Conservative management of chylous ascites after oncological surgery for peripheral neuroblastic tumors in pediatric patients.

Chylous ascites may complicate the postoperative course of abdominal surgery mainly due to the iatrogenic disruption of the lymphatic channels during extensive retroperitoneal dissection. Sparse data are available regarding treatment; however, in many cases a recommended first-line treatment approach is by way of enteral feeding, consisting of a formula high in medium-chain triglycerides (MCTs) together with a complete total parenteral nutrition teamed with somatostatin (or an equivalent). Nonetheless, the ligation of chylous fistulae, together with the application of Fibrin glue, as well as the creation of peritoneal-venous shunts have also been documented. The aims of this study are to document incidence of postoperative chylous ascites following resection of abdominal peripheral neuroblastic tumors, evaluate efficacy of the management of chylous ascites, and investigate the main risk factors. A survey was carried out over a span of six years, from March 2010 to March 2016 at Giannina Gaslini Children's Hospital involving seventy-seven children with resections of peripheral neuroblastic tumors. Incidence rate of postoperative chylous ascites following a normal diet was 9% (n=7). Treatment using total parenteral nutrition with octreotide resulted in a complete recovery from chylous ascites within a 20 day period without recurrence. Length of operative time, nephrectomy, and the extension of lymphadenectomy were all significantly associated with a higher incidence of postoperative chylous ascites (p<0.05) which also lengthened hospital stay (p<0.05) and possibly delayed beginning adjuvant chemotherapy.

Metastatic neuroblastoma in infants: are survival rates excellent only within the stringent framework of clinical trials?

INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. MATERIALS AND METHODS: Italian and Spanish metastatic INES patients' data are reported. SPSS 20.0 was used for statistical analysis. RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.

Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.

Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study.

BACKGROUND: In children older than 1 year with localised unresectable neuroblastoma (NB), treatment strategies are heterogeneous according to the national groups. The objective of this phase III non-randomised study was to evaluate the efficacy of conventional chemotherapy followed by surgery. PATIENTS AND METHODS: In the presence of surgical risk factors (SRF), six courses of chemotherapy alternating Carboplatin-Etoposide and Vincristin-Cyclophosphamide-Doxorubicin were given, and surgical resection was attempted after four. Survival analyses were performed using an intention-to-treat approach. The main objective was to achieve a 5-year survival over 80%. RESULTS: Out of 191 registered children, 160 were evaluable. There were 62.5% older than 18 months and 52.5% had unfavourable histology according to International Neuroblastoma Pathology Classification (INPC). Chemotherapy reduced the number of SRFs by one third. Delayed surgery was attempted in 86.3% of patients and was complete or nearly complete in 74%. The 5-year EFS and OS were 76.4% and 87.6% respectively, with significant better results for patients younger than 18 months or with favourable histology. CONCLUSION: This strategy provides encouraging results in children older than 1 year or 12 months with localised unresectable NB without MYCN amplification. However, in children older than 18 months and with unfavourable histology, additional treatment is recommended.

PET/CT imaging in neuroblastoma.

123Iodine-metaiodobenzylguanidine (123I-MIBG) scintigraphy is currently the tracer of choice for neuroblastoma (NB). It has high diagnostic accuracy and prognostic value for the assessment of patients after chemotherapy. A positive 123I-MIBG scan is also used for the basis of targeted radionuclide therapy with 131I-MIBG. I-123 MIBG scan however has some limitations which should be taken into account. Moreover the reasons for false negative MIBG results have not been entirely elucidated. Meticulous correlation with radiological examinations and recognition of the normal distribution pattern of 123I-MIBG in children is vital to obtain optimal results. With its technical superiorities, positron emission tomography/computed tomography (PET/CT) can be successfully introduced into the diagnostic workup of NB. Different PET tracers have been offered for imaging in patients with NB, and the efficacy of this modality has been compared with that of 123I-MIBG scan. Our review aims to analyze the present role of PET/CT imaging and radiopharmaceuticals in NB.

Two-stage phase II study of imatinib mesylate in subjects with refractory or relapsing neuroblastoma.

