Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Inibidores de Checkpoint Imunológico , Instabilidade de Microssatélites , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Metástase NeoplásicaRESUMO
KRAS G12C mutations are found in about 12-13% of LUAD samples and it is unclear whether they are associated with worse survival outcomes in resected, stage I LUAD. We assessed whether KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours and to KRAS wild-type tumours in a cohort of resected, stage I LUAD (IRE cohort). We then leveraged on publicly available datasets (TCGA-LUAD, MSK-LUAD604) to further test the hypothesis in external cohorts. In the stage I IRE cohort we found a significant association between the KRAS-G12C mutation and worse DFS in multivariable analysis (HR: 2.47). In the TCGA-LUAD stage I cohort we did not find statistically significant associations between the KRAS-G12C mutation and DFS. In the MSK-LUAD604 stage I cohort we found that KRAS-G12C mutated tumours had worse RFS when compared to KRAS-nonG12C mutated tumours in univariable analysis (HR 3.5). In the pooled stage I cohort we found that KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours (HR 2.6), to KRAS wild-type tumours (HR 1.6) and to any other tumours (HR 1.8); in multivariable analysis, the KRAS-G12C mutation was associated with worse DFS (HR 1.61). Our results suggest that patients with resected, stage I LUAD with a KRAS-G12C mutation may have inferior survival outcomes..
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Prognóstico , Neoplasias Pulmonares/patologia , MutaçãoRESUMO
BACKGROUND: In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers. METHODS: We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res). RESULTS: In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions. CONCLUSIONS: Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.
RESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy. PATIENTS AND METHODS: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study. RESULTS: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes. CONCLUSIONS: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Imunoterapia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Fator 2 Relacionado a NF-E2 , Ensaios Clínicos Controlados Aleatórios como Assunto , Microambiente TumoralRESUMO
To obtain insights into the genetic mechanisms of ageing, we studied the frequency of the simultaneous presence of polymorphisms in phase I and phase II genes and of several p53 germline mutations in a group of 66 nonagenarians and centenarians in good health, selected from a larger sample of a multicentre Italian study in Northern Italy, and in a sample of 150 young healthy volunteers of the same ethnic group. We found a statistically significant difference in the frequency of 1the GSTT1 deletion and the p53 genotypes: the absence of any p53 polymorphisms and of GSTT1 deletion, and the simultaneous presence of the three p53 polymorphisms and of GSTT1 deletion, were much more frequent in young subjects than in centenarians (41.5% versus 26.9% and 8.8% versus 3.8%, respectively). One hypothesis to explain this difference is that subjects with both GSTT1 deletion and p53 polymorphisms may accumulate carcinogens and may have reduced DNA repair ability, and thus are more at risk for cancer. Another possible explanation is that both metabolic genes and p53 act on pathways related to cell ageing and death, and therefore certain composite genetic patterns could represent a generic mechanism of protection against ageing, not just against the development of chronic diseases. It is likely that longevity is related to a complex genetic trait as well as to certain environmental exposures.
Assuntos
Glutationa Transferase/genética , Longevidade/genética , Polimorfismo Genético , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Estudos de Casos e Controles , Feminino , Humanos , Itália/epidemiologia , Masculino , Metabolismo/genética , Epidemiologia Molecular , MutaçãoRESUMO
We have created a database of published and unpublished studies on genetic susceptibility to environmental carcinogens, by bringing together many single studies that are too small to give definitive answers on the role of metabolic genes in cancer susceptibility. Possible participants were identified through a literature search of case control studies published up to June 1999 on metabolic gene polymorphisms and cancer, and invited to send their data sets without personal identifiers. Individual data from a total of over 30,000 subjects (52% cancer cases, 48% controls) have been collected. The most common type of cancer is lung, followed by bladder, head and neck, and breast. Demographic data, such as age, sex, and race were obtained for almost all the subjects. Main exposures, such as smoking, alcohol, occupational exposure were also included in a portion of the data set. The simultaneous presence of two gene polymorphisms has been assessed in 3535 controls and 3445 cases. An Advisory Committee has evaluated and approved 8 proposals to analyze the available data. This project allows the study of the main effects of genes, gene-exposure effects, ethnic and geographic differences in allele frequencies, gene-environment and gene-gene interaction as possible risk factors for cancer.
