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This study aimed to evaluate how the COVID-19 pandemic affected the psychological well-being of parents of pediatric oncology patients two years after the pandemic started. The authors' objective was to make a detailed comparison between the data collected in the current study and the data gathered in the previous research with the aim of observing any changes, whether for better or worse, at the psychological level in the caregivers of the patients in question. This research could be of great use for monitoring the psychological health of the sample and for being able to intervene promptly in the event of the worsening of the reported symptoms. Background: Family members dealing with the devastating impact of a cancer diagnosis are now facing even greater vulnerability due to the COVID-19 pandemic. Alongside the already overwhelming trauma, they must also bear the distressing burden of the infection risks. The purpose of this study was to examine and explore the effects in parents of pediatric cancer patients two years after the start of the COVID-19 pandemic to compare these data with the previous data. Methods: We conducted a single-center prospective observational study, enrolling 75 parents of 42 pediatric oncology patients. Four questionnaires (IES-R; PSS; STAI-Y and PedsQL) were given to the parents 2 years after the first evaluation. Results: The bivariate matrix of correlation found a strong significant positive correlation between IES-R and PSS scores (r = 0.526, p < 0.001) as in T1. Stress symptoms (t = 0.00, p < 0.001) and levels of anxiety (trait) (t = 0.32, p < 0.001) remained unchanged; anxiety state levels appeared to have increased (t = 0.425, p < 0.001); there was a significant decrease in the PedsQL tot (t = 5.25, p < 0.001). Conclusions: The COVID-19 pandemic has influenced the levels of stress and anxiety of parents and the quality of life of patients, also correlating with the traumatic impact of the diagnosis.

BackgroundDuring the last decade, there has been a growing number of cases of children born from pregnancy-associated cancer (PAC), however there are currently insufficient data on the follow up to be observed in this category of newborns. Objective of the study was to evaluate the neonatal outcomes of infants born to mother with PAC, the potential adverse effect of chemotherapy during pregnancy and the risk of metastasis to the fetus.MethodsMaternal clinical data and neonatal outcomes of child born to mothers diagnosed with PAC were collected; infants were divided into those were and were not exposed to chemotherapy during fetal life and their outcomes were compered.ResultsA total of 37 newborn infants from 36 women with PAC were analyzed. Preterm delivery occurred in 83.8% of the cases. No significant differences in neonatal outcomes were found between infants who were and were not exposed to chemotherapy during pregnancy. The median follow-up period was 12 months.ConclusionsPAC treatment during the second or third trimester does not seem to be dangerous for the fetus, however infants born from PAC must be carefully evaluated for to rule out the consequences of chemotherapy and exclude the presence of metastasis. Long-term follow-up, especially in children exposed to chemotherapy, should be encouraged to obtain relevant data on long-term toxicity.

Simple Summary Survivors of childhood brain tumors, because of the treatments they have undergone, have a greater risk of dying earlier from cardiovascular causes compared to the general population. The objective of this study was to evaluate differences between cardiovascular risk biomarkers and cardiopulmonary exercise test (CPET) results from childhood brain tumor survivors and healthy controls. We found worse CPET performance in survivors associated with higher endothelin-1 values compared to controls. Correlation analysis showed an inverse relationship between CPET results and leptin, emphasizing the role of radiotherapy as a possible cause in the genesis of a greater cardiovascular risk in survivors of childhood brain tumors.Abstract In recent decades, the improvement of treatments and the adoption of therapeutic protocols of international cooperation has led to an improvement in the survival of children affected by brain tumors. However, in parallel with the increase in survival, long-term side effects related to treatments have been observed over time, including the activation of chronic inflammatory processes and metabolic alterations, which can facilitate the onset of metabolic syndrome and increased cardiovascular risk. The aim of this study was to find possible statistically significant differences in the serum concentrations of early biomarkers of metabolic syndrome and in the results of cardiopulmonary exercise testing between survivors of childhood brain tumors and healthy controls. This is a prospective and observational study conducted on a group of 14 male patients who survived childhood brain tumors compared with the same number of healthy controls. The concentrations of early metabolic syndrome biomarkers [adiponectin, leptin, TNF-alpha, IL-1, IL-6, IL-10, endothelin-1, apolipoprotein B, and lipoprotein (a)] were measured and a cardiopulmonary exercise test (CPET) was performed. Results: Childhood brain tumor survivors performed worse on average

Purpose To assess the prevalence of alterations in anthropometric parameters predictive of metabolic syndrome and cardiovascular risk among childhood brain tumor survivors.Methods Anthropometric parameters predictive of metabolic syndrome and cardiovascular risk were analyzed [height, weight, BMI, waist circumference, hip circumference, waist-height ratio (WHtR), waist-hip ratio (WHR, blood pressure] of 25 patients who survived childhood brain tumors.Results 21 patients (84%) showed alteration of at least one predictive anthropometric parameter. 11 patients (44%) showed a BMI > 75th percentile and 19 patients (76%) showed a pathological WHR value. A pathological WHtR (> 0.5), was identified in 17 patients (68%); the average WHtR observed was 0.53. 9 patients (36%) showed an alteration of all three anthropometric parameters considered. Comparing this subpopulation with the subpopulation with less than three altered parameters, a greater prevalence of the combined alteration was observed in the female sex compared to the male sex (67% vs. 26%). No significant differences were observed regarding the age of diagnosis and end of treatment nor the treatments carried out (chemotherapy, radiotherapy, steroid therapy) between the two groups.Conclusion These results suggest that this population is at high risk of presenting pathological values of BMI, WHR and WHtR with consequent high risk of developing metabolic syndrome and cardiovascular diseases.

Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood-brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer s

Background: Platinum compounds are a group of fundamental chemotherapeutics used in the treatment of solid tumors, but they are burdened by side effects, such as ototoxicity. The objective of this study was to evaluate the incidence of ototoxicity caused by platinum compounds and the risk factors affecting its appearance/progression. Methods: Data from 53 patients who received platinum compounds and who had been off therapy for at least 5 years were analyzed. We collected data relating to audiometry conducted annually from the end of treatment and for at least 5 subsequent years, as well as information concerning the oncological history and comorbidities. Results: At the end of the treatment, 17 patients (32.08%) presented ototoxicity, according to the Boston SIOP Ototoxicity Scale; the risk factors included a higher serum creatinine value at diagnosis, having undergone cranial radiotherapy, and needing magnesium supplementation. After 5 years from the end of the treatment, the number of patients with exhibiting ototoxicity was 31 (58.5%); the factors that influenced the onset/progression of the damage were having undergone radiotherapy (HR 1.23; p < 0.01) and having received therapy with aminoglycosides (HR 1.27; p < 0.01). Conclusions: Ototoxicity caused by platinum compounds can occur even after the conclusion of the treatments, and the factors affecting its progression are radiotherapy and the aminoglycosides therapy.

Background: Neurofibromatosis type 1 (NF1)-related gliomas appear to have a clinical behavior different from that of sporadic cases. The purpose of the study was to investigate the role of different factors in influencing the tumor response rate of children receiving chemotherapy for their symptomatic glioma. Methods: Between 1995 and 2015, 60 patients with low-grade glioma (42 sporadic cases and 18 cases with NF1) were treated. Patients with brainstem gliomas were excluded. Thirty-nine patients underwent exclusive or postsurgical chemotherapy (vincristine/carboplatin-based regimen). Results: Disease reduction was achieved in 12 of the 28 patients (42.8%) with sporadic low-grade glioma and in 9 of the 11 patients (81.8%) with NF1, with a significant difference between the 2 groups (P < 0.05). The response to chemotherapy in both the patient groups was not significantly influenced by sex, age, tumor site, and histopathology, although disease reduction occurred more frequently in children aged under 3 years. Conclusions: Our study showed that pediatric patients with low-grade glioma and NF1 are more likely to respond to chemotherapy than those with non-NF1.

The use of peripheral blood hematopoietic stem cells for bone marrow reconstitution after myeloablative therapy is well established in children with malignant disorders. However, the peripheral blood hematopoietic stem cells collection in very low-body weight (<= 10 kg) children remains a significant challenge because of technical and clinical issues. A male newborn affected by atypical teratoid rhabdoid tumor, diagnosed prenatally, received two cycles of chemotherapy following surgical resection. After an interdisciplinary discussion, it was decided to intensify the treatment with high-dose chemotherapy followed by autologous stem cell transplantation. After 7 days of G-CSF administration the patient underwent hematopoietic progenitor cells-apheresis collection. The procedure was performed in the pediatric intensive care unit, using two central venous catheters and Spectra Optia device. The cell collection procedure was completed in 200 min, during which time 3.9 total blood volumes were processed. During apheresis we did not observe electrolyte alterations. No adverse events were recorded during or immediately following the cell collection procedure. Our report describes the feasibility of performing large volume leukapheresis without complications in an extremely low-body weight patient weighing 4.5 kg using the Spectra Optia apheresis device. No catheter-related problems occurred, and apheresis was completed without any adverse event. In conclusion, we believe that very low-body weight pediatric patients need a multidisciplinary approach to manage central venous access, hemodynamic monitoring, cell collection, prevention of metabolic complications to improve safety, feasibility, and efficiency of stem cell collection procedures.

Aminoglycosides are broad-spectrum antibiotics largely used in children, but they have potential toxic side effects, including ototoxicity. Ototoxicity from aminoglycosides is permanent and is a consequence of its action on the inner ear cells via multiple mechanisms. Both uncontrollable risk factors and controllable risk factors are involved in the pathogenesis of aminoglycoside-related ototoxicity and, because of the irreversibility of ototoxicity, an important undertaking for preventing ototoxicity includes antibiotic stewardship to limit the use of aminoglycosides. Aminoglycosides are fundamental in the treatment of numerous infectious conditions at neonatal and pediatric age. In childhood, normal auditory function ensures adequate neurocognitive and social development. Hearing damage from aminoglycosides can therefore strongly affect the normal growth of the child. This review describes the molecular mechanisms of aminoglycoside-related ototoxicity and analyzes the risk factors and the potential otoprotective strategies in pediatric patients.

Prognosis of high-risk neuroblastoma is dismal, despite intensive induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance. Patients who do not achieve a complete metastatic response, with clearance of bone marrow and skeletal NB infiltration, after induction have a significantly lower survival rate. Thus, it's necessary to further intensify treatment during this phase. 131-I-metaiodobenzylguanidine (131-I-MIBG) is a radioactive compound highly effective against neuroblastoma, with 32% response rate in relapsed/ resistant cases, and only hematological toxicity. 131-I-MIBG was utilized at different doses in single or multiple administrations, before autologous transplant or combined with high-dose chemotherapy. Subsequently, it was added to consolidation in patients with advanced NB after induction, but an independent contribution against neuroblastoma and for myelotoxicity is difficult to determine. Despite results of a 2008 paper demonstrated efficacy and mild hematological toxicity of 131-I-MIBG at diagnosis, no center had included it with intensive chemotherapy in first-line treatment protocols. In our institution, at diagnosis, 131-I-MIBG was included in a 5-chemotherapy drug combination and administered on day-10, at doses up to 18.3 mCi/kg. Almost 87% of objective responses were observed 50 days from start with acceptable hematological toxicity. In this paper, we review the literature data regarding 131-I-MIBG treatment for neuroblastoma, and report on doses and combinations used, tumor responses and toxicity. 131-I-MIBG is very effective against neuroblastoma, in particular if given to patients at diagnosis and in combination with chemotherapy, and it should be included in all induction regimens to improve early responses rates and consequently long-term survival.

