Daniela Rizzo

Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment

High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas.

Functional Loss of the Inner Retina in Childhood Optic Gliomas Detected by Photopic Negative Response

PURPOSE To determine whether the Ganzfeld ERG photopic negative response (PhNR), an assay of inner retinal activity, is altered in childhood optic glioma (OPG). METHODS Seventeen pediatric patients with a diagnosis of OPG, established on neuro-ophthalmologic and brain/orbit magnetic resonance imaging (MRI) criteria, were enrolled. The examination protocol included determination of visual acuity (VA), fundus examination, retinal nerve fiber layer (RNFL) measurement with spectral-domain optical coherence tomography (SD-OCT) and photopic ERG. Fifteen normal children served as control group. Ten of the 17 OPG patients were retested 1 to 3 months after the first examination. Photopic ERGs were recorded after 10 minutes of light adaptation in response to a Ganzfeld flash presented on a steady light-adapting background. Amplitude and peak-time of b-wave and PhNR were measured. RESULTS Compared with normal values, PhNR amplitude was significantly reduced (P < 0.0001) in the OPG group. Peak-time of PhNR as well as b-wave amplitude and peak-time were similar in both patients and controls. Losses of PhNR were found in patients with involvement of either anterior or retro-chiasmatic optic pathways. Linear regression analysis showed significant positive correlation between RNFL thickness and PhNR amplitude (r2 = 0.34, P = 0.008). Mean percentage test-retest difference for PhNR amplitude and peak-time was 12% and 6%, respectively. CONCLUSIONS These findings indicate that flash ERG PhNR can detect a loss of inner retinal function in childhood OPGs supporting the use of this technique, as an adjunct to standard psychophysical and electrophysiological tests, to monitor visual function in OPG.

Temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: a broken promise?

Abstract 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.

BRAF and MEK inhibitors in pediatric glioma: new therapeutic strategies, new toxicities

ABSTRACT Introduction: BRAF mutation was initially reported in metastatic melanomas, and more recently in a variety of human cancers. BRAF acts as a down-stream effector of growth factor signaling leading to cell cycle progression, proliferation and survival. Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma. Areas covered: Mechanisms of resistance to BRAF inhibitors have recently been described as due to the paradoxical activation of the MAPK pathway. Combination therapy with BRAF and MEK inhibition has proved capable of overcoming the resistance with effective results in patients with melanoma. Prospective studies in pediatric glioma are warranted. Combination therapy has a different toxicity profile compared to BRAF inhibitor alone. Herein we review the state-of-the-art of toxicities associated with these agents, with a special focus on children. Expert opinion: Some toxicities appear more specific to adults, due to a combination of factors, such as patient age and predisposing risk factors. Moreover, it is recommended that the co-administration of BRAF inhibitors and drugs metabolized by the cytochrome P450 system in the liver be avoided, as this can lead to significant complications secondary to pharmacological interactions.

Nerve growth factor improves visual loss in childhood optic gliomas: a randomized, double-blind, phase II clinical trial

Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss. Presently there is no strategy to prevent visual loss in this kind of tumour. This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment. A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients, aged from 2 to 23 years, with stable disease and severe visual loss. Ten patients were randomly assigned to receive a single 10-day course of 0.5 mg murine nerve growth factor as eye drops, while eight patients received placebo. All patients were evaluated before and after treatment, testing visual acuity, visual field, visual-evoked potentials, optic coherence tomography, electroretinographic photopic negative response, and magnetic resonance imaging. Post-treatment evaluations were repeated at 15, 30, 90, and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days. Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days), which were not observed in placebo-treated patients. Furthermore, in patients in whom visual fields could still be measured, visual field worsening was only observed in placebo-treated cases, while three of four nerve growth factor-treated subjects showed significant visual field enlargement. This corresponded to improved visually guided behaviour, as reported by the patients and/or the caregivers. There was no evidence of side effects related to nerve growth factor treatment. Nerve growth factor eye drop administration appears a safe, easy and effective strategy for the treatment of visual loss associated with optic pathway gliomas.