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Carcinógenos/efeitos adversos , Bases de Dados Factuais , Poluentes Ambientais/efeitos adversos , Predisposição Genética para Doença , Neoplasias/etiologia , Estudos de Casos e Controles , Exposição Ambiental , Estudos Epidemiológicos , Etnicidade , Feminino , Geografia , Humanos , Cooperação Internacional , Masculino , Epidemiologia Molecular , Neoplasias/epidemiologia , Fatores de RiscoRESUMO
The aim of this study was to investigate the association of NAT2 gene polymorphism with bladder cancer using the data derived from the International Project on Genetic Susceptibility to Environmental Carcinogens. Four case control studies conducted in four European countries, plus two case series, one from England and one from Germany, for a total of 1530 cases and 731 controls (all Caucasian) were included. The interaction between NAT2 and bladder cancer considering smoking habits and occupational exposure was studied. There was a significant association between NAT2 and bladder cancer (odds ratio: 1.42, 95% confidence interval: 1.14-1.77), with a slightly significant heterogeneity among studies. However, heterogeneity disappeared when smokers were divided into current and ex-smokers. The risk of cancer was elevated in smokers and occupationally exposed subjects, with the highest risk among slow acetylators. The increase in risk was limited, in fact, to current smokers (odds ratio = 1.74, 95% confidence interval: 0.96-3.15). This analysis confirms that the NAT2 genotype is a risk factor for bladder cancer by interacting with smoking or occupational exposures. Our observation suggests that NAT2 is not a risk factors per se but modulates the effect of carcinogens contained in tobacco smoke (probably arylamines) or associated with occupational exposures.
Assuntos
Arilamina N-Acetiltransferase/genética , Carcinógenos Ambientais/efeitos adversos , Exposição Ocupacional , Fumar/efeitos adversos , Neoplasias da Bexiga Urinária/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Inglaterra/epidemiologia , Estudos Epidemiológicos , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , Fatores de RiscoRESUMO
Drug metabolizing enzymes are involved in the detoxification of several drugs, environmental substances, and carcinogenic compounds, and their polymorphisms have been associated with risk for a variety of cancer. In this paper, we compared the frequency of polymorphisms in cytochrome P450-1A1 gene (CYP1A1), a phase 1 gene (oxidation, activation), and of two polymorphisms of glutathione S-transferase enzymes (GSTM1, GSTT1), two phase 2 genes (conjugation, detoxification). Two groups were studied and compared, i.e., 94 nonagenarians and centenarians and 418 control subjects of younger age. A significant difference in the proportion of nonagenarians and centenarians homozygotes for a GSTT1 deletion (28%) was observed in comparison to control subjects (19%, P = 0.03). The distribution of the other gene polymorphisms did not differ in the two groups. These findings on phase 2 drug-metabolizing enzyme gene polymorphisms may help in disentangling gene-environmental interactions which can have a role in successful aging and longevity, as well as in cancer incidence in the oldest old.
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Envelhecimento , Citocromo P-450 CYP1A1/genética , Glutationa Transferase/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Citocromo P-450 CYP1A1/metabolismo , Feminino , Frequência do Gene , Genótipo , Glutationa Transferase/metabolismo , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The only component of the lectin-related protein family so far reported in Lima bean (Phaseolus lunatus L.) seeds is the minor seed lectin (LBL). In the morphotype Big Lima, we have isolated and characterised two abundant lectin-related seed proteins and the corresponding cDNA clones. The clones show 93.7% nucleotide identity and encode an arcelin-like (ARL) and an alpha-amylase inhibitor-like (AIL) protein. Not considering the signal peptides, ARL and AIL polypeptides contain 239 and 233 amino acids, respectively. Each polypeptide is present in the mature protein as two glycoforms. ARL subunits (43 and 46 kDa) make up oligomers of about 125 to 130 kDa whereas AIL subunits (40 and 42 kDa) oligomerise in dimers of about 88 to 100 kDa. cDNA clones encoding two isoforms of the less abundant Lima bean lectin were also isolated. In common bean (P. vulgaris) the lectin locus encodes the lectin and the lectin-related proteins alpha-amylase inhibitor and arcelin, all plant defence proteins. Our data indicate extensive evolution of the locus also in Lima bean.
Assuntos
Fabaceae/química , Lectinas/química , Plantas Medicinais , Sequência de Aminoácidos , Clonagem Molecular , Reações Cruzadas/imunologia , Evolução Molecular , Dados de Sequência Molecular , Fragmentos de Peptídeos , Lectinas de Plantas , Proteínas de Plantas/análise , Proteínas de Plantas/química , Conformação Proteica , Sementes/química , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico , Inibidores da Tripsina , alfa-Amilases/antagonistas & inibidoresAssuntos
Angioplastia/normas , Doenças Vasculares Periféricas/terapia , Angiografia/instrumentação , Angiografia/normas , Angioplastia/economia , Angioplastia/instrumentação , Análise Custo-Benefício , Desenho de Equipamento , Estudos de Avaliação como Assunto , Humanos , Doenças Vasculares Periféricas/diagnóstico por imagem , Radiologia Intervencionista/instrumentação , Radiologia Intervencionista/normas , Sociedades Médicas , Resultado do TratamentoRESUMO
OBJECTIVE: The purpose of this study was to determine if abnormal findings on duplex sonographic examination after peripheral artery angioplasty correlate with the subsequent recurrence of a stenosis. SUBJECTS AND METHODS: We used duplex sonography to examine 35 stenoses in 23 patients within 48 hr after the patients had angioplasty to treat these stenoses. Patients were followed up for 3 years by using one or more of the following: assessment of signs and symptoms, monitoring of peripheral pulses, pulse volume recordings, and angiography. Life tables were constructed to compare long-term patency with the presence of abnormal findings seen on duplex sonograms. Abnormal findings at the dilated segment included a blood-flow velocity greater than 120 cm/sec or a residual elevated velocity ratio greater than 1.4 or 2.0 immediately after angioplasty. RESULTS: Twelve (34%) of 35 angioplasty sites showed recurrent stenosis before 36 months. Patency at 24 months was calculated for velocities less than 120 cm/sec vs velocities of 120 cm/sec or greater (41% vs 68%), for velocity ratios less than 1.4 vs ratios of 1.4 or greater (63% vs 57%), and for velocity ratios less than 2.0 vs ratios of 2.0 or greater (54% vs 74%). We found no significant difference in patency between those patients with normal findings and those with abnormal findings on duplex sonographic examination after angioplasty. CONCLUSION: Abnormal findings on duplex sonograms obtained immediately after peripheral angioplasty cannot be used to predict subacute restenosis.
Assuntos
Angioplastia com Balão , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/terapia , Artéria Femoral , Artéria Poplítea , Arteriopatias Oclusivas/fisiopatologia , Velocidade do Fluxo Sanguíneo , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/fisiopatologia , Humanos , Tábuas de Vida , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/fisiopatologia , Estudos Prospectivos , Radiografia , Recidiva , Ultrassonografia , Grau de Desobstrução VascularRESUMO
We have analyzed a group of patients treated by various urologists with both neodymium-YAG laser photoirradiation and transurethral resection in the treatment of superficial bladder carcinoma. The average hospitalization for the group of patients treated by the laser was significantly shorter than the group of patients treated by transurethral resection of the bladder tumor. The complications were similar. The cost savings to patients treated by laser photoirradiation appears to be significantly greater in laser groups of patients as opposed to conventional transurethral resection techniques.
