RESUMO
PURPOSE: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations. DESIGN: Retrospective case series from academic referral centers. PARTICIPANTS: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene. METHODS: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping. MAIN OUTCOME MEASURES: Clinical characterization of UM patients with germline alterations in known cancer genes. RESULTS: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively). CONCLUSIONS: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.
Assuntos
Genes Neoplásicos/genética , Predisposição Genética para Doença/genética , Melanoma/genética , Proteínas de Neoplasias/genética , Neoplasias Uveais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Sequenciamento do ExomaRESUMO
Uveal melanoma (UM) is the most common phenotype in patients with germline BAP1 mutation. This study aimed to identify selection criteria for BAP1 germline testing and assessed the role of large deletion/duplication and epigenetic inactivation. One hundred seventy-two UM patients with high risk of hereditary cancer were included. Germline variants in BAP1 were assessed by direct sequencing and large deletion/duplication by multiplex ligation-dependent probe amplification. BAP1 expression in unaffected choroid tissue from a patient with UM was assessed by quantitative RT-PCR and methylation by pyrosequencing. Twenty-eight patients had one or more germline sequence variants in BAP1; seven of these were pathogenic. One hundred forty patients were assessed for large deletion/duplication and in one BAP1 whole gene deletion was detected. In total, eight patients (4.7%) had pathogenic alterations in BAP1 with the highest frequencies of in patients with a personal/family history of ≥2 BAP1-related cancers 6/16 (38%), age of onset <35 years 4/21 (19%) and familial UM 6/34 (18%). One of 19 non-tumor choroid tissues tested showed uncharacteristically low expression as compared to the controls decrease in BAP1 RNA expression but no evidence of constitutional promotor hypermethylation was detected. UM patients with a strong personal or family history of cancers associated with BAP1, early age of onset and familial UM should be assessed for germline variants in BAP1, including large deletions.
Assuntos
Corioide/metabolismo , Deleção de Genes , Mutação em Linhagem Germinativa , Melanoma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/metabolismoRESUMO
The BAP1-tumor predisposition syndrome (BAP1-TPDS) has been recently identified to predispose patients to a variety of cancers and preneoplastic lesions. About 130 unrelated probands have been identified worldwide; however, the impact of the syndrome is suspected to be much larger given the diversity of the cancer phenotype. To evaluate the frequency of germline BAP1 mutations in the general and cancer populations, we analyzed the Exome Aggregation Consortium (ExAC), a database that contains 53105 exomes of unrelated individuals unaffected by cancer (general population) and exomes of 7601 unrelated individuals affected by cancer provided by the Cancer Genome Atlas (TCGA, cancer subjects). BAP1 null variants were seen at much higher frequency in the cancer subjects (0.0526%) compared to the general population (0.00188%) with a relative risk of 27.93 and (P = 0.0011, [95% CI: 3.122-249.883], Fisher's exact test). We also studied a reported BAP1 null variant, c.1203T > G, p.T401* (rs200156887), observed commonly in the general population. Sequencing and restriction fragment polymorphism of the RT-4 cell line that contains this variant revealed that it is in fact a 3bp deletion/insertion, c.1201_1203delinsGAG, a likely benign missense alteration p.Y401E explaining the relative high frequency of this variant in the general population. In conclusion, germline null mutations in BAP1 have a significantly higher frequency in cancer patients than the general population. Given the low frequency of reported families with BAP1-TPDS, our results suggest that the syndrome is underreported especially in patients with cancer.
Assuntos
Predisposição Genética para Doença , Neoplasias/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Bases de Dados Genéticas , Exoma/genética , Feminino , Humanos , Masculino , Neoplasias/patologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Two polymorphisms, rs755622 and rs5844572, in the promoter region of the macrophage migration inhibitory factor (MIF) gene influence the basal and/or induced transcriptional activity and have been linked to several inflammatory and autoimmune diseases. The aim of this study was to investigate the association between these two polymorphisms and disease susceptibility in patients with biliary atresia (BA). Allele frequencies of rs755622 and rs5844572 were assessed in 60 Egyptian infants with a confirmed diagnosis of BA. DNA was extracted from archival material. For the rs755622, samples were tested using Taqman real-time PCR, and for the rs5844572, samples were tested using fluorescence-based genotyping. The allele frequency in the general population was assessed in 141 healthy adults from the same geographical location. No statistical differences were observed in the allele frequencies of either rs755622 or rs5844572 between BA patients and controls. The homozygous and heterozygous short repeats (5/5, or 5/X) of rs5844572 were observed more frequently (16/28, 57.1%) in BA patients with mild to moderate fibrosis compared with those with marked fibrosis (10/32, 31.3%). The difference was statistically significant (P = 0.032). In conclusion, we observed no association between MIF rs755622 and rs5844572 polymorphisms and susceptibility to BA; however, the rs5844572 could be linked to the rate of progression of the disease and extent of fibrosis.
