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1.
Pediatr Blood Cancer ; 71(11): e31297, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39217426

RESUMEN

BACKGROUND: The prognosis for patients with central nervous system (CNS) retinoblastoma (RB) (trilateral or stage 4b metastatic RB) treated with high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT) remains poor. The impact of irradiation when administered as part of upfront therapy post HDC-ASCT on treatment outcomes and survival is unknown. METHODS: We performed a retrospective review of all patients with CNS RB (seven stage 4b, eight trilateral, one pineal lesion belonging to methylation group RB) who underwent induction chemotherapy with an intent to proceed to HDC-ASCT at two institutions. RESULTS: Twelve of 16 patients (n = 75%) achieved an objective response to induction chemotherapy, while four patients had progressive/refractory disease; two patients responded to subsequent therapy and proceeded to ASCT, and two patients did not. Seven of 14 patients who underwent HDC-ASCT, received radiotherapy as part of upfront therapy post HDC-ASCT in the form of craniospinal irradiation (CSI) (n = 3), intraventricular radioimmunotherapy (n = 3), or both CSI and intraventricular radioimmunotherapy (n = 1). The Kaplan-Meier estimate of overall survival for these patients was 62.5% at 5 years; no patients developed second malignant neoplasms within the radiation fields. For the seven patients who did not receive radiotherapy, the overall survival was 28.6% at 5 years. CONCLUSIONS: CSI (23.4 Gy) alone or in conjunction with intraventricular RIT may have clinical utility in eliminating persistent MRD post HDC-ASCT, contributing to improved disease-free survival in patients with CNS RB. This treatment strategy merits evaluation in a prospective, multicenter clinical trial for patients with CNS metastatic RB.


Asunto(s)
Irradiación Craneoespinal , Radioinmunoterapia , Retinoblastoma , Trasplante Autólogo , Humanos , Masculino , Femenino , Estudios Retrospectivos , Preescolar , Irradiación Craneoespinal/métodos , Radioinmunoterapia/métodos , Retinoblastoma/terapia , Retinoblastoma/patología , Retinoblastoma/mortalidad , Niño , Lactante , Terapia Combinada , Tasa de Supervivencia , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias de la Retina/terapia , Neoplasias de la Retina/patología , Neoplasias de la Retina/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adolescente , Estudios de Seguimiento , Trasplante de Células Madre , Pronóstico , Quimioterapia de Inducción , Trasplante de Células Madre Hematopoyéticas/métodos
2.
Cell ; 137(6): 1018-31, 2009 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-19524506

RESUMEN

Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRgamma transcription factor and a human-specific RXRgamma consensus binding site, and proliferation required RXRgamma, as well as the cone-specific thyroid hormone receptor-beta2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.


Asunto(s)
Proliferación Celular , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Retinoblastoma/metabolismo , Transducción de Señal , Animales , Supervivencia Celular , Humanos , Ratones , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-myc/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Receptor gamma X Retinoide/metabolismo , Receptores beta de Hormona Tiroidea/metabolismo , Trasplante Heterólogo
3.
Retina ; 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39089006

RESUMEN

PURPOSE: Circulating tumor DNA (ctDNA) in plasma has been identified in many cancers, including retinoblastoma at diagnosis. We have previously shown that with treatment (enucleation or ophthalmic artery chemosurgery (OAC)) all ctDNA disappears; and if there is persistent plasma ctDNA after treatment metastases develop. The purpose of this study was to determine how the ctDNA RB1 variant allele frequency (VAF) changes in patients with retinoblastoma who have delayed treatment. METHODS: Circulating tumor DNA RB1 was detected and VAF was measured at diagnosis and again prior to any intervention at some time later ranging from 2 to 28 days. RESULTS: Four patients with five ctDNA RB1 mutations were detected at diagnosis and VAF was increased on re-evaluation of the same RB1 mutations in ctDNA. CONCLUSION: In this small cohort, every patient (4) and every RB1 mutation (5) plasma level VAF% increased when measured at two time periods before treatment was instituted suggesting that growing tumors demonstrate increasing plasma ctDNA.

