Platinum compounds are widely used in the treatment of pediatric tumors such as neuroblastoma, germ-cell tumors, osteosarcoma, retinoblastoma, hepatoblastoma, brain tumors (low-grade gliomas and medulloblastoma/PNET), and relapsed and refractory lymphomas. The three major platinum compounds (cisplatin, carboplatin, and oxaliplatin) have a similar pharmacokinetics profile and mechanism of action, but the differences in their chemical structure are responsible for their different antitumor activity and toxicity. In this review, we have described the main characteristics of cisplatin, carboplatin, and oxaliplatin, focusing on their toxic effects and possible strategies to prevent them to improve the clinical outcomes in pediatric cancer patients. The underlying mechanism of each platinum-related toxicity is shown together with the clinical manifestations. Furthermore, possible preventive strategies are suggested to reduce the negative impact of platinum compounds on the quality of life of children with cancer. Cisplatin seems to be mostly ototoxic and nephrotoxic, carboplatin mainly produces myelosuppression, whereas oxaliplatin induces predominantly peripheral sensory neurotoxicity. In contrast, nausea and vomiting can be linked to all platinum compounds, although cisplatin exerts the strongest emetic effect. A correct knowledge of pharmacokinetics and toxicological profile of platinum compounds may aid physicians prevent their toxicity on auditory, nervous, renal, and bone marrow function, improving the quality of life of pediatric cancer patients.
SummaryThe management of refractory autoimmune cytopenias in childhood is challenging due to the lack of established evidence on escalating treatments. The long-term efficacy of immunosuppressive drugs was evaluated in children with refractory autoimmune cytopenias referred to the Haematology Unit of the Gaslini Children's Hospital between 2001 and 2014. Patients were grouped into three categories: autoimmune lymphoproliferative syndrome (ALPS), ALPS-related syndrome (at least one absolute/primary additional criterion for ALPS) and primary autoimmune cytopenia (PAC, cytopenia with no other immunological symptoms/signs). Fifty-eight children (aged 1-16 years) entered the study: 12 were categorized with ALPS, 24 were ALPS-related and 22 had PAC. Five didn't receive treatment. Fiftythree were initially treated with steroids/intravenous immunoglobulin. Fourteen responded, whereas 39 did not. Of these 39 patients, 34 (87%) received mycophenolate mofetil (MMF) as second/further-line treatment and 22 (65%) responded. Within these 34 subjects, ALPS patients responded better (11/11, 100%) than the two other groups pooled together (11/23, 48%; P = 0Á002). Sirolimus was given as second/further-line treatment to 16 children, and 12 (75%) responded, including 8 who previously failed MMF therapy. Median follow-up was 3Á46 years. MMF and Sirolimus were well-tolerated and enabled partial/complete and sustained remission in most children. These drugs may be successfully and safely used in children with refractory autoimmune cytopenias with or without ALPS/ALPSrelated disorders and may represent a valid second/further line option.
Hemophagocytic 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.
Hepatic veno-occlusive disease (VOD) is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy. Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. Several treatment options have been tested; the most convincing approach to date is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy.
Deletions of the short arm of chromosome 9 are associated with two distinct clinical entities. Small telomeric 9p24.3 deletions cause genital anomalies in male subjects, ranging from disorder of gonadal sex to genital differentiation anomalies, while large terminal or interstitial deletions result in 9p-malformation syndrome phenotype. The critical region for non-syndromic 46,XY sex reversal was assigned to a 1 Mb interval of chromosome 9p, extending from the telomere to the DMRT genes cluster. The 9p-syndrome was assigned to bands 9p22.3p24.1, but a phenotypic map has not been established for this condition, probably because of the lack of detailed molecular and/or phenotypic characterization, as well as frequent involvement of additional chromosome rearrangements. Here, we describe a unique patient with a small isolated 9p terminal deletion, characterized by array-CGH and FISH, who shows a complex phenotype with multiple physical anomalies, resembling the 9p-syndrome, disorder of sex development with gonadoblastoma, congenital heart defect and epilepsy. The observed deletion includes the 46,XY sex-reversal critical region, excluding the region so far associated with the 9p-syndrome. Genotype-phenotype correlations are tentatively established comparing our patient to seven other previously reported males with isolated terminal 9p deletions, finely defined at a molecular level. Our observations expand the 9p deletion clinical spectrum, and add significantly to the definition of a 9p-syndrome critical region.
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.
Chemoradiotherapy with TMZ followed by adjuvant TMZ did not improve the poor prognosis associated with DIPG in children.
Parietal chest wall tuberculosis is an extremely rare manifestation of tuberculosis (TB) in children. We present the case of a 15 month-old girl presenting with a chest wall lesion initially thought to be of neoplastic origin and eventually diagnosed as chest wall TB, which was treated with surgical debridement and specific antitubercular therapy. The girl had not-measurable 25-hidroxy-vitamin D levels, an increasingly recognized risk factor for the development of active TB. To our knowledge, in the English literature there are no similar described cases in such young infants. This case highlight the possibility of dealing with TB and its different manifestations also in low TB burden countries, due to continuously increasing migration flows. A detailed history is a key point to reach the diagnosis. Moreover, our case confirm the possible non casual relationship between TB and low 25-hidroxy-vitamin D levels, pointing out the importance of measuring its levels in all TB patients and considering its supplementation in addition to specific antitubercular therapy.
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