RESUMO
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC. METHODS: This was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories. RESULTS: We identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival. CONCLUSIONS: GVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/mortalidade , Adulto , Estudos Retrospectivos , Idoso , Predisposição Genética para Doença , Adulto Jovem , Biomarcadores Tumorais/genética , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples. METHODS: Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR (epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS (Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1 (c-ros oncogene 1)-unknown gene fusion, and MET (MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated. RESULTS: Overall, a median DNA concentration of 3.3 ng/µL (range 0.1-10.0 ng/µL) and 13.4 ng/µL (range 2.0-45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2-11.9 ng/µL) and 9.3 ng/µL (range 0.5-18.0 ng/µL) were also detected. KRAS exon 2 p.G12C, EGFR exon 19 p.E736_A750del hotspot mutations, and ROS1 aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7%) centers detected MET exon 14 skipping mutation. CONCLUSIONS: Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice.
RESUMO
Los neurofibromas laríngeos (NFL) son tumores benignos poco frecuentes de localización principalmente supraglótica. Se manifiestan con síntomas obstructivos de la vía aérea. El tratamiento es la resección completa del tumor mediante abordaje endoscópico; se reserva la cirugía abierta para tumores de gran extensión. Se presenta el caso de un paciente pediátrico con localización atípica de NFL asociado a neurofibromatosis tipo 1 (NF1). Se realizó resección endoscópica del tumor y la anatomía patológica informó neurofibroma plexiforme. Es importante sospechar de esta patología en todo niño con estridor inspiratorio atípico progresivo. Se sugiere seguimiento a largo plazo por la alta probabilidad de recidiva.
Laryngeal neurofibromas (LNFs) are rare benign tumors mainly located in the supraglottis. LNFs occur with airway obstruction symptoms. The treatment is complete resection via an endoscopic technique; the open approach is reserved for large tumors. Here we describe the case of a pediatric patient with LNF of atypical location associated with neurofibromatosis type 1 (NF-1). The tumor was resected with an endoscopic technique, and the pathological study reported a plexiform neurofibroma. It is important to suspect this condition in any child with atypical, progressive inspiratory stridor. Long-term follow-up is recommended due to the high rate of recurrence
Assuntos
Humanos , Masculino , Lactente , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Neurofibroma Plexiforme/cirurgia , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/diagnóstico , Laringe/patologia , Sons Respiratórios/etiologia , EndoscopiaRESUMO
Laryngeal neurofibromas (LNFs) are rare benign tumors mainly located in the supraglottis. LNFs occur with airway obstruction symptoms. The treatment is complete resection via an endoscopic technique; the open approach is reserved for large tumors. Here we describe the case of a pediatric patient with LNF of atypical location associated with neurofibromatosis type 1 (NF-1). The tumor was resected with an endoscopic technique, and the pathological study reported a plexiform neurofibroma. It is important to suspect this condition in any child with atypical, progressive inspiratory stridor. Long-term follow-up is recommended due to the high rate of recurrence.
Los neurofibromas laríngeos (NFL) son tumores benignos poco frecuentes de localización principalmente supraglótica. Se manifiestan con síntomas obstructivos de la vía aérea. El tratamiento es la resección completa del tumor mediante abordaje endoscópico; se reserva la cirugía abierta para tumores de gran extensión. Se presenta el caso de un paciente pediátrico con localización atípica de NFL asociado a neurofibromatosis tipo 1 (NF1). Se realizó resección endoscópica del tumor y la anatomía patológica informó neurofibroma plexiforme. Es importante sospechar de esta patología en todo niño con estridor inspiratorio atípico progresivo. Se sugiere seguimiento a largo plazo por la alta probabilidad de recidiva.
