Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Indóis/uso terapêutico , Indóis/efeitos adversos , Pessoa de Meia-Idade , Feminino , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , IdosoAssuntos
Toxinas Botulínicas Tipo A , Úlcera da Córnea , Entrópio , Humanos , Úlcera da Córnea/tratamento farmacológico , Recém-Nascido , Entrópio/tratamento farmacológico , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/uso terapêutico , Masculino , Feminino , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/uso terapêuticoRESUMO
Purpose: Epigenetic alterations in uveal melanoma (UM) are still neither well characterized, nor understood. In this pilot study, we sought to provide a deeper insight into the possible role of epigenetic alterations in the pathogenesis of UM and their potential prognostic relevance. To this aim, we comprehensively profiled histone post-translational modifications (PTMs), which represent epigenetic features regulating chromatin accessibility and gene transcription, in UM formalin-fixed paraffin-embedded (FFPE) tissues, control tissues, UM cell lines, and healthy melanocytes. Methods: FFPE tissues of UM (n = 24), normal choroid (n = 4), human UM cell lines (n = 7), skin melanocytes (n = 6), and uveal melanocytes (n = 2) were analyzed through a quantitative liquid chromatography-mass spectrometry (LC-MS) approach. Results: Hierarchical clustering showed a clear separation with several histone PTMs that changed significantly in a tumor compared to normal samples, in both tissues and cell lines. In addition, several acetylations and H4K20me1 showed lower levels in BAP1 mutant tumors. Some of these changes were also observed when we compared GNA11 mutant tumors with GNAQ tumors. The epigenetic profiling of cell lines revealed that the UM cell lines MP65 and UPMM1 have a histone PTM pattern closer to the primary tissues than the other cell lines analyzed. Conclusions: Our results suggest the existence of different histone PTM patterns that may be important for diagnosis and prognosis in UM. However, further analyses are needed to confirm these findings in a larger cohort. The epigenetic characterization of a panel of UM cell lines suggested which cellular models are more suitable for epigenetic investigations.
Assuntos
Melanoma , Neoplasias Uveais , Humanos , Histonas , Projetos Piloto , Melanoma/metabolismo , Melanócitos/metabolismo , Neoplasias Uveais/patologia , Linhagem Celular , Espectrometria de MassasRESUMO
Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth "WHO Classification of Eye Tumors" (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.
Assuntos
Melanoma , Melanose , Neoplasias Cutâneas , Humanos , Melanoma/diagnóstico , Melanoma/patologia , Prognóstico , Reprodutibilidade dos Testes , Amarelo de Eosina-(YS) , Hematoxilina , Melanócitos , Neoplasias Cutâneas/patologia , Melanose/patologia , Organização Mundial da Saúde , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: The clinical diagnosis as well as the treatment approach of periocular tumors in childhood and adolescence can be challenging. Knowledge of the most important differential diagnoses and their clinicopathological correlation is helpful for the treatment approach. OBJECTIVE: The clinical and histological characteristics of various eyelid tumors in childhood and adolescence are presented taking the excision frequencies into consideration. MATERIAL AND METHODS: The frequencies and clinicopathologic correlation of the most important eyelid tumors (nâ¯= 485) are presented based on the data of the ophthalmopathology laboratory of the University Eye Hospital Bonn from 1998-2023. RESULTS: The most frequent tumor in childhood and adolescence is chalazion (57.3%), followed by dermoid cysts (16.7%) and molluscum contagiosum (9.6%). Other lesions of childhood and adolescence include pilomatrixoma (2.1%), hemangioma and other vascular malformations (4.7%) and rare differential diagnoses, such as subcutaneous calcifying nodules and xanthogranuloma. Guidance on the approach in different age groups is presented in the form of a decision tree. CONCLUSION: Tumors in children and adolescents are mostly benign, yet there are important indications for excision. A histological examination of any excised tissue in childhood and adolescence is obligatory because unexpected findings are not uncommon and the spectrum of lesions also differs from that in adulthood. Knowledge of the histological picture can be very helpful in the preoperative clinical classification and for planning further procedures.
