Filomena Pierri

Platinum compounds in children with cancer: toxicity and clinical management

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.

Safety and efficacy of propofol administered by paediatricians during procedural sedation in children.

The aim of this study was to determine the safety and the efficacy of paediatrician‐administered propofol in children undergoing different painful procedures.

Comparison of propofol versus propofol-ketamine combination in pediatric oncologic procedures performed by non-anesthesiologists.

Limited data are available on the best option (short acting sedatives, opioids, or ketamine) in oncologic procedural sedation performed by non‐anesthesiologists. The aim of the present prospective study is to compare the safety and efficacy of propofol–ketamine versus propofol alone, managed by trained pediatricians, in children with cancer undergoing painful procedures.

Topical nerve growth factor as a visual rescue strategy in pediatric optic gliomas: a pilot study including electrophysiology.

Background. To date, no specific therapy is available for optic glioma (OG)–induced visual loss. Objective. To evaluate the effects on visual function of murine nerve growth factor (NGF) eye drop administration in children with severe visual impairment due to low-grade OGs. Methods. Five patients with OGs and advanced optic nerve atrophy were assessed before and after a single 10-day course of 1 mg murine NGF topical administration by clinical evaluation, visual evoked potentials (VEPs), and brain magnetic resonance imaging (MRI). VEPs, the main functional outcome measure, were recorded at baseline and 1, 30, 45, 90, and 180 days posttreatment. MRI examinations were performed at baseline and at 180 days after NGF treatment. Six untreated control patients with OGs also underwent serial VEPs, clinical testing, and MRI assessments. Results. After NGF treatment, median VEPs amplitude showed a progressive increase from the baseline values (P < .01). VEPs reached a maximum amplitude at 90 days (170% increase) and declined at 180 days, still remaining above the baseline level. Perception of spontaneous visual phosphenes was noted in all patients after NGF administration. MRI showed stable tumor size. In controls, clinical findings and VEPs did not show any significant change over the observation period. Conclusions. The findings from the study show that NGF administration may be an effective and safe adjunct therapy in children with optic atrophy due to OGs. The beneficial effect on optic nerve function suggests a visual rescuing mechanism exerted by murine NGF on the residual viable optic pathways.

New insights into the molecular mechanisms underlying sensitivity/resistance to the atypical retinoid ST1926 in acute myeloid leukaemia cells: the role of histone H2A.Z, cAMP-dependent protein kinase A and the proteasome.

ST1926 is an atypical retinoid and a promising anti-tumour agent with selective apoptotic activity on the leukaemic blast. The anti-tumour activity of the compound has been associated with its capacity to induce DNA double stranded breaks. Target profiling by affinity chromatography coupled to mass spectrometry led to the identification of histone H2A.Z as a protein capable of binding ST1926 specifically. The result was confirmed by studies involving Surface Plasmon Resonance (SPR). This indicates that H2A.Z is a primary target of ST1926 and links the perturbations of the histone pathway observed by microarray analysis to the DNA damage and apoptotic responses caused by the atypical retinoid. Comparison of the whole-genome gene-expression profiles of the ST1926-sensitive NB4 and the ST1926-resistant NB4.437r cell lines demonstrated differential expression of numerous genes. Network analysis of the data indicated enrichment of the cellular pathways controlling cAMP (cyclic adenosine-monophosphate)-dependent signal transduction, proteasome-dependent protein degradation and nuclear histones in NB4.437r cells. Pharmacological inhibition of cAMP-dependent protein kinase A with H89 partially reverted resistance of NB4.437r cells to ST1926. Conversely, inhibition of the proteasome with MG132 or bortezomib blocked the apoptotic response afforded by ST1926 in the NB4 cell line. This last effect was associated with a dramatic reduction in the DNA damage caused by the atypical retinoid. The results corroborate the idea that DNA damage is an important determinant of ST1926 apoptotic activity. More importantly, they demonstrate a proactive role of the proteasome in the DNA damaging and ensuing apoptotic response observed upon the challenge of acute myeloid leukaemia cells with ST1926.

Nerve Growth Factor Eye Drop Administration Improves Visual Function in a Patient With Optic Glioma

Background. Spontaneous visual improvement in people with an optic glioma (OG) of the anterior or retrochiasmatic optic pathways is rare. Objective. To evaluate the effects on visual function of nerve growth factor (NGF) eye drop administration in a patient with severe visual impairment due to a low-grade OG. Methods. A 45-year-old woman with OG and long-standing optic nerve atrophy was assessed before and after 2 NGF treatment courses. The drug used was 2.5S murine NGF. One milligram of NGF, diluted in saline solution, was administered onto the conjunctiva of both eyes for 10 consecutive days 3 times a day for each treatment. The follow-up was performed by clinical, neuroradiologic, and electrophysiological tests (electroretinogram and visual evoked potentials [VEPs]) at the end of each treatment and 30 and 60 days later. Results. A repeated subjective and objective improvement of visual function (>3 lines visual acuity; >40° visual field; >50% VEP amplitude increase, Wilcoxon test P < .01) was recorded after NGF treatment. These measures tended to deteriorate toward baseline values 60 days from the end of each NGF treatment. No ocular or systemic side effects were observed throughout treatment. Conclusions. Conjunctival NGF may be a beneficial adjunct therapy for visual loss in patients with OG, possibly exerting its effects on residual viable optic pathways.

