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1.
Clin Cancer Res ; 25(24): 7303-7311, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811016

RESUMO

PURPOSE: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. PATIENTS AND METHODS: Patients ages 1 to <18 years who had BRAF V600-mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. RESULTS: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26-62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64-94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). CONCLUSIONS: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600-mutant pLGG.

2.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065

RESUMO

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
3.
Palliat Support Care ; : 1-10, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31699178

RESUMO

OBJECTIVES: Retinoblastoma is the most common primary intraocular tumor of childhood with >95% survival rates in the US. Traditional therapy for retinoblastoma often included enucleation (removal of the eye). While much is known about the visual, physical, and cognitive ramifications of enucleation, data are lacking about survivors' perception of how this treatment impacts overall quality of life. METHODS: Qualitative analysis of an open-ended response describing how much the removal of an eye had affected retinoblastoma survivors' lives and in what ways in free text, narrative form. RESULTS: Four hundred and four retinoblastoma survivors who had undergone enucleation (bilateral disease = 214; 52% female; mean age = 44, SD = 11) completed the survey. Survivors reported physical problems (n = 205, 50.7%), intrapersonal problems (n = 77, 19.1%), social and relational problems (n = 98, 24.3%), and affective problems (n = 34, 8.4%) at a mean of 42 years after diagnosis. Three key themes emerged from survivors' responses; specifically, they (1) continue to report physical and intrapersonal struggles with appearance and related self-consciousness due to appearance; (2) have multiple social and relational problems, with teasing and bullying being prominent problems; and (3) reported utilization of active coping strategies, including developing more acceptance and learning compensatory skills around activities of daily living. SIGNIFICANCE OF RESULTS: This study suggests that adult retinoblastoma survivors treated with enucleation continue to struggle with a unique set of psychosocial problems. Future interventions can be designed to teach survivors more active coping skills (e.g., for appearance-related issues, vision-related issues, and teasing/bullying) to optimize survivors' long-term quality of life.

4.
Clin Cancer Res ; 25(24): 7294-7302, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31506385

RESUMO

PURPOSE: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers. PATIENTS AND METHODS: This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target. RESULTS: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily. CONCLUSIONS: In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31259824

RESUMO

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.

6.
Lancet Oncol ; 20(7): 1011-1022, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31151904

RESUMO

BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients. METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported. INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1. FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

7.
J Neurooncol ; 143(1): 79-86, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810873

RESUMO

BACKGROUND AND PURPOSE: Baseline diffusion or apparent diffusion coefficient (ADC) characteristics have been shown to predict outcome related to DIPG, but the predictive value of post-radiation ADC is less well understood. ADC parametric mapping (FDM) was used to measure radiation-related changes in ADC and compared these metrics to baseline ADC in predicting progression-free survival and overall survival using a large multi-center cohort of DIPG patients (Pediatric Brain Tumor Consortium-PBTC). MATERIALS AND METHODS: MR studies at baseline and post-RT in 95 DIPG patients were obtained and serial quantitative ADC parametric maps were generated from diffusion-weighted imaging based on T2/FLAIR and enhancement regions of interest (ROIs). Metrics assessed included total voxels with: increase in ADC (iADC); decrease in ADC (dADC), no change in ADC (nADC), fraction of voxels with increased ADC (fiADC), fraction of voxels with decreased ADC (fdADC), and the ratio of fiADC and fdADC (fDM Ratio). RESULTS: A total of 72 patients were included in the final analysis. Tumors with higher fiADC between baseline and the first RT time point showed a trend toward shorter PFS with a hazard ratio of 6.44 (CI 0.79, 52.79, p = 0.083). In contrast, tumors with higher log mean ADC at baseline had longer PFS, with a hazard ratio of 0.27 (CI 0.09, 0.82, p = 0.022). There was no significant association between fDM derived metrics and overall survival. CONCLUSIONS: Baseline ADC values are a stronger predictor of outcome compared to radiation related ADC changes in pediatric DIPG. We show the feasibility of employing parametric mapping techniques in multi-center studies to quantitate spatially heterogeneous treatment response in pediatric tumors, including DIPG.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Adolescente , Algoritmos , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/radioterapia , Criança , Imagem de Difusão por Ressonância Magnética/métodos , Estudos de Viabilidade , Feminino , Glioma/mortalidade , Glioma/radioterapia , Humanos , Masculino , Ponte , Estudos Retrospectivos , Análise Espaço-Temporal , Análise de Sobrevida , Resultado do Tratamento
8.
Br J Ophthalmol ; 103(9): 1272-1277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30361279

