Francisco Felix

Potential Role for Valproate in the Treatment of High-Risk Brain Tumors of Childhood—Results from a Retrospective Observational Cohort Study

Although substantial progress has been made in pediatric brain tumor management, patients with brainstem tumors and high-grade gliomas, as well as patients less than 3 years of age with high-risk malignant tumors, have a poorer prognosis. The authors have been treating these patients with radiotherapy and standard carboplatin and vincristine chemotherapy. Since January 2007 the authors have been using valproate as anticonvulsant for prophylaxis. The authors performed a retrospective cohort analysis of pediatric patients with high-risk brain tumors treated with chemotherapy, radiotherapy, and valproate prophylaxis, comparing this group with a historical control. The 2007–2008 group was comprised of 22 patients, 15 with brainstem tumors (7 diffuse intrinsic pontine glioma [DIPG], 3 focal, the remaining infiltrating with a solid portion), 4 with diencephalic tumors (2 thalamic), and 3 with supratentorial high-grade tumors (1 glioblastoma, 1 recurrent grade III ependymoma, 1 with gliomatosis). There were 15 patients alive (68%) after a mean follow-up time of 19 months. Survival function comparison by log rank test was highly significant (P = .004) with a hazard ratio of 0.31 (0.14–0.70). Radiological response showed 3 complete responses (14%), 8 partial responses (36%), 5 stable diseases (23%), and 5 progresssive diseases (23%). The authors hypothesize that valproate may have potentiated the antiangiogenic effect of vincristine, diminished expression of resistance to carboplatin, and sensitized tumor cells to radiotherapy. The authors suggest that clinical trials of carboplatin and vincristine associated with oral continuous low-dose valproate are indicated for pediatric patients with high-risk brain tumor.

Cloak and dagger: the case for adult onset still disease and hemophagocytic lymphohistiocytosis

Adult onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. Systemic onset juvenile idiopathic arthritis (SoJIA) is the preferred nomenclature of Still’s disease. Strong association with so-called macrophage activation syndrome (MAS) may provide a clue to the understanding of the distinctive pathogenetic features of SoJIA. MAS is a severe, potentially life-threatening complication characterized by the excessive activation of well-differentiated macrophages. It is more appropriately named autoimmune disease associated reactive hemophagocytic lymphohistiocytosis (ReHLH), a subset of a histiocytic disorder: class II histiocytosis hemophagocytic lymphohistiocytosis (HLH). The relation of SoJIA with HLH is still under debate. We propose that MAS, HLH, SoJIA, and AOSD are indeed the same disease, in different clinical presentations that may be classified based on severity and laboratory findings, but with essentially the same physiopathogenesis. We propose that the case described by Hong & Lee (Rheumatol Int 2008) was actually an AOSD-associated MAS/RHS/ReHLH fulminant disease.

Pediatric acute promyelocytic leukemia: all-transretinoic acid therapy in a Brazilian pediatric hospital.

Acute promyelocytic leukemia (APL) is an uncommon form of pediatric acute nonlymphocytic leukemia. It is characterized by clinical (refractory coagulopathy), morphologic (promyelocytic differentiation arrest), and cytogenetic t(15;17) hallmarks. The introduction of all-transretinoic acid (ATRA) or tretinoin, a biologic response modifier, in its therapy was followed by dramatic improvement in its outcome. To show the results of APL treatment in our hospital, we reviewed the information about 15 patients less than 18 years old, newly diagnosed with APL between November 2002 and November 2006. The diagnosis was made upon examination of bone marrow aspirates. The clinical charts were searched for data regarding clinical presentation, diagnosis, initial response with induction therapy, toxicity of ATRA, and antracyclic drug (daunorubicin). The median age was 10 years; the male-to-female ratio was 2:1. Fourteen patients received induction chemotherapy. Thirteen achieved complete remission. Six patients showed signs of coagulopathy. Only 1 patient was diagnosed with ATRA syndrome. There was a death owing to sepsis before the beginning of the therapy and 2 relapses with death associated with the therapy discontinuation. Preliminary results are encouraging and confirm that ATRA is safe and efficacious as first choice therapy for APL.

Analysis of survival and prognostic factors of pediatric patients with brain tumor

OBJECTIVES To estimate survival and evaluate prognostic factors of pediatric patients with central nervous system (CNS) tumors treated in a single center. METHODS Retrospective analysis of survival of 103 children with primary brain tumors diagnosed consecutively from January 2000 to December 2006. Cox regression was used for multivariate analysis of factors that affect overall survival to define possible prognostic factors. RESULTS Median and mean ages were 7.2 and 7.6 years. There was a male predominance (1.22:1). Most patients had medulloblastomas or primitive neuroectodermal tumors (PNET, 38%), or low-grade astrocytomas (18%). The anatomic site of most tumors was the cerebellum (49%) and the brain stem (21%). Five-year survival after diagnosis was 84% for low-grade astrocytomas and 51% for medulloblastomas and PNET. Prognostic factors for overall survival were histopathological type (high-grade astrocytomas and ependymomas; hazard ratio = 3.7 to 3.9), surgery (hazard ratio of 0.5 for completely resected tumors) and radiotherapy (hazard ratio of 0.5 for patients who underwent radiotherapy). CONCLUSIONS Overall survival of pediatric patients with brain tumors in this study was similar to that found in populations of the United States and Europe. The prognostic factors defined for overall survival are also similar to those published in previous studies.

