RESUMEN
The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.
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Astrocitos/metabolismo , Carcinogénesis/metabolismo , Transdiferenciación Celular , Neoplasias Cerebelosas/metabolismo , Meduloblastoma/metabolismo , Comunicación Paracrina , Animales , Linaje de la Célula , Neoplasias Cerebelosas/patología , Modelos Animales de Enfermedad , Femenino , Proteínas Hedgehog/metabolismo , Xenoinjertos , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Meduloblastoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Microambiente TumoralRESUMEN
It has previously been reported that antioxidant vitamins can help reduce the risk of vision loss associated with progression to advanced age-related macular degeneration (AMD), a leading cause of visual impairment among the elderly. Nonetheless, how oxidative stress contributes to the development of choroidal neovascularization (CNV) in some AMD patients and geographic atrophy (GA) in others is poorly understood. Here, we provide evidence demonstrating that oxidative stress cooperates with hypoxia to synergistically stimulate the accumulation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE), resulting in increased expression of the HIF-1-dependent angiogenic mediators that promote CNV. HIF-1 inhibition blocked the expression of these angiogenic mediators and prevented CNV development in an animal model of ocular oxidative stress, demonstrating the pathological role of HIF-1 in response to oxidative stress stimulation in neovascular AMD. While human-induced pluripotent stem cell (hiPSC)-derived RPE monolayers exposed to chemical oxidants resulted in disorganization and disruption of their normal architecture, RPE cells proved remarkably resistant to oxidative stress. Conversely, equivalent doses of chemical oxidants resulted in apoptosis of hiPSC-derived retinal photoreceptors. Pharmacologic inhibition of HIF-1 in the mouse retina enhanced-while HIF-1 augmentation reduced-photoreceptor apoptosis in two mouse models for oxidative stress, consistent with a protective role for HIF-1 in photoreceptors in patients with advanced dry AMD. Collectively, these results suggest that in patients with AMD, increased expression of HIF-1α in RPE exposed to oxidative stress promotes the development of CNV, but inadequate HIF-1α expression in photoreceptors contributes to the development of GA.
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Neovascularización Coroidal , Atrofia Geográfica , Degeneración Macular Húmeda , Ratones , Animales , Humanos , Anciano , Epitelio Pigmentado de la Retina/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Inhibidores de la Angiogénesis , Degeneración Macular Húmeda/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Agudeza Visual , Neovascularización Coroidal/genética , Neovascularización Coroidal/prevención & control , Neovascularización Coroidal/metabolismo , Oxidantes/metabolismo , Hipoxia/metabolismoRESUMEN
In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.
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Neoplasias Cerebelosas/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , ARN Nuclear Pequeño/genética , Adolescente , Adulto , Empalme Alternativo , Proteínas Hedgehog/metabolismo , Humanos , Mutación , Sitios de Empalme de ARN , Empalme del ARNRESUMEN
NF2-related schwannomatosis (NF2) is a rare autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas and multiple meningiomas. This case report presents the extremely rare occurrence of an anaplastic meningioma in a 12-year-old male with previously undiagnosed NF2. The patient presented with a history of abdominal pain and episodic emesis, gait unsteadiness, right upper and lower extremity weakness, and facial weakness. He had sensorineural hearing loss and wore bilateral hearing aids. MR imaging revealed a sizable left frontoparietal, dural-based meningioma with heterogeneous enhancement with mass effect on the brain and midline shift. Multiple additional CNS lesions were noted including a homogenous lesion at the level of T5 indicative of compression of the spinal cord. The patient underwent a frontotemporoparietal craniotomy for the removal of his large dural-based meningioma, utilizing neuronavigation and transdural ultrasonography for precise en bloc resection of the mass. Histopathology revealed an anaplastic meningioma, WHO grade 3, characterized by brisk mitotic activity, small-cell changes, high Ki-67 proliferation rate, and significant loss of P16. We report an anaplastic meningioma associated with an underlying diagnosis of NF2 for which we describe clinical and histopathological features.
