Feasibility and results of an intraarterial chemotherapy program for the conservative treatment of retinoblastoma in Argentina.

BACKGROUND: The feasibility and results of intraarterial chemotherapy, also termed ophthalmic artery chemosurgery (OAC), for retinoblastoma in less developed countries have seldom been reported. PROCEDURE: A retrospective evaluation of a program of OAC in Argentina from 2010 to 2015. RESULTS: Ninety-seven eyes from 81 patients (61 bilateral) were analyzed. In 35 eyes, OAC was given as primary therapy and in 62 it was used for the treatment of tumors with partial response or those relapsing after systemic chemoreduction with focal therapy or external-beam radiotherapy. Twenty-two primarily treated eyes had group D and 13 groups B/C. A total of 400 procedures were carried out. Chemotherapy used included combinations of melphalan, carboplatin, and topotecan. There was no mortality associated with OAC. Toxicity included fever and neutropenia in five (1.25%), hypotension and bradycardia during anesthesia in two and femoral thrombosis in one, eyelid edema in nine, and neutropenia or thrombocytopenia in 28 cycles. With a median follow-up of 48.7 months (range 12-79), the 3-year probability of event-free survival (pEFS) (enucleation and/or radiotherapy were considered events) was comparable for patients who received first-line therapy and those treated at relapse (0.65 vs. 0.63, P = 0.5). In the former, the pEFS was 0.91 and 0.43 for groups B/C and D, respectively (P = 0.01). Two patients died of extraocular dissemination after refusal of enucleation. CONCLUSIONS: OAC was feasible with low toxicity. pEFS improved in all groups compared to the previous experience with systemic chemotherapy reducing the use of radiotherapy. The overall mortality associated with OAC is comparable to our previous experience with systemic chemoreduction.

Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma.

PURPOSE: To assess the antitumor activity, toxicity, and plasma pharmacokinetics of the combination of melphalan and topotecan for superselective ophthalmic artery infusion (SSOAI) treatment of children with retinoblastoma. DESIGN: Single-center, prospective, clinical pharmacokinetic study. PARTICIPANTS: Twenty-six patients (27 eyes) with intraocular retinoblastoma. METHODS: Patients with an indication for SSOAI received melphalan (3-6 mg) and topotecan (0.5-1 mg; doses calculated by age and weight). Plasma samples were obtained for pharmacokinetic studies, and a population approach via nonlinear mixed effects modeling was used. Safety and efficacy were assessed and compared with historical cohorts of patients treated with melphalan single-agent SSOAI. MAIN OUTCOME MEASURES: Melphalan and topotecan pharmacokinetic parameters and efficacy and safety parameters. RESULTS: Twenty-seven eyes from 26 consecutive patients received 66 cycles of SSOAI melphalan and topotecan in combination. All 5 eyes treated as primary therapy responded to the combination chemotherapy and were preserved. Sixteen of the 22 eyes with relapsed or resistant tumors responded, but 3 of them ultimately underwent enucleation at a median of 8 months (range, 7.9-9.1 months). The incidence of grade III and IV neutropenia was 10.6% and 1.5%, respectively, which was comparable with historical controls of single-agent SSOAI melphalan. No episode of fever neutropenia was observed, and no patient required transfusion of blood products. The large variability in melphalan pharmacokinetics was explained by body weight (P <0.05). Concomitant topotecan administration did not influence melphalan pharmacokinetic parameters. There was no effect of the sequence of melphalan and topotecan administration in plasma pharmacokinetics. CONCLUSIONS: A regimen combining melphalan and topotecan for SSOAI treatment of retinoblastoma is active and well tolerated. This combination chemotherapy previously showed synergistic pharmacologic activity, and we herein provide evidence of not increasing the hematologic toxicity compared with single-agent melphalan.

Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma.

BACKGROUND: Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients. PATIENTS AND METHODS: Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy. RESULTS: No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42-0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications. CONCLUSIONS: IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile.