4.
Cancer ; 129(20): 3275-3286, 2023 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-37382208

RESUMEN

BACKGROUND: Despite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival. METHODS: A retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti-CTLA-4 and anti-PD-1 therapies. Differences in overall survival were analyzed using Kaplan-Meier analysis. RESULTS: A total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow-up was 19.8 months (range, 2-127 months) and median overall survival was 21.8 months (95% CI, 16.6-31.3). Female sex, anti-CTLA-4, and anti-PD-1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20-0.78), 0.44 (0.20-0.97), and 0.42 (0.22-0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28-7.13) and 2.84 (1.29-6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08-0.56) and 0.04 (0.002-0.26), respectively. CONCLUSIONS: Development of extrahepatic-only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2-fold reductions in risk of death. PLAIN LANGUAGE SUMMARY: Metastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma.


Asunto(s)
Melanoma , Neoplasias de la Úvea , Humanos , Femenino , Ipilimumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Melanoma/tratamiento farmacológico
5.
Ophthalmology ; 130(6): 598-607, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36739981

RESUMEN

PURPOSE: To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value. DESIGN: Retrospective analysis. PARTICIPANTS: Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center. METHODS: Patients' demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome. MAIN OUTCOME MEASURES: Metastasis-free survival (MFS). RESULTS: Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61-6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86-4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P = 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%-62.8%). CONCLUSIONS: Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Asunto(s)
Melanoma , Neoplasias de la Úvea , Humanos , Pronóstico , Estudios Retrospectivos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/metabolismo , Neoplasias de la Úvea/diagnóstico , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/patología , Perfilación de la Expresión Génica/métodos
6.
Pediatr Blood Cancer ; 70(1): e29921, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35934994

RESUMEN

BACKGROUND: Stage 4a metastatic retinoblastoma (RB) is curable with intensive multimodality therapy including myeloablative chemotherapy with autologous stem cell transplant (HDC-ASCT) and involved field radiation therapy (IFRT). To our knowledge, no data exist on the impact of (a) pre-ASCT disease status, and (b) IFRT to sites of metastatic disease post ASCT on survival. PROCEDURE: We retrospectively reviewed patients with stage 4a metastatic RB who underwent induction chemotherapy followed by HDC-ASCT, with or without IFRT, to residual tumor sites at Memorial Sloan Kettering Cancer Center (MSKCC) (n = 24). RESULTS: The degree of postinduction response prior to ASCT did not affect outcome, with 5-year overall survival (OS) of 68% and 86% in patients who achieved complete response (CR) and very good partial response (VGPR)/partial response (PR) prior to ASCT, respectively. IFRT administered post ASCT in patients with possible residual bony metastatic disease increases the likelihood of developing osteosarcoma in the radiation field. CONCLUSION: OS for patients with stage 4a metastatic RB treated with ASCT with VGPR or PR to pretransplant chemotherapy was not significantly different from patients with CR. In addition, IFRT does not seem to be required for bony disease control and increased the likelihood of developing osteosarcoma.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Osteosarcoma , Neoplasias de la Retina , Retinoblastoma , Humanos , Supervivencia sin Enfermedad , Estudios Retrospectivos , Retinoblastoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante Autólogo , Neoplasias de la Retina/terapia , Resultado del Tratamiento
7.
Ophthalmic Plast Reconstr Surg ; 39(6): e182-e183, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37326495

RESUMEN

The authors report the case of a multiple myeloma recurrence isolated to the lacrimal gland. The patient is a 54-year-old man with a medical history of IgA kappa multiple myeloma status post multiple lines of chemotherapy and stem cell transplantation (×2) who was presumed to be without evidence of disease. Six years following the transplant, he presented with a lacrimal gland tumor with a biopsy consistent with multiple myeloma. Systemic disease evaluation at that time, including positron emission tomography scan, bone marrow biopsy, and serum analysis, were negative. To the best of the authors' knowledge, no prior reports exist describing an isolated lacrimal gland recurrence of multiple myeloma with ultrasound and MRI imaging.