Assuntos
Atresia Biliar/complicações , Fibrose/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo Genético , Atresia Biliar/genética , Feminino , Fibrose/complicações , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Regiões Promotoras GenéticasRESUMO
The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.
Assuntos
Síndromes Neoplásicas Hereditárias/genética , Fenótipo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Carcinoma de Células Renais/genética , Colangiocarcinoma/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Renais/genética , Neoplasias Hepáticas/genética , Masculino , Melanoma/genética , Mesotelioma/genética , Pessoa de Meia-Idade , Mutação , Linhagem , Neoplasias Cutâneas/genética , Neoplasias Uveais/genética , Adulto JovemAssuntos
Regulação da Expressão Gênica , Proteínas de Choque Térmico Pequenas/genética , RNA/genética , Retina/metabolismo , Descolamento Retiniano/genética , Regulação para Cima , Cadeia A de alfa-Cristalina/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Feminino , Proteínas de Choque Térmico Pequenas/biossíntese , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Retina/patologia , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia , Cadeia A de alfa-Cristalina/biossínteseAssuntos
Membrana Epirretiniana/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Descolamento Retiniano/genética , Vitreorretinopatia Proliferativa/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Membrana Epirretiniana/patologia , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Descolamento Retiniano/patologia , Estados Unidos , Vitreorretinopatia Proliferativa/patologia , Adulto JovemRESUMO
OBJECTIVE: Study the frequency of codon 7 (c.747 G>T, p. R249S) mutation associated with Aflatoxin B1 (AFB1) exposure in Egyptian patients with hepatocellular carcinoma (HCC). METHODS: We utilized restriction fragment polymorphism and direct sequencing to assess codon 7 mutations in 104 hepatocellular carcinomas. The expression of TP53 protein in the tumors were assessed in 44 tumors by a monoclonal rabbit antibody. RESULTS: We identified a single 1/104 (1%) with c.747 G>T, p. R249S variant. 28/44 (63.6%) tumors showed no or occasional (less than < 5%) nuclear staining; 9/44 (20.4%) showed mild to moderate (5-49%) and 7/44 (15.9%) showed strong ≥ 50% staining. CONCLUSION: We observed much lower frequency of TP53 gene than previously published results suggesting geographical alterations in AFB1 exposure in Egypt.
Assuntos
Aflatoxinas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Coelhos , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Aflatoxinas/efeitos adversos , Genes p53 , Egito/epidemiologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mutação , Aflatoxina B1/efeitos adversos , Códon/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Germline pathogenic variants in the tumor suppressor gene BAP1 are associated with the hereditary tumor predisposition syndrome with susceptibility to uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other cancers. Germline BAP1 pathogenic variants are rare in the non-cancer general population with an estimated carrier frequency of 1:19,898 but more common in cancer patients with a carrier frequency of 1:1299. In the following we present the first report of a family with two unique BAP1 pathogenic variants. Retrospective case report of a family with two unique pathogenic variants in BAP1. A male (proband) was referred to our ocular oncology clinic for second opinion for his multiple independent uveal melanomas at ages 65, 68 and 71. Given his personal history of squamous cell carcinoma at age 61, renal cell carcinoma at age 63, and family history of atypical meningioma, basal cell carcinoma, pancreatic and prostate cancers he was assessed for germline pathogenic variants in BAP1 through our ongoing research study. Sanger sequencing identified the American founder pathogenic variant, c.1717delC, pL573Wfs*3, that was confirmed in a clinical laboratory. Both the proband's brother and nephew tested negative for the familial variant through single site cascade genetic testing. However, based on the personal history of multiple basal cell carcinoma in the nephew and family history of pancreatic and laryngeal cancers (both not known to be associated with BAP1-TPDS), a large cancer panel testing was recommended for the nephew. His panel testing revealed a different BAP1 pathogenic variant, c.605G>A, p. Trp202*. This variant was not detected in the proband or the proband's brother. Based on the frequency of germline BAP1 variants in the cancer population, the chance of occurrence of two different BAP1 variants in a family with cancer history is 5.9 × 10-7. This case report provides support for the importance of offering large panel cascade genetic testing, rather than single site testing for only the family pathogenic variant, for all at risk family members especially when the family variant cannot explain all the cancers in the family.