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Neoplasias Meníngeas , Meningioma , Neurofibromatosis , Humanos , Masculino , Meningioma/cirugía , Meningioma/complicaciones , Meningioma/diagnóstico por imagen , Meningioma/patología , Niño , Neoplasias Meníngeas/cirugía , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Neurofibromatosis/complicaciones , Neurofibromatosis/cirugía , Neurofibromatosis/diagnóstico por imagen , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/cirugía , Neurofibromatosis 2/diagnóstico por imagen , Neurilemoma/cirugía , Neurilemoma/complicaciones , Neurilemoma/diagnóstico por imagen , Neurilemoma/patología , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/complicaciones , Imagen por Resonancia MagnéticaRESUMEN
Li-Fraumeni syndrome (LFS) is caused by a pathogenic germline variant at the TP53 locus and is associated with an increased predisposition to a variety of cancers. The neoplasms most frequently associated with LFS are sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. In this case report, we present a 43-year-old male diagnosed with an ocular adnexal sebaceous carcinoma of the right upper eyelid who was confirmed to have LFS with subsequent genetic testing. The mutational profile of both the patient's genetic screen and tumor sequencing were congruent, demonstrating the same pathogenic loss-of-function TP53 variant. This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had important implications for personalized patient care, including identification of contraindicated treatment interventions and the imaging modalities necessary for vigilant follow-up screening.
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Drug delivery nanoparticles (NPs) based entirely on materials generally recognized as safe that provide widespread parenchymal distribution following intracranial administration via convection-enhanced delivery (CED) are introduced. Poly(lactic-co-glycolic acid) (PLGA) NPs are coated with various poloxamers, including F68, F98, or F127, via physical adsorption to render particle surfaces non-adhesive, thereby resisting interactions with brain extracellular matrix. F127-coated PLGA (F127/PLGA) NPs provide markedly greater distribution in healthy rat brains compared to uncoated NPs and widespread coverage in orthotopically-established brain tumors. Distribution analysis of variously-sized F127/PLGA NPs determines the average rat brain tissue porosity to be between 135 and 170 nm while revealing unprecedented brain coverage of larger F127/PLGA NPs with an aid of hydraulic pressure provided by CED. Importantly, F127/PLGA NPs can be lyophilized for long-term storage without compromising their ability to penetrate the brain tissue. Further, 65- and 200-nm F127/PLGA NPs lyophilized-reconstituted and administered in a moderately hyperosmolar infusate solution show further enhance particle dissemination in the brain via osmotically-driven enlargement of the brain tissue porosity. Combination of F127/PLGA NPs and osmotic tissue modulation provides a means with a clear regulatory path to maximize the brain distribution of large NPs that enable greater drug loading and prolong drug release.
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Nanopartículas , Neoplasias , Ratas , Animales , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ácido Poliglicólico , Ácido Láctico , Portadores de Fármacos , Encéfalo , Tamaño de la PartículaRESUMEN
Chemical exchange saturation transfer (CEST) imaging is an important molecular magnetic resonance imaging technique that can image numerous low-concentration biomolecules with water-exchangeable protons (such as cellular proteins) and tissue pH. CEST, or more specially amide proton transfer-weighted imaging, has been widely used for the detection, diagnosis, and response assessment of brain tumors, and its feasibility in identifying molecular markers in gliomas has also been explored in recent years. In this paper, after briefing on the basic principles and quantification methods of CEST imaging, we review its early applications in identifying isocitrate dehydrogenase mutation status, MGMT methylation status, 1p/19q deletion status, and H3K27M mutation status in gliomas. Finally, we discuss the limitations or weaknesses in these studies.