Asunto(s)
Neoplasias del Ojo , Trasplante de Células Madre Hematopoyéticas , Aparato Lagrimal , Mieloma Múltiple , Masculino , Humanos , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Aparato Lagrimal/diagnóstico por imagen , Aparato Lagrimal/patología , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias del Ojo/diagnóstico , Neoplasias del Ojo/patología , Recurrencia
8.
Br J Cancer ; 124(7): 1312-1319, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33473166

RESUMEN

BACKGROUND: Increased sarcoma and melanoma risks after hereditary retinoblastoma are well established, whereas less is known about epithelial subsequent malignant neoplasms (SMNs) and risks for multiple (≥2) SMNs. METHODS: Leveraging long-term follow-up and detailed histologic information, we quantified incident SMN risk among 1128 hereditary and 924 nonhereditary retinoblastoma survivors (diagnosed 1914-2006; follow-up through 2016). Standardised incidence ratios (SIRs) compared cancer risk after retinoblastoma relative to the general population. We estimated cumulative incidence accounting for competing risk of death. RESULTS: Hereditary survivors had statistically significantly increased SMN risk (N = 239; SIR = 11.9; 95% confidence interval [CI] 10.4-13.5), with SIRs >80-fold for sarcomas, nasal cavity tumours and pineoblastoma. Significantly increased risks were also observed for melanoma and central nervous system, oral cavity and breast SMNs (SIRs = 3.1-17), but not the uterus, kidney, lung, bladder, pancreas or other types. Cumulative incidence 50 years following hereditary retinoblastoma was 33.1% (95% CI 29.0-37.2) for a first SMN and 6.0% (95% CI 3.8-8.2) for a second SMN. SMN risk was not increased after nonhereditary retinoblastoma (N = 25; SIR = 0.8; 95% CI 0.5-1.2). CONCLUSION: Beyond the established sarcoma and melanoma risks after hereditary retinoblastoma, we demonstrate increased risk for a more limited number of epithelial malignancies than previously suggested. Cumulative incidence estimates emphasise long-term SMN burden after hereditary retinoblastoma.


Asunto(s)
Supervivientes de Cáncer/estadística & datos numéricos , Predisposición Genética a la Enfermedad , Neoplasias Primarias Secundarias/epidemiología , Neoplasias de la Retina/complicaciones , Retinoblastoma/complicaciones , Adulto , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/patología , Pronóstico , Neoplasias de la Retina/genética , Retinoblastoma/genética , Tasa de Supervivencia , Estados Unidos
9.
Invest New Drugs ; 39(2): 426-441, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33200242

RESUMEN

Intraocular retinoblastoma treatment has changed radically over the last decade, leading to a notable improvement in ocular survival. However, eyes that relapse remain difficult to treat, as few alternative active drugs are available. More challenging is the scenario of central nervous system (CNS) metastasis, in which almost no advancements have been made. Both clinical scenarios represent an urgent need for new drugs. Using an integrated multidisciplinary approach, we developed a decision process for prioritizing drug selection for local (intravitreal [IVi], intrathecal/intraventricular [IT/IVt]), systemic, or intra-arterial chemotherapy (IAC) treatment by means of high-throughput pharmacological screening of primary cells from two patients with intraocular tumor and CNS metastasis and a thorough database search to identify clinical and biopharmaceutical data. This process identified 169 compounds to be cytotoxic; only 8 are FDA-approved, lack serious toxicities and available for IVi administration. Four of these agents could also be delivered by IT/IVt. Twelve FDA-approved drugs were identified for systemic delivery as they are able to cross the blood-brain barrier and lack serious adverse events; four drugs are of oral usage and six compounds that lack vesicant or neurotoxicity could be delivered by IAC. We also identified promising compounds in preliminary phases of drug development including inhibitors of survivin, antiapoptotic Bcl-2 family proteins, methyltransferase, and kinesin proteins. This systematic approach may be applied more broadly to prioritize drugs to be repurposed or to identify novel hits for use in retinoblastoma treatment.


Asunto(s)
Descubrimiento de Drogas/organización & administración , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Línea Celular Tumoral , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Infusiones Intraventriculares , Inyecciones Espinales , Inyecciones Intravítreas , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Neoplasias de la Retina/patología , Retinoblastoma/patología
10.
Exp Eye Res ; 204: 108439, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33444583