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Melanoma , Síndromes Neoplásicas Hereditárias , Neoplasias Cutâneas , Humanos , Masculino , Pessoa de Meia-Idade , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Predisposição Genética para Doença , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/genética , Ubiquitina Tiolesterase/genéticaRESUMO
We report a case of hepatic lymphoepithelioma-like carcinoma-hepatocellular carcinoma subtype (LEL-HCC) in a 41-year-old man with chronic hepatitis C virus (HCV) infection. The patient presented with abdominal pain and further assessment revealed a hypoechoic mass on ultrasonography. Serum alpha-fetoprotein (AFP) was 13·6 ng/dl. The patient was diagnosed as hepatocellular carcinoma based on the established triphasic computed tomography (TCT) diagnostic criteria and he underwent a surgical resection of the mass. Microscopic examination showed sheets and cords of malignant epithelial cells intermixed with heavy lymphoid infiltrate, with more than 100 tumor-infiltrating lymphocytes (TILs) per 10 high-power-field (HPF). Based on immunohistochemical studies, the malignant cells were positive for Hep Par 1 and glypican 3, focally positive for cytokeratin 7 (CK7), and negative for cytokeratin 20 (CK20). TILs were diffusely positive for cluster of differentiation 3 CD3 with an approximately equal CD4/CD8 ratio. The patient was recurrence free at 25 months after surgery, as evident by CT and serum alpha-fetoprotein level. LEL-HCC is a rare variant of HCC with a relatively better prognosis. Exploring the potential for immune modulator-based therapy in this subset of tumors is highly recommended.
Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Neoplasias Hepáticas , Masculino , Humanos , Adulto , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , alfa-Fetoproteínas , Hepatite C Crônica/complicaçõesRESUMO
The aim of the study was to investigate the molecular genetics of uveal melanoma (UM) metastases and correlate it with disease progression. Twelve pathologically confirmed UM metastases from 11 patients were included. Molecular genetic alterations in chromosomes 3 (including the BAP1 region), 8q, 6p, and 1p were investigated by microsatellite genotyping. Mutations in codon 209 of GNAQ and GNA11 genes were studied by restriction-fragment length polymorphism (RFLP). We identified monosomy of chromosome 3 in tumors from four patients with an average survival of 5 months (range 1-8 months) from time of diagnosis of metastatic disease. In contrast, tumors with either disomy or partial chromosome 3 alterations showed significantly slower metastatic disease progression with an average survival of 69 months (range 40-123 months, p = 0.003). Alterations in chromosomal arms 1p, 6p, and 8q and mutations in either GNAQ or GNA11 showed no association with disease progression. Prominent mononuclear inflammatory infiltrate was observed in tumors from patients with slowly progressive disease. In conclusion, in UM metastases, monosomy 3 is associated with highly aggressive, rapidly progressive disease while disomy or partial change of 3 and prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis. These findings should be considered when designing clinical trials testing effectiveness of various therapies of metastatic UM.
Assuntos
Cromossomos Humanos Par 3/genética , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/genética , Melanoma/genética , Monossomia/genética , Neoplasias Uveais/genética , Adulto , Idoso , Códon , Análise Mutacional de DNA , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Genótipo , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Melanoma/mortalidade , Melanoma/secundário , Melanoma/terapia , Repetições de Microssatélites , Pessoa de Meia-Idade , Biologia Molecular , Polimorfismo de Fragmento de Restrição , Taxa de Sobrevida , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Neoplasias Uveais/terapiaRESUMO
OBJECTIVE: To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer. DESIGN: A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing. RESULTS: Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 CâT (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients. CONCLUSION: This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.