RESUMO

BACKGROUND/AIMS: Enucleation for retinoblastoma is performed less often in the past decade due to increasingly widespread alternative therapies, but enucleation remains an important option. There is a paucity of reports on the current incidence of metastases and metastatic deaths in unilateral retinoblastoma from US centres. METHODS: Retrospective chart review at five tertiary retinoblastoma centres in the USA for unilateral retinoblastoma patients treated with primary enucleation, 2007-2017, with >1 year of follow-up or treatment failure. RESULTS: Among 228 patients (228 eyes), there were nine metastases (3.9%) and four deaths (1.7%). The Kaplan-Meier estimate at 5 years for metastasis-free survival was 96% (95% CI, 94% to 99 %), and for overall survival was 98% (95% CI 96% to 100%). All metastases were evident within 12 months. Histopathology revealed higher risk pathology (postlaminar optic nerve and/or massive choroidal invasion) in 62 of 228 eyes (27%). Of these higher risk eyes, 39 received adjuvant chemotherapy. There were four subsequent metastases in this higher risk pathology with adjuvant chemotherapy group, with three deaths. Of the nine overall with metastases, seven (78%) showed higher risk pathology. All metastatic patients were classified as Reese-Ellsworth V and International Classification of Retinoblastoma Groups D or E. Initial metastases presented as orbital invasion in seven of nine cases. CONCLUSIONS: Primary enucleation for unilateral retinoblastoma results in a low rate of metastatic death, but is still associated with a 3.9% chance of metastases within a year of enucleation. Most but not all patients who developed metastases had higher risk histopathological findings.

9.
Cancer ; 125(6): 963-971, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521100

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.


Assuntos
Sistema Hematopoético/imunologia , Histiocitose de Células de Langerhans/complicações , Fígado/imunologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Baço/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/imunologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Prognóstico , Estudos Retrospectivos , Baço/patologia , Adulto Jovem
10.
Ophthalmol Retina ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31948910

RESUMO

PURPOSE: Magnetic resonance imaging (MRI) has been used for baseline brain imaging and afterward as a screening tool for trilateral retinoblastoma (TRB), but there is no consensus on timing or frequency of screening worldwide. In this study, a cohort of hereditary retinoblastoma patients at increased risk for TRB was identified and the usefulness of aggressive neuroimaging was examined. DESIGN: Retrospective review of the medical records and MRI reports of patients with retinoblastoma treated at Memorial Sloan Kettering Cancer Center between January 1, 2006, and December 31, 2016. PARTICIPANTS: Three hundred forty-nine total patients with retinoblastoma, including 215 hereditary retinoblastoma patients in the screening group. METHODS: We reviewed 804 MRI studies of the orbit or brain. Patient and disease characteristics, including laterality, family history, and gene mutation status were analyzed. The impression of every MRI was coded 1 to 5, each value representing a different abnormality. MAIN OUTCOME MEASURES: We calculated the incidence of TRB in patients with germline disease as well as the incidence of screening MRI scans showing TRB. RESULTS: Among our hereditary retinoblastoma screening cohort (n=215) 4 patients with TRB were identified on screening MRI. All 4 patients showed bilateral disease, pineal gland tumors, and a latency period of at least 1 year. Three of the 4 were deceased by the end of the study. The incidence of TRB diagnosis was 1.9% (95% confidence interval [CI], 0.7%-4.9%). Of the 804 screening MRI scans performed on the screening cohort, 691 (86%) were unremarkable and 4 reported a lesion suspicious for TRB. The overall incidence of detecting TRB on screening MRI in the at-risk cohort was 0.5% (95% CI, 0.2%-1.3%) with a number needed to treat of 202. CONCLUSIONS: All cases of TRB in our center during the study period developed before the patient was 3 years of age and after a total of only 4 lifetime MRIs. Overall survival from TRB was not improved as a result of screening, and many false-positive results required additional, subsequent MRI scans with anesthesia.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30552129