Aneurismas cerebrales en la infancia: un solo nombre para diferentes enfermedades / Cerebral aneurysms in infancy: a name for different diseases

Objetivo. Resaltar la heterogeneidad de los aneurismas cerebrales en la población pediátrica. Material y método. 19 pacientes con 20 aneurismas intracraneanos fueron tratados en nuestro Hospital en los ultimos 6 años.Resultados. La edad media fue de 12 años (rango 10 meses a 17 años). 65 %de los aneurismas fueron saculares, 25% fusiformes, hubo un aneurisma infeccioso y otro lenticuloestriado distal. Los pacientes con aneurismas saculares fueron predominantemente varones y se manifestaron más comúnmente con hemorragia intracraneana (92%). Los aneurismas fusiformes se originaron posteriormente a una disección o fueron crónicos con trombo mural y ejerciendo efecto de masa. La terapéutica fue diferente según el tipo aneurismático. Conclusión. Los aneurismas pediátricos son un grupo heterogéneo de enfermedades arteriales intracraneanas con manifestaciones clínicas, morfología y terapéutica diferentes.

Aneurismas cerebrales en la infancia: un solo nombre para diferentes enfermedades / Cerebral aneurysms in infancy: a name for different diseases

Objetivo. Resaltar la heterogeneidad de los aneurismas cerebrales en la población pediátrica. Material y método. 19 pacientes con 20 aneurismas intracraneanos fueron tratados en nuestro Hospital en los ultimos 6 años.Resultados. La edad media fue de 12 años (rango 10 meses a 17 años). 65 %de los aneurismas fueron saculares, 25% fusiformes, hubo un aneurisma infeccioso y otro lenticuloestriado distal. Los pacientes con aneurismas saculares fueron predominantemente varones y se manifestaron más comúnmente con hemorragia intracraneana (92%). Los aneurismas fusiformes se originaron posteriormente a una disección o fueron crónicos con trombo mural y ejerciendo efecto de masa. La terapéutica fue diferente según el tipo aneurismático. Conclusión. Los aneurismas pediátricos son un grupo heterogéneo de enfermedades arteriales intracraneanas con manifestaciones clínicas, morfología y terapéutica diferentes.(AU)

Cerebral aneurysms in children: are we talking about a single pathological entity?

PURPOSE: The objective of this article is to highlight the fact that cerebral aneurysms in children are heterogeneous unlike in the adult population. MATERIAL AND METHODS: This is a retrospective review of 17 children with intracranial aneurysms who were managed at a single institution from 2004 to 2009. RESULTS: The median age was 12 years (range 10 months-17 years). Sixty-five percent of the aneurysms were saccular and 24% were fusiform. There was one infectious and one distal lenticulostriate aneurysm. Patients with saccular aneurysms were predominantly male and presented more commonly with intracranial hemorrhage (91%). The fusiform aneurysms were dissecting in nature or chronic with intramural thrombus and mass effect. The treatment was dependent upon the type and location of the aneurysm. CONCLUSION: Pedriatic aneurysms are a heterogeneous group of intracranial arterial diseases with different etiologies, diverse morphology, and dissimilar clinical manifestations.

Neurosurgical vascular malformations in children under 1 year of age.

