Camillo Boglino

Features and outcome of neuroblastoma detected before birth

BACKGROUND/PURPOSE The growing use of routine ultrasonography during pregnancy is leading to an increasing number of prenatally diagnosed neuroblastomas. Optimal strategy has not yet been defined for these patients, because knowledge on this particular neuroblastoma (NB) population is still limited. However, definite guidelines are needed to avoid inadequate treatment. The authors analyzed the cases of antenatally detected NB (ADNB) reported in the Italian Neuroblastoma Registry during the past 6 years to elucidate the features of this subset of NB. METHODS The Italian Neuroblastoma Registry was reviewed for the period January 1993 to December 1998 to collect clinical, radiographic, surgical, and histopathological data on ADNB cases. NB stage was evaluated according to INSS criteria. All patients had undergone imaging (computed tomography or magnetic resonance imaging) of the primary tumor and bone marrow biopsy before surgical resection. RESULTS Seventeen patients were identified. Primary tumour site was adrenal glands in 16 cases and retroperitoneal ganglia in 1. Stage distribution was stage I, 13 cases; stage II-A, 1 case; stage II-B, 1 case; stage IV-S, 2 cases. All cases underwent primary tumour resection. Mean age at surgery was 4 weeks. Resection of primary tumor was radical in 16 cases, partial in 1. All tumors were characterised by favourable histology according to Shimada classification. N-myc gene amplification was studied in 14 patients. N-myc amplification was detected only in a newborn with stage II-A NB, who died of massive bleeding 2 days after tumor resection. DNA index and 1p deletion were studied in 11 and 8 patients, respectively. Both diploidy and deletion of 1p were observed in a newborn who subsequently died of disease progression despite surgery, chemotherapy, and radiation therapy. Fourteen of 17 patients currently are alive and free of disease, and one with IV-S NB and short follow-up is alive with disease. CONCLUSIONS Our data give evidence that in most cases infants with ADNB represent a subset of patients with excellent outcome. Aggressive treatment may not always be necessary. Infants with ADNB with unfavorable features should undergo early surgical excision, whereas patients with favourable features could be observed awaiting spontaneous regression of the mass, reserving delayed surgery for tumors that increase in size or do not regress.

D-CECaT: a breakthrough for patients with neuroblastoma.

In view of the high relapse rate following chemotherapy for patients with advanced neuroblastoma (NB) and primitive neuroectodermal tumors (PNET), we designed a novel chemotherapy program which incorporated the iron chelator deferoxamine. The purpose of the deferoxamine was to sensitize the cells to standard chemotherapy. The D-CECaT regimen contained (in mg/m2): deferoxamine 4500 during days 1–5; cyclophosphamide 600 mg over days 6 and 7; etoposide 300 mg over days 7 and 8; carboplatin 100 mg over days 7 and 8; and thiotepa 30 mg over days 6–8. Between October 1989 and May 1992 we entered 23 advanced NB and two PNET patients. Sepsis occurred in four courses, nausea and vomiting in 30 courses, and 50 courses required blood and platelets. Responses observed in previously untreated patients with stage III NB: six out of six CR (17 + to 41 + months), with stage IV NB, nine out of 11 CR (14 + to 28 + months), two out of 11 VGPR (22 + months), with stage IV PNET two out of two CR (1 + to 35 + months). With previously treated and failed stage IV NG, two out of six VGPR for 19 + and 20 months, and four out of six PR 1, 8, 9 and 11 months. Median survival for 19 new patients was 22 + months (6 to 41 + months; two patients in CR died at 7 months during adjuvant autologous marrow transplant). In conclusion, D-CECaT is an effective initial cytoreductive regimen for advanced stage NB/PNET patients. Additional patients and studies are required to determine its use as an alternative to autologous bone marrow transplantation.

Spinal cord vascular injuries following surgery of advanced thoracic neuroblastoma: an unusual catastrophic complication.

BACKGROUND Spinal cord injury is a possible complication associated with removal of thoracic dumbbell neuroblastomas. Our experience with two children whose postsurgical course was complicated by midthoracic spinal cord ischemia is reported there. Permanent paraplegia resulted in both. PROCEDURE AND RESULTS Preoperative awareness of the origin and distribution of the Adamkiewicz artery (arteria radiculomedullaris magna, ARMM) and of the possible collateral pathways for spinal cord blood supply may be helpful in the planning of operations that involve dissection in the midthoracic posterior mediastinum. Otherwise, a flaccid paraplegia may result. CONCLUSIONS The syndrome is presumed to be triggered by a spasm, an embolism, or a iatrogenic interruption of the ARMM.