RESUMO

NUTM1-rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1-rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the BRD4-NUTM1 fusion gene defining a distinct clinicopathologic entity-NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA-NUTM1 fusion. Whole-genome sequencing identified the presence of complex rearrangements resulting in a MGA-NUTM1 fusion gene in the absence of other significant somatic mutations. Genetic rearrangement was confirmed by fluorescence in situ hybridization, and expression of the fusion gene product was confirmed by transcriptomic analysis. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1-22) and NUTM1 (exons 3-8). Histopathologically, both cases were high-grade spindle cell sarcomas without specific differentiation markers. In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1-rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA-NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high-grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Sarcoma/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Criança , Feminino , Fusão Gênica/genética , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Recombinação Genética/genética , Sarcoma/metabolismo , Sarcoma Sinovial/genética , Fatores de Transcrição/genética , Translocação Genética/genética , Sequenciamento Completo do Genoma/métodos
12.
J Neurooncol ; 140(3): 717-725, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30392092

RESUMO

BACKGROUND: The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG. METHODS: Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on "Head-Start" I and II protocols (HSI and HSII). Treatment included Induction with 4-5 cycles of one of three intensive chemotherapy regimens followed by Consolidation with one cycle of marrow-ablative chemotherapy (thiotepa, carboplatin and etoposide) with autologous hematopoietic cell rescue (AHCR). Irradiation was required for children over 6 years of age or for those with residual tumor at the end of Consolidation. RESULTS: We had two long-term survivors who were found retrospectively to harbor low-grade glial tumors and thus were not included in the survival analysis. Of the remaining 13 patients, the 1-year event-free (EFS) and overall (OS) survival for these children were 31% (95% CI 9-55%) and 38% (95% CI 14-63%), respectively. Median EFS and OS were 6.6 (95% CI 2.7, 12.7) and 8.7 months (95% CI 6.9, 20.9), respectively. Eight patients developed progressive disease during study treatment (seven during Induction and one at the end of Consolidation). Ten children received focal irradiation, five for residual tumor (three following Induction and two following Consolidation) and five due to disease progression. CONCLUSIONS: Children with high-grade BSG did not benefit from this intensive chemotherapy strategy administered prior to irradiation.


Assuntos
Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/radioterapia , Quimioterapia de Consolidação , Glioma/tratamento farmacológico , Glioma/radioterapia , Quimioterapia de Indução , Protocolos de Quimioterapia Combinada Antineoplásica , Medula Óssea/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Resultado do Tratamento
13.
Neoplasia ; 20(8): 757-763, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29940303

RESUMO

PURPOSE: To evaluate the management and outcomes of naïve bilateral retinoblastoma treated at a single-center over a 5-year period during the era of ophthalmic artery chemosurgery (OAC) and intravitreous chemotherapy. METHODS: Retrospective cohort study of 46 patients (92 eyes) with naïve bilateral retinoblastoma treated at Memorial Sloan Kettering Cancer Center between January 2012 and February 2017. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response. Patient, ocular, ocular progression-free, ocular recurrent event-free, and second ocular survivals were assessed by Kaplan-Meier estimates. Retinal toxicity was evaluated by electroretinography. Snellen visual acuity and complete blood count metrics were recorded. RESULTS: Sixty-four eyes (70%) in 41 patients (89%) received ophthalmic artery chemosurgery as part of their treatment. Twenty-six patients (56%) received tandem OAC (bilateral simultaneous infusions). Seven eyes were primarily enucleated. No eye receiving initial OAC was enucleated. There was a single secondary enucleation in an eye initially treated with focal therapy with anterior chamber recurrence. The 3-year Kaplan-Meier estimates for overall ocular, secondary ocular (survival after treatment for recurrence), progression-free, and recurrent event-free survival were 91.3% [95% confidence interval (CI) 83.4-95.5], 98.7% (95% CI 91.3-99.8), 91.5% (95% CI 83.0-95.8), and 78.9% (95% CI 68.2-86.3), respectively. Overall and secondary ocular survivals were 100% for International Classification of Retinoblastoma (ICRB) groups A-C. Overall ocular survival was 91.5% (95% CI 70-97.8) for ICRB group D and 71.4% (95% CI 47.1-79.4) for group E. Secondary ocular survival was 95.4% (95% CI 71.8-99.3) for ICRB group D and 100% for group E. There were no treatment-related deaths, three patients developed trilateral retinoblastoma (one died), and one patient (who did not receive OAC) developed metastatic disease and is in remission at 32-month follow-up. CONCLUSION: The majority (89%) of bilateral retinoblastoma patients in the current era and at this center were treated with OAC. This has resulted in saving a historic number of eyes. A quarter of eyes developed recurrent disease (defined as recurrent disease requiring any treatment including focal), the majority of which occurred in the first year after treatment, and all but one was saved. There has been no compromise in patient survival.