Fibromyalgia and Related Medically Unexplained Symptoms: A Lost Link Between Cardiovascular and Nociception Modulation

Objectives: Fibromyalgia syndrome [FMS] is one of the most common causes of widespread pain and fatigue, associated with significant morbidity. It is characterized by chronic widespread body pain and a defined number of tender points, as well as multisystem-related alterations. There is considerable diagnostic overlap with chronic fatigue syndrome. Mainstay theory states that these findings could be caused by a central sensitization phenomenon that would lead to diffused hyperalgesia. Until now, however, little is known about the nature of this central sensitization and the possible causative events that lead to it. We sought to review the current evidence about FMS, its relation to cardiovascular alterations [dysautonomia], and to propose a new model upon its physiopathogenesis. Findings: Fibromyalgia syndrome patients have a greater incidence of orthostatic intolerance, characterized by pre-syncope symptoms and a relentless activated sympathetic system, perhaps causally related to FMS. Independent authors have theorized that orthostatic intolerance has a causal link to FMS. Recently it has been demonstrated that alterations in small vessel tone and endothelial function of skeletal muscle or splanchnic vascular beds are crucial to the development of orthostatic intolerance. Conclusions: We propose two novel hypotheses: FMS would be related to a derangement in cardiovascular autonomic control secondary to endothelial function disturbance and this cardiovascular derangement could correlate with attenuation of supraspinal descending nociceptive inhibition through an integrated central nervous system modulation.

Treatment of children and adolescents with hemangioma using propranolol: preliminary results from a retrospective study

CONTEXT AND OBJECTIVE Hemangiomas are the commonest vascular tumors during childhood. In 2008, the effect of propranolol for treating capillary hemangiomas was demonstrated. Other similar results followed, showing that it rapidly reduces lesion volume. The objective here was to evaluate children and adolescents with hemangiomas that were treated with propranolol. DESIGN AND SETTING Retrospective study, conducted in a childrens hospital. METHODS Patients aged 0-19 years with or without previous treatment, who were treated between January 2009 and December 2010, were included. The response was assessed by comparing the lesion appearance between the start of treatment and the last consultation. We considered partial or complete responses as the response to treatment. RESULTS Sixty-nine patients with a median follow-up of 11 months (mean age: 31 months) were included. Of these, 58 patients were recently diagnosed and 11 had had previous treatment. A response (partial or complete) was seen in 60 patients (87%). Among the capillary hemangioma cases, responses were seen in 50 out of 53 (94%), while in other lesion types, it was 10 out of 16 (63%) (P = 0.3; chi-square). Responses in patients less than one year of age were seen in 37 out of 38 (97%), whereas in those over one year of age, in 23 out of 31 (74%) (P = 0.4; chi-square). Side effects were uncommon and mild. CONCLUSIONS Propranolol seemed to be effective for treatment of hemangiomas in children and adolescents, and not just in the proliferative stage, with responses in almost all the patients.

Valproic Acid May Be Tested in Patients With H3F3A-Mutated High-Grade Gliomas

TO THE EDITOR: The first report of a possible effect of valproic acid in the outcomes of patients with glioblastoma by Happold et al was published in Journal of Clinical Oncology nearly at the same time as the first-ever description of the driver role of histone mutations in a human cancer, coincidentally in pediatric and young adult patients with glioblastoma. Since, a few retrospective reports have added clinical information that fuel the hypothesis that valproic acid affects the survival of patients with glioblastoma through the histone deacetylase (HDAC)-inhibiting effect. Now, the report of Happold et al may have seemingly poured cold water on this idea. Without a shadow of doubt, their report is the best evidence about this question that has been provided so far. Although a number of well-grounded critiques to their findings may be put forward, these will be mostly worthless given the weaknesses of the previous evidence. One particular type of bias that seems to be common in retrospective accounts of would-be repurposed drugs is the immortal time bias (or survivor bias). This kind of problem arises when one has to forcefully add pretherapy events (deaths, in this case) to the nontreated group because such patients never had the opportunity to receive the therapy of interest (ie, they have died before). It is easy and amusing to demonstrate that any such arrangement of an observational cohort study will necessarily suggest a beneficial effect of the treatment. As Happold et al cited, our group originally published retrospective data that suggest a possible effect of valproic acid in pediatric patients with brain tumors. Our original account included a heterogeneous group of patients, but since, we published other reports on more homogeneous cohorts of patients with mixed results. Recently, we presented a poster at a Brazilian Society of Pediatric Oncology congress with new data on the outcome of patients with diffuse intrinsic pontine glioma (DIPG) treated with a contemporary radiochemotherapy protocol and valproic acid (Fig 1). We showed a small cohort of nine patients with DIPG treated with valproic acid throughout the observation time. The group had a 6-month survival of 86% and a 12-month survival of 64%. Although this could be regarded as reassuring and an indication for further investigation, we acknowledge that the number of patients was too small and that any comparison would be severely underpowered. However, one of the mainstays of investigational clinical science (and one that is too frequently forgotten) is to gather prior information about the therapy of interest and the target cohort. Mixed results from mixed groups of patients are hardly conclusive of anything, so we must examine thoroughly the rationale for any proposed treatment. In this particular case, mounting evidence points to a subset of pediatric high-grade gliomas that depend on histone H3.3 (H3F3A gene) mutations. To be specific, pediatric patients with DIPG andmidline glioblastomas that harbor the H3F3A-K27Mmutation comprise a subgroup with a particularly poor prognosis compared with other patients. Mutations K27M of H3.3 and H3.1 histones define two mutually exclusive DIPG subgroups that differ in biology, behavior, and prognosis. The H3F3A-K27M mutant cells seem to globally lose methylation markers of H3.3 and undergo a bulk derepression of epigenetically silenced genes while they focally gain methylation H3.3 sites, thus repressing the expression of selected genes. Although its mechanism is incompletely understood, H3F3A-K27M may render tumor cells more sensitive to HDAC inhibitors like valproic acid. So, a strong rationale from recently gathered evidence exists for the use of HDAC inhibitor drugs in patients with H3 mutant tumors. Most of these patients will be children, adolescents, and young adults with DIPG and midline glioblastomas. We propose that future trials that explore this possibility select patients by this molecular marker, including those with DIPG and glioblastoma with H3F3A-K27M mutation, and exclude other patients who may not benefit from the treatment.