Nutritional status plays a vital role in the growth of children. In pediatric patients, disease-related malnutrition is a dynamic and multifactorial process supported by several factors such as inflammation, increased energy expenditure, decreased intake or reduced utilization of nutrients. In pediatric patients with malignancies, sarcopenia may coexist with malnutrition, amplifying its negative impact on prognosis. Careful monitoring of nutritional status both at diagnosis and during chemotherapy treatment allows early detection of the risk and/or presence of malnutrition. A rapid and personalized nutritional intervention can improve adherence to treatment, reduce complications and improve the patients' quality of life.

Background: We evaluated nutritional and sarcopenia status and their clinical impact in pediatric patients affected by bone and soft tissue sarcomas. Methods: Body mass index (BMI), prognostic nutritional index (PNI), and total psoas muscle area (tPMA) at diagnosis and after 12 months were analyzed. tPMA was measured from single cross-sectional computed tomography (CT) images at L4-L5. Age-specific and sex-specific tPMA Z-scores were retrieved from an online calculator. Results: A total of 21 patients were identified between February 2013 and December 2018. Twelve patients (57.1%) experienced sarcopenia at diagnosis, although not statistically associated with overall survival (OS) (p = 0.09). BMI Z-score, PNI, and tPMA Z-score significantly decreased between diagnosis and after 12 months of treatment (p < 0.05). Univariate analysis showed significant associations between poor OS and the presence of metastasis (p = 0.008), the absence of surgery (p = 0.005), PNI decrease (p = 0.027), and the reduction in tPMA > 25% (p = 0.042) over the 12 months. Conclusions: Sarcopenia affects more than half of the patients at diagnosis. Decreased PNI during 12 months of treatment has significant predictive value for OS. The role of tPMA derived from CT scan among pediatric patients with sarcoma should be investigated in further prospective and larger studies.

Background: We evaluated nutritional and sarcopenia status and their clinical impact in pediatric patients affected by bone and soft tissue sarcomas. Methods: Body mass index (BMI), prognostic nutritional index (PNI), and total psoas muscle area (tPMA) at diagnosis and after 12 months were analyzed. tPMA was measured from single cross-sectional computed tomography (CT) images at L4-L5. Age-specific and sex-specific tPMA Z-scores were retrieved from an online calculator. Results: A total of 21 patients were identified between February 2013 and December 2018. Twelve patients (57.1%) experienced sarcopenia at diagnosis, although not statistically associated with overall survival (OS) (p = 0.09). BMI Z-score, PNI, and tPMA Z-score significantly decreased between diagnosis and after 12 months of treatment (p < 0.05). Univariate analysis showed significant associations between poor OS and the presence of metastasis (p = 0.008), the absence of surgery (p = 0.005), PNI decrease (p = 0.027), and the reduction in tPMA > 25% (p = 0.042) over the 12 months. Conclusions: Sarcopenia affects more than half of the patients at diagnosis. Decreased PNI during 12 months of treatment has significant predictive value for OS. The role of tPMA derived from CT scan among pediatric patients with sarcoma should be investigated in further prospective and larger studies.

The management of chronic refractory pain (non-neoplastic and cancer-related pain) remains a therapeutic challenge. The continuous intrathecal (IT) administration of drugs may play an important role in the possible management options. Intrathecal drug delivery devices (IDDDs) may be effective for patients with refractory chronic pain. Therefore, they may be adopted for non-oncologic pain in patients with compression fractures, spondylolisthesis, spondylosis, back surgery failure syndrome and spinal stenosis. Oncologic patients can benefit from these treatments in a variable way according to tumor characteristics, prognosis, periprocedural imaging and risk of disease progression. In this review, we describe the most commonly used drugs (opioids and non-opioids), their pharmacokinetic and pharmacodynamic features and indications of use. The most used drugs are morphine, hydromorphone, fentanyl, methadone, bupivacaine, clonidine, and ketamine. Patient evaluation before the device implantation should be based on clinical examination, medical records assessment and psychometric evaluation. The infusion pumps available on the market are both non-programmable (with continuous IT deliver of drugs) and programmable (with variable deliver of drugs according to their flow rate). Moreover, we describe the procedure of implantation and the potential complications of IT drug delivery (such as bleeding, infection, loss of cerebrospinal fluid, wound seroma, loss of catheter pump propellant).

Transdermal delivery system (TDDS) is a non-invasive and less expensive method for drug delivery. Despite its feasibility, only a restricted group of drugs can be delivered by TDDS, because of the little permeability of skin. Moreover, TDDS is limited to lipophilic drugs with small molecular masses and it is not indicated for peptides, macromolecules and hydrophilic drugs. Among opioids, fentanyl and buprenorphine are suitable for transdermal administration only for chronic pain management (not for acute pain). However, opioid TDDS still remains off-label for chronic pain management in children. In this review, we describe the main features of the adhesive TDDS and the main characteristics of pediatric skin and the differences from the adult one. Moreover, we focus on fentanyl and buprenorphine patches and their non-invasive mechanism of action, and on the main aspects that make them suitable for pain management among the pediatric population.

The spleen is a secondary lymphoid organ that belongs to the reticular-endothelial system, directly connected to blood circulation. The spleen is greatly involved in the immune response, especially against capsulated bacteria. Splenectomy plays a fundamental role in the treatment of numerous pediatric hematologic disorders. Taking into account all the possible complications (especially infections) linked to this procedure, alternatives to total splenectomy have been sought. Partial splenectomy has been proposed as a treatment that allows the reduction of infectious risk. This approach has proven safe and feasible in most patients, but multicentric and prospective studies are necessary to more accurately define the indications for performing partial splenectomy. However, vaccinations and antibiotic prophylaxis remain fundamental for preventing serious infections, even in the case of partial splenectomy. We review anatomical and functional properties of the spleen, with a focus on medical or surgical indications to splenectomy, aiming to give practical educational information to patients and their families after splenectomy. Furthermore, we discuss the feasibility of partial splenectomy in children with hematologic diseases who require splenectomy.