Assuntos
Laringe , Neurofibroma Plexiforme , Neurofibromatose 1 , Humanos , Criança , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Neurofibroma Plexiforme/diagnóstico , Neurofibroma Plexiforme/cirurgia , Neurofibroma Plexiforme/complicações , Laringe/patologia , Endoscopia , Sons Respiratórios/etiologiaRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a very heterogeneous disease. Several gene expression and mutation profiling approaches were used to classify it, and all converged to the identification of distinct molecular subtypes, with some overlapping across different approaches. However, a standardised tool to routinely classify TNBC in the clinics and guide personalised treatment is lacking. We aimed at defining a specific gene signature for each of the six TNBC subtypes proposed by Lehman et al. in 2011 (basal-like 1 (BL1); basal-like 2 (BL2); mesenchymal (M); immunomodulatory (IM); mesenchymal stem-like (MSL); and luminal androgen receptor (LAR)), to be able to accurately predict them. METHODS: Lehman's TNBCtype subtyping tool was applied to RNA-sequencing data from 482 TNBC (GSE164458), and a minimal subtype-specific gene signature was defined by combining two class comparison techniques with seven attribute selection methods. Several machine learning algorithms for subtype prediction were used, and the best classifier was applied on microarray data from 72 Italian TNBC and on the TNBC subset of the BRCA-TCGA data set. RESULTS: We identified two signatures with the 120 and 81 top up- and downregulated genes that define the six TNBC subtypes, with prediction accuracy ranging from 88.6 to 89.4%, and even improving after removal of the least important genes. Network analysis was used to identify highly interconnected genes within each subgroup. Two druggable matrix metalloproteinases were found in the BL1 and BL2 subsets, and several druggable targets were complementary to androgen receptor or aromatase in the LAR subset. Several secondary drug-target interactions were found among the upregulated genes in the M, IM and MSL subsets. CONCLUSIONS: Our study took full advantage of available TNBC data sets to stratify samples and genes into distinct subtypes, according to gene expression profiles. The development of a data mining approach to acquire a large amount of information from several data sets has allowed us to identify a well-determined minimal number of genes that may help in the recognition of TNBC subtypes. These genes, most of which have been previously found to be associated with breast cancer, have the potential to become novel diagnostic markers and/or therapeutic targets for specific TNBC subsets.
Assuntos
Transcriptoma , Neoplasias de Mama Triplo Negativas , Humanos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Análise em Microsséries , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/genética , FemininoRESUMO
Mitotane is the only approved drug for treating adrenocortical carcinoma (ACC). The regimen added to mitotane is chemotherapy with etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Target-therapy agents represent a new promising approach to cancer therapy. Among these, a preeminent role is played by agents that interfere with cell-cycle progression, such as CDK4/6-inhibitors. Here, we investigate whether ribociclib could induce a cytotoxic effect both in ACC cell line and patient-derived primary cell cultures, alone or in combined settings. Cell viability was determined by 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide assay, whereas cell proliferation was evaluated by direct count. Binary combination experiments were performed using Chou and Talalay method. Gene expression was analyzed by quantitative RT-PCR, whereas protein expression was evaluated by immunofluorescence. A double staining assay revealed that ribociclib induced a prevalent apoptotic cell death. Cell-cycle analysis was performed to evaluate the effect of ribociclib treatment on cell-cycle progression in ACC cell models. Our results indicate that ribociclib was cytotoxic and reduced the cell proliferation rate. The effect on cell viability was enhanced when ribociclib was combined with progesterone and/or mitotane. The effect of ribociclib on cell-cycle progression revealed a drug-induced cell accumulation in G2 phase. The positive relationship underlined by our results between ribociclib, progesterone, and mitotane strengthen the clinical potential of this combination.
Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Aminopiridinas/administração & dosagem , Antineoplásicos/administração & dosagem , Mitotano/administração & dosagem , Progesterona/administração & dosagem , Purinas/administração & dosagem , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , HumanosRESUMO
PURPOSE: Struma ovarii (SO) is a highly specialized ovarian teratoma, consisting of thyroid tissue. Rarely, carcinomas histologically identical to their thyroid counterparts may occur, and are comprehensively defined as malignant struma ovarii (MSO). Their optimal management is controversial, and the molecular profile of the malignant counterpart in the ovary is incompletely known. In this study, the clinicopathological and molecular features of six MSO from different Italian Institutions were analysed, to explore genetic profiles of potential therapeutic interest. METHODS: The histopathological features and immunoprofile (according to the known markers Galectin-3, HBME1, cytokeratin 19 and CD56) were reviewed. In addition, all cases underwent genetic analysis with a next-generation sequencing (NGS) hot spot cancer panel detecting mutations in 50 genes involved in cancerogenesis. RET/PTC rearrangements and TERT promoter alterations were also evaluated. RESULTS: Papillary carcinoma in all similar to its thyroid counterpart was found in five of six cases, including classical (two tumors) and follicular variant (three tumors) types. The last case was a poorly differentiated carcinoma. An activating gene mutation, was detected in five of six cases, including two NRAS, two BRAF, and one JAK3 oncogene mutations. No alterations were found in the other panel genes, nor in TERT promoter, or in RET chromosomal regions. CONCLUSIONS: MSO is a rare condition. Papillary carcinoma is the predominant malignant type, sharing both histomorphological and molecular features of its thyroid counterpart. Interestingly, the single case of poorly differentiated carcinoma displayed a JAK3 mutation. The presence of such driving mutation could be of potential interest in guiding postoperative treatment.
Assuntos
Neoplasias Ovarianas , Estruma Ovariano , Neoplasias da Glândula Tireoide , Feminino , GTP Fosfo-Hidrolases , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinase 3 , Proteínas de Membrana , Mutação , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Estruma Ovariano/genéticaRESUMO
PURPOSE: Papillary thyroid microcarcinoma (mPTC) is defined as a papillary thyroid cancer sized 10 mm or less. Despite their generally indolent clinical course and good prognosis, a subset of mPTCs shows potentially aggressive behaviour. METHODS: To search for predictors of clinical outcome of mPTCs, we retrospectively evaluated the genetic tumour profile of 100 patients (23 M/77 F, mean age ± SD 53.8 ± 13.4 years) with histologically confirmed mPTCs through analysis of BRAF, NRAS and TERT promoter mutations as well as RET/PTC translocations. RESULTS: Mean follow-up period was 8.4 ± 3.6 years. In 55 cases, mPTC were detected incidentally after surgery. Capsular invasion, bilateralism and multifocality were found in 11/100, 17/100 and 24/100 cases, respectively, while lymph-nodes metastases were present at diagnosis in 9/100 cases. After 3.5 ± 2.0 years, tumour relapse occurred in 6/100 cases and was locoregional in five (two in the thyroid bed, three in laterocervical lymph-nodes), while lung metastasis occurred in one case. Biochemical persistence of disease was seen in 1/100 case. Mutations occurred in 55/100 cases; BRAFV600E was the most frequently detected (49/100) and was associated with higher tumour size, bilateralism and follicular variant but not with capsular invasion. RET/PTC rearrangements were found in 2/100 cases, NRASQ61R in 4/100, while no mutations of TERT promoter gene were detected. Despite the observed association between BRAFV600E mutation and unfavourable histopathological features, we found no direct association with tumour recurrence, distant metastases and mortality. CONCLUSION: In our study, the search for the most frequent genetic alterations as prognostic markers in mPTCs would not have changed the therapeutic strategy.
