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PURPOSE: To describe the clinical and molecular spectrum of Stargardt disease (STGD) in a cohort of Argentinean patients. METHODS: This retrospective study included 132 subjects comprising 95 probands clinically diagnosed with STGD and relatives from 16 of them. Targeted next-generation sequencing of the coding and splicing regions of ABCA4 and other phenocopying genes (ELOVL4, PROM1, and CNGB3) was performed in 97 STGD patients. RESULTS: We found two or more disease-causing variants in the ABCA4 gene in 69/95 (73%) probands, a single ABCA4 variant in 9/95 (9.5%) probands, and no ABCA4 variants in 17/95 (18%) probands. The final analysis identified 173 variants in ABCA4. Seventy-nine ABCA4 variants were unique, of which nine were novel. No significant findings were seen in the other evaluated genes. CONCLUSION: This study describes the phenotypic and genetic features of STGD1 in an Argentinean cohort. The mutations p.(Gly1961Glu) and p.(Arg1129Leu) were the most frequent, representing almost 20% of the mutated alleles. We also expanded the ABCA4 mutational spectrum with nine novel disease-causing variants, of which eight might be associated with South American natives.
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Importance: Multi-institutional collaborative studies that include large patient populations for the management of retinoblastoma with histopathological risk factors could provide important information for patient management. Objective: To evaluate the implementation of a strategy for the management of nonmetastatic unilateral retinoblastoma in children based on standardized diagnostic and treatment criteria. Design, Setting, and Participants: This single-arm prospective study applied a strategy based on a single-center experience. The setting was a multicenter study in Latin America (Grupo de America Latina de Oncologia Pediatrica [GALOP]). Participants were children with nonmetastatic unilateral retinoblastoma (staged with the International Retinoblastoma Staging System). The study opened on July 1, 2008, and closed on December 31, 2014. Follow-up was updated until June 30, 2017. Interventions: Stage 0 patients (without enucleation) were given conservative therapy without a protocol. Stage I patients (with enucleation and no residual tumor) were divided into a high-risk group (retrolaminar invasion and/or scleral invasion) and a low-risk group (all remaining patients). High-risk children received adjuvant chemotherapy with 4 alternating cycles of regimen 1 (cyclophosphamide [65 mg/kg/d] [plus sodium-2-mercaptoethane sulfonate], idarubicin hydrochloride [10 mg/m2/d], and vincristine sulfate [0.05 mg/kg/d]) and 4 cycles of regimen 2 (carboplatin [500 mg/m2/d, days 1 and 2] and etoposide [100 mg/m2/d, days 1-3]). Low-risk children did not receive adjuvant therapy. Children with buphthalmia received neoadjuvant and adjuvant chemotherapy for a total of 8 cycles. Main Outcomes and Measures: Probability of event-free survival (extraocular relapse and death from any cause were considered events). Results: Among 187 children registered in the study, 175 were evaluable (92 [52.5%] female; median age, 22 months; age range, 3-100 months). Forty-two were stage 0 children, 84 were stage I low-risk children, and 42 were stage I high-risk children; there were 7 children in the buphthalmia group. With a median follow-up of 46 months, the 3-year probability of event-free survival was 0.97 (95% CI, 0.94-0.99), and the probability of overall survival was 0.98 (95% CI, 0.94-1.00). Stage 0 patients had no events, stage I low-risk patients had 1 event (orbital relapse treated with second-line therapy), stage I high-risk patients had 2 events (1 central nervous system relapse and 1 death from sepsis), and the buphthalmia group had 1 event (orbital relapse, followed by central nervous relapse and death). Conclusions and Relevance: Adjuvant therapy may be effective for high-risk unilateral retinoblastoma but is toxic, and neoadjuvant chemotherapy for buphthalmus appears feasible.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Enucleação Ocular , Feminino , Humanos , Hidroftalmia/complicações , Idarubicina/administração & dosagem , Lactente , Masculino , Mesna/administração & dosagem , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias da Retina/mortalidade , Neoplasias da Retina/patologia , Retinoblastoma/mortalidade , Retinoblastoma/patologia , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
BACKGROUND: Few studies were reported from developing countries regarding patient outcome and ocular survival in children with bilateral retinoblastoma treated with chemoreduction compared to external beam radiotherapy (EBRT). PROCEDURE: We undertook a retrospective study of three treatment eras: (1) (1988-1995) n = 68 when EBRT was used as primary conservative therapy; (2) (1995-2003) n = 46 when carboplatin-based systemic chemoreduction was introduced and (3) (2003-2009) (n = 83) when additional periocular chemotherapy was added for advanced tumors and pre-enucleation chemotherapy was given for those with massive buphthalmia. RESULTS: The probability of 5-year disease-free survival was 0.94 (95% confidence interval [CI] 0.91-0.98%) without significant differences among the three eras. Chemoreduction reduced the use of EBRT from 84.6% to 68.7% in eras 1 and 3, respectively (P = 0.008), which was more evident in cases with less advanced disease. Chemoreduction also significantly improved the 5-year probability of preservation of eyes with advanced disease from 0.13 (95% CI 0.04-0.27) during era 1 to 0.49 (95% CI 0.34-0.62) in era 3 (P < 0.0001). Chemoreduction was not associated with changes in the probability of extraocular relapse, which was reduced after the introduction of pre-enucleation chemotherapy. Second malignancies occurred in nine cases, acute myeloid leukemia being the most fatal one. Trilateral retinoblastoma occurred in three cases and all of them had been exposed to chemotherapy. CONCLUSIONS: Chemoreduction reduced the need for EBRT in eyes with less advanced disease and improved the preservation of eyes with advanced disease while its effects on secondary malignancies or trilateral disease remain unclear.