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PURPOSE: To describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1). METHODS: We performed exome sequencing, brain magnetic resonance imaging, neuropathology, electron microscopy, western blotting, and transcriptomic and metabolic analyses in 7 NIT1-small vessel disease patients from 5 unrelated pedigrees. RESULTS: The first identified patients were 3 siblings, compound heterozygous for the NIT1 c.727C>T; (p.Arg243Trp) variant and the NIT1 c.198_199del; p.(Ala68∗) variant. The 4 additional patients were single cases from 4 unrelated pedigrees and were all homozygous for the NIT1 c.727C>T; p.(Arg243Trp) variant. Patients presented in mid-adulthood with movement disorders. All patients had striking abnormalities on brain magnetic resonance imaging, with numerous and massively dilated basal ganglia perivascular spaces. Three patients had non-lobar intracerebral hemorrhage between age 45 and 60, which was fatal in 2 cases. Western blotting on patient fibroblasts showed absence of NIT1 protein, and metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Brain autopsy revealed large electron-dense deposits in the vessel walls of small and medium sized cerebral arteries. CONCLUSION: NIT1-small vessel disease is a novel, autosomal recessively inherited cerebral small vessel disease characterized by a triad of movement disorders, massively dilated basal ganglia perivascular spaces, and intracerebral hemorrhage.
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Hemorragia Cerebral , Doenças de Pequenos Vasos Cerebrais , Transtornos dos Movimentos , Linhagem , Humanos , Feminino , Masculino , Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/patologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Pessoa de Meia-Idade , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Hemorragia Cerebral/diagnóstico por imagem , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Alelos , Adulto , Idoso , Sistema Glinfático/patologia , Sistema Glinfático/diagnóstico por imagem , Sequenciamento do Exoma , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Aminoidrolases/genéticaRESUMO
Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.
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Heterozigoto , Hidropisia Fetal , Mutação de Sentido Incorreto , Humanos , Feminino , Mutação de Sentido Incorreto/genética , Hidropisia Fetal/genética , Hidropisia Fetal/patologia , Gravidez , Derrame Pleural/genética , Derrame Pleural/patologia , Caderinas/genética , Sequenciamento do Exoma , Polaridade Celular/genéticaRESUMO
BACKGROUND: Glioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms remain incompletely understood. OBJECTIVES: To identify tumor-expressed genes and signaling pathways that associate with glioblastoma-related VTE by using next generation RNA-sequencing (RNA-Seq). METHODS: The tumor gene expression profile of 23 glioblastoma patients with VTE and 23 glioblastoma patients without VTE was compared using an unpaired analysis. Ingenuity Pathway Analysis (IPA) core analysis was performed on the top 50 differentially expressed genes to explore associated functions and pathways. Based on full RNA-Seq data, molecular glioblastoma subtypes were determined by performing cluster analysis. RESULTS: Of the 19,327 genes, 1246 (6.4 %) were differentially expressed between glioblastoma patients with and without VTE (unadjusted P < 0.05). The most highly overexpressed gene was GLI1, a classical target gene in the Sonic Hedgehog (Shh) signaling pathway (log2 fold change: 3.7; unadjusted P < 0.0001, adjusted P = 0.219). In line, Shh signaling was among the top canonical pathways and processes associated with VTE. The proportion of patients with the proneural/neural glioblastoma subtype was higher among those with VTE than controls. CONCLUSION: Shh signaling may be involved in the development of glioblastoma-related VTE.
