Cancer risk in people with epilepsy using valproate-sodium.

OBJECTIVES: Based on reports of antitumour properties of sodium-valproate, we hypothesised that valproate has a cancer-protective effect in people with epilepsy. We aimed to determine cancer risk in people with epilepsy using sodium-valproate. MATERIALS AND METHODS: Continuous data for 2997 people with epilepsy who had been prescribed valproate for at least two years, and for 11,988 unexposed people were provided by the UK General Practice Research Database. Hazard ratios (HRs) for all cancers and individual cancers between the exposed and unexposed groups, with smoking and alcohol consumption and age as covariates, were calculated using the Cox proportional hazards method. RESULTS: Exposure to valproate had no influence on the incidence of the composite of all cancers [HR: 1.19, 95% CI: 0.97-1.47, P = 0.10]; there was, however, a significant excess of colon cancers [HR: 3.95, 95% CI: 1.97-7.92, P = 0.001] and a trend towards an excess of prostate neoplasms [HR: 2.15, 95% CI: 0.92-5.02, P = 0.08] and in addition, a trend towards reduced incidence of breast cancer [HR: 0.40, 95% CI: 0.14-1.30, P = 0.08] in the exposed group. CONCLUSIONS: The lack of an inverse association between valproate use and hazard ratios for all cancers and several individual cancer sites does not lend support for a cancer-protective role for valproate.

[The VIP-secreting tumor as a differential diagnosis of protracted diarrhea in pediatrics]. / Der VIP-produzierende Tumor in der Pädiatrie als Differenzialdiagnose der protrahierten Diarrhö

BACKGROUND: Vasoactive intestinal peptide (VIP) can be produced by mature neurogenic tumors. Pathologically elevated VIP plasma levels cause secretory diarrhea with excessive loss of water and electrolytes. Despite the clinical severity diagnosis of a VIP-secreting tumor is often delayed and subsequently its extirpation as the mainstay of therapy. PATIENTS: We report on two patients with ganglioneuroblastoma and secretory diarrhea. We contrast the case of a 13-month-old boy with advanced symptoms of secretory diarrhea, high VIP plasma levels, and late diagnosis to the case of a 14-month-old boy with mild secretory diarrhea and normal VIP plasma levels but positive proof of VIP in tumor tissue. Reviewing the literature we found 57 cases of pediatric VIP-secreting tumors. RESULTS: The clinical situation is characterized by the typical symptoms of secretory diarrhea with hypokalemia and metabolic acidosis. Histopathology predominantly reveals ganglioneuroblastoma or ganglioneuroma. The symptoms mostly stop after complete resection of the tumor whereas lack of resection is associated with elevated mortality rates. CONCLUSIONS: In case of prolonged therapy-resistant secretory diarrhea the existence of a VIP-secreting tumor should be considered. Diagnostic work-up should include the assessment of VIP plasma levels, catecholamines in urine, and appropriate imaging techniques in order to rule out or confirm the possibility of a VIP producing tumor.

Valproic acid induces differentiation of a supratentorial primitive neuroectodermal tumor.

In preclinical models the antiepileptic drug valproic acid induces differentiation of neoplastic cells, representing an evolving anticancer approach that takes into account that malignant cells resemble immature progenitor cells capable of terminal differentiation. The authors report on a child suffering from a relapsing supratentorial primitive neuroectodermal tumor that received valproic acid for epilepsy treatment over 7 months before the relapse. In contrast to the initial tumor, the relapsing tumor showed glial differentiation and low proliferation index. This is the first report of a relapsed supratentorial primitive neuroectodermal tumor that shows histologically confirmed signs of tumor cell differentiation induction.

Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid.

Differentiation induction is a distinct concept in the treatment of malignant diseases, considering that malignant cells share many features with immature progenitor cells that are capable of terminal differentiation. Treatment of tumor cells with short-chain fatty acid treatment of erythroid progenitors in vitro and in vivo induces cellular differentiation resulting in gamma-globin, i.e., fetal hemoglobin synthesis. Valproic acid (VPA) is a branched-chain fatty acid that is able to inhibit growth of human and rodent tumor cells and to induce a mature phenotype. The antitumoral effects observed in preclinical studies were reached at concentrations that are readily achieved in patients treated with VPA for epilepsy. Hypothesizing that anticonvulsive VPA levels may be used for antitumoral differentiation induction therapy of pediatric malignant tumors, the authors studied fetal hemoglobin-inducing capacity of VPA in children treated with VPA for epilepsy. Fetal hemoglobin was significantly increased in 30 children with epilepsy treated with VPA monotherapy for at least 3 months when compared to untreated control patients. Furthermore, fetal hemoglobin levels correlated with VPA serum levels. The study confirms the dose-dependent stimulating effect of VPA on fetal hemoglobin synthesis at anticonvulsive doses. The results suggest that nontoxic VPA levels reached in pediatric epilepsy patients should be capable of inducing cellular differentiation of pediatric malignant tumors for therapeutic purposes. Broad clinical experience with VPA and its low toxicity further encourage the evaluation of VPA in pediatric oncology for differentiation induction therapy.