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia , Enucleação Ocular , Hidroftalmia/prevenção & controle , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hidroftalmia/diagnóstico , Lactente , Recém-Nascido , Masculino , Prognóstico , Neoplasias da Retina/mortalidade , Retinoblastoma/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Terapia de Salvação , Administração Intravenosa , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Humanos , Injeções Intra-Arteriais , Injeções Intraoculares , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Artéria Oftálmica , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Estudos Retrospectivos , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/uso terapêutico , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Adulto JovemRESUMO
PURPOSE: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI). METHODS: The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan. RESULTS: Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9-138.7] vs. 13.6 ng/mL [5.5-15.3], respectively; P < 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 ng·hour/mL [247.6-347.2] and 48.9 ng·hour/mL [11.8-63.4], respectively; P < 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 ng·hour/mL [6.8-13.4] vs. 18.7 ng·hour/mL [6.3-21.7]; P = 0.54). CONCLUSION: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.
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Artéria Oftálmica/metabolismo , Inibidores da Topoisomerase I/farmacocinética , Topotecan/farmacocinética , Corpo Vítreo/metabolismo , Animais , Área Sob a Curva , Disponibilidade Biológica , Cateterismo , Cromatografia Líquida de Alta Pressão , Infusões Intra-Arteriais , Injeções Intraoculares , Sus scrofaRESUMO
The presenting features of retinoblastoma in developing countries and their correlation with disease stage and patient survival are poorly known and they may be useful as background information for planning early diagnosis initiatives. Therefore, we undertook a retrospective review of 508 patients (467 evaluable, 296 unilateral) treated in Argentina from 1988 to 2008. Patients presented at an older age than reported from high-income countries [mean age 24 mo (range, 0 to 165 mo), 31 mo for unilateral (range, 0 to 165 mo), and 13.3 mo (range, 0 to 62 mo) for bilateral disease]. Leukocoria was the most common presenting sign (n=402, 86%). Strabismus was the only complaint in 25 (5.3%) patients. Forty-two patients (9%) presented with an enlarged eyeball and 37 (7.9%) with a red eye. Retinoblastoma was diagnosed in 22 (4.7%) asymptomatic children. These patients and those with strabismus alone were significantly younger and had a significantly better survival. Children presenting with enlarged eyeballs were significantly older and had significantly lower survival. In multivariable analysis older age and presentation with enlarged eyeballs were independently associated to advanced stage and mortality (P<0.001). Retinoblastoma is diagnosed in later stages in our setting and presentation with eye enlargement and increasing age at diagnosis correlate with worse outcome.
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Neoplasias da Retina/patologia , Retinoblastoma/patologia , Estrabismo/patologia , Adolescente , Argentina , Criança , Pré-Escolar , Países em Desenvolvimento , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Neoplasias da Retina/economia , Neoplasias da Retina/mortalidade , Retinoblastoma/economia , Retinoblastoma/mortalidade , Estudos Retrospectivos , Estrabismo/economia , Estrabismo/mortalidade , Taxa de SobrevidaRESUMO
BACKGROUND: Few prospective studies about the management of unilateral retinoblastoma with pathology risk factors (PRFs) have been published. METHODS: Patients (n = 114) were divided into four groups: Group 1 (initial chemoreduction) (n = 17). Groups 2 and 3, included patients initially enucleated with no, or lower risk PRFs: (n = 65) and with higher risk PRFs (n = 30), respectively. The later included postlaminar optic nerve involvement (PLONI) (n = 23), tumor at resection margin of optic nerve (n = 5) or isolated scleral invasion (n = 2). Group 3 received adjuvant chemotherapy including a total eight cycles of carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. Orbital radiotherapy (45 Gy) was given to patients with invasion to the resection margin. Group 4 included patients with metastatic disease (n = 2). They were given neoadjuvant therapy followed by surgery and high-dose chemotherapy and autologous stem cell rescue. RESULTS: Five-year event-free survival is 0.94 (1 for Group 1, 0.94 for Group 2, 0.96 for Group 3, and 0 for Group 4). Events included. Group 2: Systemic relapse (n = 2) and combined orbital and CNS relapse (n = 1). Relapsing patients had PLONI (n = 2) and isolated focal choroidal invasion (n = 1). Group 3: CNS relapse (n = 1) in a patient with tumor at the resection margin of optic nerve. Group 4: CNS relapse (n = 2). Only one relapsed patient survived. Eight of 17 eyes treated conservatively were preserved. CONCLUSIONS: The survival of patients with unilateral retinoblastoma was excellent and 60% were spared from adjuvant treatment. Our intensive regimen was likely to be effective for prevention of metastasis in patients with higher risk PRFs.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Criança , Pré-Escolar , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos , Recidiva , Reprodutibilidade dos Testes , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/secundário , Retinoblastoma/diagnóstico , Retinoblastoma/secundário , Fatores de Risco , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.