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Glioblastoma , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Glioblastoma/complicações , Glioblastoma/genética , Glioblastoma/patologia , Estudos de Casos e Controles , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Transdução de Sinais/genética , RNARESUMO
BACKGROUND: Becker muscular dystrophy (BMD) is an X-linked disorder characterized by slow, progressive muscle damage and muscle weakness. Hallmarks include fibre-size variation and replacement of skeletal muscle with fibrous and adipose tissues, after repeated cycles of regeneration. Muscle histology can detect these features, but the required biopsies are invasive, are difficult to repeat and capture only small muscle volumes. Diffusion-tensor magnetic resonance imaging (DT-MRI) is a potential non-invasive alternative that can calculate muscle fibre diameters when applied with the novel random permeable barrier model (RPBM). In this study, we assessed muscle fibre diameters using DT-MRI in BMD patients and healthy controls and compared these with histology. METHODS: We included 13 BMD patients and 9 age-matched controls, who underwent water-fat MRI and DT-MRI at multiple diffusion times, allowing RPBM parameter estimation in the lower leg muscles. Tibialis anterior muscle biopsies were taken from the contralateral leg in 6 BMD patients who underwent DT-MRI and from an additional 32 BMD patients and 15 healthy controls. Laminin and Sirius-red stainings were performed to evaluate muscle fibre morphology and fibrosis. Twelve ambulant patients from the MRI cohort underwent the North Star ambulatory assessment, and 6-min walk, rise-from-floor and 10-m run/walk functional tests. RESULTS: RPBM fibre diameter was significantly larger in BMD patients (P = 0.015): mean (SD) = 68.0 (25.3) µm versus 59.4 (19.2) µm in controls. Inter-muscle differences were also observed (P ≤ 0.002). Both inter- and intra-individual RPBM fibre diameter variability were similar between groups. Laminin staining agreed with the RPBM, showing larger median fibre diameters in patients than in controls: 72.5 (7.9) versus 63.2 (6.9) µm, P = 0.006. However, despite showing similar inter-individual variation, patients showed more intra-individual fibre diameter variability than controls-mean variance (SD) = 34.2 (7.9) versus 21.4 (6.9) µm, P < 0.001-and larger fibrosis areas: median (interquartile range) = 21.7 (5.6)% versus 14.9 (3.4)%, P < 0.001. Despite good overall agreement of RPBM and laminin fibre diameters, they were not associated in patients who underwent DT-MRI and muscle biopsy, perhaps due to lack of colocalization of DT-MRI with biopsy samples. CONCLUSIONS: DT-MRI RPBM metrics agree with histology and can quantify changes in muscle fibre size that are associated with regeneration without the need for biopsies. They therefore show promise as imaging biomarkers for muscular dystrophies.
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Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/patologia , Laminina , Músculo Esquelético/patologia , Fibras Musculares Esqueléticas/patologia , Imageamento por Ressonância MagnéticaRESUMO
Purpose: Heavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether pigmentation should be included in prognostic tests. Design: Retrospective comparison of clinical, histopathological, and genetic features and survival in UM with different pigmentation. Participants: A total of 1058 patients with UM from a White European population with diverse eye colors enucleated between 1972 and 2021. Methods: Cox regression and log-rank tests were used for survival analysis; the chi-square test and Mann-Whitney U test were used for correlation analysis. Main Outcome Measures: Uveal melanoma-related survival based on tumor pigmentation and chromosome status, correlation of tumor pigmentation with prognostic factors. Results: The 5-year UM-related mortality was 8% in patients with nonpigmented tumors (n = 54), 25% with lightly pigmented tumors (n = 489), 41% with moderately pigmented tumors (n = 333), and 33% with dark tumors (n = 178) (P < 0.001). The percentage of tumors with monosomy 3 (M3) or 8q gain increased with increasing pigmentation (31%, 46%, 62%, and 70% having M3 [P < 0.001], and 19%, 43%, 61%, and 63% having 8q gain [P < 0.001] in the 4 increasing pigment groups, respectively). BRCA-associated protein 1 (BAP1) loss (known for 204 cases) was associated with increased tumor pigmentation (P = 0.001). Cox regression analysis on survival showed that when chromosome status and pigmentation were both included, pigmentation was not an independent prognostic indicator. Preferentially expressed antigen in melanoma (PRAME) expression was a significant prognostic marker in light tumors (P = 0.02) but not in dark tumors (P = 0.85). Conclusions: Patients with moderately and heavily pigmented tumors showed a significantly higher UM-related mortality than patients with unpigmented and light tumors (P < 0.001), supporting prior reports on the relation between increased tumor pigmentation and a worse prognosis. Although we previously showed that a dark eye color was associated with tumor pigmentation, we now show that the tumor's genetic status (chromosome 3 and 8q/BAP1 status) is also related to tumor pigmentation. When pigmentation and chromosome 3 status are both included in a Cox regression analysis, pigmentation is not an independent prognostic factor. However, evidence from this and previous studies shows that chromosome changes and PRAME expression have a stronger association with survival when they occur in light tumors than in dark ones. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