Assuntos
Doenças do Tecido Conjuntivo , Neoplasias Palpebrais , Doenças do Cabelo , Molusco Contagioso , Lesões Pré-Cancerosas , Neoplasias Cutâneas , Humanos , Criança , Adolescente , Neoplasias Palpebrais/diagnóstico , Diagnóstico Diferencial , Neoplasias Cutâneas/diagnóstico , Molusco Contagioso/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Cabelo/diagnósticoRESUMO
The purpose of this study was to investigate Müller cells during the fetal development of the human eye. Müller cells in eyes of 39 human fetuses (11-38 weeks of gestation, WOG) and 6 infants (5 died of abusive head trauma, AHT, aged 1-9 months) were immunohistochemically stained and investigated for spatial and temporal immunoreaction of nestin, CD44, collagen IX and GFAP, which are stem cell markers or markers of intermediate filaments, respectively, in one of the hitherto largest cohorts of fetal eyes. Müller cells could be detected immunohistochemically as early as 12 WOG by immunohistochemical staining with nestin. Nestin was more strongly expressed in Müller cells of the peripheral retina and a centroperipheral gradient of immunoreaction over time was observed. CD44 was predominantly expressed in fetal eyes of the late second and early third trimester between (23 and 27 WOG) and significantly stronger in the infant eyes. Collagen IX labeling in the central retina was significantly stronger than in more peripheral sectors and increased with fetal age. GFAP staining in Müller cells was seen in the eye of a fetus of 38 WOG who died postnatally and in the infant eyes with and without history of AHT. Additionally, GFAP staining was present in the astrocytes of fetal and infant eyes. All examined markers were expressed by Müller cells at different developmental stages highlighting the plasticity of Müller cells during the development of the human eye. GFAP should be cautiously used as a marker for AHT as it was also expressed in fetal astrocytes and Müller cells in eyes without history of AHT.
Assuntos
Colágeno Tipo IX , Células Ependimogliais , Proteína Glial Fibrilar Ácida , Receptores de Hialuronatos , Nestina , Retina , Colágeno Tipo IX/metabolismo , Células Ependimogliais/citologia , Células Ependimogliais/metabolismo , Feto , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Lactente , Nestina/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Retina/embriologia , Retina/metabolismoAssuntos
Edema da Córnea , Ceratocone , Doença Aguda , Humanos , Ceratocone/diagnóstico , Ceratocone/terapia , Acuidade VisualRESUMO
BACKGROUND: Keratoconus is classified as a corneal ectasia and is a multifactorial disease. In those affected, mostly adolescent patients visual deterioration occurs due to the development of irregular astigmatism. Treatment by corneal cross-linking (CXL) has been indicated in progressive disease for several years. OBJECTIVE: To present the pathophysiology and histological changes in keratoconus as well as wound healing processes after CXL and their potential complications. MATERIAL AND METHODS: Histological changes in keratoconus as well as wound healing processes after CXL and their potential complications are presented based on histological examination of corneal specimens with keratoconus with and without a condition after CXL. Relevant literature and own data are analyzed and discussed. RESULTS: Besides inflammatory processes, atopic and genetic dispositions play a role in the development of keratoconus. The histological characteristics of keratoconus include changes in the epithelium, Bowman's layer and stroma. Wound healing processes after CXL include healing of the surface epithelium and transient loss of keratocytes and nerve fibers. CONCLUSION: Keratoconus shows characteristic histopathological changes, such as epithelial irregularities, stromal thinning and breaks of Bowman's layer, whereas the endothelium and Descemet's membrane remain unchanged (apart from cases of corneal hydrops). After CXL wound healing processes can be followed primarily in vivo by confocal microscopy. Complications after CXL are rare. Persistent loss of keratocytes can be clinically manifested as a visually relevant scar.
Assuntos
Ceratocone , Adolescente , Colágeno , Substância Própria , Topografia da Córnea , Reagentes de Ligações Cruzadas/uso terapêutico , Humanos , Ceratocone/terapia , Fármacos Fotossensibilizantes/uso terapêutico , Riboflavina/uso terapêutico , Raios Ultravioleta , CicatrizaçãoRESUMO
BACKGROUND: PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer. Emerging evidence suggests that an interaction between PPARγ and DNMTs (DNA methyltransferase) plays a role in cancer that is yet to be defined. METHODS: The configuration of the repeating elements was performed with CAP3 and MAFFT, and the structural modelling was conducted with HDOCK. An evolutionary action scores algorithm was used to identify oncogenic variants. A systematic bioinformatic appraisal of PPARγ and DNMT1 was performed across 29 tumor types and UM available in The Cancer Genome Atlas (TCGA). RESULTS: PPAR-responsive elements (PPREs) enriched with Alu repeats are associated with different genomic regions, particularly the promotor region of DNMT1. PPARγ-DNMT1 co-expression is significantly associated with several cancers. C-terminals of PPARγ and DNMT1 appear to be the potential protein-protein interaction sites where disease-specific mutations may directly impair the respective protein functions. Furthermore, PPARγ expression could be identified as an additional prognostic marker for UM. CONCLUSIONS: We hypothesize that the function of PPARγ requires an additional contribution of Alu repeats which may directly influence the DNMT1 network. Regarding UM, PPARγ appears to be an additional discriminatory prognostic marker, in particular in disomy 3 tumors.