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Neoplasias Encefálicas , Glioma , Humanos , Marcadores Genéticos , Imagen por Resonancia Magnética/métodos , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/química , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/química , Protones , Isocitrato Deshidrogenasa/genéticaRESUMEN
The purpose of this study was to evaluate the value of amide proton transfer-weighted (APTw) MRI radiomic features for the differentiation of tumor recurrence from treatment effect in malignant gliomas. Eighty-six patients who had suspected tumor recurrence after completion of chemoradiation or radiotherapy, and who had APTw-MRI data acquired at 3 T, were retrospectively analyzed. Using a fluid-attenuated inversion recovery (FLAIR) image-based mask, radiomics analysis was applied to the processed APTw and structural MR images. A chi-square automatic interaction detector decision tree was used for classification analysis. Models with and without APTw features were built using the same strategy. Tenfold cross-validation was applied to obtain the overall classification performance of each model. Sixty patients were confirmed as having tumor recurrence, and the remainder were confirmed as having treatment effect, at median time points of 190 and 171 days after therapy, respectively. There were 525 radiomic features extracted from each of the processed APTw and structural MR images. Based on these, the APTw-based model yielded the highest accuracy (86.0%) for the differentiation of tumor recurrence from treatment effect, compared with 74.4%, 76.7%, 83.7%, and 76.7% for T1 w, T2 w, FLAIR, and Gd-T1 w, respectively. Model classification accuracy was 82.6% when using the combined structural MR images (T1 w, T2 w, FLAIR, Gd-T1 w), and increased to 89.5% when using these structural plus APTw images. The corresponding sensitivity and specificity were 85.0% and 76.9% for the combination of structural MR images, and 85.0% and 100% after adding APTw image features. Adding APTw-based radiomic features increased MRI accuracy in the assessment of the treatment response in post-treatment malignant gliomas.
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Glioma , Protones , Humanos , Amidas , Recurrencia Local de Neoplasia/diagnóstico por imagen , Estudios Retrospectivos , Glioma/diagnóstico por imagen , Glioma/terapiaRESUMEN
High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.
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Astrocitoma , Neoplasias Encefálicas , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Homocigoto , Eliminación de Secuencia , Astrocitoma/genética , Astrocitoma/patología , Mutación/genética , Metilación de ADN/genéticaRESUMEN
Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte-endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Müller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.
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Retinopatía Diabética/enzimología , Retinopatía Diabética/prevención & control , Epóxido Hidrolasas/antagonistas & inhibidores , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Proteínas Portadoras/metabolismo , Membrana Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Ependimogliales , Ácidos Grasos Insaturados/metabolismo , Femenino , Humanos , Uniones Intercelulares/efectos de los fármacos , Uniones Intercelulares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Elastasa Pancreática/metabolismo , Pericitos/efectos de los fármacos , Pericitos/patología , Presenilina-1/metabolismo , Retina/efectos de los fármacos , Retina/enzimología , Retina/metabolismo , Retina/patología , Solubilidad , Cuerpo Vítreo/metabolismoRESUMEN
The mitogen-activated protein kinase pathway is one of the most frequently altered pathways in cancer. It is involved in the control of cell proliferation, invasion, and metabolism, and can cause resistance to therapy. A number of aggressive malignancies, including melanoma, colon cancer, and glioma, are driven by a constitutively activating missense mutation (V600E) in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) component of the pathway. Mitogen-activated protein kinase kinase (MEK) inhibition is initially effective in targeting these cancers, but reflexive activation of mammalian target of rapamycin (mTOR) signaling contributes to frequent therapy resistance. We have previously demonstrated that combination treatment with the MEK inhibitor trametinib and the dual mammalian target of rapamycin complex 1/2 inhibitor TAK228 improves survival and decreases vascularization in a BRAFV600E mutant glioma model. To elucidate the mechanism of action of this combination therapy and understand the ensuing tumor response, we performed comprehensive unbiased proteomic and phosphoproteomic characterization of BRAFV600E mutant glioma xenografts after short-course treatment with trametinib and TAK228. We identified 13,313 proteins and 30,928 localized phosphosites, of which 12,526 proteins and 17,444 phosphosites were quantified across all samples (data available via ProteomeXchange; identifier PXD022329). We identified distinct response signatures for each monotherapy and combination therapy and validated that combination treatment inhibited activation of the mitogen-activated protein kinase and mTOR pathways. Combination therapy also increased apoptotic signaling, suppressed angiogenesis signaling, and broadly suppressed the activity of the cyclin-dependent kinases. In response to combination therapy, both epidermal growth factor receptor and class 1 histone deacetylase proteins were activated. This study reports a detailed (phospho)proteomic analysis of the response of BRAFV600E mutant glioma to combined MEK and mTOR pathway inhibition and identifies new targets for the development of rational combination therapies for BRAF-driven tumors.