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BACKGROUND AND OBJECTIVES: Patients with glioblastoma have a high risk of developing venous thromboembolism (VTE). However, the role of underlying genetic risk factors remains largely unknown. Therefore, the aim of this study was to discover whether genetic aberrations in glioblastoma associate with VTE risk. METHODS: In this cohort study, all consecutive patients diagnosed with glioblastoma in two Dutch hospitals between February 2017 and August 2020 were included. Targeted DNA next-generation sequencing of all glioblastomas was performed for diagnostic purposes and included mutational status of the genes ATRX, BRAF, CIC, FUBP1, H3F3A, IDH1, IDH2, PIK3CA, PTEN and TP53 and amplification/gain or deletion of BRAF, CDKN2A, EGFR, NOTCH1 and PTEN. The primary outcome was VTE within three months before glioblastoma diagnosis until two years after. Cumulative incidences were determined using competing risk analysis adjusting for mortality. Univariable Cox regression analysis was performed to determine hazard ratios. RESULTS: From 324 patients with glioblastoma, 25 were diagnosed with VTE. Patients with a CDKN2A deletion had a 12-month adjusted cumulative incidence of VTE of 12.5 % (95%CI: 7.3-19.3) compared with 5.4 % (95%CI: 2.6-9.6) in patients with CDKN2A wildtype (p = 0.020), corresponding to a HR of 2.53 (95%CI: 1.12-5.73, p = 0.026). No significant associations were found between any of the other investigated genes and VTE. CONCLUSION: This study suggests a potential role for CDKN2A deletion in glioblastoma-related VTE. Therefore, once independently validated, CDKN2A mutational status may be a promising predictor to identify glioblastoma patients at high risk for VTE, who may benefit from thromboprophylaxis.
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Glioblastoma , Tromboembolia Venosa , Humanos , Glioblastoma/complicações , Glioblastoma/genética , Estudos de Coortes , Tromboembolia Venosa/tratamento farmacológico , Anticoagulantes/uso terapêutico , Proteínas Proto-Oncogênicas B-raf , Fatores de Risco , Proteínas de Ligação a DNA , Proteínas de Ligação a RNARESUMO
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.
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Cardiomiopatias , Cardiomiopatia Dilatada , Lactente , Camundongos , Animais , Humanos , Criança , Feminino , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Volume Sistólico , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas com Domínio LIM/genética , Função Ventricular EsquerdaRESUMO
BACKGROUND: IDH1/2 wildtype (IDHwt) glioma WHO grade 2 and 3 patients with pTERT mutation and/or EGFR amplification and/orâ +â 7/-10 chromosome gain/loss have a similar overall survival time as IDHwt glioblastoma patients, and are both considered glioblastoma IDHwt according to the WHO 2021 classification. However, differences in seizure onset have been observed. This study aimed to compare the course of epilepsy in the 2 glioblastoma subtypes. METHODS: We analyzed epilepsy data of an existing cohort including IDHwt histologically lower-grade glioma WHO grade 2 and 3 with molecular glioblastoma-like profile (IDHwt hLGG) and IDHwt glioblastoma patients. Primary outcome was the incidence proportion of epilepsy during the disease course. Secondary outcomes included, among others, onset of epilepsy, number of seizure days, and antiepileptic drug (AED) polytherapy. RESULTS: Out of 254 patients, 78% (50/64) IDHwt hLGG and 68% (129/190) IDHwt glioblastoma patients developed epilepsy during the disease (Pâ =â .121). Epilepsy onset before histopathological diagnosis occurred more frequently in IDHwt hLGG compared to IDHwt glioblastoma patients (90% vs 60%, Pâ <â .001), with a significantly longer median time to diagnosis (3.5 vs 1.3 months, Pâ <â .001). Median total seizure days was also longer for IDHwt hLGG patients (7.0 vs 3.0, Pâ =â .005), and they received more often AED polytherapy (32% vs 17%, Pâ =â .028). CONCLUSIONS: Although the incidence proportion of epilepsy during the entire disease course is similar, IDHwt hLGG patients show a significantly higher incidence of epilepsy before diagnosis and a significantly longer median time between first seizure and diagnosis compared to IDHwt glioblastoma patients, indicating a distinct clinical course.