RESUMEN

The use of intravitreal chemotherapy has revolutionized the treatment of advanced intraocular retinoblastoma, as intravitreal melphalan has enabled difficult-to-treat vitreous tumor seeds to be controlled, leading to many more eyes being saved. However, melphalan hydrochloride (MH) degrades rapidly in solution, increasing logistical complexity with respect to time between medication preparation and administration for intravitreal administration under anesthesia for retinoblastoma. A new propylene glycol-free melphalan (PGFM) formulation has greater stability and could therefore improve access and adoption of intravitreal chemotherapy, allowing more children to retain their eye(s). We compared the efficacy and toxicity of both formulations, using our rabbit xenograft model and clinical patient experience. Three weekly 12.5 µg intravitreal injections of MH or PGFM (right eye), and saline (left eye), were administered to immunosuppressed rabbits harboring human WERI-Rb1 vitreous seed xenografts. Residual live cells were quantified directly, and viability determined by TUNEL staining. Vitreous seeds were reduced 91% by PGFM (p = 0.009), and 88% by MH (p = 0.004; PGFM vs. MH: p = 0.68). All residual cells were TUNEL-positive (non-viable). In separate experiments to assess toxicity, three weekly 12.5 µg injections of MH, PGFM, or saline were administered to non-tumor-bearing rabbits. Serial electroretinography, optical coherence tomography (OCT) and OCT-angiography were performed. PGFM and MH both caused equivalent reductions in electroretinography amplitudes, and loss of retinal microvasculature on OCT-angiography. The pattern of retinal degeneration observed on histopathology suggested that segmental retinal toxicity associated with all melphalan formulations was due to a vitreous concentration gradient-effect. Efficacy and toxicity were assessed for PGFM given immediately (within 1 h of reconstitution) vs. 4 h after reconstitution. Immediate- and delayed-administration of PGFM showed equivalent efficacy and toxicity. In addition, we evaluated efficacy and toxicity in patients (205 eyes) with retinoblastoma vitreous seeds, who were treated with a total of 833 intravitreal injections of either MH or PGFM as standard of care. Of these, we analyzed 118 MH and 131 PGFM monotherapy injections in whom serial ERG measurements were available to model retinal toxicity. Both MH and PGFM caused reductions in electroretinography amplitudes, but with no statistical difference between formulations. Comparing those patient eyes treated exclusively with PGFM versus those treated exclusively with MH, efficacy for tumor control and globe salvage was equivalent (PGFM vs. MH: 96.2% vs. 93.8%, p = 0.56), but PGFM-treated eyes received fewer injections than MH-treated eyes (average 3.2 ± 1.9 vs. 6.4 ± 2.1 injections, p < 0.0001). Taken together, these rabbit experiments and our clinical experience in retinoblastoma patients demonstrate that MH and PGFM have equivalent efficacy and toxicity. PGFM was more stable, with no decreased efficacy or increased toxicity even 4 h after reconstitution. We therefore now use PGFM over traditional MH for our patients for intravitreal treatment of retinoblastoma.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Melfalán/uso terapéutico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Cuerpo Vítreo/patología , Animales , Antineoplásicos Alquilantes/toxicidad , Electrorretinografía , Femenino , Angiografía con Fluoresceína , Humanos , Etiquetado Corte-Fin in Situ , Lactante , Inyecciones Intravítreas , Masculino , Melfalán/toxicidad , Siembra Neoplásica , Preparaciones Farmacéuticas , Conejos , Retina/fisiopatología , Neoplasias de la Retina/patología , Retinoblastoma/patología , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Pediatr Blood Cancer ; 68(2): e28770, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33063942

RESUMEN

Retinoblastoma survivors with a germline RB1 mutation are at elevated risk for secondary (nonocular) malignancy, but their risk for low-grade glioma (LGG) is unknown. We performed a retrospective review of the Memorial Sloan Kettering Cancer Center and the NCI databases that revealed that three of the 837 5-year survivors of hereditary retinoblastoma were diagnosed with an LGG and a fourth patient (but unilateral and without a germline mutation) was identified at another center. Retinoblastoma survivors may be at increased risk for LGG.


Asunto(s)
Glioma/genética , Neoplasias Primarias Secundarias/genética , Neoplasias de la Retina/genética , Proteínas de Unión a Retinoblastoma/genética , Retinoblastoma/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Cerebelo/patología , Femenino , Predisposición Genética a la Enfermedad/genética , Glioma/patología , Humanos , Masculino , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias de la Retina/patología , Neoplasias de la Retina/terapia , Retinoblastoma/patología , Retinoblastoma/terapia , Lóbulo Temporal/patología , Adulto Joven
12.
Pediatr Blood Cancer ; 68(5): e28845, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33355996