Optic pathway gliomas (OPG) are a common cancer in children with neurofibromatosis type 1.OPGs can cause clinical symptoms such as reduction of visual acuity, alterations of the visual field, pallor of the optical papilla, strabismus, endocrinological alterations up to diencephalic syndrome.The current guidelines provide for wait and see as the main approach if the tumor is not causing visual deterioration and adapting treatment only in the event of significant impairment of the visual function. Therefore, it is essential to early detect the visual deterioration changes as well as the identification of children eligible for treatment. © 2020 This is an Open Access article licensed under a Creative Commons license: Attribution 4.0 International (CC-BY).

Adolescents and young adults (AYA) patients with cancer show specific biological, sociodemographic and behavioral features, with lower survival rates than younger group. Gynecologic malignancies that occur among AYA requires a multidisciplinary management and a tailored model of care, in order to enhance the early diagnosis, the adherence to the treatment, the enrollment in clinical trials, the rate of survival and the quality of life (QoL). In this article, we review the main gynecological tumors that may occur in AYA, with a focus on the clinical signs at the diagnosis and the modality of treatment. In addition, we proposed a model of multidisciplinary and personalized care for AYA with gynecological tumors, which can help the clinicians to manage the specific gynecologic concerns, such as ovarian failure, contraception, fertility, late psychosocial effects.

Opioids are essential for the treatment of pain, which is a serious symptom for children and adolescents affected by cancer. Intranasal opioids may be very useful for the treatment of breakthrough pain in children and adolescents with cancer, for their little invasiveness, ease of administration, rapid onset of action, and high bioavailability. Intranasal drug delivery may be influenced by anatomical and physiological factors (nasal mucosa absorption area, mucociliary clearance, enzymatic activity, anatomical anomalies, chronic or inflammatory alterations of nasal mucosa), drug-related factors (molecular weight, solubility), and delivery device. Fentanyl is a lipophilic opioid commonly proposed for intranasal use among pediatric patients, but no studies have been conducted yet about intranasal use of other available opioids for management of pediatric cancer pain. In this review, we analyze several elements which may influence absorption of intranasal opioids in children and adolescents, with a focus on pharmacokinetics and therapeutic aspects of each opioid currently available for intranasal use.

Definitive diagnosis of pediatric liver masses can be challenging, because clinical manifestations are nonspecific, and ultimate diagnosis may be delayed. We describe 2 patients with liver masses that initially were misdiagnosed and treated as infectious hepatic lesions. Only after histologic examination the correct diagnosis of undifferentiated embryonal sarcoma of the liver was defined. Both patients underwent a complete tumor resection followed by chemotherapy with a favorable outcome.

The central nervous system (CNS) may be considered as a sanctuary site, protected from systemic chemotherapy by the meninges, the cerebrospinal fluid (CSF) and the blood-brain barrier (BBB). Consequently, parenchymal and CSF exposure of most antineoplastic agents following intravenous (IV) administration is lower than systemic exposure. In this review, we describe the different strategies developed to improve delivery of antineoplastic agents into the brain in primary and metastatic CNS tumors. We observed that several methods, such as BBB disruption (BBBD), intra-arterial (IA) and intracavitary chemotherapy, are not routinely used because of their invasiveness and potentially serious adverse effects. Conversely, intrathecal (IT) chemotherapy has been safely and widely practiced in the treatment of pediatric primary and metastatic tumors, replacing the neurotoxic cranial irradiation for the treatment of childhood lymphoma and acute lymphoblastic leukemia (ALL). IT chemotherapy may be achieved through lumbar puncture (LP) or across the Ommaya intraventricular reservoir, which are both described in this review. Additionally, we overviewed pharmacokinetics and toxic aspects of the main IT antineoplastic drugs employed for primary or metastatic childhood CNS tumors (such as methotrexate, cytosine arabinoside, hydrocortisone), with a concise focus on new and less used IT antineoplastic agents.

Background: We report our experience and outcomes about the management of Askin's tumors [AT], which are rare primitive neuroectodermal tumors (PNETs) that develop within the soft tissue of the thoracopulmonary region, typically in children and adolescents. Methods: We retrospectively analyzed the charts of 9 patients affected by AT (aged 6-15 years), treated at the Paediatric Oncology Unit of Gemelli University Hospital in Rome between January 2001 and December 2016. Results: All nine patients underwent to biopsy followed by neoadjuvant chemotherapy. At the end of the neoadjuvant chemotherapy, they underwent to surgical removal of the residual tumor. Five patients with positive tumor margins and/or necrosis< 90% received local radiotherapy. Two patients with metastasis received an intensified treatment, with the addition of high dose adjuvant chemotherapy followed by peripheral blood stem cells rescue. No statistically significant correlation was found between outcome and gender; the presence of any metastasis and the radiotherapy. The overall survival was 65.14 months (95% confidence interval [95%CI], 45.81-84.48), and the 5 years survival was 60%, at a median follow-up of 53.1 months. Conclusion: Our study confirms that a multimodal treatment with surgery, chemotherapy, and radiotherapy may increase the survival in AT pediatric patients.