PURPOSE: This study aims to analyze the clinical and radiological findings, timing and type of treatment, and outcome in children under 1 year of age that presented with neurosurgical vascular malformations. METHODS: A retrospective review of 23 children under 1 year of age with neurosurgical vascular malformations was performed at a single institution between 1999 and 2009. RESULTS: The lesions found in this age group were: 10 vein of Galen aneurysmal malformations (VGAMs), 5 arteriovenous malformations (AVM), 2 pial arteriovenous fistulas (AVF; 1 in the brain and 1 in the spinal cord), 2 cavernous malformations, 2 dural sinus malformations (DSMs) in the posterior fossa with negative angiography which after surgery turned out to be embryonal malformations of dural sinuses, 1 sacular aneurysm, and 1 dural arteriovenous fistula (DAVF) that drained toward the vein of Galen. Of the 10 patients with VGAM, 8 presented choroidal type and 2 mural type. Two patients with choroidal VGAM were born in dramatically severe clinical condition; therefore, we decided to withhold aggressive treatment, and they died within 48 h after birth. The other eight patients with choroidal VGAM received endovascular treatment between 1 and 3 staged embolizations. In four of them, total occlusion was achieved and subtotal and partial in the others. One patient had complications and evolved with severe developmental delay. Another patient with partial occlusion died, and another patient with previous developmental delay stopped treatment because of parental decision making. Five patients evolved with normal development and one with mild delay. Only one patient required shunt. Hydrocephalus was solved after endovascular treatment in the rest of the patients. Regarding the five AVMs, four were treated with microsurgical approach achieving total resection of the lesion and normal developmental milestones except for one patient with brainstem AVM that was admitted with quadriparesis and coma. In the patient with basal ganglia AVM, the lesion spontaneously disappeared. From the two pial AVFs, the frontal one was microsurgically treated and the spinal one received endovascular session achieving 50% of lesion occlusion for which further treatment is needed. The two cavernous malformations were operated achieving total resection with normal development. The two children with DSM received surgical resection without complications and normal development. The rare case of sacular aneurysm at this age was occluded at the time of diagnostic procedure due to the bad clinical condition of the patient and the hematoma was removed immediately in the operating room. The only case of DAVF died of respiratory intercurrence after three sessions of endovascular treatment. CONCLUSIONS: In this neonatal age group (first year of life), we can find the whole range of neurosurgical vascular pathology: VGAM, AVM, cavernous malformation, DSM, pial AVF, DAVF, and sacular aneurysm. VGAM is the most frequent vascular malformation during the first year of age. The early treatment of vascular malformations prevents its adverse effects on a developing brain. A multidisciplinary team composed by endovascular and surgical specialists is necessary to discuss and treat each case.

Patología vascular en pacientes menores de un año / Cerebrovascular pathology in infants

Objetivo. Analizar nuestra experiencia en patología neuroquirúrgica vascular en los pacientes menores de un año.Material y método. Entre el 1/1/89 y el 1/6/09 se trataron en el Servicio de Neurocirugía del Hospital Nacional de Pediatría Juan P. Garrahan 235 pacientes con malformación vascular del SNC. De ellos 19 (8%) eran menores de un año;11 fueron varones y 8 mujeres, con una edad media de 4,5 meses al diagnóstico, en un rango desde prenatal a 1 año. Se analizaron las historias clínicas y los estudios neurradiológicos de cada uno de ellos.Resultados. Todos los pacientes fueron estudiados con TAC inicial excepto las malformaciones aneurismáticas de la vena de Galeno (MAVG) que se diagnosticaron en un principio, con ecografía. En 16/19 pacientes se realizó angiografía digital cerebral, y en uno de los casos se efectuó angiografía espinal, hallándose la malformación a ese nivel. Los tipos de lesiones halladas fueron: 6 MAVG (4 coroideas y 2 murales), 6 malformaciones arteriovenosas (MAV), 2 fístulas arteriovenosas (A-V) piales (1 cerebral y 1 medular), 1 fístula A-Vmedular, 1 cavernoma, 1 aneurisma sacular y 2 malformaciones embrionarias en fosa posterior. Conclusión. Es remarcable la variabilidad y complejidad de las malformaciones vasculares del SNC en el primer año de vida. Es necesaria la integración del equipo endovascular al neuroquirúrgico, no sólo para el diagnóstico, sino también para completar o facilitar el tratamiento de alguna de estas lesiones. Las malformaciónes vasculares más frecuentes en este grupo son la MAVG y las MAV , seguidas de las fístulas A-V.

Objective. To analyze our experience in neurosurgical vascular disease in patients under one year. Materials and Methods. Between 1/1/89 and 1/6/09 we treated at the Department of Neurosurgery of the Hospital Nacional de Pediatría Juan P. Garrahan 235 patients with vascular malformation of the central nervous system. Of these19 (n = 19; 8%) were infants under one year, 11 were males and 8 females, mean age at diagnosis 4.5 months (range from prenatal to 1 year). We evaluated all charts and neuroradiologic studies of each patient. Results. All patients were studied with initial CT scan except one patient with Vein of Galen Aneurysmal Malformation (VGAM)who was diagnosed antenatal by ultrasound. The types of lesions were 6 VGAM (4 choroidal type and 2 mural type), 6 Arteriovenous Malformations (AVM), 2 Pial Arteriovenous Fistulas(1 brain and 1 spinal), 1 spinal Dural Arteriovenous Fistula, 1 Cavernoma, 1 Aneurysm and 2 Embryologic Dural Sinus Malformations at the posterior fossa. Conclusion. It is remarkable variability and complexity ofvascular malformations of the central nervous system in the first year of life. It is necessary to integrate the endovascular neurosurgical team, not only for diagnosis but also to complement or facilitate the treatment of any of theses vascular disease. The most frequent vascular malformations in our group were the VGAM and the AVM followed by AV Fistulas.