RESUMEN

BACKGROUND: This study aimed to identify best practices for treating 13q deletion syndrome (13q-) patients with retinoblastoma in the era of super-selective ophthalmic artery chemosurgery (OAC) and intravitreal injection therapy (IVIT). METHODS: Retrospective study of 21 eyes from 14 patients with retinoblastoma and 13q- who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between May 2006 and May 2020, with a mean follow up of 3.7 years. Ocular survival, patient survival, and treatment toxicities were assessed. RESULTS: Nine of the 12 eyes that underwent OAC/IVIT at MSKCC have been progression free for at least 1 year since their last treatments. Fifteen out of 26 OAC cycles resulted in grade 3-4 hematologic toxicity. There was one death from sepsis in the setting of intravenous chemotherapy (IVC) for metastatic disease that occurred after OAC/IVIT therapy. The 2-year Kaplan-Meier ocular survival estimate for the whole cohort was 75% and for the eyes that received OAC or IVIT at MSKCC 83%. For OAC hematologic toxicities, one platelet transfusion and two filgrastim doses were administered, and one patient was hospitalized for neutropenic fevers. CONCLUSIONS: The majority of 13q- eyes treated with OAC/IVIT-based regimens can be cured, and there were no deaths related to complications from OAC or IVIT. 13q- Patients did have increased risk of systemic treatment complications, even from super-selective chemotherapies. Despite these toxicities, only one patient developed febrile neutropenia, one patient required a blood product transfusion, and two patients received filgrastim for both OAC and IVC complications. PRÉCIS: Children with 13q deletion syndrome with retinoblastoma managed with intra-arterial and intravitreal chemotherapy have excellent patient and ocular survival with acceptable toxicity.


Asunto(s)
Antineoplásicos/administración & dosificación , Trastornos de los Cromosomas/complicaciones , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Deleción Cromosómica , Cromosomas Humanos Par 13 , Femenino , Humanos , Lactante , Infusiones Intraarteriales , Masculino , Neoplasias de la Retina/genética , Retinoblastoma/genética , Estudios Retrospectivos , Resultado del Tratamiento
13.
Pediatr Blood Cancer ; 68(4): e28873, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33501778

RESUMEN

We assessed breast, cervical, and colorectal cancer screening practices in adult retinoblastoma (Rb) survivors and non-Rb controls. We found that most Rb survivors adhered to general population cancer screening recommendations. Rates did not differ among Rb survivors and non-Rb controls, or among survivors by laterality, even though bilateral survivors reported higher levels of concern about future health and cancer risk. Older age, being overweight/obese, and lack of recent contact with medical personnel were independently associated with decreased utilization of Pap smear among female Rb survivors. Future studies are warranted to determine whether these associations might provide an opportunity for intervention.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer , Neoplasias de la Retina/diagnóstico , Retinoblastoma/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Factores de Edad , Anciano , Supervivientes de Cáncer , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Retina/epidemiología , Retinoblastoma/epidemiología , Adulto Joven
14.
Retina ; 41(1): 208-212, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-32106160

RESUMEN

PURPOSE: To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg). METHODS: Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye. RESULTS: Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04). CONCLUSION: Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.


Asunto(s)
Melfalán/administración & dosificación , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Cuerpo Vítreo/patología , Adolescente , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Niño , Preescolar , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Inyecciones Intravítreas , Masculino , Melfalán/efectos adversos , Siembra Neoplásica , Neoplasias de la Retina/diagnóstico , Retinoblastoma/diagnóstico , Estudios Retrospectivos , Resultado del Tratamiento
15.
Ophthalmology ; 127(2): 240-248, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31708274