Assuntos
Antineoplásicos/uso terapêutico , Olho/efeitos dos fármacos , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Pré-Escolar , Intervalo Livre de Doença , Eletrorretinografia/métodos , Olho/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Infusões Intra-Arteriais/métodos , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Artéria Oftálmica/efeitos dos fármacos , Artéria Oftálmica/patologia , Neoplasias da Retina/patologia , Estudos Retrospectivos
14.
Lancet Oncol ; 19(8): 1040-1050, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29914796

RESUMO

BACKGROUND: Diffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma. METHODS: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3 + 3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort. FINDINGS: From April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200. INTERPRETATION: Convection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma. FUNDING: National Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma/tratamento farmacológico , Radioimunoterapia/métodos , Anticorpos Monoclonais Murinos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intraventriculares , Radioisótopos do Iodo/administração & dosagem , Masculino
15.
Cancer Discov ; 8(9): 1130-1141, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29880583

RESUMO

BRAFV600E hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAFV600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAFL514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAFL514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence.Significance: In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in BRAF have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in BRAF (V600E/L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance. Cancer Discov; 8(9); 1130-41. ©2018 AACR.See related commentary by Romano and Kwong, p. 1064This article is highlighted in the In This Issue feature, p. 1047.


Assuntos
Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Neoplasias Encefálicas/tratamento farmacológico , Progressão da Doença , Humanos , Imidazóis/uso terapêutico , Masculino , Oximas/uso terapêutico , Multimerização Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/química , Sequenciamento Completo do Exoma
16.
JAMA Ophthalmol ; 136(6): 637-641, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29710339

RESUMO

Importance: Retinoblastoma survivors are at risk for adverse oculo-visual outcomes. Limited data are available regarding long-term vision-targeted health-related quality of life (HRQoL) of adult retinoblastoma survivors. Objective: To examine vision-targeted HRQoL as reported on the 25-item National Eye Institute Visual Field Questionnaire for overall and specific scale scores among adult survivors of retinoblastoma. Design, Setting, and Participants: The Retinoblastoma Survivor Study is a retrospective cohort of adult retinoblastoma survivors treated at 3 academic medical centers in New York between 1932 and 1994. Participants completed a comprehensive questionnaire between April 2008 and June 2010. Items were scored in January 2013 and preliminary analyses were performed in July 2015. Models were finalized in May 2017. Main Outcomes and Measures: Self-reported vision-targeted HRQoL as reported on the 25-item National Eye Institute Visual Field Questionnaire. Items are scored from 0 to 100, with 100 representing the highest quality of life. Results: Among 470 adult retinoblastoma survivors (53.6% with bilateral disease; 52.1% female; 86.4% white and non-Hispanic; mean age at study, 43.3 years; range, 18.0-77.0 years), 86% had at least 1 eye removed (1 eye, 74.5%; both eyes, 11.5%); 56.5% were previously treated with radiotherapy; and 61.3% rated their eyesight as excellent/good while 16.2% reported complete blindness. The overall mean (SD) VFQ composite score for all survivors was 81.1 (17.2) (mean [SD] score for unilateral retinoblastoma survivors, 91.4 [7.7]; bilateral retinoblastoma survivors, 72.3 [18.2]; difference between survivors with unilateral and bilateral disease, 19.1 [95% CI, 16.5-21.7; P < .001]). Prior exposure to radiotherapy was not associated with decreased overall VFQ (ß = -0.08; 95% CI, -0.15 to 0.002; P = .06) but was related to a few specific subdomains of visual functioning. Conclusions and Relevance: These findings suggest retinoblastoma-related oculo-visual problems are associated with functional status and vision-targeted HRQoL of adult survivors, particularly among those with bilateral disease.