Assuntos
Adenocarcinoma/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Neoplasias Pulmonares/genética , Melanoma/genética , Meningioma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 3/metabolismo , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Testes Genéticos , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Meningioma/metabolismo , Meningioma/patologia , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologiaRESUMO
Recent evidence suggests that PALB2 variants may increase risk for the development of uveal melanoma and uveal melanocytic neoplasms. Here we report a case of an atypical choroidal nevus in a patient with a personal history of cancer and pathogenic PALB2 germline variant. A 75-year-old white female presented with an elevated predominantly amelanotic choroidal lesion OS. On examination and ophthalmic imaging, the mass measured 8.8 mm × 6.5 mm × 1.5 mm. The mass showed predominantly medium to high reflectivity on diagnostic A-scan and acoustic hollowing on B-scan. OCT over the lesion showed no subretinal fluid. The patient has a personal history of breast cancer and gastric adenoma and a strong family history of cancer. The patient was found to have a pathogenic truncating variant in PALB2 (rs118203998 c.3549C > A, p.Y1183*). Together with our previous findings of pathogenic PALB2 variants in uveal melanoma patients, this new finding of an atypical choroidal nevus in a patient with a pathogenic PALB2 germline variant suggests that pathogenic PALB2 variants may be a risk factor for uveal melanocytic neoplasms. This finding warrants further assessment of the prevalence and progression of uveal melanocytic neoplasms in PALB2 pathogenic variant carriers.
Assuntos
Melanoma , Nevo , Neoplasias Uveais , Idoso , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Predisposição Genética para Doença , Humanos , Melanoma/genética , Melanoma/patologiaRESUMO
BACKGROUND: Chronic pain symptoms are distressing conditions that necessitate regular visits to pain therapists and may require interventions, however, the COVID-19 pandemic has caused patients and their therapists to limit both visits and interventions with the transition to telehealth, with little or no preparation or training. This has resulted in the extensive use of over-the counter analgesia and corticosteroids. OBJECTIVES: Our study aimed to evaluate the effect of the COVID-19 pandemic on the rates of counseling and interventional pain management therapies (IPMT), and determine the effects of implementing an infection control program (ICP) and mandating personal protective equipment (PPE) on these rates. STUDY DESIGN: Prospective multicenter survey, based on an online self-assessed questionnaire. SETTING: Departments of Anesthesia, Pain, Intensive Care Unit, Physical Medicine, Rheumatology, and Rehabilitation at Egyptian University hospitals. METHODS: A self-assessed questionnaire was uploaded on Google forms and links were sent to enrolled therapists with an identification number to allow self-administration and privacy. Feedback was analyzed by 2 authors who were blinded to the identity of the responders. RESULTS: A total of 57.9% of responders increased their patients' contact by phone and video conference. Within 1-4 months after the outbreak began, 59% stopped in-person contact and 38.2% stopped their IPM practice. Prescriptions of analgesics and oral steroids increased by about 50%. The majority of responders complained of a shortage of ventilation appliances in their workplaces. About 50% of them always use ICP, 85% use surgical masks, 61% use gloves, and 45% wear gowns when meeting with patients. After the application of PPE, 45.5% of responders increased their consultation rate and 40% increased their rate of IPMT. LIMITATIONS: This study is limited to being a national study, and so lacked comparative data. CONCLUSION: The COVID-19 outbreak seriously affected the rates of in-person consultations and IPMT for patients with chronic pain and increased the rates of consumption of analgesia and oral steroids. Most responders reported a shortage of PPE especially ventilation appliances in workplaces. A high percentage of responders lack interest in ICP and PPE, despite the positive effects of its application on consultation and IPMT rates.