RESUMEN

PURPOSE: Cutaneous melanoma metastatic to the vitreous is very rare. This study investigated the clinical findings, treatment, and outcome of patients with metastatic cutaneous melanoma to the vitreous. Most patients received checkpoint inhibition for the treatment of systemic disease, and the significance of this was explored. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: Fourteen eyes of 11 patients with metastatic cutaneous melanoma to the vitreous. METHODS: Clinical records, including fundus photography and ultrasound results, were reviewed retrospectively, and relevant data were recorded for each patient eye. MAIN OUTCOME MEASURES: Clinical features at presentation, ophthalmic and systemic treatments, and outcomes. RESULTS: The median age at presentation of ophthalmic disease was 66 years (range, 23-88 years), and the median follow-up from diagnosis of ophthalmic disease was 23 months. Ten of 11 patients were treated with immune checkpoint inhibition at some point in the treatment course. The median time from starting immunotherapy to ocular symptoms was 17 months (range, 4.5-38 months). Half of eyes demonstrated amelanotic vitreous debris. Five eyes demonstrated elevated intraocular pressure, and 4 eyes demonstrated a retinal detachment. Six patients showed metastatic disease in the central nervous system. Ophthalmic treatment included external beam radiation (30-40 Gy) in 6 eyes, intravitreous melphalan (10-20 µg) in 4 eyes, enucleation of 1 eye, and local observation while receiving systemic treatment in 2 eyes. Three eyes received intravitreous bevacizumab for neovascularization. The final Snellen visual acuity ranged from 20/20 to no light perception. CONCLUSIONS: The differential diagnosis of vitreous debris in the context of metastatic cutaneous melanoma includes intravitreal metastasis, and this seems to be particularly apparent during this era of treatment with checkpoint inhibition. External beam radiation, intravitreous melphalan, and systemic checkpoint inhibition can be used in the treatment of ophthalmic disease. Neovascular glaucoma and retinal detachments may occur, and most eyes show poor visual potential. Approximately one quarter of patients demonstrated ocular disease that preceded central nervous system metastasis. Patients with visual symptoms or vitreous debris in the context of metastatic cutaneous melanoma would benefit from evaluation by an ophthalmic oncologist.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias del Ojo/tratamiento farmacológico , Neoplasias del Ojo/secundario , Inmunoterapia/métodos , Melanoma/patología , Melfalán/uso terapéutico , Neoplasias Cutáneas/patología , Cuerpo Vítreo/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven , Melanoma Cutáneo Maligno
16.
Ophthalmology ; 127(11): 1549-1557, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32422154

RESUMEN

PURPOSE: To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. DESIGN: We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. PARTICIPANTS: Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. METHODS: Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. MAIN OUTCOME MEASURES: Diagnosis and mortality from subsequent neoplasm. RESULTS: Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. CONCLUSIONS: This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.


Asunto(s)
Predisposición Genética a la Enfermedad , Guías como Asunto , Neoplasias de la Retina/diagnóstico , Retinoblastoma/diagnóstico , Medición de Riesgo , Estudios de Seguimiento , Salud Global , Humanos , Incidencia , Neoplasias de la Retina/epidemiología , Neoplasias de la Retina/genética , Retinoblastoma/epidemiología , Retinoblastoma/genética , Factores de Riesgo
17.
Pediatr Blood Cancer ; 67(7): e28389, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32386119

RESUMEN

BACKGROUND: Germline retinoblastoma (Rb) survivors are at lifelong risk for developing subsequent malignancies (SMNs). Optimal surveillance modalities are needed to detect SMN at an early stage in this high-risk cohort. We investigated the use of rapid whole-body magnetic resonance imaging (WB-MRI) as a noninvasive screening modality in this cohort. PROCEDURE: WB-MRI was performed in asymptomatic preadolescent, adolescent, or young adult survivors of germline Rb from February 1, 2008 to December 31, 2018 at a tertiary cancer center. We calculated sensitivity and specificity of WB-MRI and rate of false-positive findings requiring additional evaluation. RESULTS: Overall, 110 WB-MRI were performed in 47 germline Rb survivors (51% female; median age at initial WB-MRI: 15.5 years [range 8-25.3]). Patients received 1-10 annual WB-MRI examinations (median: two). Thirteen patients had an abnormal WB-MRI; three findings were deemed to be likely benign and were not evaluated further. Ten patients required dedicated imaging and three required biopsy; two patients were diagnosed with localized high-grade osteosarcoma, while the other eight had benign findings. One patient was diagnosed with secondary osteosarcoma 3 months after normal WB-MRI. In total, there were 96 true negatives, 11 false positives, two true positives, and one false negative. The sensitivity of WB-MRI in this cohort was 66.7% (95% confidence interval [CI], 14.2-96.0) and the specificity was 89.7% (95% CI, 83.6-93.7). CONCLUSIONS: Based on our 10-year experience, surveillance WB-MRI appears to have limited utility as a surveillance modality for SMN in germline Rb survivors. Alternate screening modalities should be investigated.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias de la Retina/terapia , Retinoblastoma/terapia , Imagen de Cuerpo Entero/métodos , Adolescente , Adulto , Supervivientes de Cáncer , Niño , Femenino , Estudios de Seguimiento , Células Germinativas , Humanos , Incidencia , Masculino , Neoplasias Primarias Secundarias/diagnóstico por imagen , Neoplasias Primarias Secundarias/epidemiología , New York/epidemiología , Vigilancia de la Población , Pronóstico , Neoplasias de la Retina/patología , Retinoblastoma/patología , Estudios Retrospectivos , Tasa de Supervivencia , Adulto Joven
18.
Nature ; 514(7522): 385-8, 2014 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-25252974

RESUMEN

Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear. Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.