Background: Carboplatin based regimens have demonstrated activity in pediatric patients with low grade gliomas (LGG). However, carboplatin hypersensitivity reactions (CHRs) may be a major problem leading to premature cessation of an effective therapy. The objectives of this study were to describe the prevalence, characteristics and management of CHR. Methods: We performed a retrospective review of children with LGG treated between January 1994 and July 2015 with carboplatin and vincristine who had a documented CHR. We identified two groups: the first was treated following the schema proposed by Packer et al., and re-exposed to carboplatin using a desensitization protocol; the second was treated according to protocol SIOP LGG 2004 and re-exposed with the infusion time prolonged. Results: CHRs were observed in 16 patients (34%) out of 47. Hypersensitivity reactions occurred in 6 patients (20.7%) of the first, and 10 patients (55.5%) of the second group, respectively. The grade 2 reactions were the most common. The median number of carboplatin doses administered at the first episode of CHR was 7 (range, 3-9) for the first group, and 8.5 (range, 5-11) for the second, respectively. Six patients were re-exposed to carboplatin using a desensitization protocol; 10 with a prolonged infusion time. Overall success rate for re-exposition was 43.75% (100% and 10%, respectively) (P = 0.001). Conclusions: Our results show that re-exposure is a safe alternative to abandoning carboplatin. Desensitization showed greater effectiveness compared to a prolonged infusion time, which allowed the patients to receive effective treatment without adverse reactions.

emophagocytic lymphohistiocytosis is a potentially fatal disorder resulting from excessive activation and non-malignant proliferation of T lymphocytes and macrophages. Neoplasms, autoimmune disorders and systemic infections can cause secondary hemophagocytic syndrome. The association of hemophagocytic syndrome and visceral leishmaniasis is rarely found in childhood. We report a case of an infant affected by hemophagocytic lymphohistiocytosis secondary to visceral leishamniasis and describe all cases of hemophagocytic syndrome associated with visceral leishamniasis in childhood reported in literature, focusing on clinical manifestation, diagnosis and treatment.

ongenital thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy, inherited with autosomal recessive mode as a dysfunction or severe deficiency of ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin 1 repeats Nr. 13), caused by mutations in the ADAMTS-13 gene. About 100 mutations of the ADAMTS-13 gene were identified so far, although only a few characterised by in vitro expression studies. A new Asp to Gly homozygous mutation at position 173 of ADAMTS-13 sequence was identified in a family of Romanian origin, with some members affected by clinical signs of TTP. In two male sons, this mutation caused a severe (< 3%) deficiency of ADAMTS-13 activity and antigen level, associated with periodic thrombocytopenia, haemolytic anaemia and mild mental confusion. Both parents, who are cousins, showed the same mutation in heterozygous form. Expression studies of the mutant ADAMTS-13, performed in HEK293 cells, showed a severe decrease of the enzyme's activity and secretion, although the protease was detected inside the cells. Molecular dynamics found that in the D173G mutant the interface area between the metalloprotease domain and the disintegrin-like domain significantly decreases during the simulations, while the proline-rich 20 residues linker region (LR, 285-304) between them undergoes extensive conformational changes. Inter-domain contacts are also significantly less conserved in the mutant compared to the wild-type. Both a decrease of the inter-domain contacts along with a substantial conformational rearrangement of LR interfere with the proper maturation and folding of the mutant ADAMTS-13, thus impairing its secretion.

Background: The purpose of this study was to assess the efficacy and toxicity of radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG). Methods: Patients younger than 18 years with newly diagnosed DIPG were enrolled. Children were treated with focal RT along with concurrent daily TMZ. Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ was given every 28 days up to 12 cycles or progression disease. Results: Fifteen children with a median age of 9 years were enrolled. Fourteenth out of the 15 patients completed the chemoradiotherapy. The toxicity associated with TMZ was primarily haematopoietic. At a median follow-up of 15 months 13 children had died and 2 children were alive with progressive disease. No patient experienced complete response (CR). The median time to progression was 7·15 months. Conclusion: Chemoradiotherapy with TMZ followed by adjuvant TMZ did not improve the poor prognosis associated with DIPG in children.

Background: Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. Patients and Methods: Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. Results: Median age at initial SEC was 104 days (IQR 47-234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7-34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P=0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P=0.039) and grade 3 motor deficit (P=0.084). Conclusions: Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted. © 2014 Wiley Periodicals, Inc.

The treatment of children with malignant glioma remains challenging. The aim of this multicenter phase I study is to establish the recommended dose (RD) of the combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with relapsed or refractory malignant glioma and brainstem glioma at diagnosis. A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by a classical 3 + 3 design. Cohorts of patients were enrolled at 4 different levels: (1) TMZ 120 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (2) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (3) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10; (4) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-12. Therapy was administered in 28-day courses. A total of 118 courses were administered to 18 patients with a median age of 11.2 years. At dose level 1, none displayed toxicity. Of the 6 patients at dose level 2, 1 patient had dose limiting toxicity (DLT). None of the 3 patients at dose level 3 had DLT. At dose level 4, grade III/IV thrombocytopenia and neutropenia were observed in 2 out of the 6 patients enrolled. Therefore, the MTD was established at dose level 3. The RD for phase II trial in children with malignant glial is TMZ 150 mg/m(2) for 5 days and VP-16 50 mg/m(2) for 10 days every 28 days.

In this brief report we have described eight children affected by optic pathway/hypothalamus gliomas and treated with carboplatin and/or cisplatin, which developed a derangement of sodium and water metabolism, due to diabetes insipidus (DI) or to syndrome of inappropriate antidiuretic hormone secretion (SIADH) after surgical resection. In four out of these eight patients the treatment with platinum compounds produced prolonged haematological toxicity and in five out of them it caused neurosensorial bilateral hypoacusia. In addition cisplatin worsened electrolytes disturbances. Hence children with DI or SIADH should be carefully monitored before, during and after the treatment with platinum compounds.

The number of oral anticancer agents has greatly increased in recent years. It is a well-known fact that food intake can induce significant variations in the bioavailability of these drugs. The aim of this review is to describe the interactions between diet and oral anticancer drugs in terms of the possible effects of such interactions on reducing the antineoplastic activity of the drug or increasing its side effects.

Thrombocytopenia-absent radius (TAR) syndrome is characterised by bilateral absence of the radii in the presence of both thumbs and hypomegakaryocytic thrombocytopenia. We report our experience of three patients affected by TAR syndrome presenting with different clinical manifestations focusing on the management of these patients.

Wiskott-Aldrich syndrome (WAS) is characterized by primary immunodeficiency, thrombocytopenia and eczema. Patients with WAS have an increased risk to develop tumors. Non-Hodgkin lymphoma (NHL) represents the most common malignancy occurring in WAS-affected patients, diffuse-large-B-cell lymphoma is the most frequently encountered variant. We describe a case of a patient with WAS and NHL in the pharynx, an atypical tumor site presentation. The patient was successfully treated with a reduced dose chemotherapy regimen plus anti-CD20 monoclonal antibody. He is in complete remission 3 years from the start of treatment. Pediatr Blood Cancer 2012;59:318-319. © 2011 Wiley Periodicals, Inc.

In patients with chronic congenital haemolytic disorders, human Parvovirus B19 (HPV B19) is frequently involved in pure red-cell aplastic crises. Furthermore, it may inhibit three-lineage haematopoiesis in the bone marrow, causing severe pancytopenia. In such patients, Epstein Barr virus (EBV) infection also seems to share the same mechanism as HPV B19 in inducing bone marrow aplasia, but at present the clinical effect of an infection sustained by both viruses is unknown.

BACKGROUND: The prognosis of patients with advanced neuroblastoma (NB) remains poor. Major and early responses have an important bearing on treatment outcome. Iodine-131-metaiodobenzylguanidine (131I-MIBG) has the potential to deliver large doses of radiation specifically to NB cells. We evaluated the toxicity of, and response to, a novel induction regimen that included 131I-MIBG combined with cisplatin, cyclophosphamide, etoposide, vincristine, and doxorubicin. PROCEDURE: Thirteen children over 1 year of age with advanced NB at diagnosis were investigated extensively. 131I-MIBG was administered on day 10; this was preceded by chemotherapy in the five patients in group 1 (described in our previous study), and both preceded and followed by chemotherapy in the eight patients in group 2. The final induction regimen (used for group 2) lasted 1 month. Evaluation was performed 40 days after the start of treatment. RESULTS: In both groups 1 and 2, the extent of hematologic toxicity, which was the only side effect, was similar to that seen with chemotherapy alone. Doses of 131I-MIBG as high as 16.6 mCi/kg showed no evidence of toxicity, even in patients with extensive bone marrow infiltration. Overall, we recorded two patients with a complete response (CR), six very good partial responses (VGPR), four partial responses (PR), and one mixed response (MR). In group 2, CR/VGPR were observed in patients treated with higher doses of 131I-MIBG. CONCLUSIONS: The results of this pilot study show that 131I-MIBG, in combination with chemotherapy, appears to play an important role in a new and effective induction regimen for advanced NB.

Astroblastoma is a rare glial tumor occurring in older children and defined by histological criteria as low or high-grade. We describe two children with high-grade astroblastoma. The first patient, with multiple recurrences of a frontoparietal tumor, died 10 years from diagnosis after progression of the disease despite surgery, radiotherapy and chemotherapy. The second patient underwent subtotal resection of a temporal mass; the residual tumor progressed five months after radiotherapy, but after a subsequent gross total resection the patient is now in complete remission 54 months from diagnosis. Although both patients had high-grade astroblastomas, there were histological differences between the two tumors, in particular regarding the proliferative index, which was 30% and 5-10%, respectively. High-grade astroblastoma is usually treated with surgery and radiotherapy, but may have an unpredictable behavior even when tumor excision is deemed complete. The two cases reported here illustrate the variable clinical course of this rare tumor. The proliferative index may be a useful tool to better define prognosis

Errors involving patients receiving intrathecal chemotherapy are a significant problem in oncology. Despite the improvement in the management of antineoplastic agents, unintentional intrathecal administration of chemotherapic drugs that are indicated only for systemic administration or intrathecal overdose of drugs regularly used for intrathecal chemotherapy, continue to occur. These events can result in severe neurotoxicity, usually fatal in outcome. We review reported cases of medication errors in intrathecal administration of chemotherapy described in the literature. Diverse rescue therapies have been proposed but the most effective means of managing these errors remains prevention.

BACKGROUND: The prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient. METHODS: A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3+3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (2) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (3) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10; (4) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7 years. RESULTS: None of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3. CONCLUSION: The recommended phase II dose in children is TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10 every 28 d. The combination was well tolerated and demonstrated antitumour activity.

Epileptic seizures are a common clinical problem in children with brain tumors. The conventional antiepileptic drugs (AEDs) permit a good seizure control in most of these children. An emerging problem is the possible interactions between AEDs and chemotherapeutic drugs, because many of these drugs are metabolized by the cytochrome P450. The aim of this article is to propose a novel therapeutic approach for new-onset epilepsy in children with brain tumors. Among the new AEDs not metabolized by the P450 system, levetiracetam seems to be a promising AED owing to its pharmacokinetic features, efficacy, and safety

Familial adenomatous polyposis is an inherited disorder characterized by the development of hundreds of colorectal adenomas during adolescence, which in many cases will transform into colorectal cancer by the fourth decade of life, along with the development of various malignant tumors including hepatoblastoma. We report on a female patient with a de novo interstitial deletion of 5q21.3-q23.3, encompassing the APC gene, associated with adenomatous polyposis and early colorectal cancer, hepatoblastoma, epidermoid cysts, mental retardation, several mild dysmorphic signs and lower limb venous thrombosis.