Massive venous thrombosis of inferior vena cava as primary manifestation of renal Ewing's sarcoma

We report an extraordinarily rare case of a 17-year-old male with an extraskeletal Ewings sarcoma (ESS) of the kidney and a massive thrombosis involving the inferior vena cava (IVC), from the iliac axis to the right atrium. This onset resembled renal cell carcinoma (RCC), although histological examination revealed it was an extraskeletal Ewings sarcoma/peripheral neuro-ectodermal tumor (EES/PNET). EES/PNET should benefit from neoadjuvant chemotherapy to reduce the risk of metastasis and of recurrent disease due to delay in suitable treatment. Therefore, in the presence of a renal mass with tumor extension of IVC, it is reasonable to bear in mind that other tumors, apart from RCC, could occur. In such cases, a US or CT-scan guided biopsy could be useful.

Azole interactions with multidrug therapy in pediatric oncology

Patients with cancer receive multidrug therapy. Antineoplastic agents and supportive care drugs are often administered together, leading to potential drug–drug interactions. These interactions may have significant clinical implications in terms of toxicity or a decrease in the efficacy of the treatment administered. Here, we focus on the role of azoles and their main pharmacokinetic interactions with the principal classes of drugs used in pediatric oncology. The co-administration of azoles and antineoplastic agents, corticosteroids, immunosuppressants, antacids, antiemetics, antiepileptic drugs and analgesics was investigated, and a practical guide on the management of these drugs when administered together is provided.

Effective tumour necrosis factor-blocking therapy reduces reactive oxygen metabolite level in rheumatoid arthritis

Objective To assess circulating levels of derived reactive oxygen metabolites (ROMs) in patients with active rheumatoid arthritis (RA), before and during antitumour necrosis factor (TNF)-α therapy. Methods Patients with active RA and failed previous treatment with disease-modifying antirheumatic drugs received subcutaneous anti-TNF-α for 52 weeks. Circulating hydrogen peroxide was quantified as a marker of oxidative stress at baseline and at 24 and 52 weeks. Results The study included 40 patients. Circulating dROM levels were significantly reduced compared with baseline after 24 and 52 weeks’ of anti-TNF-α treatment (33.2 ± 10.0 mgH2O2/dl, 29.5 ± 7.0 mgH2O2/dl and 29.3 ± 9.0 mgH2O2/dl, respectively). There was a significant direct correlation between disease activity score and ROM levels. Conclusion TNF-α inhibition can control disease activity and reduce circulating levels of reactive oxygen species in patients with RA.

Gastric adenocarcinoma presenting as thrombotic microangiopathy in a 14-year-old girl

Gastric adenocarcinoma is rare in childhood and often presents with disseminated malignancy at diagnosis due to aspecific symptoms leading to delay in diagnosis. A familial predisposition for gastrointestinal cancer is suggested for the development of this early-onset adenocarcinoma. We report the case of a 14-year-old girl with a familial history of colorectal, liver, and breast cancers affected by metastatic gastric adenocarcinoma, who first presented with thrombotic microangiopathy. Thrombotic microangiopathy as first clinical presentation of metastatic gastric cancer is an exceptional event in childhood and represents a challenge for pediatricians. Gastric adenocarcinoma should be suspected in young patients with a significant familial history and also in the absence of initial specific signs, so as to provide correct diagnosis and appropriate treatment.

Intravenous Immunoglobulin therapy for anti-E hemolytic disease in the newborn.

Anti-E alloimmunisation is a less common cause of haemolytic disease in the newborn (HDN) and is usually associated with mild to moderate clinical manifestations, that are often less severe than anti-D immunisation. Conventional treatments for HDN are phototherapy and exchange transfusion, the latter still representing a high-risk procedure. Currently, intravenous immunoglobulin has been used as alternative treatment for HDN to reduce the need for exchange transfusion, as well as the length of phototherapy and hospitalisation. We report a case of anti-E HDN treated successfully with intravenous immunoglobulin, as adjuvant treatment to phototherapy.