ABSTRACT.Purpose: To report the efficacy and complications of intra-ophthalmic artery melphalan (IAM) for treatment of patients with advanced intra-ocular retinoblastoma. Methods: Patients with newly diagnosed, unilateral, group D retinoblastoma were included in a phase II protocol. Children with relapsed-refractory disease after systemic chemoreduction were later treated under the same guidelines. Melphalan (3-5 mg/procedure) was injected through a 1.2 F microcatheter placed into the ophthalmic artery every 21 days. Results: Eleven patients (12 eyes, eight as primary treatment) received 33 IAM procedures. The phase II protocol closed prematurely because of low accrual. The IAM technique was overall safe and could be performed successfully in 31 of 33 (94%) attempts. After the second administration of IAM, very good partial response was achieved in all treated eyes. With a median follow-up time of 29.5 months (range 6-57), ocular salvage was achieved in 7 of 12 (58%) eyes. No systemic adverse events were observed. Two patients developed diffuse arteriolar sclerosis, hyperpigmentation of the retinal pigment epithelium and partial retinal atrophy after the second IAM. Both eyes were preserved with no tumour activity, good motility and perception of light, 56 and 30 months after the last IAM treatment. Multinucleated macrophages with intracytoplasmic foreign material were found in the choroid and the retina in 2 of 5 enucleated eyes. Conclusion: Our study reports the activity and reproducibility of IAM in advanced retinoblastoma but also underlines the challenges of performing prospective studies on this treatment modality. Toxicity was limited to only ocular vascular events.
Oxcarbazepine (OXC), a 10-keto analogue of carbamazepine, is an antiepileptic drug licensed for the treatment of partial seizures in children and adults, as monotherapy or adjunctive therapy [1]. In humans, OXC is rapidly metabolized in liver to 10-monohydroxy-carbazepine (MHD), its active metabolite. MHD blocks voltage-sensitive sodium channels, stabilizing hyperexcited neuronal membranes, thereby inhibiting repetitive firing and decreasing the propagation of synaptic impulses [2]. Recently, successful use of OXC in the management of disruptive behaviours in autistic patients has also been reported [3].Despite the fact that experience with OXC in the paediatric age is still limited, several observational studies indicate that the drug has a good long-term tolerability profile [4,5]. In clinical practice, the most commonly observed adverse events are rash, fatigue, nausea and somnolence [4]. Only four cases of OXC acute overdose have been reported to date [6][7][8][9], none of them in a paediatric patient. We describe the case of a 13-year-old boy who presented with somnolence after the ingestion of 15 g of OXC, and provide concomitant serum concentrations of both OXC and MHD.A 13-year-old boy (weight 60 kg, height 175 cm) was brought to the Emergency Department by his mother because of accidental ingestion of 250 ml of Trileptal™ suspension (OXC solution, 60 mg l -1 ; Novartis, Barcelona, Spain) 1 h before; he had vomited shortly after the intake. No other drugs had been ingested. The patient had been diagnosed with autism spectrum disorder at the age of 4 years and was receiving risperidone (1 mg three times a day; Risperdal Flas™, Janssen-Cilag, Madrid, Spain) from the age of 10 years, together with behaviour modification. Treatment with OXC (300 mg twice daily) had been implemented 6 months earlier to treat persistent aggression towards others and head banging, with good tolerance to treatment and improvement in his disruptive behaviour.On admission, the patient's vital signs were as follows: blood pressure 105/47; pulse 75 beats min -1 ; respiratory rate 15 breaths min -1 ; haemoglobin saturation while breathing room air, 99%; temperature 36.9°C. He was somnolent (minimal Glasgow Coma Scale 13) but arousable to pain stimuli. Normal tendon and pupillary reflexes were present. Nystagmus and tremor were not observed; gait disturbances were not evaluable. The rest of the physical examination was unremarkable. The ECG was within normal limits (sinus rhythm, QRS 85 ms, and QTc 410 ms), and laboratory testing showed normal values for complete blood count, blood gases, protein and albumin levels, kidney and liver functions, and electrolyte concentrations.
The addition of midostaurin to standard chemotherapy (cytarabine and daunorubicin) has shown significant improvements in the survival of patients with acute myeloid leukemia with the FLT3 mutation (FLT3-AML). The objective of this study was to determine whether this intervention would be cost-effective in Spain. Methods: A partitioned survival model with five health states was developed (diagnosis and induction, complete remission, no complete remission, transplantation and death). A lifetime time horizon and the Spanish National Health System perspective were adopted. During the first three years, permanence in the different health states was determined according to the results of the RATIFY study. In successive years, the death rates of the Spanish population adjusted by a factor to reflect long-term disease-related mortality were used. Utilities were obtained from the literature. Pharmacological costs (first and second line) and the costs of other health resources (hospitalizations, visits and tests) were included. The robustness of the model was evaluated by deterministic and probabilistic sensitivity analyses. Results: The addition of midostaurin resulted in 1.46 life years gained (LYG) and 1.23 quality-adjusted life years (QALY) gained and implied an additional cost of € 47,955, resulting in an incremental cost-effectiveness ratio (ICER) of € 32,854/LYG and an incremental cost-utility ratio of € 38,985/QALY. In the univariate sensitivity analysis, the threshold of € 50,000/QALY was not exceeded in any case; taking into consideration potential discounts of 20-40% in the PVL of midostaurin the ICER would be below € 30,000/QALY, a commonly accepted threshold in Spain. In the probabilistic analysis, when the threshold was € 50,000/QALY, midostaurin was cost-effective in 82.3% of simulations. Conclusion:According to our modeling, midostaurin, in combination with standard chemotherapy, could be an efficient alternative for the treatment of FLT3-AML in Spain.
Mediterranean theileriosis, caused by Theileria annulata, is endemic in Minorca (Balearic Islands, Spain). The present study analyzes the prevalence of piroplasm infections in cattle in Minorca using reverse line blot (RLB) macroarrays, as well as the effect of herd tick control on those prevalence levels. One hundred and nineteen animals from 12 herds were sampled in representative areas of the island. Information was gathered regarding tick control for the animals (frequency and acaricide used) in each herd. More than 87% of the animals were positive for the presence of piroplasm species. Theileria annulata and Theileria buffeli were observed in all sampled herds (mean prevalence 53.3% for T. annulata and 69.75% for T. buffeli). The mean prevalence was 5.7% for Babesia bigemina. A significantly higher prevalence of Theileria spp. was observed in herds that grazed in, or near, forested areas. Theileria annulata prevalence was significantly lower in herds that followed tick control and was related to the frequency of the applied treatments. Theileria buffeli and B. bigemina prevalences were not affected by tick control for the herds. The results indicate that despite tick control, Mediterranean theileriosis remains endemic in Minorca. Adequate control measures and vaccination approaches are required to improve the situation of Mediterranean theileriosis on the island.
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