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Antineoplásicos/administração & dosagem , Corioide/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Retina/efeitos dos fármacos , Esclera , Topotecan/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Corioide/metabolismo , Implantes de Medicamento , Epinefrina/administração & dosagem , Poliésteres , Coelhos , Retina/metabolismo , Distribuição Tecidual , Topotecan/farmacocinéticaRESUMO
PURPOSE: To identify the maximum tolerated dose and dose-limiting toxicity of periocular topotecan in patients with relapsed or resistant intraocular retinoblastoma who are facing imminent enucleation. METHODS: For this phase I study, a starting dose of 0.5 mg of periocular topotecan administered through a 25-gauge needle was given with intrapatient escalation at a rate of 0.5 mg/cycle according to toxicity, up to a maximum dose of 2 mg. Two courses separated by 2 weeks were scheduled. Plasma levels of topotecan were measured by high-performance liquid chromatography in patients with available intravenous catheters. RESULTS: Seven eyes of five patients were treated with a total of 14 courses of periocular topotecan. Only mild orbital edema occurred, and grade 1 vomiting developed in the first patient that was controlled with ondansetron for the following courses. Dose-limiting toxicity was not reached and the maximum tolerated dose was set at the target dose of 2 mg (n=5 eyes). Lactone topotecan systemic exposure was lower than 55 ng/mL x h and it correlated linearly with dose in this small cohort. Even though the study was not designed to assess response, one eye was preserved after a partial response, but the remaining six were enucleated, either after a short period of disease stabilization followed by further therapy with other agents in five patients or by rapidly progressive disease in one. CONCLUSIONS: The dose limiting toxicity was not reached. Up to 2 mg of periocular topotecan could be given safely, but further studies are necessary to determine its effect on retinoblastoma (ClinicalTrials.gov number, NCT00460876).
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Antineoplásicos/administração & dosagem , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Topotecan/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Enucleação Ocular , Humanos , Imageamento por Ressonância Magnética , Dose Máxima Tolerável , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/metabolismo , Retinoblastoma/diagnóstico , Retinoblastoma/metabolismo , Tomografia Computadorizada por Raios X , Topotecan/efeitos adversos , Topotecan/farmacocinéticaRESUMO
BACKGROUND: There is little information on the outcome of patients with retinoblastoma and tumor at the resection margin of the optic nerve. PROCEDURE: Retrospective evaluation of three successive prospective protocols. Twenty-six consecutive patients were analyzed (International Staging System-IRSS-stage 2 = 21, stage 3 = 5) from three successive prospective protocols (1988-2006). Patients with stage 2 were enucleated upfront and those with stage 3 had neoadjuvant chemotherapy followed by enucleation and adjuvant therapy. Both groups received adjuvant chemotherapy and orbital radiotherapy after enucleation. Patients in protocol 1 received 1 year of the lower-dose chemotherapy regimen including cyclophosphamide, vincristine and doxorubicin along with intrathecal chemotherapy. Patients of protocols 2 and 3 received a more intense and shorter intravenous regimen including carboplatin and etoposide alternating with cyclophosphamide, idarubicin and vincristine with no intrathecal treatment. The components of protocol 2 and 3 were similar except for the dose of carboplatin which was 10% lower in protocol 3. RESULTS: Thirteen were treated in protocol 1 and 13 in protocols 2 and 3. The probability of event-free survival was 0.70 at 5 years. Events included: CNS relapse = 3, second malignancies = 3, death in complete remission = 2. There were no significant differences in outcome between protocols or stages. Endocrinological disturbances related to the hypothalamus-hypophysis axis were evident in 6/8 patients evaluated. Severe orbital sequelae occurred in 12 cases. CONCLUSIONS: A substantial number of patients with tumor at the resection margin of the optic nerve can be cured with current therapy; however, therapy related sequelae are frequent.