RESUMO
This case report describes an adverse side effect from long-term denosumab therapy in a patient with metastatic breast cancer. The patient presented with extensive invasive cervical root resorption affecting most of her dentition. There were no other identified risk factors. As the treatment of breast cancer evolves leading to improved survival, and the number of cancer survivors increases, it is expected that dental practitioners will see a growing number of patients who are on long-term denosumab. Comprehensive dental examinations including radiographs are warranted to identify unusual or unexpected findings such as invasive cervical root resorption. © 2022 Australian Dental Association.
Assuntos
Neoplasias da Mama , Reabsorção da Raiz , Reabsorção de Dente , Austrália , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Denosumab/efeitos adversos , Odontólogos , Feminino , Humanos , Papel Profissional , Reabsorção da Raiz/diagnóstico por imagem , Reabsorção da Raiz/etiologiaRESUMO
SUMMARY: This work describes two novel workflows for variant calling that extend the widely used algorithms of Strelka2 and FreeBayes to call somatic mutations from multiple related tumour samples and one matched normal sample. We show that these workflows offer higher precision and recall than their single tumour-normal pair equivalents in both simulated and clinical sequencing data. AVAILABILITY AND IMPLEMENTATION: Source code freely available at the following link: https://atlassian.petermac.org.au/bitbucket/projects/DAW/repos/multisamplevariantcalling and executable through Janis (https://github.com/PMCC-BioinformaticsCore/janis) under the GPLv3 licence. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Neoplasias , Software , Humanos , Fluxo de Trabalho , Algoritmos , Neoplasias/genéticaRESUMO
BACKGROUND: The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma. PATIENTS AND METHODS: Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n = 29). RESULTS: ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20 months. ctDNA detection predicted patients at high risk of relapse at baseline [relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5-5.6; P = 0.002] and postoperatively (HR 10; 95% CI 4.3-24; P < 0.001). ctDNA detection at baseline [HR 2.9; 95% CI 1.3-5.7; P = 0.003 and postoperatively (HR 11; 95% CI 4.3-27; P < 0.001] was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status. CONCLUSION: Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.
Assuntos
DNA Tumoral Circulante/sangue , Melanoma/sangue , Recidiva Local de Neoplasia/sangue , Neoplasias Cutâneas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours. PATIENTS AND METHODS: Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684). RESULTS: PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling [39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive; P < 0.001] and where a surrogate IHC-based classifier was used [19% (56/302) of basal-like tumours were PD-L1 immune cell positive; P < 0.001]. Moreover, CD274 (PD-L1) amplification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26-1.07; P = 0.08) in ER-negative disease. CONCLUSIONS: Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed. NEAT CLINICALTRIALSGOV: NCT00003577.
Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Carcinoma Basocelular/imunologia , Carcinoma Basocelular/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Basocelular/patologia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Linfócitos do Interstício Tumoral/patologia , Estadiamento de Neoplasias , Estudos Observacionais como Assunto , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise Serial de TecidosRESUMO
Next-generation sequencing studies have provided further evidence to support the notion that cancer is a disease characterized by Darwinian evolution. Today, we often fail to capture this evolution and treatment decisions, even in the metastatic setting, are often based on analysis of primary tumor diagnosed years ago. Currently, this is considered a major reason for treatment failures in cancer care. Recent technological advances in the detection and characterization of circulating tumor cells and circulating tumor DNA might address this and allow for treatment tailoring based on real-time monitoring of tumor evolution. In this review, we summarize the most important recent findings in the field, focusing on challenges and opportunities in moving these tools forward in clinical practice.
Assuntos
DNA de Neoplasias/sangue , Neoplasias/diagnóstico , Células Neoplásicas Circulantes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/sangue , Neoplasias/genéticaRESUMO
BACKGROUND: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. PATIENTS AND METHODS: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. RESULTS: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). CONCLUSIONS: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.
Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Linfócitos T CD8-Positivos/patologia , Linfócitos do Interstício Tumoral/patologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores de Progesterona/metabolismo , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidadeRESUMO
BACKGROUND: High-throughput evaluation of tissue biomarkers in oncology has been greatly accelerated by the widespread use of tissue microarrays (TMAs) and immunohistochemistry. Although TMAs have the potential to facilitate protein expression profiling on a scale to rival experiments of tumour transcriptomes, the bottleneck and imprecision of manually scoring TMAs has impeded progress. METHODS: We report image analysis algorithms adapted from astronomy for the precise automated analysis of IHC in all subcellular compartments. The power of this technique is demonstrated using over 2000 breast tumours and comparing quantitative automated scores against manual assessment by pathologists. RESULTS: All continuous automated scores showed good correlation with their corresponding ordinal manual scores. For oestrogen receptor (ER), the correlation was 0.82, P<0.0001, for BCL2 0.72, P<0.0001 and for HER2 0.62, P<0.0001. Automated scores showed excellent concordance with manual scores for the unsupervised assignment of cases to 'positive' or 'negative' categories with agreement rates of up to 96%. CONCLUSION: The adaptation of astronomical algorithms coupled with their application to large annotated study cohorts, constitutes a powerful tool for the realisation of the enormous potential of digital pathology.