Brachiocephalic vein for percutaneous ultrasound-guided central line positioning in children: A 20-month preliminary experience with 109 procedures

Ultrasound‐guided (USG) cannulation of the brachiocephalic vein (BCV) is gaining worldwide consensus for central venous access in children. This study reports a 20‐month experience with this approach in children.

Enhanced cell cycle perturbation and apoptosis mediate the synergistic effects of ST1926 and ATRA in neuroblastoma preclinical models

SummaryRetinoic acid therapy is nowadays an important component of treatment for residual disease of stage IV neuroblastoma after multimodal therapy. Nevertheless, arising resistance and treatment toxicity could represent relevant limiting factors. In the present study, we show that retinoic acid enhances the cytostatic and apoptogenic properties of the novel adamantyl retinoid ST1926 in a panel of neuroblastoma cells with different p53 status and caspase 8 expression, resulting in synergistic effects as assessed by Combination Index and Isobologram analysis. Under conditions where the two drugs alone produced no toxic effects, their combination resulted in enhanced G2-M arrest and sub-G1 population as shown by BrdU pulse-chase and labeling experiments. PARP cleavage, caspase 3, 8 and 9 activation and modulation of DR4 and FAS were indicative of enhanced apoptosis triggered by the co-incubation of the two drugs whereas neither ST1926-mediated genotoxic damage nor ATRA-differentiating effects were affected by the combined treatment. Caspase-3 and 8-mediated apoptosis appeared to play an important role in the drugs synergism. In fact, the addition of a pan-caspase inhibitor ZVAD-FMK reverted this effect in SK-N-DZ cells, and synergism was confined to limited drugs doses in HTLA cells not expressing caspase-8. Although not modulated, p53 appeared to enhance cells responsiveness to retinoid/ATRA combination. In vivo studies in the most sensitive neuroblastoma model SK-N-DZ, confirmed enhanced activity of the drugs combination vs single treatments. The study provides important lines of evidence that such a drugs combination could represent a less toxic and more effective approach for maintenance treatment in children with neuroblastoma.

Neuroprotective role of nerve growth factor in hypoxic-ischemic injury. From brain to skin

Hypoxic-ischemic injuries (HII) of the brain, optic pathways, and skin are frequently associated with poor neurological and clinical outcome. Unfortunately, no new therapeutic approaches have been proposed for these conditions. Recently, experimental and clinical studies showed that nerve growth factor (NGF) can improve neurological deficits, visual loss and skin damage after HII. Based on these studies, we report the effects of NGF administration in different lesions of the brain, optic pathways and skin. 2.5S NGF purified and lyophilized from male mouse submaxillary glands was utilized for the treatment. NGF administration was started in absence of recovery after conventional and standardized treatment. One mg NGF was administered via the external catheter into the brain, by drop administration in the eye, and by subcutaneous administration in the skin. We treated 4 patients: 2 children with hypoxic-ischemic brain damage, an adult patient with an optic glioma-induced visual loss and a child with a severe crush syndrome of the lower left limb. After NGF treatment, we observed an amelioration of both neurological and electrophysiological function of the brain, a subjective and objective improvement of visual function, and a gradual improvement of ischemic skin lesion. No side effects were related to NGF treatment in all patients studied. Our observation shows that NGF administration may be an effective and safe adjunct therapy in patients with severe HII. The beneficial and prolonged effect on nerve function suggests a neuroprotective mechanism exerted by NGF on the residual viable neurological pathways of these patients.

Spontaneous Pneumomediastinum, Pneumopericardium and Pneumorrhachis as potential complications of 2009 pandemic influenza A (H1N1) virus infection in healthy children

We report on two cases of spontaneous pneumomediastinum and pneumopericardium, in one case associated with pneumorrhachis, occurring in two children suffering from the novel influenza H1N1 virus infection. At the admission both children presented with fever, violent dry cough, dyspnea and tachypnea. Radiological studies showed sizeable pneumomediastinum and pneumopericardium in both patients. One of the patients also a pneumorrachis. Children were initially treated by intravenous broad-spectrum antibiotics, antipyretics and a cough sedative. Oral Oseltamivir (60 mg twice daily for 5 days) was administered after the diagnosis of influenza A (H1N1) virus infection. Patients’ clinical condition quickly improved and children were discharged with a partial resolution of their radiological findings. Although these conditions are usually self-limiting and without respiratory or systemic consequences, their prompt recognition in children with H1N1 influenza virus infection is essential to establish fast and adequate therapy mainly related to the control of cough and the commencement of antiviral treatment.