RESUMO
ABSTRACT: Compared with penetrating keratoplasty (PK), Descemet membrane endothelial keratoplasty (DMEK) is characterized as lower risk for complications such as immunological graft reaction and faster and better postoperative visual recovery. In patients with endothelial graft failure after PK, DMEK can be used to regenerate PK graft transparency. The surgical technique for DMEK in this specific situation is still under debate, particularly regarding stripping of Descemet membrane (DM) from the failed PK and diameter of the DMEK graft. Here we report a case of a 75-year-old female patient with a failed graft 16 years after PK for Fuchs endothelial dystrophy, who underwent uneventful DMEK surgery. Stripping of DM in this particular case was performed outside the failed PK and demonstrated a biomechanically stable junction between the PK donor and the host DM. Histopathologic analysis of the excised DM showed continuous extracellular matrix connecting the host and donor DM, indicating primary intention wound healing after PK at this tissue level. This case demonstrates that after PK, a biomechanically stable and histologically continuous DM can enable Descemetorhexis outside the failed graft and transplantation of a DMEK graft larger than the previous PK. This may provide more endothelial cells for transplantation.
Assuntos
Lâmina Limitante Posterior/fisiologia , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Distrofia Endotelial de Fuchs/cirurgia , Ceratoplastia Penetrante , Cicatrização/fisiologia , Idoso , Feminino , Sobrevivência de Enxerto , Humanos , Estudos Retrospectivos , Acuidade VisualRESUMO
PURPOSE: Identify risk factors for endophthalmitis after strabismus surgery (EASS) and relate these to incidence and outcome. METHODS: Ophthalmologists, who had operated, diagnosed or treated EASS, completed a case record form with 71 questions in six domains: Preoperative, Surgery, Perforation, Postoperative, Outcome and Experts' opinion. To estimate the age-specific incidence per number of strabismus operations in the Netherlands during 1994-2013, the age distribution of Dutch cases was compared with the age-specific rates of strabismus surgery in the Dutch Registry of Strabismus Operations and with population data. Exploratory data analysis was performed. The immune state was evaluated in six patients. Five enucleated eyes were studied histopathologically. RESULTS: None of the 26 patients (27 eyes with EASS) were between 9 and 65 years old, except for one patient with retinal haemorrhage followed by endophthalmitis. In the Netherlands during 1994-2013, the rate of EASS was approximately one per 11 000 strabismus operations, but one per 4300 for children aged 0-3 and one per 1000 for patients 65 and older. Endophthalmitis was diagnosed on postoperative day 1-4 in children aged 0-3. In all 15 children aged 0-5, the 16 affected eyes were phthisical, eviscerated or enucleated. The involved eye muscle had been recessed in 25 of 27 cases. It was a medial rectus in 15 of 16 children aged 0-6. It was a lateral (6), inferior (2) or medial (1) rectus in elderly. Scleral perforation went unnoticed in all children (no record in three) and in two of seven elderly (no record in two). Histopathology showed transscleral scarring compatible with scleral perforation in four patients but, in a two-year-old girl who had EASS together with a transient medial rectus palsy, the sclera underneath the former suture tract was not perforated but did contain the long posterior ciliary artery. CONCLUSIONS: Endophthalmitis after strabismus surgery (EASS) affects children and elderly, with a grave outcome in young children. It occurs after recession of the medial rectus muscle in children, and it may occur without scleral perforation. Age and perforation are key determinants that interact with other factors that determine the occurrence and fulminance of EASS.
Assuntos
Endoftalmite/etiologia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/efeitos adversos , Complicações Pós-Operatórias/etiologia , Medição de Risco/métodos , Esclera/lesões , Estrabismo/cirurgia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Endoftalmite/epidemiologia , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco , Adulto JovemRESUMO
Emerging evidence suggests an inverse association between cancer and neurodegenerative diseases (NDD). Although phenotypically different, both diseases display a significant imbalance in the ubiquitination/deubiquitination processes. Therefore, we particularly investigated the expression of ubiquitin C-terminal hydrolases (UCHs: UCH-L1, UCH-L3, UCH-L5 and BAP1), a subfamily of deubiquitinating enzymes (DUBs), using publically available datasets (GTEx, TCGA) and observed altered expression of UCH-L1, UCH-L3, UCH-L5 in 17 cancer types. Interestingly, UCH-L1 (known to be enriched in neurons and interacting with the Parkinson's disease-associated protein α-synuclein) appeared to be a prognostic indicator of unfavorable outcome in endometrial and urothelial cancer, while increased expression of UCH-L3 and UCH-L5 was associated with poor survival in liver and thyroid cancer, respectively. In normal tissues, UCH-L1 was found to be strongly expressed in the cerebral cortex and hypothalamus, while UCH-L3 expression was somewhat higher in the testis. The occurrence of mutation rates in UCHs also suggests that BAP1 and UCH-L5 may play a more dominant role in cancers than UCH-L1 and UCH-L3. We also characterized the functional context and configuration of the repeat elements in the promoter of DUBs genes and found that UCHs are highly discriminatory for catabolic function and are mainly enriched with LINE/CR1 repeats. Regarding the thesis of an inverse association between cancer and NDD, we observed that among all DUBs, UCHs are the one most involved in both entities. Considering a putative therapeutic potential based on presumed common mechanisms, it will be useful to determine whether other DUBs can compensate for the loss of UCH activity under physiological conditions. However, experimental evidence is required to substantiate this argument.