Severe hyperleukocytosis caused by acute lymphoblastic leukaemia (ALL) is associated with an increased risk of early death due to the intracranial haemorrhage. We report on a boy who presented with ALL with an extremely high leukocyte count, who developed neurological deterioration due to multiple intracerebral haemorrhages. Adequate measures for managing this medical emergency include appropriate supportive measures and initiation of therapy to prevent symptoms of leukostasis. Aggressive measures as a decompressive craniectomy should be considered to improve the poor outcome observed in this subset of patients

Central pontine and extrapontine myelinolysis are uncommon disorders characterized by distinctive clinical features and typical findings on neuroimaging. Only a few cases are reported in the pediatric age group. We describe the case of a leukemic, malnourished 14-year-old boy with a high serum sodium concentration that gradually increased to 170 mmol/L. During a septic shock episode, hydration with a low sodium concentration at the rate of 104 mL/h for 24 h was administered. A rapid correction of the high serum sodium occurred, exceeding 0.5 mmol/L/h. The following day the patient developed rapid and progressive neurological impairment with clinical features characteristic of central pontine and extrapontine myelinolysis. Magnetic resonance imaging confirmed the diagnosis 11 days later. The patient was treated with steroids and intravenous immunoglobulins. He achieved an almost full neurological recovery and radiological improvement. The reported case demonstrates that central pontine and extrapontine myelinolysis can occur after excessively rapid correction of hypernatremia

A 3-month-old male infant was admitted to hospital with anemia. Follow-up controls revealed the presence of specific cytomegalovirus (CMV) antibodies. Virus was isolated from urine, blood, and saliva. At 7 months of age, he presented with melena. Polymerase chain reaction (PCR) of biopsy samples from the duodenum was positive for CMV. Anemia resolved after starting antiviral therapy with oral valganciclovir.

Cranial irradiation (CI) is an effective way to prevent central nervous system (CNS) leukemia in children with acute leukemia (AL). However, it is still unclear whether the antileukemic effect of CI is mediated by alteration of blood-brain barrier (BBB) permeability and consequent increased levels of systemically administered drugs or whether it simply results from a direct cytolytic effect on leukemic cells in the meninges at diagnosis. We evaluated the influence of CI on BBB permeability to 1-beta-D-arabinofuranosylcytosine (ara-C) in 23 children with AL undergoing CI for CNS leukemia prophylaxis. CI was administered at 18 Gy (16 patients) and 24 Gy (7 patients). ara-C levels were measured in cerebrospinal fluid (CSF) and plasma before, during, and after CI. Two doses were evaluated: 75 mg/m2/day (12 patients) and 480 mg/m2/day (11 patients). CSF and plasma ara-C levels were measured when steady state was achieved. CSF:plasma ratios, obtained before, during, and after CI, were compared by an ANOVA model for repeated measures and by Tukey's test. At the 75-mg/m2/day dose, the mean values of ara-C CSF:plasma ratios before, during, and after CI were 0.20, 0.27, and 0.27, respectively. At the 480-mg/m2/day dose, the mean CSF:plasma ratios before, during, and after CI were 0.09, 0.12, and 0.13, respectively. No significant differences were observed when CSF:plasma ratios were compared before and during, during and after, and before and after CI. Our results indicate that CI at the doses used for CNS prophylaxis in AL does not significantly alter the BBB as far as ara-C is concerned

An infant with Kawasaki syndrome presenting with fever, rash, and a high percentage of neutrophils with toxic granulation is reported. The peripheral blood smears of the patient showed a high proportion of neutrophils with marked vacuoles and toxic granulations. The reactive changes in neutrophils could be helpful in the early detection of the disease, especially in infants younger than 6 months of age who are at high risk for development of coronary artery disease.

Cranial irradiation (CI) is an effective way to prevent central nervous system (CNS) leukemia in children with acute leukemia (AL). However, it is still unclear whether the antileukemic effect of CI is mediated by alteration of blood-brain barrier (BBB) permeability and consequent increased levels of systemically administered drugs or whether it simply results from a direct cytolytic effect on leukemic cells in the meninges at diagnosis. We evaluated the influence of CI on BBB permeability to 1-beta-D-arabinofuranosylcytosine (ara-C) in 23 children with AL undergoing CI for CNS leukemia prophylaxis. CI was administered at 18 Gy (16 patients) and 24 Gy (7 patients). ara-C levels were measured in cerebrospinal fluid (CSF) and plasma before, during, and after CI. Two doses were evaluated: 75 mg/m2/day (12 patients) and 480 mg/m2/day (11 patients). CSF and plasma ara-C levels were measured when steady state was achieved. CSF:plasma ratios, obtained before, during, and after CI, were compared by an ANOVA model for repeated measures and by Tukey's test. At the 75-mg/m2/day dose, the mean values of ara-C CSF:plasma ratios before, during, and after CI were 0.20, 0.27, and 0.27, respectively. At the 480-mg/m2/day dose, the mean CSF:plasma ratios before, during, and after CI were 0.09, 0.12, and 0.13, respectively. No significant differences were observed when CSF:plasma ratios were compared before and during, during and after, and before and after CI. Our results indicate that CI at the doses used for CNS prophylaxis in AL does not significantly alter the BBB as far as ara-C is concerned.