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Benzoxazoles/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Fosfoproteínas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinonas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzoxazoles/farmacología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Femenino , Glioma/genética , Glioma/metabolismo , Humanos , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Proteómica , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/farmacología , Pirimidinas/farmacología , Pirimidinonas/farmacologíaRESUMEN
Mpox is an emerging zoonotic infection with potentially severe ocular and periocular consequences, particularly in immunocompromised patients. This report summarizes 2 cases of fulminant mpox presenting in patients with AIDS. In the first case, confluent lesions resulted in orbital compartment syndrome and total eyelid necrosis. In the second case, eyelid involvement was accompanied by corneal melt and perforation. Despite aggressive medical and surgical treatment, both patients developed permanent loss of vision and ultimately expired.
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Mpox , Humanos , Cara , PárpadosRESUMEN
Giant cell arteritis (GCA) is often categorised as "active" or "healed" on temporal artery biopsy (TAB). The purpose of this study was to compare the initial clinical presentation of patients with GCA according to active versus healed arteritis on TAB. A retrospective chart review was performed for patients with biopsy-proven GCA (BP-GCA) at a single academic medical institution from a previously reported cohort. The arteritis on TAB was categorised as "active" or "healed" based on the pathological reports. Demographic information, clinical presentation, past medical history, and test results were collected from the date of TAB. These baseline characteristics were entered into the GCA Risk Calculator. Of 85 patients with BP-GCA, 80% had active and 20% had healed disease according to histopathology. A higher percentage of those with active arteritis had ischaemic optic neuropathy (ION) (36% versus 6%, p = .03), elevated erythrocyte sedimentation rates (92% versus 63%, p = .01), elevated C-reactive protein levels (79% versus 46%, p = .049), GCA risk score > 7.5% (99% sensitivity, 100% versus 71%, p < .001), higher mean GCA risk calculator scores (neural network p = .001; logistic regression p = .002). Patients with healed arteritis were less likely to have visual manifestations than the active arteritis group (38% versus 71%, p = .04). Patients with active vasculitis on biopsy had higher rates of ION and elevated inflammatory markers, as well as higher predictive scores from the GCA risk calculator. Further research is needed regarding correlation of biopsy findings and risk of complications or relapses.
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PURPOSE: To evaluate targetable mutations and molecular genetic pathways in conjunctival melanoma with clinical correlation. DESIGN: Observational case series. PARTICIPANTS: Patients with conjunctival melanoma. MAIN OUTCOME MEASURES: Mutational profile of the tumor by next-generation sequencing (NGS), alternative lengthening of telomeres (ALT) by fluorescence in situ hybridization (FISH), and ATRX immunohistochemistry. Outcomes at 2 years and 5 years of tumor-related metastasis and death were recorded. RESULTS: Of the 101 patients, mean age at presentation was 60 years, 52% were male, and 88% were White. The NGS panels initially targeted BRAF only (n = 6, 6%), BRAF/NRAS (n = 17, 17%), and BRAF/NRAS/NF1 (n = 10, 10%). Sixty-eight tumors were tested with the expanded 592-gene panel. Next-generation sequencing identified high-frequency mutations in NF1 (29/74, 39%), BRAF (31/101, 31%), NRAS (25/95, 26%), and ATRX (17/68, 25%). Of those with an ATRX mutation, 12 (71%) had an additional NF1 mutation. A subset analysis of 21 melanomas showed that the ATRX mutation was associated with loss of ATRX protein expression and ALT. Loss of ATRX expression and ALT were present in both intraepithelial and invasive tumors, suggesting that an ATRX mutation is an early event in conjunctival melanoma progression. The NF1 and ATRX mutations were associated with tarsal (vs. nontarsal) tumors (NF1: 28% vs. 9%, P = 0.035, ATRX: 41% vs. 14%, P = 0.021) and orbital (vs. nonorbital) tumors (ATRX: 24% vs. 2%, P = 0.007). ATRXMUT (vs. ATRXWT) tumors were associated with a lower 2-year rate of metastasis (0% vs. 24%, P = 0.005). NRASMUT (vs. NRASWT) tumors were associated with a greater 2-year rate of metastasis (28% vs. 14%, P = 0.07) and death (16% vs. 4%, P = 0.04), with a 5-fold increased risk of death (relative risk, 5.45 [95% confidence interval, 1.11-26.71], P = 0.039). CONCLUSIONS: This study confirms the high frequency of previously documented BRAF and NRAS mutations and recently reported ATRX and NF1 mutations in conjunctival melanoma. An NRAS mutation implied increased risk for metastasis and death. Loss of ATRX and ALT may be early events in conjunctival melanoma development.
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Neoplasias de la Conjuntiva , Melanoma , Neoplasias Cutáneas , Neoplasias de la Conjuntiva/genética , Neoplasias de la Conjuntiva/patología , Análisis Mutacional de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Melanoma/genética , Melanoma/patología , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/patologíaRESUMEN
Tumors of the central nervous system (CNS) often display a wide morphologic spectrum that has, until recently, been the sole basis for tumor classification. The introduction of the integrated histomolecular diagnostic approach in CNS tumors has facilitated a classification system that is increasingly data-driven and with improved alignment to clinical outcome. Here, we report a previously uncharacterized glioma type (n = 31) using unsupervised clustering analysis of DNA methylation array data from approximately 14,000 CNS tumor samples. Histologic examination revealed circumscribed growth and morphologic similarities to pleomorphic xanthoastrocytoma (PXA), astroblastoma, ependymoma, polymorphous neuroepithelial tumor of the young (PLNTY), and IDH-wildtype glioblastoma (GBM). Median age (46.5 years) was significantly older than other circumscribed gliomas and younger than GBM. Dimensionality reduction with uniform manifold approximation and projection (UMAP) and hierarchical clustering confirmed a methylation signature distinct from known tumor types and methylation classes. DNA sequencing revealed recurrent mutations in TP53 (57%), RB1 (26%), NF1 (26%), and NF2 (14%). BRAF V600E mutations were detected in 3/27 sequenced cases (12%). Copy number analysis showed increased whole chromosome aneuploidy with recurrent loss of chromosome 13 (28/31 cases, 90%). CDKN2A/B deletion (2/31, 6%) and MGMT promoter methylation (1/31, 3%) were notably rare events. Most tumors showed features of a high-grade glioma, yet survival data showed significantly better overall survival compared to GBM (p < 0.0001). In summary, we describe a previously uncharacterized glioma of adults identified by a distinct DNA methylation signature and recurrent loss of chromosome 13.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Monosomía , Mutación , Proteína p53 Supresora de Tumor , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Cromosomas Humanos Par 13 , Humanos , Persona de Mediana Edad , Mutación/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
In-situ hybridization provides a convenient and reliable method to detect human papillomavirus (HPV) infection in formalin-fixed paraffin-embedded tissue. Cases of conjunctival papillomas, conjunctival intraepithelial neoplasia (CIN), conjunctival carcinoma in situ (cCIS), and invasive squamous cell carcinoma (SCC), in which low-risk (LR) and/or high-risk (HR) HPV types were evaluated by RNA or DNA in-situ hybridization, were retrospectively identified. LR HPV types were frequently detected in conjunctival papillomas (25/30, 83%), including 17/18 (94%) with RNA probes, compared to 8/12 (75%) with DNA probes. None of the CIN/cCIS or SCC cases were positive for LR HPV by either method. HR HPV was detected by RNA in-situ hybridization in 1/16 (6%) of CIN/cCIS cases and 2/4 (50%) of SCC cases, while DNA in-situ hybridization failed to detect HPV infection in any of the CIN/cCIS lesions. Reactive atypia and dysplasia observed in papillomas was generally associated with the detection of LR HPV types. Collectively, our findings indicate RNA in-situ hybridization may provide a high-sensitivity approach for identifying HPV infection in squamous lesions of the conjunctiva and facilitate the distinction between reactive atypia and true dysplasia. There was no clear association between HPV infection and atopy in papillomas or dysplastic lesions.
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Alphapapillomavirus , Carcinoma in Situ , Carcinoma de Células Escamosas , Neoplasias de la Conjuntiva , Papiloma , Infecciones por Papillomavirus , Alphapapillomavirus/genética , Carcinoma in Situ/diagnóstico , Carcinoma de Células Escamosas/patología , Conjuntiva/patología , Neoplasias de la Conjuntiva/diagnóstico , Neoplasias de la Conjuntiva/genética , ADN Viral/genética , Humanos , Papiloma/complicaciones , Papiloma/patología , Papillomaviridae/genética , ARN , Estudios RetrospectivosRESUMEN
A 61-year-old man underwent left medial wall and floor fracture repair with a Suprafoil® implant. He had postoperative orbital congestion and lower eyelid swelling that persisted for over seven weeks. Examination demonstrated hyperglobus with supraduction, infraduction, and adduction deficits. Imaging revealed a 3.7 × 3.6 × 2.6 cm isodensity along the implant, thought to be hematoma. The patient elected to pursue exploration and possible drainage. Intraoperatively, there was no hematoma; rather, we found a fibroinflammatory rind along the periorbita surrounding the implant. This was biopsied, and the implant was removed, as the fractures had sufficiently healed. Pathology showed dense fibroconnective tissue with associated inflammation. The patient completed a steroid taper with improvement in all symptoms and resolution of diplopia. To our knowledge, this is the first reported case of such a prominent orbital inflammatory reaction to nylon foil, a departure from the delayed hematic cysts typically associated with these implants.
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Fracturas Orbitales , Implantes Orbitales , Masculino , Humanos , Persona de Mediana Edad , Fracturas Orbitales/diagnóstico por imagen , Fracturas Orbitales/cirugía , Nylons , Fijación de Fractura , Estudios Retrospectivos , Hematoma , Inflamación/diagnóstico por imagen , Inflamación/etiologíaRESUMEN
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with optic neuritis. First, we show extensive C3 expression in astrocytes (C3+/GFAP+ cells) and significant RGC loss (RBPMS+ cells) in post-mortem retinas from people with MS compared to retinas from non-MS individuals. A patient with progressive MS with a remote history of optic neuritis showed marked reactive astrogliosis with C3 expression in the inner retina extending into deeper layers in the affected eye more than the unaffected eye. To study whether C3 mediates retinal degeneration, we utilized global C3-/- EAE mice and found that they had less RGC loss and partially preserved neurites in the retina compared with C3+/+ EAE mice. C3-/- EAE mice had fewer axonal swellings in the optic nerve, reflecting reduced axonal injury, but had no changes in demyelination or T cell infiltration into the CNS. Using a C3-tdTomato reporter mouse line, we show definitive evidence of C3 expression in astrocytes in the retina and optic nerves of EAE mice. Conditional deletion of C3 in astrocytes showed RGC protection replicating the effects seen in the global knockouts. These data implicate astrocyte C3 expression as a critical mediator of retinal neuronal pathology in EAE and MS, and are consistent with recent studies showing C3 gene variants are associated with faster rates of retinal neurodegeneration in human disease.
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Complemento C3/metabolismo , Esclerosis Múltiple/patología , Enfermedades Neuroinflamatorias/patología , Células Ganglionares de la Retina/patología , Animales , Astrocitos/inmunología , Astrocitos/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Humanos , Ratones , Esclerosis Múltiple/inmunología , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/patología , Enfermedades Neuroinflamatorias/inmunología , Nervio Óptico/patología , Neuritis Óptica/inmunología , Neuritis Óptica/patologíaRESUMEN
Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
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Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Adolescente , Adulto , Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Estudios de Cohortes , Femenino , Humanos , Masculino , Meduloblastoma/mortalidad , Meduloblastoma/patología , Supervivencia sin Progresión , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy. Oncologic drivers of ocular sebaceous carcinoma are incompletely understood. METHODS: A retrospective search of our pathology archives for OA sebaceous carcinoma identified 18 primary resection specimens. Immunohistochemistry for p16 and ZEB1 and RNA in situ hybridization for high-risk human papillomavirus (HPV) subtypes were performed. RESULTS: High-risk HPV was demonstrated in 2/11 (18%) cases. p16 overexpression was observed in 10/11 (91%). No association between gender, age at presentation, tumor location, intraepithelial spread, tumor size, and T stage was observed between HPV-driven and nonviral cases. High expression of ZEB1 was observed in the intraepithelial component of 4/14 (28%) cases and in the subepithelial component of 1/13 (7%) cases. ZEB1 overexpression was not associated with HPV status, T stage, or tumor size. CONCLUSION: As previously described by others, our findings suggest that a subset of OA sebaceous carcinomas may arise via an HPV-dependent pathway. However, unlike high-risk HPV-driven carcinomas of the oropharynx, we did not identify an association between HPV-status and prognostic features. Furthermore, p16 expression was not a useful surrogate marker for HPV-driven disease. ZEB1 overexpression is not associated with HPV in our cohort of ocular sebaceous carcinoma.