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Neoplasias Encefálicas , Epilepsia , Glioblastoma , Glioma , Humanos , Glioblastoma/patologia , Neoplasias Encefálicas/patologia , Glioma/patologia , Mutação , Convulsões , Anticonvulsivantes , Isocitrato Desidrogenase/genéticaRESUMO
BACKGROUND: Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of arterial thromboembolism (ATE) in these patients is largely unknown. Our aim was to assess the cumulative incidence, predictors, and prognostic impact of VTE, ATE, and MB on subsequent complications and mortality. METHODS: Cohort study of 967 consecutive patients diagnosed with glioblastoma between 2004-2020 in two hospitals. Patients were followed from 6 months before date of histopathological glioblastoma diagnosis up to 2 years after, or until an outcome of interest (VTE, ATE, and MB) or death occurred, depending on the analysis. Cumulative incidences were estimated with death as competing risk. Cox regression was used to identify predictors and the prognostic impact. RESULTS: A total of 101 patients were diagnosed with VTE, 50 with ATE, and 126 with MB during a median follow-up of 15 months (interquartile range 9.0-22). The adjusted 1-year cumulative incidence of VTE was 7.5% (95% confidence interval [CI] 5.9-9.3), of ATE 4.1% (95% CI 3.0-5.6), and of MB 12% (95% CI 9.6-14). Older age, type of surgery, and performance status were predictors of VTE. Incident VTE during follow-up was associated with MB (adjusted HR 4.7, 95% CI 2.5-9.0). MB and VTE were associated with mortality (adjusted HR 1.7, 95% CI 1.3-2.1 and 1.3, 95% CI 1.0-1.7, respectively). CONCLUSION: We found considerable incidences of VTE and MB in glioblastoma patients, with both complications associated with poorer prognosis. Our observations emphasize the need for prospective studies to determine optimal thromboprophylaxis and VTE treatment strategy in these patients.
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Glioblastoma , Trombose , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Estudos de Coortes , Glioblastoma/complicações , Hemorragia/diagnóstico , Hemorragia/epidemiologia , Humanos , Incidência , Estudos Prospectivos , Fatores de Risco , Trombose/tratamento farmacológico , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologiaRESUMO
PURPOSE: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors. DESIGN: We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color. PARTICIPANTS: A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH). METHODS: Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors. MAIN OUTCOME MEASURES: Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status. RESULTS: Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals. CONCLUSIONS: Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases.
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Melanoma , Neoplasias Uveais , Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Cor de Olho/genética , Humanos , Iris/patologia , Melanoma/patologia , Prognóstico , Neoplasias Uveais/patologiaRESUMO
PURPOSE: To employ an off-resonance saturation method to measure the mineral-iron pool in the postmortem brain, which is an endogenous contrast agent that can give information on cellular iron status. METHODS: An off-resonance saturation acquisition protocol was implemented on a 7 Tesla preclinical scanner, and the contrast maps were fitted to an established analytical model. The method was validated by correlation and Bland-Altman analysis on a ferritin-containing phantom. Mineral-iron maps were obtained from postmortem tissue of patients with neurological diseases characterized by brain iron accumulation, that is, Alzheimer disease, Huntington disease, and aceruloplasminemia, and validated with histology. Transverse relaxation rate and magnetic susceptibility values were used for comparison. RESULTS: In postmortem tissue, the mineral-iron contrast colocalizes with histological iron staining in all the cases. Iron concentrations obtained via the off-resonance saturation method are in agreement with literature. CONCLUSIONS: Off-resonance saturation is an effective way to detect iron in gray matter structures and partially mitigate for the presence of myelin. If a reference region with little iron is available in the tissue, the method can produce quantitative iron maps. This method is applicable in the study of diseases characterized by brain iron accumulation and can complement existing iron-sensitive parametric methods.
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Distúrbios do Metabolismo do Ferro , Ferro , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , MineraisRESUMO
OBJECTIVE: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. MATERIALS AND METHODS: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan-Meier's methodology and Cox proportional hazards models. RESULTS: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6-26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. CONCLUSION: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy.