Cranial irradiation (CI) is an effective way to prevent central nervous system (CNS) leukemia in children with acute leukemia (AL), However, it is still unclear whether the antileukemic effect of CI is mediated by alteration of blood-brain barrier (BBB) permeability and consequent increased levels of systemically administered drugs or whether it simply results from a direct cytolytic effect on leukemic cells in the meninges at diagnosis, We evaluated the influence of CI on BBB permeability to 1-beta-D-arabinofuranosylcytosine (ara-C) in 23 children with AL undergoing CI for CNS leukemia prophylaxis. CI was administered at 18 Gy (16 patients) and 24 Gy (7 patients), ara-C Bevels were measured in cerebrospinal fluid (CSF) and plasma before, during, and after CI, Two doses were evaluated: 75 mg/m(2)/day (12 patients) and 480 mg/m(2)/day (11 patients), CSF and plasma ara-C levels were measured when steady state was achieved. CSF:plasma ratios, obtained before, during, and after CI, were compared by an ANOVA model for repeated measures and by Tukey's test, At the 75-mg/m(2)/day dose, the mean values of ara-C CSF:plasma ratios before, during, and after CI were 0.20, 0.27, and 0.27, respectively, At the 480-mg/m(2)/day dose, the mean CSF:plasma ratios before, during, and after CI were 0.09, 0.12, and 0.13, respectively, No significant differences were observed when CSF:plasma ratios were compared before and during, during and after, and before and after CI, Our results indicate that CI at the doses used for CNS prophylaxis in AL does not significantly alter the BBB as far as ara-C is concerned.

Rhabdoid tumor of the kidney (RTK) is a quite rare malignant neoplasm of early childhood. It has a very unfavourable prognosis, since it tends to give early metastases and shows a poor response to chemotherapy regimens. We report a case of an infant with RTK, who had a rapidly progressive course. Based upon our case and the review of the literature, we would like to stress the importance of a differential diagnosis with another kidney cancer, namely Wilms tumor, which is more frequent and has by far a better prognosis.

We developed an animal model to evaluate the 125-I-metaiodobenzylguanidine (125-I-mIBG) biodistribution in tumor bearing mice. Six weeks old nude-atimic mice were subcutaneously injected with 30 x 10(6) cells of the human neuroblastoma (NB) cell line SH-SY5Y. TE-671, a rhabdomyosarcoma cell line, was used as a control tumor without a specific mIBG uptake mechanism. In order to prevent possible tumor rejection mediated by NK activity the anti asialo GM1 antiserum was administered intraperitoneally once a week for 4 weeks. The maximum anti asialo mediated effect was obtained by administering the first dose the same day as the cell implant. In this group of animals by 9 weeks 98\% of mice had a measurable tumor. We have utilized this model to evaluate the biodistribution of 125-I-mIBG given as two different formulations: standard preparation with a specific activity of 84 mCi/mg and the no carrier added (n.c.a.) formulation with a specific activity of approximatelly 8,000 mCi/mg. Our preliminary results indicate that the biodistribution of the two different formulations in the various organs are similar. Therefore it appears that n.c.a. mIBG should not cause an increased toxicity in possible normal target organs such as heart or adrenals. Additional experiments will be performed in this model to ascertain if there is a potential advantage of the clinical use of n.c.a. mIBG over the standard preparation.

Neuroblastoma (NB), a childhood radiosensitive tumor, is very aggressive and malignant; in its disseminated form, despite very intensive chemotherapy, prognosis continues to be dismal. Owing to its capacity to concentrate in NE lesions, large doses of 131-I-MIBG, have given very encouraging therapeutic results in patients resistant to conventional therapy as well as at diagnosis. We recently reported the first attempt in combination therapy (CO-TH) using 131-I-MIBG and cisplatin. This new form of CO-TH appears very effective in obtaining a rapid and excellent response in relapsed patients. In this report, we describe the results of further experience with CO-TH in disseminated NE. We have attempted to verify to what extent interaction between the effects of the two agents may produce therapeutic benefit, and we have sought the optimization of CO-TH use. Three stage IV NE patients were treated with CO-TH. The following treatment schedule, was planned: day 1, cisplatin 50 mg/m(2) i.v. over 6 h; day 2, 131-I-MIBG 100-130 mCi at high specific activity (-1.1 Gbq/mg) i.v. over 6 h followed, a week later, by the same treatment combination. The therapeutic results were encouraging. However, hematological toxicity continued to represent a major limiting factor. In view of the overall effectiveness of CO-TH, at the price of lasting hematological toxicity, it may be indicated as a consolidation regimen some time before conditioning chemotherapy for autologous bone marrow transplantation.

For years there has been no substantial improvement in survival rates of children with advanced neuroblastoma (NB). NB is a radiosensitive tumor. Since promising results are obtained with aggressive chemotherapy, it might be expected that even better results could be obtained from a high radiation dosage. But delivery of high radiation doses is limited by host intolerance. {[I-131]Metaiodobeuzylguanidine ([I-131]MIBG), a radioiodinated aralkylguanidine, is capable of competing with norepinephrine for uptake into neuroadrenergic tissue and derived tumors. Targeted radiotherapy with elevated doses has been pioneered by several groups, as a high dose of radioactivity can be selectively delivered to tumor cells, with an acceptable systemic toxicity. We briefly review here the latest research achievements and the progress that has been made with the use of this new treatment modality in patients with advanced NB. Encouraging results have been obtained with [I-131]MIBG in patients with resistant disease; however, a promise for the future may lie in tentative therapeutic approaches with [I-131]MIBG used at the time of diagnosis. The toxicity of [I-131]MIBG de novo contrasted with previous experience in [I-131]MIBG therapy in pretreated patients with relapses, since bone marrow depression did not appear to be very significant. We have recently investigated a new therapeutic approach to stage IV NB using a combination of [I-131]MIBG and cisplatin. Our results, although preliminary, suggest that this combined therapy is most effective in pretreated stage IV NB. However, relatively severe and long-lasting hematologic toxicity has been observed. We are at present trying to reduce the possible toxic synergism between cisplatin and [I-131]MIBG. Th, real therapeutic potential of radioiodinated MIBG in patients with NE has not yet fully explored. Future improvements may result from the contribution of further clinical and research investigations.}