BACKGROUND: Cure rate for subjects with refractory or relapsing metastatic neuroblastoma is <5%. In the search for a novel therapy, continuous daily oral administration of imatinib mesylate was evaluated. PATIENTS AND METHODS: Twenty-four subjects were enrolled in a two-stage study. Imatinib was administered for the first 4 weeks (cycle) at 170 mg/sqm b.i.d. If no major toxicity occurred, the dose was escalated to 300 mg/sqm b.i.d. for a maximum of 12 cycles. Clinical response and toxicity were evaluated according to international criteria. Pharmacokinetics (PK) profiles and tyrosine hydroxylase (TH) mRNA expression were also determined in a subset of subjects. RESULTS: Five (21%) complete responses, with one subject still alive at 68 months, and 2 (8%) partial responses lasting up to 29 months were obtained. No grade 4 toxicity was observed. At steady-state, PK exposure (69.7 µg h/ml) was similar to that of adults receiving 1000 mg/die. Responses appear to correlate with the absence or presence of metastasis in the bone marrow (BM) alone, with low TH expression levels at study entry and low imatinib exposure. CONCLUSIONS: Imatinib mesylate was well-tolerated and effective in the subset of subjects with low BM infiltration as only site of metastasis. Study identifier EudraCT: 2005-005778-63.

Role of low-cost thyroid follow-up in children treated with radiotherapy for primary tumors at high risk of developing a second thyroid tumor.

AIM: Differentiated thyroid cancer (DTC) is uncommon in childhood and data on its prevalence as a second malignant neoplasm (SNM) after radiotherapy (RT) for malignancies are limited. We evaluated: 1) the incidence DTC in pediatric-oncologic patients treated with RT; 2) the relationship between DTC, RT and the features of the first malignancy; 3) the usefulness of thyroid follow-up in irradiated oncological patients. METHODS: We have followed up 252 patients treated with RT out of 966 oncologic pediatric patients. Thyroid follow-up included TSH level evaluation and neck ultrasonography. In the presence of thyroid nodule/s ≥1 cm and/or with ultrasonography suspicious for malignancy, fine needle aspiration biopsy (FNAB) was performed. When papillary/follicular lesions were detected by cytology, thyroidectomy was performed. If DTC was confirmed, patients underwent radioactive iodine (RAI) treatment. RESULTS: At least one thyroid nodule was detected in 106 irradiated patients (42%): 45 patients underwent FNAB and 27 underwent thyroidectomy. Seventeen DTC (6.7%) were found on histology. A higher incidence of DTC was seen in patients with neuroblastoma (38%) or Wilms' tumor (18%). One third of DTC showed capsule invasion, and one fourth node involvement. Eleven patients, treated with a single RAI treatment, showed undetectable thyroglobulin levels after rh-TSH-stimulation. Five patients underwent at least two RAI treatments: four patients showed complete remission and one patient partial remission. CONCLUSION: A high rate of DTC, often with invasive features, was observed in children treated with RT for primary tumors. This finding underlines the usefulness of thorough low-cost thyroid follow-up in this high-risk population.

Intraoperative bronchoscopy for bronchial carcinoid parenchymal-sparing resection: a pediatric case report.

Bronchial carcinoid tumors are the most common primary pulmonary neoplasm in the pediatric population. The widely accepted treatment for carcinoid tumors is surgical, specifically aiming at being as much as conservative on lung parenchyma, while the entire tumor is resected. A brief case is described, highlighting the importance and advantages of a surgical and endoscopic combined approach.

Sequential intensified chemotherapy with stem cell rescue for children and adolescents with desmoplastic small round-cell tumor.