Asunto(s)
Células Fotorreceptoras Retinianas Conos/metabolismo , Células Fotorreceptoras Retinianas Conos/patología , Proteína de Retinoblastoma/metabolismo , Retinoblastoma/metabolismo , Retinoblastoma/patología , Transformación Celular Neoplásica , Factores de Transcripción E2F/metabolismo , Regulación Neoplásica de la Expresión Génica , Genes de Retinoblastoma/genética , Xenoinjertos , Humanos , Proteína Proto-Oncogénica N-Myc , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Especificidad de Órganos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Retinoblastoma/genética , Proteína de Retinoblastoma/deficiencia , Proteína de Retinoblastoma/genética , Proteína p107 Similar a la del Retinoblastoma/metabolismo , Proteína p130 Similar a la del Retinoblastoma/deficiencia , Proteína p130 Similar a la del Retinoblastoma/metabolismo , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Células Madre/metabolismo , Células Madre/patología
19.
J Pediatr Hematol Oncol ; 42(3): 238-243, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31259824

RESUMEN

We attempted to investigate the potential role for apparent diffusion coefficient (ADC) to diagnose trilateral retinoblastoma (TRb) by retrospectively reviewing brain magnetic resonance images of retinoblastoma patients. Observations: The median ADC measured 620.95 for TRb (n=6) and 1238.5 for normal pineal gland in bilateral retinoblastoma (n=8). Monitoring ADC trends aided in establishing the appropriate diagnoses in 3 patients (2 TRb, 1 benign pineal cyst). Conclusions: Our results provide baseline reference data and describe the importance of downward trending ADC which should prompt consideration of TRb. Unchanged high/nonrestricted values (>1000) may distinguish those with benign pineal tissue and obviate invasive neurosurgical procedures.


Asunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Neuroimagen/métodos , Neoplasias de la Retina/diagnóstico por imagen , Retinoblastoma/diagnóstico por imagen , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias de la Retina/patología , Retinoblastoma/patología , Estudios Retrospectivos
20.
Retina ; 40(4): 758-764, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30633085

RESUMEN

PURPOSE: To evaluate the subfoveal choroidal thickness (SFCT) and vascular architecture in the fellow eyes of patients with circumscribed choroidal hemangioma (CCH). METHODS: In this retrospective observational study, patients were selected from outpatient ophthalmology clinics at the Memorial Sloan Kettering Cancer Center and Vitreous Retina Macula Consultants of New York. Subfoveal choroidal thickness was measured using enhanced depth imaging spectral domain optical coherence tomography from the outer portion of Bruch membrane to the choroidal-scleral interface. Choroidal vascular architecture was qualitatively examined. The main outcome measure was SFCT in fellow eyes of patients with CCH, which was compared with an age- and gender-matched control group. RESULTS: Thirty-one fellow eyes (15 right eyes and 16 left eyes) of patients with CCH (23 males and 8 females) were examined. The fellow eye had a mean SFCT of 361.2 ± 99.9 µm compared with 252.0 ± 77.6 µm in the control group (P < 0.0001). Vascular architecture was disorganized in 13 (42%) fellow eyes and 1 (3%) control eye (P < 0.0001), with no apparent gradient of vessel sizes or discrete choroidal layers. The normal association between older age and a thinner choroid existed in control eyes but not in fellow eyes. Hemangioma thickness measured by ultrasound and the presence of subfoveal fluid in the CCH eye did not correlate with the fellow-eye SFCT. CONCLUSION: In patients with CCH, fellow eyes had thicker SFCT when compared with age- and gender-matched control eyes. Choroidal architecture was often irregular, without segmented vascular layers. These findings suggest that inherent choroidal changes may exist in patients with CCH.


Asunto(s)
Neoplasias de la Coroides/diagnóstico , Coroides/patología , Hemangioma/diagnóstico , Vasos Retinianos/patología , Agudeza Visual , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Angiografía con Fluoresceína/métodos , Estudios de Seguimiento , Fóvea Central/patología , Fondo de Ojo , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodos , Adulto Joven
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