Importance of local treatment in pediatric soft tissue sarcomas with microscopic residual after primary surgery: Results of the Italian Cooperative Study RMS-88

BACKGROUND The goal of primary excision in soft tissue sarcomas is the complete removal of the tumor by a nonmutilating procedure. However, microscopic residuals may be left after a conservative procedure because of inadequate preoperative assessment or difficulties during the operation. The purpose of this report is to describe the treatment and the outcome in patients, enrolled in the Italian Cooperative Study RMS-88, with microscopic residuals after primary excision (IRS Group IIa). PROCEDURE Microscopic residuals were evident at histology in 52 of 90 patients who had a macroscopic complete primary excision: 25 rhabdomyosarcomas (RMS) and 27 nonrhabdo-soft tissue sarcomas (NRSTS). Eighteen patients were treated with primary reexcision (PRE) and chemotherapy (CT) using VA or IVA regimens; 27 patients received radiation therapy (RT; 40 Gy) and IVA; 7 children in whom PRE was not feasible and RT could not be administered for age <3 years were treated with CT (IVA) alone. RESULTS Of the 18 patients who underwent a successful PRE + CT, the local relapses were 3 (16.6%); of 27 cases who had RT + CT there were 4 local relapses (14.8%); 3 local relapses occurred in those 7 patients in whom CT alone was administered (43%). CONCLUSIONS Microscopic residuals after primary surgery were difficult to manage because of the absence of a measurable target. PRE represented the treatment of choice for children <3 years of age who cannot receive RT and for paratesticular sites. PRE and RT showed similar results in achieving local control in extremity and trunk sites, but they could not always avoid local recurrence. In particular PRE was not effective in tumors larger than 5 cm. If microscopic residuals could not be avoided and PRE was not possible, adequate RT was effective both for RMS and for NRSTS.

Pulmonary Blastomas of Childhood: Histologic, Immunohistochemical, Ultrastructural Aspects and Therapeutic Considerations

Pulmonary blastomas are rare neoplasms typically occurring in patients of pediatric age, clinically characterized by fever, respiratory distress, and radiologic findings of a pulmonary cystic and/or solid mass with partial or complete obliteration of emithorax. Their behavior is aggressive and outcome is poor due to frequent relapses and metastases. The histological, immunohistochemical, and ultrastructural aspects of a personal series of 6 cases of pulmonary blastoma are described and the differences between childhood and adult types are stressed. Due to the aggressiveness of these rare tumors, therapeutic management is quite difficult. The expression of the transmembrane tyrosin kinase receptor c-kit in all the solid cases of this series leads the authors to hypothize new possible therapeutic implications for these tumors.

Glutathione Transferase P1 Polymorphism in Neuroblastoma Studied by Endonuclease Restriction Mapping

Abstract Several members of the different glutathione transferase (GST) gene classes are polymorphic. Particular interest has been focused on the GSTP class because this gene class is up-regulated during the early stage of oncogenesis and is significantly overexpressed in many human tumors. It has also been shown that high levels of GSTP1 expression are associated directly with tumor drug resistance and with poor patient survival. Our aim was to understand the possible association between GSTP1 polymorphism and cellular response to chemotherapeutic drugs in neuroblastoma. In fact, several antineoplastic drugs used in the neuroblastoma high-risk chemotherapeutic protocol are potential substrates of GSTP1-1 (etoposide, adriamycin and carboplatin). The GSTP1 genotype homozygote *A/*A was identified in 11 patients independent of their response to the chemotherapeutic treatment. Only four patients had a heterozygote genotype A*/B*. Therefore, based on our preliminary data, we were not able to conclude that GSTP1 polymorphism had an impact on patient response to treatment in neuroblastoma.

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours.

Multiple defects in apoptotic pathways have been described in peripheral neuroblastic tumours (NTs). Mitosis–karyorrhexis index (MKI) is a reliable morphological marker identifying favourable and unfavourable NTs. The extent to which apoptotic processes contribute to determine the clinical significance of MKI is still undefined. Apoptosis was investigated in a series of 110 peripheral NTs by comparing MKI to immunohistochemical and molecular apoptotic features. High MKI was found in 55 out of 110 NTs (50%) and was associated with advanced stage (P=0.007), neuroblastoma (NB) histological category (P=0.024), MYCN amplification (P<0.001), and poor outcome (P=0.011). Overall survival probability was 45% in patients with high MKI compared to 73% in patients with low MKI. In the same 110 NTs, the expression of Bcl-2, Bcl-XL, Bax and Mcl-1 was studied by immunohistochemistry, but no significant associations were found with clinicohistological features. Microarray analysis of apoptotic genes was performed in 40 out of 110 representative tumours. No significant association was found between the expression of apoptotic genes and MKI or clinicohistological features. Proliferative activity was assessed in 60 out of 110 representative tumours using Ki67 immunostaining, but no significant correlations with MKI or clinicobiological features were found. In NTs, the combination of apoptosis and proliferation as expressed by MKI is a significant prognostic parameter, although neither of them is per se indicative of the clinicobiological behaviour and outcome.