Assuntos
Proteínas Proto-Oncogênicas B-raf , Neoplasias da Glândula Tireoide , Carcinoma Papilar , Humanos , Mutação , Recidiva Local de Neoplasia/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genéticaRESUMO
OBJECTIVES/HYPOTHESIS: To identify factors associated to increased risk of extra-laryngeal spread in pediatric patients with recurrent respiratory papillomatosis (RRP). STUDY DESIGN: Retrospective chart review. METHODS: A retrospective study was conducted evaluating the clinical charts of patients younger than 16 years with histopathologically confirmed RRP treated between January 2014 and December 2018. Characteristics of patients with and without extra-laryngeal disease dissemination were compared. Odds ratios were calculated and multivariate logistic regression analysis was performed. RESULTS: Data from 82 patients were analyzed. Mean age at symptom onset was 42 months. Fifteen (18.29%) patients had extra-laryngeal spread (ELS) at time of diagnosis and in four, the disease continued to spread to other sites. Of 67 patients with disease restricted to the larynx, 17 (25.37%) developed ELS during the disease course. Human papilloma virus (HPV) typing was performed in 49 (59.8%) patients; in 28 (57.1%) HPV subtype 6 was identified and in 21 (42.9%) HPV subtype 11. ELS was found in 11 patients with serotype 11 (52.38%) and in seven patients with serotype 6 (25%) (P = .048). Statistically significant differences for ELS were also found for age at diagnosis younger than 5 years (P = .045), presence of tracheostomy (P = .031), and need for adjuvant therapy (P = .010). CONCLUSIONS: Age at diagnosis of RRP younger than 5 years and presence of tracheostomy were factors related to ELS. A statistically significant association between infection with HPV subtype 11 and ELS were also observed. Adjuvant medication might be considered a protective factor against ELS. Laryngoscope, 131:1652-1656, 2021.
Assuntos
Doenças da Laringe/diagnóstico , Infecções por Papillomavirus/diagnóstico , Infecções Respiratórias/diagnóstico , Índice de Gravidade de Doença , Adolescente , Antivirais/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada/métodos , Terapia Combinada/estatística & dados numéricos , Papillomavirus Humano 11/isolamento & purificação , Papillomavirus Humano 6/isolamento & purificação , Humanos , Lactente , Doenças da Laringe/terapia , Doenças da Laringe/virologia , Masculino , Microcirurgia/estatística & dados numéricos , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , Fatores de Proteção , Infecções Respiratórias/terapia , Infecções Respiratórias/virologia , Estudos Retrospectivos , Fatores de Risco , Traqueostomia/estatística & dados numéricosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Targeting the MAPK pathway by combined inhibition of BRAF and MEK has increased overall survival in advanced BRAF-mutant melanoma in both therapeutic and adjuvant clinical settings. However, a significant proportion of tumors develop acquired resistance, leading to treatment failure. We have previously shown p63 to be an important inhibitor of p53-induced apoptosis in melanoma following genotoxic drug exposure. Here, we investigated the role of p63 in acquired resistance to MAPK inhibition and show that p63 isoforms are upregulated in melanoma cell lines chronically exposed to BRAF and MEK inhibition, with consequent increased resistance to apoptosis. This p63 upregulation was the result of its reduced degradation by the E3 ubiquitin ligase FBXW7. FBXW7 was itself regulated by MDM2, and in therapy-resistant melanoma cell lines, nuclear accumulation of MDM2 caused downregulation of FBXW7 and consequent upregulation of p63. Consistent with this, both FBXW7-inactivating mutations and MDM2 upregulation were found in melanoma clinical samples. Treatment of MAPK inhibitor-resistant melanoma cells with MDM2 inhibitor Nutlin-3A restored FBXW7 expression and p63 degradation in a dose-dependent manner and sensitized these cells to apoptosis. Collectively, these data provide a compelling rationale for future investigation of Nutlin-3A as an approach to abrogate acquired resistance of melanoma to MAPK inhibitor targeted therapy. SIGNIFICANCE: Upregulation of p63, an unreported mechanism of MAPK inhibitor resistance in melanoma, can be abrogated by treatment with the MDM2 inhibitor Nutlin-3A, which may serve as a strategy to overcome resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Proteínas Supressoras de Tumor/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima/efeitos dos fármacos , Adulto JovemRESUMO
Los anillos vasculares tienen una incidencia del 1 % entre las enfermedades cardiovasculares congénitas. Constituyen una malformación embriológica en la que el arco aórtico, sus ramas o las arterias pulmonares provocan presión sobre la tráquea y/o el esófago. Anatómicamente, se dividen en dos grupos, dependiendo de cómo rodean la tráquea y el esófago: completo o incompleto. La sintomatología suele iniciarse en los primeros meses de vida con estridor bifásico o espiratorio que aumenta con el llanto y la alimentación, tos traqueal de tonalidad metálica, infecciones respiratorias recurrentes, episodios de apnea refleja y cianosis, sibilancias, hiperextensión cervical, retracción esternal e intercostal, y dificultad en la alimentación. Se realizó un análisis retrospectivo de 28 pacientes con diagnóstico de anillo vascular que concurrieron a la consulta en el Servicio de Endoscopía Respiratoria del Hospital Garrahan entre enero de 2015 y septiembre de 2017.
