Negative pressure treatment for necrotizing fasciitis after chemotherapy

We describe 2 cases of children with malignant disease who developed severe mucositis with perineal necrotizing fasciitis during severe neutropenia after chemotherapy. Treatment with topical negative pressure therapy with silver foam dressing, together with large spectrum antibiotics, resolved the problem with complete closure of the wound after 30 and 36 days of treatment, respectively

First-line treatment of acute lymphoblastic leukemia with pegasparaginase.

open2noAcute lymphoblastic leukemia (ALL) accounts for almost 4000 cases annually in the United States, approximately two thirds of which are in children and adolescents. Treatment results of ALL have improved considerably in the past decade, due to an optimal stratification of patients and a rational use of different antileukemic agents among which L-asparaginase (L-ASNase) plays a fundamental role. This drug has been used in pediatric ALL chemotherapy protocols for almost 3 decades. In the 1970s and 1980s a chemically modified form of this enzyme called pegasparaginase (PEG-ASNase) was rationally synthesized to decrease immunogenicity of the enzyme and prolong its half-life. The different advantages of PEG-ASNase have been demonstrated in many clinical studies, the last of which underline the utility of this drug in front-line therapy of ALL. In this review, we discuss the pharmacological advantages and clinical potential of PEG-ASNase and its important use in first-line treatment of ALL.openMasetti R;Pession AMasetti R;Pession

Pitfalls, prevention, and treatment of hyperuricemia during tumor lysis syndrome in the era of rasburicase (recombinant urate oxidase)

Along with hydration and urinary alkalinization, allopurinol has been the standard agent for the management of hyperuricemia in patients with a high tumor burden at risk of tumor lysis syndrome; however, this agent often fails to prevent and treat this complication effectively. Rasburicase (recombinant urate oxidase) has been shown to be effective in reducing uric acid and preventing uric acid accumulation in patients with hematologic malignancies with hyperuricemia or at high risk of developing it. Rasburicase acts at the end of the purine catabolic pathway and, unlike allopurinol, does not induce accumulation of xanthine or hypoxanthine. Its rapid onset of action and the ability to lower pre-existing elevated uric acid levels are the advantages of rasburicase over allopurinol. Rasburicase represents an effective alternative to allopurinol to promptly reduce uric acid levels, improve patient’s electrolyte status, and reverse renal insufficiency. The drug, initially studied in pediatric patients with acute lymphoblastic leukemia and aggressive non-Hodgkin lymphoma, seems to show comparable benefit in adults with similar lymphoid malignancies or at high risk of tumor lysis syndrome. Current and future trials will evaluate alternative doses and different schedules of rasburicase to maintain its efficacy while reducing its cost. The review provides a comprehensive and detailed review of pathogenesis, laboratory, and clinical presentation of TLS together with clinical studies already performed both in pediatric and adult patients

The Role of HDACs Inhibitors in Childhood and Adolescence Acute Leukemias

Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs) are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs) are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia

Fatal anaphylaxis to wheat after gluten-free diet in an adolescent with celiac disease

n/

Synergistic cytotoxic effect of l-asparaginase combined with decitabine as a demethylating agent in pediatric T-ALL, with specific epigenetic signature

T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on the ASNS gene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of the ASNS gene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with low ASNS expression due to hypermethylation of the ASNS promoter, while it did not restore sensitivity in the resistant cell lines characterized by higher ASNS expression

Update on Febrile Neutropenia in Pediatric Oncological Patients Undergoing Chemotherapy