Assuntos
COVID-19 , Dor Crônica , Humanos , SARS-CoV-2 , Manejo da Dor , Pandemias/prevenção & controle , Dor Crônica/terapia , Estudos Prospectivos , Transmissão de Doença Infecciosa do Paciente para o Profissional , Equipamento de Proteção IndividualRESUMO
The clinical significance of partial chromosome 3 alteration in uveal melanoma is still not clear. Also, the reported frequencies vary considerably in the published literature from 0 to 48%. The aims of the following study were to identify the frequency, molecular pathology and potential clinical significance of partial chromosome 3 alteration in uveal melanoma. We studied 47 uveal melanomas with an average follow-up of 36 months. Of these, 14 had confirmed metastasis. Allelic imbalance/loss of heterozygosity was studied using microsatellite markers on chromosome 3 enriched in markers located in the previously reported smallest regions of deletion overlap. Chromosomal alterations were assessed by conventional cytogenetics or comparative genomic hybridization (CGH) in a subset of patients. Utilizing genotyping, partial chromosome 3 alteration was detected in 14/47 tumors (30%). In the 23 tumors with available cytogenetic/CGH, partial chromosome 3 alteration was detected in 8/23 (38%) and was caused by both gains (4/8) and losses (4/8) of chromosome 3 with high frequency of complex chromosome 3 aberrations detected by cytogenetics. Out of the 14 tumors with confirmed metastasis, only 1 showed partial chromosome 3 alteration and the remaining showed monosomy 3. By limiting the aggressive disease marker to monosomy 3, genotyping showed 93% sensitivity and 67% specificity for detection of aggressive uveal melanoma. In conclusion, partial chromosome 3 alterations are common in uveal melanoma and mostly caused by complex cytogenetic changes leading to partial gains and/or partial losses of chromosome 3. Partial chromosome 3 alteration is not likely to be associated with highly aggressive uveal melanoma that metastasizes within the first 3 years after treatment. Microsatellite-based genotyping of chromosome 3 is highly sensitive for detection of aggressive uveal melanoma.
Assuntos
Cromossomos Humanos Par 3/genética , Melanoma/genética , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Feminino , Genótipo , História do Século XVII , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Masculino , Melanoma/mortalidade , Melanoma/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Reação em Cadeia da Polimerase , Neoplasias Uveais/mortalidadeRESUMO
In the following study we investigated the utility of molecular genetic testing of the DNA extracted from routinely stained and processed smears from uveal melanoma (UM). Smears from five uveal melanoma cell lines and 12 primary tumors were prepared and stained with Papanicolaou and Romanowsky stains. Genotyping was carried out utilizing 14 microsatellite markers on chromosomes 3, 6 and 8. Mutational screening for alterations in GNAQ and GNA11 genes was carried out by restriction fragment length polymorphism. The results were compared to those obtained through direct sequencing of frozen tumor tissues. High quality DNA was extracted from the stained slides with no difference in the efficiency of DNA extraction between the two staining techniques. The extracted DNA was of adequate quality for genotyping and mutational screening. DNA extracted from approximately 200 tumor cells is sufficient for reproducible testing of allelic imbalances and for studying the common somatic mutations in GNAQ and GNA11 genes. In conclusion, we presented the feasibility of utilizing routinely stained cytology smears from UM for molecular genetic testing. The DNA obtained is of sufficient quality to carry out genotyping for markers on chromosome 3, 6 and 8, as well as screening for somatic mutations in GNAQ and GNA11 genes.
Assuntos
DNA de Neoplasias/análise , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Neoplasias Uveais/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Análise Mutacional de DNA , DNA de Neoplasias/isolamento & purificação , Estudos de Viabilidade , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Genótipo , Técnicas de Genotipagem , Técnicas de Preparação Histocitológica , Humanos , Melanoma/patologia , Repetições de Microssatélites/genética , Técnicas de Diagnóstico Molecular , Polimorfismo de Fragmento de Restrição , Células Tumorais Cultivadas , Neoplasias Uveais/patologiaRESUMO
PURPOSE: To estimate point prevalence of uveal melanoma in the patients with germline BAP1 pathogenic variant. DESIGN: Cohort study with risk assessment using Bayesian analysis. METHODS: The point prevalence estimate was obtained by Bayes's rule of reverse conditional probabilities. The probability of uveal melanoma given that BAP1 mutation exists was derived from the prevalence of uveal melanoma, prevalence of germline BAP1 pathogenic variants, and the probability of germline BAP1 pathogenic variant given that uveal melanoma is present. Confidence intervals (CIs) for each variable were calculated as the mean of Bernoulli random variables and for the risk estimate, by the delta method. The age at diagnosis and the gender of the uveal melanoma patients with BAP1 germline pathogenic variants obtained from previous publications or from authors' unpublished cohort was compared with those in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The point prevalence of uveal melanoma in patients with the germline BAP1 pathogenic variants in the US population was estimated to be 2.8% (95% CI, 0.88%-4.81%). In the SEER database, the median age at diagnosis of uveal melanomas was 63 (range 3-99 years) with a male-to-female ratio of 1.01:1. In comparison, uveal melanoma cases with BAP1 germline pathogenic variants from the US population (n = 27) had a median age at diagnosis of 50.5 years (range 16-71). CONCLUSIONS: Quantification of the risk of developing uveal melanoma can enhance counseling regarding surveillance in patients with germline BAP1 pathogenic variant.