Vascular rings account for 1 % of the congenital cardiovascular diseases. They constitute an embryological malformation in which the aortic arch, its branches, or the pulmonary arteries cause pressure on the trachea and/or oesophagus. Anatomically, they are divided into two groups -complete or incomplete- depending on how they surround the trachea and/or the oesophagus. Symptom onset is usually in the first months of life with biphasic or expiratory stridor that increases with crying and feeding, a metallic tracheal cough, recurrent respiratory infections, episodes of apnea and cyanosis, wheezing, cervical hyperextension, sternal and intercostal retraction, and feeding difficulties. A retrospective analysis of 28 patients with vascular rings seen at the Department of Respiratory Endoscopy at Garrahan Paediatric Hospital between January 2015 and September 2017 is presented.
Assuntos
Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Anel Vascular/diagnóstico por imagem , Artéria Subclávia , Tronco Braquiocefálico , Angiografia por Tomografia Computadorizada , Anel Vascular/cirurgia , Anel Vascular/terapiaRESUMO
El absceso periamigdalino es la complicación más frecuente de la amigdalitis aguda bacteriana, definido como la presencia de pus entre la cápsula periamigdalina y el músculo constrictor superior de la faringe. Habitualmente, su presentación es unilateral; es rara su afectación bilateral. Es más frecuente en adultos y poco común en niños. Cuando es bilateral, el paciente presenta odinofagia, trismus, sialorrea, fiebre y voz gutural, síntomas que comparte con el absceso unilateral, pero, en el examen físico, se evidencia abombamiento de ambos pilares anteriores, edema de úvula y paladar blando, sin asimetrías de las estructuras faríngeas. Se requiere un alto nivel de sospecha clínica para lograr el diagnóstico temprano. El manejo de la vía aérea, que podría ser dificultoso, es un aspecto importante en el tratamiento. Se presenta el caso clínico de un niño con absceso periamigdalino bilateral; se describe el proceso diagnóstico y terapéutico.
Peritonsillar abscess is the most common complication of acute bacterial tonsillitis, defined as the presence of purulent exudate between the peritonsillar capsule and the superior constrictor muscle of the pharynx. Usually, its presentation is unilateral; its bilateral involvement is rare. It is more common in adults, being uncommon in children. Clinically, it presents odynophagia, trismus, sialorrhea, fever, guttural voice, symptoms that it shares with the unilateral abscess, evidencing in the physical examination bulging of both anterior pillars, edema of the uvula and soft palate, but without asymmetries of pharyngeal structures. A high level of clinical suspicion is required to achieve early diagnosis. The management of the airway, which could be difficult, is an important aspect in the treatment. It is reported the clinical case of a child with bilateral peritonsillar abscess, the diagnostic and therapeutic process.