Análise de sobrevida e fatores prognósticos de pacientes pediátricos com tumores cerebrais

OBJETIVOS: Realizar analise de sobrevida e avaliar, atraves de analise multivariada, a influencia de diversas variaveis na sobrevida, definindo fatores prognosticos de pacientes pediatricos com tumores do sistema nervoso central (SNC) tratados em um unico centro. METODOS: Analisamos, retrospectivamente, a sobrevida de 103 criancas portadoras de tumores cerebrais primarios, diagnosticadas consecutivamente no periodo entre janeiro de 2000 e dezembro de 2006. Analise multivariada de fatores influenciando a sobrevida global por regressao de Cox foi usada para definir possiveis fatores prognosticos. RESULTADOS: A mediana e a media de idade foram de 7,2 e 7,6 anos. Houve predominância do sexo masculino (relacao 1,22:1). A maioria dos pacientes tinha meduloblastoma ou tumores neuroectodermicos primitivos (PNET, 38%) ou astrocitomas de baixo grau (18%). As topografias mais comuns foram cerebelar (49%) e tronco cerebral (21%). A sobrevida, 5 anos apos o diagnostico, foi de 84% para astrocitomas de baixo grau e 51% para meduloblastomas e PNET. Fatores prognosticos para a sobrevida global foram histopatologico (astrocitomas de alto grau e ependimomas, razao de risco entre 3,7 e 3,9), cirurgia (razao de risco 0,5 para tumores completamente ressecados) e radioterapia (razao de risco 0,5 para pacientes que receberam radioterapia). CONCLUSOES: A sobrevida global de pacientes pediatricos com tumores cerebrais neste estudo e comparavel aquela dos registros populacionais dos Estados Unidos e Europa. Os fatores de prognostico definidos para sobrevida global tambem se assemelham aqueles previamente publicados.

Neurogenetics Can Help Turn Pain Concepts More Objective

The review of Paller et al. about sex differences in pain phenomena [1] focused mainly on psychosocial factors. We agree with them about the great complexity of pain and pain associated behavior. The mutual and two-way interference of biological and psychosocial factors in the resulting pain phenomena are still not completely understood. Our point here is the frequent misuse of pain psychosocial concepts that we see in technical and nontechnical literature. Almost everyone has preconceived ideas about suffering and pain, and these ideas commonly have to do with punishment and prize. It is hard to separate adequately these ideas even from scientific research. For example, one frequent although somewhat fuzzy concept in specialized literature is “catastrophizing.” Its exact meaning eludes even specialists. There seems to …

Cyclosporin safety in a simplified rat brain tumor implantation model

Brain cancer is the second neurological cause of death. A simplified animal brain tumor model using W256 (carcinoma 256, Walker) cell line was developed to permit the testing of novel treatment modalities. Wistar rats had a cell tumor solution inoculated stereotactically in the basal ganglia (right subfrontal caudate). This model yielded tumor growth in 95% of the animals, and showed absence of extracranial metastasis and systemic infection. Survival median was 10 days. Estimated tumor volume was 17.08 ± 6.7 mm(3) on the 7(th) day and 67.25 ± 19.8 mm(3) on 9(th) day post-inoculation. Doubling time was 24.25 h. Tumor growth induced cachexia, but no hematological or biochemical alterations. This model behaved as an undifferentiated tumor and can be promising for studying tumor cell migration in the central nervous system. Dexamethasone 3.0 mg/kg/day diminished significantly survival in this model. Cyclosporine 10 mg/kg/day administration was safely tolerated.