The RMS4.99 study was designed to explore the role of early sequential intensified chemotherapy (SICT) with PBSC rescue in patients with soft tissue sarcoma with a poor prognosis. Fourteen patients with desmoplastic small round-cell tumor (DSRCT) were included in this study. Initial chemotherapy was followed by a course of CY and etoposide with subsequent PBSC harvest, then three consecutive intensified chemotherapy combinations followed by PBSC rescue and G-CSF administration: first cycle thiotepa (150 mg/m(2) x 2 on day 1) and melphalan (60 mg/m(2) on day 2), second cycle CY (2 g/m(2) on days 1 and 2) and thiotepa (150 mg/m(2) x 2 on day 3), third cycle melphalan (80 mg/m(2) on day 1). The interval between cycles had to be kept as short as possible. Then patients underwent surgery or radiotherapy or both, after which six courses of vincristine, actinomycin D, CY were administered. Ten patients received SICT, which was well tolerated. With a median follow-up of 27 months only three patients are alive without evidence of disease. The 3-year event-free and overall survival rates were 15.5 and 38.9%, respectively. The prognosis for pediatric patients with DSRCT did not improve after administering intensified chemotherapy early in their treatment, so different strategies are needed.

Detection of GD2-positive cells in bone marrow samples and survival of patients with localised neuroblastoma.

The impact of bone marrow (BM) GD2-positive cells on survival has been evaluated in 145 Italian children with localised neuroblastoma (NB) evaluated at diagnosis by anti-GD2 immunocytochemistry. Nineteen of these (13.1%) were found to be BM GD2-positive, with the number of positive cells ranging between 1 and 155 out of 1 x 10(6) total cells analysed. Seven/19 (38.8%) GD2-positive vs 12/126 (9.5%) GD2-negative patients relapsed. The 5-year event-free survival (EFS) and overall survival of the GD2-positive patients was significantly worse than that of the GD2-negative ones (62.2 vs 89.9%, P<0.001; and 74.9 vs 95.9%, P=0.005, respectively). GD2 positivity was not associated to other known risk factors, and in particular to Myc-N amplification and 1p deletion. Among Myc-N-negative patients, the EFS of those negative for both GD2 and 1p deletion was significantly better than in children positive for either one of these two markers (EFS=96.9 vs 66.0%, P<0.001). In conclusion, GD2 positivity may represent a prognostic marker for patients with non-metastatic NB without Myc-N amplification, and its combination with genetic alterations might help identifying patients that require a more careful follow-up.

European intergroup studies (MMT4-89 and MMT4-91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors.

PURPOSE: Final results are presented from two consecutive European studies for patients with metastatic rhabdomyosarcoma (RMS) to identify prognostic variables and determine the value of high-dose chemotherapy (HDCT) in complete remission. PATIENTS AND METHODS: A total of 174 patients aged 3 months to 18 years participated. From 1989 to 1991, patients received four cycles of intensive multiagent chemotherapy. From 1991 to 1995, patients achieving complete remission received consolidation with HDCT. All received local therapy (surgery, radiation therapy) according to response. RESULTS: At a median follow-up of 8 years, 5-year overall survival (OS) and event-free survival (EFS) for the whole group were 24% and 20%, respectively. No statistical difference was found between HDCT and standard chemotherapy (5-year OS, 36% v 27%; EFS 29% v 23%). Univariate analysis identified primary tumor in parameningeal, extremity, or other sites; age younger than 1 year and older than 10 years; bone or bone marrow metastases; multiple metastases; and multiple sites of metastases as unfavorable prognostic factors for OS and EFS. Multivariate analysis identified unfavorable site, bone or bone marrow involvement, and unfavorable age as independently unfavorable factors. Two subgroups were identified. Those with fewer than two unfavorable factors had 5-year EFS and OS of 40% and 47%, respectively. Patients with > or = two unfavorable factors had 5-year EFS and OS of 7.5% and 9%, respectively. CONCLUSION: A minority of patients with metastatic RMS have better survival than overall results for this population suggest. Those in the highest risk group have such poor survival that they are candidates for first-line novel therapies. There is no evidence that consolidation with HDCT improves outcome.

Home care for children following haematopoietic stem cell transplantation.