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BACKGROUND: Evidence indicates that inflammatory processes are involved in radicular pain as well as in resorption of herniated disc tissue. Furthermore there are indications that the presence of vertebral end plate pathology (Modic changes; MC) is associated with a negative effect on inflammation. It is hypothesized that in patients with MC, the (possibly bacterial induced) inflammation will be accompanied by pro inflammatory cytokines that worsen the outcome, and that in patients without MC, the inflammation is accompanied by cytokines that induce a resorption process to accelerate recovery. METHODS: This prospective cohort study will include 160 lumbar and 160 cervical patients (total of 320), which are scheduled for surgery for either a lumbar or cervical herniated disc with ages between 18 and 75. The main and interaction effects of local bacterial infection (culture), inflammatory cells in disc material (immunohistology), MC (MRI), and blood biomarkers indicating inflammation or infection (blood sample evaluation) will be evaluated. Clinical parameters to be evaluated are leg pain on the 11 point NRS pain scale, Oswestry (lumbar spine) or Neck (cervical spine) Disability Index, Global Perceived Recovery, Womac Questionnaire, and medication status, at baseline, and after 6, 16, 26 and 52 weeks. DISCUSSION: Gaining insight in the aetiology of pain and discomfort in radiculopathy caused by a herniated disc could lead to more effective management of patients. If the type of inflammatory cells shows to be of major influence on the rate of recovery, new immunomodulating treatment strategies can be developed to decrease the duration and intensity of symptoms. Moreover, identifying a beneficial inflammatory response in the disc through a biomarker in blood could lead to early identification of patients whose herniations will resorb spontaneously versus those that require surgery. TRIAL REGISTRATION: prospectively enrolled at trialregister.nl, ID: NL8464 .
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Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Radiculopatia , Adolescente , Adulto , Idoso , Humanos , Inflamação , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: To evaluate the management of conjunctival melanoma with local excision and adjuvant brachytherapy. SUBJECTS/METHODS: Data of all patients who received local excision and adjuvant brachytherapy for conjunctival melanoma between 1999 and 2016 in a Dutch national referral centre were reviewed. A protocol with Sr-90 was used until 2012, a protocol with Ru-106 was used hereafter. Local recurrence, metastasis, survival, visual acuity and treatment complications were assessed. RESULTS: A total of 58 patients was identified: 32 patients were treated with Sr-90 and 26 with Ru-106. Mean follow-up time was 97.3 months (143.1 months after Sr-90, and 40.2 months after Ru-106). All lesions were epibulbar, the median tumour thickness was 0.9 mm. Local recurrence occurred in 13/58 cases (22%), with a 5-year recurrence rate of 21%. Local recurrence occurred equally often in both protocols, with 5-year recurrence rates of 19% (Sr-90) versus 23% (Ru-106) (p = 0.68). Metastasis developed in 3/58 cases (5%), with 2 cases after Sr-90, and 1 after Ru-106 (p = 1.00). The most reported complications were pain (29%), dry eyes (21%), symblepharon (9%), ptosis (12%) and cataract (9%). No severe corneal or scleral complications were observed. Median visual acuity was 1.00 pre-surgery, at the end of follow-up this was 1.00 (Sr-90) and 0.95 (Ru-106). CONCLUSION: Local excision with adjuvant brachytherapy provides good tumour control with excellent visual outcome and mild side effects in patients with limited conjunctival melanoma. Results after Sr-90 or Ru-106 were comparable; a choice for either treatment may be based on experience of the clinician and availability of materials.
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Braquiterapia , Neoplasias da Túnica Conjuntiva , Melanoma , Neoplasias da Túnica Conjuntiva/radioterapia , Humanos , Melanoma/radioterapia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Esclera , Resultado do TratamentoRESUMO
BACKGROUND: To relate conjunctival melanoma characteristics to local control. METHODS: Retrospective, registry-based interventional study with data gathered from 10 ophthalmic oncology centres from 9 countries on 4 continents. Conjunctival melanoma patients diagnosed between January 2001 and December 2013 were enrolled in the study. Primary treatments included local excision, excision with cryotherapy and exenteration. Adjuvant treatments included topical chemotherapy, brachytherapy, proton and external beam radiotherapy (EBRT). Cumulative 5-year and 10-year Kaplan-Meier local recurrence rates were related to clinical and pathological T-categories of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. RESULTS: 288 patients had a mean initial age of 59.7±16.8 years. Clinical T-categories (cT) were cT1 (n=218,75.7%), cT2 (n=34, 11.8%), cT3 (n=15, 5.2%), cTx (n=21,7.3%) with no cT4. Primary treatment included local excision (n=161/288, 55.9%) followed by excision biopsy with cryotherapy (n=108/288, 37.5%) and exenteration (n=5/288, 1.7%). Adjuvant therapies included topical mitomycin (n=107/288, 37.1%), plaque-brachytherapy (n=55/288, 19.1%), proton-beam (n=36/288, 13.5%), topical interferon (n=20/288, 6.9%) and EBRT (n=15/288, 5.2%). Secondary exenteration was performed (n=11/283, 3.9%). Local recurrence was noted in 19.1% (median=3.6 years). Cumulative local recurrence was 5.4% (3.2-8.9%), 19.3% (14.4-25.5%) and 36.9% (26.5-49.9%) at 1, 5 and 10 years, respectively. cT3 and cT2 tumors were twice as likely to recur than cT1 tumours, but only cT3 had statistically significantly greater risk of local recurrence than T1 (p=0.013). Factors such as tumour ulceration, plica or caruncle involvement and tumour thickness were not significantly associated with an increased risk of local recurrence. CONCLUSION: This multicentre international study showed that eighth edition of AJCC tumour staging was related to the risk of local recurrence of conjunctival melanoma after treatment. The 10-year cumulative local recurrence remains high despite current management.