Assuntos
Qualidade de Vida/psicologia , Neoplasias da Retina/psicologia , Retinoblastoma/psicologia , Sobreviventes/psicologia , Visão Ocular/fisiologia , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia , Neoplasias da Retina/fisiopatologia , Neoplasias da Retina/terapia , Retinoblastoma/fisiopatologia , Retinoblastoma/terapia , Estudos Retrospectivos , Perfil de Impacto da Doença , Inquéritos e Questionários , Adulto Jovem
17.
PLoS One ; 13(4): e0195395, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29698399

RESUMO

PURPOSE: To report on the rate and timing of retinal reattachment and outcomes for retinoblastoma children who have total retinal detachments at presentation to our center and were treated with intra-arterial chemotherapy (ophthalmic artery chemosurgery, OAC). PATIENTS AND METHODS: Single-center retrospective review of retinoblastoma patients who presented with total retinal detachments and were subsequently treated with OAC at MSKCC between May 2006 and July 2016. Endpoints were retinal detachment resolution, visual function, ERG amplitude, ocular survival, and patient survival from metastases. RESULTS: 87 eyes of 84 retinoblastoma patients were included. Using a survival multistate model, by 36 months of follow-up, there was a 54% cumulative probability of complete retinal reattachment and a 76% probability of partial reattachment. 24% of eyes that completely reattached received only OAC without any prior or adjuvant treatments. Eyes that completely reattached were significantly more likely to have been diagnosed at a younger age (p<0.0001) and to have greater initial ERG values (p = 0.006). At final follow-up, 14% of eyes had gained at least 25 µV of ERG activity, and 8.0% had achieved hand motion vision or better, including one to 20/60. 13% of eyes were enucleated. No patient died from metastatic disease, and only one developed metastases. CONCLUSION: OAC can successfully treat previously considered "non-salvageable" retinoblastoma eyes with total retinal detachments, promote retinal reattachment in the majority of eyes, and preserve ocular and patient survival.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Descolamento Retiniano/etiologia , Neoplasias da Retina/complicações , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/complicações , Retinoblastoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Pré-Escolar , Eletrorretinografia , Feminino , Seguimentos , Humanos , Lactente , Infusões Intra-Arteriais , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Artéria Oftálmica , Retina/efeitos dos fármacos , Retina/fisiopatologia , Descolamento Retiniano/fisiopatologia , Descolamento Retiniano/terapia , Estudos Retrospectivos , Análise de Sobrevida , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Resultado do Tratamento
18.
J Neurooncol ; 138(2): 435-445, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29511977

RESUMO

We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/terapia , Ependimoma/fisiopatologia , Ependimoma/terapia , Adolescente , Neoplasias Encefálicas/epidemiologia , Criança , Pré-Escolar , Gerenciamento Clínico , Ependimoma/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
19.
Pediatr Blood Cancer ; 65(5): e26947, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29350463

RESUMO

BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.


Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Vemurafenib/uso terapêutico , Adolescente , Antineoplásicos/farmacocinética , Criança , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Melanoma/genética , Melanoma/patologia , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Distribuição Tecidual , Vemurafenib/farmacocinética
20.
J Neurooncol ; 136(1): 95-104, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29019042

RESUMO

Medulloblastoma (MB) is rare in adults and treatment guidelines are consequently not well-established. Few modern series have reported long-term follow-up and treatment sequelae. We examined long-term outcomes of adult MB patients at one institution. Records of 29 consecutive patients (18 male, 11 female) aged ≥ 18 years who received radiotherapy (RT) for primary MB from 1990 to 2016 were reviewed. Median age at diagnosis was 28 years (range 18-72 years). Seventeen patients were standard risk and 12 were high risk. Nineteen patients had gross total resection, seven had subtotal resection, and three had biopsy only. Median craniospinal irradiation and boost doses were 36 Gy (range 23.4-39.6 Gy) and 55.8 Gy (range 54-59.4 Gy), respectively. Of 24 patients receiving chemotherapy, 20 received concurrent + adjuvant and 4 received adjuvant only. At median follow-up of 9.0 years (range 1.1-20.5 years), five patients recurred: four in the posterior fossa and one in both the posterior fossa and above the tentorium. Five patients died: two of disease progression and three after possible treatment complications (seizure, lobar pneumonia, and multifactorial sepsis). At last follow-up, 23 patients were alive with no evidence of disease. Long-term effects include executive dysfunction (n = 17), weakness/ataxia (n = 16), and depression/anxiety (n = 13). Kaplan-Meier estimates of 10-year overall survival and failure-free survival are 83% (95% confidence interval [CI] 59-93%) and 79% (CI 55-91%), respectively. Despite encouraging disease control in this cohort, long-term sequelae may limit quality of life. Multimodality pediatric regimens using lower RT doses may be considered to reduce treatment-related morbidity.


Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/radioterapia , Meduloblastoma/diagnóstico , Meduloblastoma/radioterapia , Adolescente , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
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