The quality of life of patients who undergo haematopoietic stem cell transplantation (HSCT) is affected by long periods of hospitalisation for the treatment of several complications. On this basis, 28 children who underwent 29 HSCTs were included in the Home Care (HC) programme of the Paediatric Haematology and Oncology Department of the Gaslini Children's Hospital to be discharged earlier. A total of 17 children were assisted for haematologic follow-up and support therapy administration. The remaining children were followed up for graft- versus-host disease and/or cytomegalovirus infection. Overall activity consisted of 1232 i.v. therapies, 501 blood tests, 58 red blood cell or platelet transfusions, 107 procedures on Central Venous Catheter. Median duration of the assistance per child was 25 days (range 1235) for a total of 1598 days. A total of 822 accesses at home replaced 459 and 363 out-patient and in-patient days of hospitalisation. The average cost per patient receiving HC (EUR 4,252) was significantly lower (P<0.01) when compared to the average cost per patient admitted to the hospital to undergo the same procedures (EUR 14,693). This report shows that HC is feasible for children following HSCT, that it reduces the discomfort of the patients and their families, and that it reduces costs.

Localized unresectable neuroblastoma: results of treatment based on clinical prognostic factors.

BACKGROUND: We previously reported that stage 3 neuroblastoma comprises (i) a low-risk group including all infants (age 0-11 months) as well as older children with non-abdominal primaries, and (ii) a high-risk group made up of children >1 year of age with abdominal primaries. Aggressive chemotherapy was effective only in the latter group. PATIENTS AND TREATMENT: On this basis, in 1990 we designed a new protocol by which all low-risk patients received standard-dose chemotherapy, while the high-risk ones received very aggressive chemotherapy. RESULTS: Between November 1990 and December 1997 a total of 95 eligible and evaluable children were enrolled: 47 were low-risk (35 infants and 12>1 year of age at diagnosis and having non-abdominal primaries), and 48 were high-risk (being >1 year of age and having abdominal primaries). Of the 47 low-risk patients, five relapsed and four subsequently died. The 5-year overall survival (OS) was 91%. Of the 48 patients in the high-risk group, 22 relapsed or progressed, 18 of whom died from their disease and two from toxicity, and one was lost to follow-up. The 5-year OS was 60%. Univariate analysis showed that age, site of primary, risk-group, urine vanillylmandelic excretion, plasma levels of lactate dehydrogenase, ferritin and neurone-specific enolase, and MYCN status correlated with outcome. However, multivariate analysis showed that only MYCN status retained prognostic value. CONCLUSIONS: In low-risk stage 3 neuroblastoma, standard-dose chemotherapy is associated with an excellent chance of being cured. Aggressive chemotherapy is effective for high-risk patients, but results are still unsatisfactory. MYCN gene amplification is a prognostic indicator for most, but not all, treatment failures.

Bacillus sphaericus bacteraemia in children with cancer: case reports and literature review.

In the period 1989-1999, Bacillus sphaericus was demonstrated to cause 12 out of 469 (2%) episodes of bacteraemia in children with cancer or receiving bone marrow transplant at G. Gaslini Children's Hospital, Genoa, Italy. Neutropenia was present in five episodes, six episodes, (all without neutropenia) were related to the presence of a central venous catheter, and one episode occurred in a patient with intestinal graft vs. host disease and gut colonization. All patients survived. Ciprofloxacin was the only drug active against all the isolated strains.Bacillus sphaericus represents a new cause of infection in the immunocompromised host, with low aggressiveness, but a peculiar pattern of antibiotic susceptibility.

Megatherapy combining I(131) metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma.

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I(131) MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1-11.1 mCi/kg of I(131) MIBG 7-10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m(2) followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I(131) MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I(131) MIBG and in 9/15 treated without it. Grade 1-2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I(131) MIBG developed transient interstitial pneumonia. Another child who also received I(131) MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment.

[A case of acute lymphoblastic leukemia with an unusual presentation and slow development]. / Leucemia Linfoblastica Acuta (LLA). Descrizione di un caso ad esordio inusuale e lento decorso.

The authors describe the case of a 3-year-old girl with acute lymphoblastic leukemia which was diagnosed several months after the appearance of the first symptoms. The delay can be attributed to the vague symptoms at onset in the form of a single laterocervical adenopathy which responded to antibiotic and antiphlogistic therapy, the total absence of any indicative hematological symptoms and the patient s persistent excellent general conditions. In the light of this unusual case, the authors stress the need to carry out invasive diagnostic tests on lymph node lesions that are often defined as aspecific given that they may occasionally disguise more severe lymphoproliferative diseases.