Assuntos
Algoritmos , Automação , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Processamento de Imagem Assistida por Computador , Análise Serial de Tecidos , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Estudos de Coortes , Citoplasma/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Variações Dependentes do Observador , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Reprodutibilidade dos Testes , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Proliferation has emerged as a major prognostic factor in luminal breast cancer. The immunohistochemical (IHC) proliferation marker Ki67 has been most extensively investigated but has not gained widespread clinical acceptance. METHODS: We have conducted a head-to-head comparison of a panel of proliferation markers, including Ki67. Our aim was to establish the marker of the greatest prognostic utility. Tumour samples from 3093 women with breast cancer were constructed as tissue microarrays. We used IHC to detect expression of mini-chromosome maintenance protein 2, Ki67, aurora kinase A (AURKA), polo-like kinase 1, geminin and phospho-histone H3. We used a Cox proportional-hazards model to investigate the association with 10-year breast cancer-specific survival (BCSS). Missing values were resolved using multiple imputation. RESULTS: The prognostic significance of proliferation was limited to oestrogen receptor (ER)-positive breast cancer. Aurora kinase A emerged as the marker of the greatest prognostic significance in a multivariate model adjusted for the standard clinical and molecular covariates (hazard ratio 1.3; 95% confidence interval 1.1-1.5; P=0.005), outperforming all other markers including Ki67. CONCLUSION: Aurora kinase A outperforms other proliferation markers as an independent predictor of BCSS in ER-positive breast cancer. It has the potential for use in routine clinical practice.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/mortalidade , Antígeno Ki-67/análise , Proteínas Serina-Treonina Quinases/análise , Adulto , Idoso , Aurora Quinase A , Aurora Quinases , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Estrogênio/biossíntese , Análise Serial de Tecidos , Adulto JovemRESUMO
BACKGROUND: Tissue micro-arrays (TMAs) are increasingly used to generate data of the molecular phenotype of tumours in clinical epidemiology studies, such as studies of disease prognosis. However, TMA data are particularly prone to missingness. A variety of methods to deal with missing data are available. However, the validity of the various approaches is dependent on the structure of the missing data and there are few empirical studies dealing with missing data from molecular pathology. The purpose of this study was to investigate the results of four commonly used approaches to handling missing data from a large, multi-centre study of the molecular pathological determinants of prognosis in breast cancer. PATIENTS AND METHODS: We pooled data from over 11,000 cases of invasive breast cancer from five studies that collected information on seven prognostic indicators together with survival time data. We compared the results of a multi-variate Cox regression using four approaches to handling missing data - complete case analysis (CCA), mean substitution (MS) and multiple imputation without inclusion of the outcome (MI-) and multiple imputation with inclusion of the outcome (MI+). We also performed an analysis in which missing data were simulated under different assumptions and the results of the four methods were compared. RESULTS: Over half the cases had missing data on at least one of the seven variables and 11 percent had missing data on 4 or more. The multi-variate hazard ratio estimates based on multiple imputation models were very similar to those derived after using MS, with similar standard errors. Hazard ratio estimates based on the CCA were only slightly different, but the estimates were less precise as the standard errors were large. However, in data simulated to be missing completely at random (MCAR) or missing at random (MAR), estimates for MI+ were least biased and most accurate, whereas estimates for CCA were most biased and least accurate. CONCLUSION: In this study, empirical results from analyses using CCA, MS, MI- and MI+ were similar, although results from CCA were less precise. The results from simulations suggest that in general MI+ is likely to be the best. Given the ease of implementing MI in standard statistical software, the results of MI+ and CCA should be compared in any multi-variate analysis where missing data are a problem.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma/metabolismo , Carcinoma/mortalidade , Interpretação Estatística de Dados , Viés , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Carcinoma/diagnóstico , Carcinoma/epidemiologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Imuno-Histoquímica/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prognóstico , Reprodutibilidade dos Testes , Projetos de Pesquisa , Análise de Sobrevida , Análise Serial de Tecidos/estatística & dados numéricosRESUMO
BACKGROUND/AIMS: Optimal delivery of intraperitoneal (i.p.) chemotherapy is dependent on adequate drug distribution. An accurate understanding of the limitations of i.p. distribution is critical if we are to improve cytotoxic delivery through this route. METHODS: Using repeated scintigraphic peritoneography we investigated peritoneal fluid distribution in patients receiving i.p. therapy. Both early (1-6 h) and late (24-48 h) images were performed. The peritoneal cavity was divided into six regions; pouch of Douglas, left and right paracolic gutters, left and right subphrenic spaces and the right subhepatic space. The distribution in each region was classified as absent (0), faint (1) or intense (2). A total distribution score was calculated from the summation of distribution values for each of the six regions. Distribution was then graded according to the total distribution score as follows: Grade 0 = 0-3; Grade 1 = 4-6; Grade 2 = 7-9; and Grade 3 = 10-12. RESULTS: Twenty-six participants were included in the study: all 26 patients had early imaging performed and 21 of these also had late imaging. Thirteen (50%) and 15 (71%) patients had grade 1 or 2 i.p. distribution on early and late imaging respectively. The most common abdominal regions to show maldistribution were the subphrenic spaces. CONCLUSIONS: This study highlights the deficiencies of distribution following i.p. drug delivery, with the majority of patients demonstrating multiple regions of faint or absent uptake on scintigraphic peritoneography imaging. Future large clinical studies investigating i.p. chemotherapy should include analyses of i.p. distribution to improve our understanding of optimal drug delivery through this route.