Assuntos
Humanos , Masculino , Criança , Adolescente , Sialorreia , Infecções Bacterianas , Trismo , Tonsilite , AbscessoRESUMO
Hotspot codon 132 mutations (R132xIDH1m) are frequent in intrahepatic cholangiocarcinoma (ICC), are druggable by anti-IDH1m agents, and could represent a marker of disease progression. Developing an assay to identify R132xIDH1m would provide a useful tool to select patients benefitting from targeted treatments. We tested a quantitative real-time allele-specific polymerase chain reaction (qPCR)-based method to detect the main R132xIDH1m in an Italian ICC series (n = 61) of formalin-fixed paraffin-embedded (FFPE) samples, and on circulating-free DNA samples. The outcomes were compared with nested PCR/Sanger sequencing. Reconstitution experiments of plasmids harboring the different R132xIDH1m mixed with wild-type (WT) DNA demonstrated that qPCR is able to detect at least 2% of all mutated allele. High efficiency was also observed on patient-derived mutated DNA mixed with WT DNA (up to 10% and 0.3 ng of mutated template); qPCR detected 16.4% of mutated samples (one R132G, three R132C and six R132L) while nested PCR/Sanger sequencing only 8.2% (four R132L and one R132G). In a single patient with an R132C-mutated tumor, qPCR was also performed on plasma samples collected at four time-points, observing an increase correlating with disease progression. In conclusion, we developed a qPCR assay which could represent a fast, inexpensive and sensitive tool both for detection of R132xIDH1m in ICC samples and monitoring disease progression from liquid biopsy.
RESUMO
Bilateral vocal cord paralysis (BVCP) is the second most common cause of neonatal stridor. The aim of this study was to describe the demographic features, aetiology, comorbidities, and management of our patients with BVCP. MATERIAL AND METHODS: We conducted a retrospective review of the clinical charts of all patients diagnosed with BVCP seen at the Department of Respiratory Endoscopy between 2011 and 2015. RESULTS: 47 patients were included. Mean age at diagnosis was 1 month and male sex predominated (63%). The aetiology was congenital in 59% and acquired in 41% of the infants. The cause was most frequently idiopathic in the former group and secondary to postoperative injury in the latter. Overall, 42 patients (89%) required tracheostomy, without statistically significant differences between the causes. Of all the patients, 39% regained vocal-cord mobility; 44% of those with congenital BVCP, 31% of those with acquired BVCP and 62.5% with idiopathic BVCP. In five patients a laryngotracheoplasty was performed with a posterior costal cartilage graft and one underwent posterior cordectomy. All were decannulated. In one patient vocal-cord lateralization was performed, avoiding tracheostomy. CONCLUSION: BVCP was most commonly of congenital cause and was mainly idiopathic within this group of patients, with a slight male preponderance. A high percentage of patients required tracheostomy. A higher recovery rate of vocal-cord mobility was observed in idiopathic BVCP, which allowed for successful decannulation. In this series, decannulation was possible in all patients that underwent surgery; however, further studies with comparison of techniques and objective assessment of swallowing and phonation are necessary.
Assuntos
Paralisia das Pregas Vocais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Paralisia das Pregas Vocais/complicações , Paralisia das Pregas Vocais/etiologia , Paralisia das Pregas Vocais/patologia , Paralisia das Pregas Vocais/terapiaRESUMO
Genetic predisposition to cutaneous malignant melanoma (CMM) involves highly penetrant predisposing genes and low and intermediate penetrant predisposing alleles. However, the missing heritability in (CMM) is still high. For such and in order to identify new genetic factors for CMM, we conducted an exome sequencing study in high-risk CMM patients. Two rounds of exome sequencing were successively performed in 33 and 27 high-risk patients. We focused on genes carrying rare nonsense, frameshift, and splice variants (allelic frequency <1%) that were present in both series of exomes. An extension study was then conducted in a large cohort (1 079 CMM patients and 1 230 Caucasian ethnically matched healthy controls), and the inactivating variants frequency was compared between groups using two-sided Fisher exact test. Two TP53AIP1 truncating mutations were identified in four patients: a frameshift c.63_64insG, p.Q22Afs*81 in two patients from the same family and in the proband of a second family; and a nonsense mutation c.95 C > A, p.Ser32Stop in a patient with multiple CMMs. In all patients, TP53AIP1 truncating variants were strongly associated with CMM risk (two-sided Fisher exact test = 0.004, OR = 3.3[1.3-8.5]). Additionally, we showed that TP53AIP1 mRNA was strongly down-regulated throughout different phases of melanoma progression. TP53AIP1 gene is a TP53 target which plays a key role by inducting apoptosis in response to UV-induced DNA damage. Constitutional mutations of TP53AIP1 had previously been involved in susceptibility to prostate cancer. Our results show that constitutional truncating TP53AIP1 mutations predispose to CMM in the French population. Replication studies in other populations should be performed.
Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Melanoma/genética , Mutação , Neoplasias Cutâneas/genética , Estudos de Casos e Controles , Estudos de Coortes , Éxons , França , Humanos , Íntrons , Nevo/genética , Estudos Prospectivos , RNA Mensageiro/genética , População Branca , Sequenciamento do ExomaRESUMO
Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21WAF1/CIP1; iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer.
Assuntos
Neoplasias da Próstata/metabolismo , Receptor Notch1/metabolismo , Idoso , Carcinogênese , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Genes Supressores de Tumor , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptor Notch1/genética , Transdução de SinaisRESUMO
Differently from most transformed cells, cutaneous melanoma expresses the pleiotropic factor thrombospondin-1 (TSP-1). Herein, we show that TSP-1 (RNA and protein), undetectable in four cultures of melanocytes and a RGP melanoma, was variously present in 13 cell lines from advanced melanomas or metastases. Moreover, microarray analysis of 55 human lesions showed higher TSP-1 expression in primary melanomas and metastases than in common and dysplastic nevi. In a functional enrichment analysis, the expression of TSP-1 correlated with motility-related genes. Accordingly, TSP-1 production was associated with melanoma cell motility in vitro and lung colonization potential in vivo. VEGF/VEGFR-1 and FGF-2, involved in melanoma progression, regulated TSP-1 production. These factors were coexpressed with TSP-1 and correlated negatively with Slug (SNAI2), a cell migration master gene implicated in melanoma metastasis. We conclude that TSP-1 cooperates with FGF-2 and VEGF/VEGFR-1 in determining melanoma invasion and metastasis, as part of a Slug-independent motility program.
Assuntos
Movimento Celular , Fator 2 de Crescimento de Fibroblastos/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/patologia , Trombospondina 1/metabolismo , Fatores de Transcrição/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Tumoral , Redes Reguladoras de Genes , Humanos , Pulmão/patologia , Melanoma/metabolismo , Camundongos , Células NIH 3T3 , Metástase Neoplásica , Fenótipo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Fatores de Transcrição da Família SnailRESUMO
Aromatase inhibitors (AIs), such as anastrozole, are established in the treatment of hormone-dependent breast cancer. However, â¼20% of patients with hormone receptor-positive breast tumors treated with anastrozole do not respond and it remains impossible to accurately predict sensitivity. Since polymorphisms in the aromatase gene may influence the response to inhibitory drugs, we evaluated the presence of rs6493497 and rs7176005 polymorphisms (mapping in the 5'-flanking region of the CYP19A1 gene coding for the aromatase protein) in a cohort of 37 patients with postmenopausal breast cancer who received three-month neoadjuvant treatment with anastrozole. We then investigated any association of the polymorphisms with changes in aromatase mRNA expression change and/or response to treatment. We also analyzed five miRNAs computationally predicted to target aromatase, to observe any association between their expression and sensitivity to anastrozole. Three samples carried the two polymorphisms and the remaining samples were wild-type for both, however, no association with response or with aromatase mRNA basal expression level or expression difference after therapy was observed. Polymorphic samples that were resistant to anastrozole showed no change or decrease in aromatase expression following AI treatment, whereas an increase in expression was observed for the polymorphic responsive samples. No statistically significant correlation was observed between miRNA and aromatase mRNA expression, or with response to anastrozole neoadjuvant treatment. These data indicate that the polymorphisms analyzed are not involved in aromatase activity and that other epigenetic mechanisms may regulate aromatase protein expression.
RESUMO
The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents.