncol. 29:272–279, 1997. © 1997 Wiley-Liss, Inc.     

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: A report from the Children's Oncology Group

Background

Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial.

Procedure

Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine.

Results

Five‐year overall survival (OS) and progression‐free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five‐year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M‐stage was prognostic. Five‐year OS and PFS for 37 patients with non‐pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/? 11.4% for those undergoing complete resection versus 10.4 +/? 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) “classic” sPNET, 8 (22%) “undifferentiated” and 13 (35%) “malignant gliomas.” There was no significant difference between the subgroups, although survival distributions approached significance when the combined “classic” and “undifferentiated” group was compared to the “malignant gliomas.”

Conclusions

Carboplatin during RT followed by 6 months of non‐intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult. Pediatr Blood Cancer 2015;62:776–783. © 2015 Wiley Periodicals, Inc.

     

Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review

We performed a systematic review to define the long‐term health problems and optimal treatment strategy for patients with neuroblastoma with intraspinal extension. Of 685 identified studies, 28 were included in this review. The burden of long‐term health problems is high; a median of 50% of patients suffered from neurological motor deficit, 34% from sphincter dysfunction, and 30% from spinal deformity. The currently available literature remains suboptimal as a guide for treatment of NBL with intraspinal extension. More well‐designed, prospective studies are needed to determine the optimal treatment strategy.     

Improvement in complete response rate,duration of response and survival with adriamycin combination chemotherapy for non-Hodgkin lymphoma: A prognostic factor comparison of two regimens

The results of a chemotherapy regimen utilizing adriamycin in combination with vincristine, prednisone plus or minus cyclophosphamide (CHOP-HOP) for the treatment of non-Hodgkin lymphoma are compared to those of a non-adriamycin containing combination (COP). The complete remission (CR) rate of 67% for CHOP-HOP in malignant lymphoma, diffuse histiocytic type (MLDH) is superior to 33% obtained with COP. In malignant lymphoma, nodular poorly differentiated lymphocytic (MLNPD), the CR rate was: CHOP-HOP 83%, COP 44%. The prognostic factors for both treatment groups were compared and found to be similar. Thus, adriamycin appears to be responsible for this improvement in CR rate. When analyzed as a group, the patients treated with CHOP-HOP had a longer survival than those treated with COP. This difference was also evident in the subgroup of patients with MLDH. The smaller subgroup of patients with MLNPD treated with CHOP-HOP did not show a significant improvement in survival. A trend for longer duration of CR in both diffuse and nodular lymphomas was also observed, but this difference did not reach statistical significance possibly due to the smaller numbers of patients. Combination chemotherapy with adriamycin has resulted in a higher CR rate and survival for patients with non-Hodgkin lymphoma particularly for the subgroup of patients with MLDH.     

Evaluation of patients with advanced neuroblastoma surviving more than 5 years after initiation of an intensive Japanese protocol: A report from the study group of Japan for treatment of advanced neuroblastoma

In January 1985, a single protocol consisting of cyclophosphamide, vincristine, tetrahydropyranyl adriamycin, and cis-platinum for the treatment of advanced neuroblastoma was begun nationwide in Japan and was found to improve clinical results significantly in terms of 2- or 3-year survival rate. Between January 1985 and December 1988, 113 eligible patients (7 infants younger than 12 months of age with stage IVA disease and 106 patients aged 12 months or older with stage III or IV disease) were enrolled and followed up for 5 years or more after initiation of treatment, as of March 1994. In this study, the usefulness of the protocol for the treatment of advanced neuroblastoma was evaluated with survival rates in relation to age, tumor site, stage, and N-myc amplification for patients surviving more than 5 years after initiation of the protocol. Fifty of the 113 patients were alive 5 years or more after initiation of the treatment, 39 without any episodes of disease recurrence. Fourteen (70%) of 20 patients with stage III, 6 (50%) of 12 with stage IVB, and 24 (30%) of 81 with stage IVA disease were alive and disease-free 5 years after initiation of the protocol. Twenty (56%) of 36 patients without N-myc amplification were alive at 5 years after initiation of the protocol. Only one patient who was alive without evidence of the disease at 5 years had recurrence afterward. © 1996 Wiley-Liss, Inc.     

Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group

Background

Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy.

Objective

We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532.

Study design

A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index.

Results

For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002).

Conclusion

In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.     

Acute lymphoblastic leukaemia with t(4; 11) follows neuroblastoma: A late effect of treatment?

The case presented is of a 7-year-old girl who developed acute lymphoblastic leukaemia (ALL) with t(4; 11)(q21; q23) 5 years after the onset of neuroblastoma and 4 months after completing treatment for a first relapse. Consideration is given to the relative importance in this case of genetic factors and chemotherapeutic drugs in the etiology of ALL.