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Terapia Combinada , Neoplasias da Túnica Conjuntiva/terapia , Melanoma/terapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Braquiterapia , Quimioterapia Adjuvante , Neoplasias da Túnica Conjuntiva/mortalidade , Neoplasias da Túnica Conjuntiva/patologia , Crioterapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prótons , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Lentes de Contato de Uso Prolongado/efeitos adversos , Lentes de Contato de Uso Prolongado/microbiologia , Infecções Oculares Fúngicas/microbiologia , Ceratite/microbiologia , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Feminino , Humanos , Voriconazol/uso terapêutico , Adulto JovemRESUMO
Purpose: A subgroup of uveal melanoma (UM) gives rise to metastases at a late stage. Our objective was to identify patient and tumor characteristics that are associated with UM-related death in patients who survived 5 years following enucleation. Methods: A retrospective analysis was performed in 583 primary UM cases, enucleated at the Leiden University Medical Center between 1983 and 2013. Univariable and multivariable Cox regression analyses were performed in the total cohort and separately in those surviving more than 5 years (n = 297). Results: In the total cohort, the median age was 62.6 years, and the median tumor diameter was 12.0 mm. Monosomy 3 was detected in 53% of cases and gain of 8q in 47%. In the cohort surviving 5 years, the median age was 59.5 years, and the median tumor diameter was 11.0 mm. Monosomy 3 and gain of 8q were detected in 33% and 31% of cases, respectively. In the total cohort, male gender (P = 0.03), tumor diameter (P < 0.001), mitotic count (P < 0.001), extravascular matrix loops (P = 0.03), extraocular growth (P < 0.001), and gain of 8q (P < 0.001) were independently associated with UM-related death. In patients surviving 5 years after enucleation, univariable analysis revealed that age (P = 0.03), tumor diameter (P < 0.001), monosomy 3 (P = 0.04), and 8q gain (P = 0.003) were associated with subsequent UM-related death. Using a multivariable analysis, only male gender (P = 0.03) and gain of 8q (P = 0.01) remained significant. Conclusions: Predictors of UM-related death change over time. Among UM patients who survived the initial 5 years following enucleation, male gender and chromosome 8q status were the remaining factors related to UM-related death later on.
Assuntos
Enucleação Ocular , Melanoma/mortalidade , Melanoma/cirurgia , Neoplasias Uveais/mortalidade , Neoplasias Uveais/cirurgia , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Neoplasias Uveais/genética , Neoplasias Uveais/patologiaRESUMO
T-staging of most eyelid malignancies includes the assessment of the integrity of the tarsal plate and orbital septum, which are not clinically accessible. Given the contribution of MRI in the characterization of orbital tumors and establishing their relations to nearby structures, we assessed its value in identifying different eyelid structures in 38 normal eyelids and evaluating tumor extension in three cases of eyelid tumors. As not all patients can receive an MRI, we evaluated those same structures on CT and compared both results. All eyelid structures were identified on MRI and CT, except for the conjunctiva on both techniques and for the tarsal muscles on CT. Histopathology confirmed the MRI findings of orbital septum invasion in one patient, and the MRI findings of intact tarsus and orbital septum in another patient. Histopathology could not confirm or exclude tarsal invasion seen on MRI on two patients. Although imaging the eyelid is challenging, the identification of most eyelid structures is possible with MRI and, to a lesser extent, with CT and can, therefore, have an important contribution to the T-staging of eyelid tumors, which may improve treatment planning and outcome.
RESUMO
In Tables 3 and 4: In the first column and row, the text reads "Mixed model test (patients with Modic changes)". This should have been just "Mixed model". The complete correct Tables 3 and 4 are given below.