: Febrile neutropenia (FN) is a common complication of chemotherapy in oncological children and one of the most important causes of morbidity and mortality in these patients. The early detection of a bacteremia and the rapid therapeutic intervention are crucial to improve the outcome. We analyzed the literature in order to clarify the epidemiology of FN in children undergoing chemotherapy, the specific factors associated with a negative outcome, the most common etiology, and the value of biological markers as a tool to make an early diagnosis or to monitor the evolution of the infection. Several studies have tried to identify specific factors that could help the clinician in the detection of an infection and in its microbiological identification. However, due to the heterogenicity of the available studies, sufficient evidence is lacking to establish the role of these risk factors in clinical practice and future research on this topic appear mandatory. Determinations of risk factors, etiology, and markers of febrile episodes in these patients are complicated by the characteristics of the underlying illness and the effects of treatments received. Although some studies have tried to develop an evidence-based guideline for the empiric management of FN in pediatrics, validated predictive scores and algorithms are still lacking and urgently needed

dMyc Functions Downstream of Yorkie to Promote the Supercompetitive Behavior of Hippo Pathway Mutant Cells

Genetic analyses in Drosophila epithelia have suggested that the phenomenon of “cell competition” could participate in organ homeostasis. It has been speculated that competition between different cell populations within a growing organ might play a role as either tumor promoter or tumor suppressor, depending on the cellular context. The evolutionarily conserved Hippo (Hpo) signaling pathway regulates organ size and prevents hyperplastic disease from flies to humans by restricting the activity of the transcriptional cofactor Yorkie (yki). Recent data indicate also that mutations in several Hpo pathway members provide cells with a competitive advantage by unknown mechanisms. Here we provide insight into the mechanism by which the Hpo pathway is linked to cell competition, by identifying dMyc as a target gene of the Hpo pathway, transcriptionally upregulated by the activity of Yki with different binding partners. We show that the cell-autonomous upregulation of dMyc is required for the supercompetitive behavior of Yki-expressing cells and Hpo pathway mutant cells, whereas the relative levels of dMyc between Hpo pathway mutant cells and wild-type neighboring cells are critical for determining whether cell competition promotes a tumor-suppressing or tumor-inducing behavior. All together, these data provide a paradigmatic example of cooperation between tumor suppressor genes and oncogenes in tumorigenesis and suggest a dual role for cell competition during tumor progression depending on the output of the genetic interactions occurring between confronted cells

End point prick test: could this new test be used to predict the outcome of oral food challenge in children with cow's milk allergy?

Background: Cow\u2019s milk allergy (CMA) is the most frequent food allergy in childhood; the trend of CMA is often characterized by a progressive improvement to achieve tolerance in the first 4 to 5 years of life. It has been observed that specific IgE (sIgE) towards cow\u2019s milk proteins decrease when the age increases. Although food allergy can be easily diagnosed, it is difficult to predict the outcome of the oral food challenge (OFC), that remains the gold standard in the diagnosis of food allergy, by allergometric tests. Methods: We considered 44 children with CMA diagnosed through OFC who returned to our Allergy and Immunology Pediatric Department between January to December 2010 to evaluate the persistence of allergy or the achievement of tolerance. On the basis of the history, we performed both allergometric skin tests and OFC in children that were still following a milk-free diet, whereas only allergometric skin tests those that had already undergone spontaneous introduction of milk protein at home without presenting symptoms. Objective: The aim of this study was to investigate the relationship between the persistence of CMA or the acquisition of tolerance and the results of the end point prick test (EPT). Results and Discussion: The OFC with cow\u2019s milk was performed on 30 children, 4 children were excluded because of a history of severe reactions to cow\u2019s milk, and 10 because they had spontaneously already taken milk food derivates at home without problems. 16/30 (53%) children showed clinical reactions and the challenge was stopped, 14/30 (47%) did not have any reaction. Comparing the mean wheal diameter of every EPT\u2019s dilution between the group of allergic children and the tolerant ones, we obtained a significant difference (p < 0.05) for the first 4 dilutions. We have also calculated sensitivity (SE), specificity (SP), the positive predictive value (PPV) and the negative predictive value (NPV) for each EPT dilution. Conclusions: EPT is a safe and cheap test, easy to be executed and that could provide good prediction of the outcome of OFC; so it might be used to avoid OFC-induced anaphylaxis in children affected by CMA. It can also help avoiding dietetic restrictions in tolerant children who show sensitization towards cow\u2019s milk proteins