Assuntos
Predisposição Genética para Doença , Melanoma/epidemiologia , Melanoma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/epidemiologia , Neoplasias Uveais/genética , Adolescente , Adulto , Idoso , Teorema de Bayes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Probabilidade , Medição de Risco , Programa de SEER , Adulto JovemRESUMO
PURPOSE: Long interspersed nuclear element 1 (LINE-1 or L1) is a dominant non-long terminal repeat (non-LTR) retrotransposon in the human genome that has been implicated in the overexpression of MET. Both the canonical MET and L1-MET transcripts are considered to play a role in hepatocellular carcinoma (HCC) development. The aim of this study was to assess the utility of canonical MET, L1-MET, and MET protein expressions as predictive biomarkers for chemo-sensitivity to MET-inhibitors in HCC cell lines in vitro. Additionally, we assessed their expression in tumour tissues from Egyptian HCC patients. METHODS: MET and L1-MET expressions were assessed by qRT-PCR in six liver cancer cell lines (SNU-387, SNU-475, SK-HEP-1, PLC/PRF/5, SNU-449 and SNU-423) and 47 HCC tumour tissues. MET protein expression was measured by western blot in cell lines and immunohistochemistry in the tumours. Cell proliferation assay was used to assess the effect of crizotinib and tivantinib on the six liver cancer cell lines in correlation with the expression of MET, L1-MET and MET. RESULTS: The antitumor effect of crizotinib and tivantinib correlated with MET gene expression but not with L1-MET transcript or MET protein expressions. No significant difference was observed between HCC tumours and non-tumour samples in MET and L1-MET transcripts expression. There were no significant correlations between the 2-year overall survival rate and the MET, L1-MET transcripts and the MET protein expression. CONCLUSION: MET RNA expression could be useful biomarker for tivantinib and crizotinib targeted therapy in HCC. The value of assessment of MET protein expression is limited.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proliferação de Células , Crizotinibe/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Células Tumorais CultivadasRESUMO
Breast cancer is the most prominent type of cancer among women. Understanding the microenvironment of breast cancer and the interactions between cells and cytokines will lead to better treatment approaches for patients. In this study, we developed a data-driven mathematical model to investigate the dynamics of key cells and cytokines involved in breast cancer development. We used gene expression profiles of tumors to estimate the relative abundance of each immune cell and group patients based on their immune patterns. Dynamical results show the complex interplay between cells and molecules, and sensitivity analysis emphasizes the direct effects of macrophages and adipocytes on cancer cell growth. In addition, we observed the dual effect of IFN-γ on cancer proliferation, either through direct inhibition of cancer cells or by increasing the cytotoxicity of CD8+ T-cells.
RESUMO
BACKGROUND: Uveal melanoma (UM) is the most common primary ocular malignancy of adults. A small group of patients was found to express familial predisposition. Moreover, it may be preceded or followed by other malignancies elsewhere in the body. We aim to compare the incidence of UM and other associated cancers and study the factors that may influence each condition. PATIENTS AND METHODS: We have collected the data from the Surveillance, Epidemiology and End Results database of nine US cancer registries for UM patients between 1973 and 2015. We calculated the standardised incidence ratios for single primary UM, first primary and second primary UM, and compared the groups for multiple factors. RESULTS: A total of 4946 patients were included in the study; 3863 with single primary UM, 646 developed a second primary malignancy following UM, and 437 patients developed second primary UM following a previous primary malignancy. The risk of developing UM increased after leukaemia, melanoma of the skin and prostate. On the other side, the risk of developing melanoma of the skin, thyroid, renal and other eye and orbit malignancies has increased significantly after initial UM. This risk was more evident in the age group between 50 and 70 years old. Cancer-specific survival was significantly higher in UM associated with other malignancies group compared with single primary UM. CONCLUSION: Our study showed a different behaviour of the UM when associated with other tumours that exceed the known spectrum of hereditary UM. Further studies are required to dissect the genetic background of this behaviour.