RESUMO
Fabry-Andersen disease is a genetically determined, progressive disease related to lysosomal storage diseases, linked to the X chromosome, characterized by impaired glycosphingolipid metabolism, due to the deficiency or absence of the enzyme α-galactosidase A. Fabry disease is a multisystem disease and is characterized by damage to vital organs - kidneys, heart, brain, with the occurrence of complications that cause an unfavorable prognosis. Autoinflammation mechanisms with signs of chronic inflammation are involved in the pathogenesis of the disease. One of the features of Fabry disease are clinical manifestations in the form of arthralgia, fever, skin lesions, which are similar to rheumatological diseases. The article presents a clinical observation of the classical type of Fabry disease with multiple organ manifestation, which required differential diagnosis with rheumatological diseases. Rheumatologists are specialists who are involved in the early diagnosis of Fabry disease, so they should have a high awareness of this sphingolipidosis.
Assuntos
Doença de Fabry , Doenças Reumáticas , Humanos , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doenças Raras/diagnóstico , Doenças Raras/complicações , Doenças Raras/metabolismo , Rim/patologia , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismo , Doenças Reumáticas/etiologia , Doenças Reumáticas/complicaçõesRESUMO
Sarcomatoid carcinoma (SC), which can occur in any organ, is a rare disease. To elucidate common characteristics of SC beyond organs, we evaluated clinicopathological and immunological features of SC defined by the single histological criterion beyond organs compared to randomly matched conventional carcinoma (non-SC) adjusted for the disease stage. Immunological features were assessed by multiplex immunohistochemistry, comparing immune cell density in tumor tissues and tumor programmed death-ligand 1 (PD-L1) expression. A total of 101 patients with SC or non-SC (31 lung, 19 esophagus, 22 pancreas, 15 liver, 4 bile duct, 6 kidney, 2 uterus and 2 ovary) were identified among 7197 patients who underwent surgery at our institute (1997-2020). SC was significantly associated with worse survival (HR: 1.571; 95% CI: 1.084-2.277; P = .017). The frequency of postoperative progression within 6 months was significantly higher for SC patients (54% vs 28%; P = .002). The immune profiling revealed the densities of CD8+ T cells (130 vs 72 cells/mm2 ; P = .004) and tumor-associated macrophages (566 vs 413 cells/mm2 ; P < .0001) and the tumor PD-L1 expression score (40% vs 5%; P < .0001) were significantly higher in SCs than in non-SCs. Among 73 SC patients with postoperative progression, multivariate Cox regression analysis showed that immunotherapy tended to be associated with favorable survival (HR: 0.256; 95% CI: 0.062-1.057; P = .060). Collectively, SCs shared clinicopathological and immunological features across organs. Our study can initiate to standardize the pathological definition of SC and provide a rationale for the investigation and development for this rare disease in a cross-organ manner.
Assuntos
Carcinoma , Neoplasias Pulmonares , Feminino , Humanos , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Prognóstico , Doenças Raras/metabolismo , Carcinoma/metabolismo , Neoplasias Pulmonares/patologiaRESUMO
The deregulation of copper homoeostasis can promote various diseases such as Menkes disease or hypertrophic cardioencephalomyopathy. We have recently synthesized solid copper(II) complexes ([Cu(His)2Cl2] and [Cu(Ser)2]), stable in physiological media and with potential as therapeutic agents. This report describes: i) the biocompatibility of these complexes at concentrations up to 100 µM using a differentiated Caco-2 cells model; ii) their transport across the intestinal epithelium using a transepithelial resistance assay and monitoring the amount of copper complexes at the apical and basolateral sides of the cells. The results suggest that the flow occurs through paracellular routes. The intracellular copper retention was <2.7% with no significant differences in intracellular copper content between 6 h and 48 h, suggesting an early copper retention process. Furthermore, this is the first evidence that demonstrates [Cu(His)2Cl2] and [Cu(Ser)2] induce transcriptional downregulation of the four major copper transporters (CTR1, DMT1, ATP7A, ATP7B), and the upregulation of the metallothionein gene expression. A remarkable finding was the increase in cytochrome c oxidase activity observed after the treatment of differentiated Caco-2 cells with copper(II) complexes at concentrations of 50-100 µM. The understanding of the transport mechanisms of these copper(II) complexes across the intestinal epithelium and of their subsequent biological activities could contribute to the development of optimal pharmaceutical formulations for the therapy of copper deficiency-related diseases.
Assuntos
Proteínas de Transporte de Cátions , Cobre , Humanos , Cobre/farmacologia , Células CACO-2 , Doenças Raras/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Mucosa Intestinal/metabolismo , ATPases Transportadoras de Cobre/genética , ATPases Transportadoras de Cobre/metabolismoRESUMO
Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinose/tratamento farmacológico , Cistinose/genética , Reposicionamento de Medicamentos , Nefropatias/tratamento farmacológico , Nefropatias/genética , Doenças Raras/tratamento farmacológico , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/efeitos da radiação , Células Cultivadas , Biologia Computacional/métodos , Cistinose/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Nefropatias/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Redes e Vias Metabólicas , Doenças Raras/genética , Doenças Raras/metabolismo , TranscriptomaRESUMO
Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for these tumours supported by high quality evidence, and knowledge regarding the impact of standard treatments (i.e., surgery, radiotherapy or chemotherapy) is commonly based on retrospective studies. Recently, new molecular techniques have led to the discovery of actionable molecular alterations. The aim of this article is to review recent progress in the molecular understanding of and therapeutic options for rare brain tumours, both in children and adults. We will discuss options such as targeting the mechanistic target of rapamycin (mTOR) pathway in subependymal giant cells astrocytomas (SEGAs) of tuberous sclerosis and BRAF V600E mutation in rare glial (pleomorphic xanthoastrocytomas) or glioneuronal (gangliogliomas) tumours, which are a model of how specific molecular treatments can also favourably impact neurological symptoms (such as seizures) and quality of life. Moreover, we will discuss initial experiences in targeting new molecular alterations in gliomas, such as isocitrate dehydrogenase (IDH) mutations and neurotrophic tyrosine receptor kinase (NTRK) fusions, and in medulloblastomas such as the sonic hedgehog (SHH) pathway.
Assuntos
Neoplasias Encefálicas , Terapia de Alvo Molecular , Mutação , Proteínas de Neoplasias , Doenças Raras , Transdução de Sinais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Doenças Raras/genética , Doenças Raras/metabolismo , Doenças Raras/terapiaRESUMO
Melanoma is derived from melanocytes located in multiple regions of the body. Cutaneous melanoma (CM) represents the major subgroup, but less-common subtypes including uveal melanoma (UM), mucosal melanoma (MM), and acral melanoma (AM) arise that have distinct genetic profiles. Treatments effective for CM are ineffective in UM, AM, and MM, and patient survival remains poor. As reprogrammed cancer metabolism is associated with tumorigenesis, the underlying mechanisms are well studied and provide therapeutic opportunities in many cancers; however, metabolism is less well studied in rarer melanoma subtypes. We summarize current knowledge of the metabolic alterations in rare melanoma and potential applications of targeting cancer metabolism to improve the therapeutic options available to UM, AM, and MM patients.
Assuntos
Melanoma/metabolismo , Redes e Vias Metabólicas/genética , Mucosa/patologia , Doenças Raras/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Uveais/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Progressão da Doença , Humanos , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Mutação , Doenças Raras/genética , Doenças Raras/mortalidade , Doenças Raras/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Neoplasias Uveais/genética , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologiaRESUMO
DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.
Assuntos
Metilação de DNA/genética , Doenças Genéticas Inatas/genética , Histonas/genética , Mutação , Doenças Raras/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/genética , Doenças Genéticas Inatas/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Humanos , Proteínas de Neoplasias/genética , Doenças Raras/metabolismo , DNA Metiltransferase 3BRESUMO
INTRODUCTION: Extrapulmonary small-cell cancer (EPSCC) is a relatively rare malignancy. The management of EPSCC is usually extrapolated from small-cell lung cancer (SCLC). In spite of the morphological similarity of the 2 malignancies, there are many differences in clinical features, prognosis, and recommendations of treatment of these disorders. The data on the correlation of clinical-pathological characteristics of EPSCC and treatment results is scarce. MATERIALS AND METHODS: This retrospective analysis of 41 consecutively treated patients diagnosed with EPSCC in 2015-2018 was performed in a tertiary medical center. The correlation between the clinical and pathological characteristics and the treatment outcome (response rate, disease-free interval, and overall medial survival) was done using the standard statistics, Kaplan-Meier method, and multivariate analyses. The stratification was done on the stage of the disease, Ki-67 proliferative index, the location of the tumor, and smoking. RESULTS: Forty-one patients were included with a median age of 66.3 years. The most common primary site was the gastrointestinal tract (28, 68.3%) including the pancreas. The most common distant metastasis site was the liver (23, 56.1%). Only 2 patients (4.9%) had brain metastases. Unlike in SCLC, most patients did not have any history of smoking (23, 56.1%). Nineteen patients with metastatic disease received systemic treatment, mostly cisplatin-based chemotherapy, with a response rate of 57.9%. The results of treatment were significantly better in patients with disseminated EPSCC with Ki-67 <55%, while its role in limited disease was nonsignificant. DISCUSSION: The results of our study show the unique entity of EPSCC. The rarity of brain metastases proves that prophylactic brain irradiation should not be recommended in practice. The provocative idea of prophylactic liver irradiation in limited-stage EPSCC of gastrointestinal origin can be evaluated in future studies. The predictive role of Ki-67 is important in metastatic EPSCC. There is probably no role of smoking in developing EPSCC.
Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Carcinoma de Células Pequenas/terapia , Cisplatino/uso terapêutico , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Tumores Neuroendócrinos/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Quimiorradioterapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Doenças Raras/metabolismo , Doenças Raras/patologia , Doenças Raras/terapia , Estudos Retrospectivos , Centros de Atenção Terciária , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Renal amyloidosis (RA) is a rare disease, typically manifested with proteinuria, nephrotic syndrome, and ultimately leads to renal failure. The present study aims to profile the proteomes of renal amyloidosis patient's serum and healthy controls, along with relative quantification to find out robust markers for RA. METHODS: In this study, 12 RA patients and their corresponding age and gender-matched healthy controls were recruited from the Nephrology department of Max Super Specialty Hospital, New Delhi. We employed gel-based proteomic approach coupled with MALDI-TOF MS to compare protein expression patterns in RA patients and controls. Furthermore, validation of differential proteins (selected) was done using bio-layer interferometry. RESULTS: Eleven proteins showed remarkably altered expression levels. Moreover, expression modulation of three proteins (LLPH, SLC25A51, and CHMP2B) was validated which corroborated with two-dimensional gel electrophoresis (2-DE) results showing significant upregulation (p < 0.05) in RA patients followed by ROC analysis which demonstrated the diagnostic potential of these proteins. A protein-protein master network was generated implicating the above identified proteins along with their interactors, fishing out the routes leading to amyloidosis. CONCLUSION: This study indicates that the identified serum proteomic signatures could improve early diagnosis and lead to possible therapeutic targets in RA.
Assuntos
Amiloidose/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Nefropatias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Nucleares/metabolismo , Proteômica , Proteínas de Ligação a RNA/metabolismo , Eletroforese em Gel Bidimensional , Feminino , Humanos , Masculino , Proteoma/análise , Proteoma/metabolismo , Doenças Raras/metabolismoRESUMO
INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung carcinoma (NSCLC), which characterized by insensitive to conventional radiotherapy and chemotherapy and poor prognosis. Except MET exon 14 alterations and other oncogene mutations, PSC commonly harbor high tumor mutational burden (TMB) and high level of PD-L1, which provide new therapeutic opportunities. Toripalimab (JS001) is IgG4 monoclonal antibody targeting PD-1, which has been approved for treatment of patients with metastatic melanoma after previous systemic therapy. PD-1 combined with radiotherapy has been tried in several cancer types. CASE PRESENTATION: We reported a case of a PSC patient with PD-L1 overexpression responding to toripalimab and after progression the patients also benefits from toripalimab combined with local radiotherapy, which provides a promising option for PSC patients. CONCLUSION: This case provides the evidence of the effective role of toripalimab and PD-1 combined with local radiotherapy in PSC patients, which was the first application as far as we know.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Indóis/uso terapêutico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Taxa de Mutação , Quinolinas/uso terapêutico , Doenças Raras/genética , Doenças Raras/metabolismo , Resultado do TratamentoRESUMO
Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next-generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Doenças Raras/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Doenças Raras/metabolismo , Doenças Raras/patologia , Receptor ErbB-2/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteína Smad4/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75NTR). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Doenças do Sistema Nervoso/terapia , Doenças Raras/terapia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Doenças do Sistema Nervoso/metabolismo , Doenças Raras/metabolismo , Transdução de SinaisRESUMO
Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2-5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Neuroendócrino/patologia , Doenças Raras/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Feminino , Humanos , Gradação de Tumores , Doenças Raras/genética , Doenças Raras/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
The leiomyoma is a benign smooth-muscle neoplasm commonly found in the female genital tract, gastrointestinal tract, or skin. Leiomyomas of the oral cavity are unusual. Oral leiomyomas are uncommon due to the paucity of the smooth muscle in the mouth (except in blood vessels) and thus the involvement of jaw bones is extremely rare. Leiomyomas have been classified as solid angiomyoma, angioleiomyoma (vascular leiomyoma), and epithelioid variants. Angioleiomyomas are benign mesenchymal tumors derived from smooth muscle, which rarely occur in the oral cavity. Malignant transformation probably does not occur but careful histopathologic examination is still necessary to differentiate these benign lesions from their malignant counterparts due to different prognosis. Although uncommon in the maxilla and mandible, they should be included in the differential diagnosis of radiolucent lesions of jaw bones. An extensive search of literature was carried out on the Medline-PubMed and Google Scholar database using the keywords such as leiomyoma, angioleiomyoma, jaw bones, maxilla, mandible, intra-osseous to thoroughly search and collect all the reported cases of intraosseous leiomyoma (but our search was not limited to these terms only). To the best of our knowledge, only 23 cases of intraosseous leiomyomas have been reported so far in the jaw bones, among which only 8 belonged to angioleiomyomas. Herein, we report the 9th case of intraosseous angioleiomyoma, one of the variants of leiomyoma and overall 24th intraosseous leiomyoma in a 6-year-old female child, together with conventional histopathologic and immunohistochemical findings.
Assuntos
Angiomioma/patologia , Neoplasias Mandibulares/patologia , Doenças Raras/patologia , Actinas/metabolismo , Angiomioma/metabolismo , Angiomioma/cirurgia , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Criança , Feminino , Humanos , Neoplasias Mandibulares/metabolismo , Neoplasias Mandibulares/cirurgia , Músculo Liso/metabolismo , Músculo Liso/patologia , Doenças Raras/metabolismo , Doenças Raras/cirurgiaRESUMO
INTRODUCTION: Ewing sarcoma (ES) is a small, round cell sarcoma that rarely occurs in solid organs, including the pancreas. A diagnostic overlap exists with other primary pancreatic neoplasms, especially for specimens from small biopsies and fine needle aspiration (FNA). To improve the diagnosis of this rare pancreatic tumor, we have reported a series of 13 cases of primary pancreatic ES and reviewed the cytopathologic, surgical pathology, clinical, and radiologic features of these neoplasms. MATERIALS AND METHODS: We performed a retrospective case review of 13 patients with a diagnosis of pancreatic ES from 2 tertiary academic medical centers. A combination of cytology and histopathologic slides were reviewed, and the patient demographics, clinical information, somatic genetics, and radiologic findings were obtained from the electronic medical records. RESULTS: Five FNA specimens from 5 patients and 8 surgical biopsy or resection specimens were identified and reviewed. The patients included 9 males and 4 females, with a median age of 27 years (range, 15-78 years). The cytology smears were highly cellular and showed a combination of complex tissue fragments and singly dispersed small round blue cells. The final diagnosis was ES for all 5 FNA specimens in accordance with the characteristic cytomorphology, diffuse and/or strong membranous immunolabeling for CD99, membranous ß-catenin, and molecular confirmation of EWSR1 using fluorescence in situ hybridization or reverse transcriptase polymerase chain reaction. CONCLUSIONS: The cytologic diagnosis of ES is challenging, especially in unusual locations such as the pancreas. However, the correct cytologic diagnosis is important because these patients will require neoadjuvant therapy before surgery. Confirmatory molecular studies should be required to render the diagnosis of pancreatic ES.
Assuntos
Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Doenças Raras/diagnóstico por imagem , Doenças Raras/patologia , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Sarcoma de Células Pequenas/diagnóstico por imagem , Sarcoma de Células Pequenas/patologia , Antígeno 12E7/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Doenças Raras/metabolismo , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Sarcoma de Ewing/metabolismo , Sarcoma de Células Pequenas/metabolismo , Adulto Jovem , beta Catenina/metabolismoRESUMO
A subgroup of androgen receptor-expressing tumors represents approximately 30 % of all triple negative tumors. The androgen receptor and its signaling pathways have a central biological role in this tumor entity. These triple negative androgen receptor-positive tumors occur in older patients and do not appear to have a better prognosis compared to other triple negative tumors. In addition to androgen receptor-expression, these tumors are genomically characterized by a high frequency of PIK3CA activating mutation. Three clinical trials reported efficacy data for anti-androgens (bicalutamide, abiraterone acetate and enzalutamide) based on strong preclinical rationale. These trials report clinical benefit rates in about one in five patients. These encouraging but still limited results make a case for the identification of predictive response factors and therapeutic combinations to improve response rates. This review will provide an update on the biological and clinical knowledge of this tumoral subgroup that opens the way to non-cytotoxic anti-androgen therapies.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Doenças Raras/metabolismo , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Acetato de Abiraterona/uso terapêutico , Fatores Etários , Idoso , Anilidas/uso terapêutico , Benzamidas , Classe I de Fosfatidilinositol 3-Quinases/genética , Ensaios Clínicos como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Previsões , Humanos , Mutação , Nitrilas/uso terapêutico , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Prognóstico , Doenças Raras/tratamento farmacológico , Transdução de Sinais , Compostos de Tosil/uso terapêuticoAssuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/metabolismo , Doenças Raras/metabolismo , China , Regulação da Expressão Gênica , Testes Genéticos , Humanos , Hepatopatias/genética , Hepatopatias/metabolismo , Mutação , Pancreatopatias/genética , Pancreatopatias/metabolismoRESUMO
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention.
Assuntos
Neoplasias/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Humanos , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doenças Raras/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Inactivating germline pathogenic variants of the DICER1 gene are responsible for a spectrum of rare diseases, which expanded a lot in recent years. The constitution of an U.S. registry with these patients and their families as well as the registration of patients in European databases of rare tumors helped to better identify diseases encountered in this syndrome but also to study its pathophysiology (major role in miRNA maturation and recently discovered functions, e.g. in genome integrity maintenance). Most encountered disorders are pediatric malignancies, mainly the pulmonary pneumoblastoma and Sertoli-Leydig tumours. However, benign pathologies such as thyroid goiters, cystic nephromas or pulmonary cystic lesions are also frequently reported. Homogeneous guidelines regimens written by the European groups working on very rare pediatric tumors are proposed but it is important to underscore that they rely on rare scientific data; therefore overall consensus remains precarious. The genetic counseling to families is still difficult due to the large observed spectrum of tumors and the incomplete penetrance. In this article, the authors update current knowledge on the DICER1 syndrome.
Assuntos
RNA Helicases DEAD-box/genética , Neoplasias/genética , Doenças Raras/genética , Ribonuclease III/genética , RNA Helicases DEAD-box/metabolismo , Feminino , Aconselhamento Genético , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Doenças Raras/diagnóstico , Doenças Raras/metabolismo , Ribonuclease III/metabolismo , SíndromeRESUMO
Genomic analysis of cancer offers the hope of identifying new treatments or aiding in the selection of existing treatments. Rare leukemias pose additional challenges in this regard as samples may be hard to acquire and when found the underlying pathway may not be attractive to drug development since so few individuals are affected. In this case, it can be useful to identify common mutational overlap among subsets of rare leukemias to increase the number of individuals that may benefit from a targeted therapy. This chapter examines the current mutational landscape of large granular lymphocyte (LGL) leukemia with a focus on STAT3 mutations, the most common mutation in LGL leukemia to date. We examined the linkage between these mutations and autoimmune symptoms and disorders, in cases of obvious and suspected LGL leukemia. We then summarized and compared mutations in a set of other rare leukemias that also have JAK/STAT signaling pathway activation brought about by genomic changes. These include T-cell acute lymphoblastic leukemia (T-ALL), T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), select peripheral T-cell lymphoma (PTCL), and adult T-cell leukemia/lymphoma (ATLL). Though STAT3 activation is common in these leukemias, the way in which it is achieved, such as the activating cytokine pathway and/or the co-mutational background, is quite diverse.