Assuntos
Cistectomia/economia , Terapia a Laser/economia , Neoplasias da Bexiga Urinária/economia , Neoplasias da Bexiga Urinária/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Custos e Análise de Custo , Cistectomia/métodos , Humanos , Tempo de Internação/economia , Pessoa de Meia-IdadeRESUMO
Fifty-one patients (86 legs) were studied from the aorta to the popliteal artery with both duplex ultrasonography and arteriography with the intention of establishing diagnostic ultrasonographic criteria for degrees of stenosis greater than 50% and determining the effect of multi-segment disease on the accuracy of these criteria. Receiver operator characteristic curves were used to determine diagnostic criteria for greater than 50%, greater than 70%, greater than 90% diameter stenoses or occlusions. A stenosis of greater than 70% was diagnosed either if the peak systolic velocity was more than 160 cm/sec (sensitivity 77%, specificity 90%) of if there was an increase in peak systolic velocity of 100% with respect to the arterial segment above the stenosis (sensitivity 80%, specificity 93%). Sequential stenoses were detected with lesser sensitivities. Ratio criteria were more accurate than peak systolic velocity for all degrees of stenosis. For detection of occlusion, duplex ultrasonography was 92% sensitive and 99% specific.
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Arteriopatias Oclusivas/diagnóstico por imagem , Perna (Membro)/irrigação sanguínea , Velocidade do Fluxo Sanguíneo , Constrição Patológica/diagnóstico por imagem , Humanos , Perna (Membro)/diagnóstico por imagem , Valor Preditivo dos Testes , Curva ROC , Radiografia , UltrassonografiaRESUMO
We reviewed our experience with 81 patients who had undergone followup needle biopsies of the prostate between 12 and 27 months after 192iridium template radiotherapy combined with external beam radiation therapy. When broken down by stage 82% of the patients with stage A2, 92% with B1, 95% with B2 and 55% with C disease demonstrated a negative biopsy and adequate local control of the cancer. We believe that in elderly patients, poor risk patients with early stage disease and stage C lesions this low morbidity, low mortality therapy offers a viable option to other modalities of treatment.
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Braquiterapia , Radioisótopos de Irídio/uso terapêutico , Próstata/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Idoso , Biópsia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia/métodosRESUMO
We describe a 2-month-old infant girl with typical clinical manifestations of the acrocallosal syndrome: characteristic face, agenesis of corpus callosum, polydactyly associated with other anomalies of the extremities, and mental retardation. The importance of a correct nosology and genetic counseling is underlined on the basis of the description of familiar cases of the syndrome.
Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso , Anormalidades Múltiplas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Feminino , Dedos/anormalidades , Genes Recessivos , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Síndrome , Dedos do Pé/anormalidades , Tomografia Computadorizada por Raios XRESUMO
Duplex ultrasound (US) was performed in 22 patients before and immediately after percutaneous transluminal balloon angioplasty (PTA) for peripheral artery stenoses or occlusions. Two patients underwent PTA on two occasions, and one patient underwent PTA of each lower extremity, resulting in 25 duplex US imaging pairs at a total of 40 PTA sites. The criterion for significant stenosis on duplex US studies was an increase in peak systolic velocity of at least 100% compared with the velocity in the arterial segment proximal to the lesion (velocity ratio, greater than or equal to 2.0). For 22 paired duplex US studies, pulse volume recordings or ankle-brachial indexes were obtained before and after PTA. After PTA, eight patients had residual high velocity ratios at 12 PTA sites. Only two of these patients had a residual hemodynamic stenosis as determined with post-PTA arteriography, pulse volume recordings, or ankle-brachial indexes. In this study, duplex US that was performed immediately after PTA for evaluation of residual stenosis was frequently misleading.
Assuntos
Angioplastia com Balão , Extremidades/irrigação sanguínea , Ultrassonografia , Angiografia , Arteriopatias Oclusivas/diagnóstico , Arteriopatias Oclusivas/fisiopatologia , Arteriopatias Oclusivas/terapia , Velocidade do Fluxo Sanguíneo , Humanos , Estudos ProspectivosRESUMO
Sonographic evaluation of 43 pregnant women with diabetes mellitus was performed in the third trimester of gestation for evidence of fetal macrosomia. The width of the soft tissues of the shoulder from the skin surface to the proximal humerus was compared with previously reported measurements for their ability to predict fetal macrosomia. The abdominal circumference and shoulder soft tissue measurements were the best individual predictors of macrosomia, but a combination of an abdominal circumference greater than the 90th percentile for gestational age or a shoulder soft tissue width greater than 12 mm was the best predictor with a sensitivity of 96%, specificity of 89%, and accuracy of 93%. The shoulder soft tissue width should be evaluated for evidence of macrosomia in diabetic pregnancies.