Patología vascular en pacientes menores de un año / Cerebrovascular pathology in infants

Objetivo. Analizar nuestra experiencia en patología neuroquirúrgica vascular en los pacientes menores de un año.Material y método. Entre el 1/1/89 y el 1/6/09 se trataron en el Servicio de Neurocirugía del Hospital Nacional de Pediatría Juan P. Garrahan 235 pacientes con malformación vascular del SNC. De ellos 19 (8%) eran menores de un año;11 fueron varones y 8 mujeres, con una edad media de 4,5 meses al diagnóstico, en un rango desde prenatal a 1 año. Se analizaron las historias clínicas y los estudios neurradiológicos de cada uno de ellos.Resultados. Todos los pacientes fueron estudiados con TAC inicial excepto las malformaciones aneurismáticas de la vena de Galeno (MAVG) que se diagnosticaron en un principio, con ecografía. En 16/19 pacientes se realizó angiografía digital cerebral, y en uno de los casos se efectuó angiografía espinal, hallándose la malformación a ese nivel. Los tipos de lesiones halladas fueron: 6 MAVG (4 coroideas y 2 murales), 6 malformaciones arteriovenosas (MAV), 2 fístulas arteriovenosas (A-V) piales (1 cerebral y 1 medular), 1 fístula A-Vmedular, 1 cavernoma, 1 aneurisma sacular y 2 malformaciones embrionarias en fosa posterior. Conclusión. Es remarcable la variabilidad y complejidad de las malformaciones vasculares del SNC en el primer año de vida. Es necesaria la integración del equipo endovascular al neuroquirúrgico, no sólo para el diagnóstico, sino también para completar o facilitar el tratamiento de alguna de estas lesiones. Las malformaciónes vasculares más frecuentes en este grupo son la MAVG y las MAV , seguidas de las fístulas A-V.(AU)

Objective. To analyze our experience in neurosurgical vascular disease in patients under one year. Materials and Methods. Between 1/1/89 and 1/6/09 we treated at the Department of Neurosurgery of the Hospital Nacional de Pediatría Juan P. Garrahan 235 patients with vascular malformation of the central nervous system. Of these19 (n = 19; 8%) were infants under one year, 11 were males and 8 females, mean age at diagnosis 4.5 months (range from prenatal to 1 year). We evaluated all charts and neuroradiologic studies of each patient. Results. All patients were studied with initial CT scan except one patient with Vein of Galen Aneurysmal Malformation (VGAM)who was diagnosed antenatal by ultrasound. The types of lesions were 6 VGAM (4 choroidal type and 2 mural type), 6 Arteriovenous Malformations (AVM), 2 Pial Arteriovenous Fistulas(1 brain and 1 spinal), 1 spinal Dural Arteriovenous Fistula, 1 Cavernoma, 1 Aneurysm and 2 Embryologic Dural Sinus Malformations at the posterior fossa. Conclusion. It is remarkable variability and complexity ofvascular malformations of the central nervous system in the first year of life. It is necessary to integrate the endovascular neurosurgical team, not only for diagnosis but also to complement or facilitate the treatment of any of theses vascular disease. The most frequent vascular malformations in our group were the VGAM and the AVM followed by AV Fistulas.(AU)

Synthesis and pharmacology of isoquinuclidine derivatives as 5-HT(3) ligands.

A series of 4-amino-5-chloro-2-methoxybenzoates and benzamides containing the 5- and 6-isoquinuclidinyl system was synthesised and evaluated for binding to 5-HT(3), 5-HT(4) and D(2) receptors. In general, the isoquinuclidine derivatives at the 5-position have shown to be more potent as 5-HT(3) ligands but they also possess 5-HT(4) and D(2) properties. However, the results show that the derivatives at the 6-position afforded the most promising compounds in terms of both receptor affinity and selectivity.