Assuntos
Líquido Ascítico/diagnóstico por imagem , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Líquido Ascítico/efeitos dos fármacos , Líquido Ascítico/metabolismo , Feminino , Humanos , Injeções Intraperitoneais , Neoplasias Ovarianas/metabolismo , CintilografiaRESUMO
BACKGROUND: Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL2), an antiapoptotic protein, has been proposed as a prognostic marker, but this effect is considered to relate to oestrogen receptor (ER) status. This study aimed to test the clinical validity of BCL2 as an independent prognostic marker. METHODS: Five studies of 11 212 women with early-stage breast cancer were analysed. Individual patient data included tumour size, grade, lymph node status, endocrine therapy, chemotherapy and mortality. BCL2, ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) levels were determined in all tumours. A Cox model incorporating the time-dependent effects of each variable was used to explore the prognostic significance of BCL2. RESULTS: In univariate analysis, ER, PR and BCL2 positivity was associated with improved survival and HER2 positivity with inferior survival. For ER and PR this effect was time dependent, whereas for BCL2 and HER2 the effect persisted over time. In multivariate analysis, BCL2 positivity retained independent prognostic significance (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.66-0.88, P<0.001). BCL2 was a powerful prognostic marker in ER- (HR 0.63, 95% CI 0.54-0.74, P<0.001) and ER+ disease (HR 0.56, 95% CI 0.48-0.65, P<0.001), and in HER2- (HR 0.55, 95% CI 0.49-0.61, P<0.001) and HER2+ disease (HR 0.70, 95% CI 0.57-0.85, P<0.001), irrespective of the type of adjuvant therapy received. Addition of BCL2 to the Adjuvant! Online prognostic model, for a subset of cases with a 10-year follow-up, improved the survival prediction (P=0.0039). CONCLUSIONS: BCL2 is an independent indicator of favourable prognosis for all types of early-stage breast cancer. This study establishes the rationale for introduction of BCL2 immunohistochemistry to improve prognostic stratification. Further work is now needed to ascertain the exact way to apply BCL2 testing for risk stratification and to standardise BCL2 immunohistochemistry for this application.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adulto , Idoso , Neoplasias da Mama/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Several recent studies have shown that screen detection remains an independent prognostic factor after adjusting for disease stage at presentation. This study compares the molecular characteristics of screen-detected with symptomatic breast cancers to identify if differences in tumour biology may explain some of the survival benefit conferred by screen detection. METHODS: A total of 1379 women (aged 50-70 years) with invasive breast cancer from a large population-based case-control study were included in the analysis. Individual patient data included tumour size, grade, lymph node status, adjuvant therapy, mammographic screening status and mortality. Immunohistochemistry was performed on tumour samples using 11 primary antibodies to define five molecular subtypes. The effect of screen detection compared with symptomatic diagnosis on survival was estimated after adjustment for grade, nodal status, Nottingham Prognostic Index (NPI) and the molecular markers. RESULTS: Fifty-six per cent of the survival benefit associated with screen-detected breast cancer was accounted for by a shift in the NPI, a further 3-10% was explained by the biological variables and more than 30% of the effect remained unexplained. CONCLUSION: Currently known biomarkers remain limited in their ability to explain the heterogeneity of breast cancer fully. A more complete understanding of the biological profile of breast tumours will be necessary to assess the true impact of tumour biology on the improvement in survival seen with screen detection.
Assuntos
Neoplasias da Mama/mortalidade , Idoso , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/classificação , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , PrognósticoRESUMO
Triple negative breast cancers are defined by the absence of oestrogen, progesterone and HER2 expression. Most triple negative cancers display distinct clinical and pathological characteristics with a high proportion of these tumours occurring at a younger age of onset and in African-American women. Triple negative tumours typically demonstrate high histological grade and are the most common breast cancer subtype in BRCA1 carriers. In addition, many of the features of triple negative cancers are similar to those identified in the basal-like molecular subtype which has recently been characterised by gene expression profiling. Although the two groups overlap, they are not synonymous. Triple negative breast cancers are of pivotal clinical importance given the lack of therapeutic options. The prognostic significance of triple negative tumours remains unclear since the group is heterogeneous and worst prognosis seems to be mostly confined to those that express basal cytokeratins or epidermal growth factor receptor (EGFR). This review focuses on outlining the pathological, molecular, and clinical features of triple negative breast cancers, discusses its prognostic value and summarises current therapeutic approaches and future directions of research.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Idade de Início , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptores ErbB/metabolismo , Feminino , Genes BRCA1/fisiologia , Genes erbB-2/fisiologia , Genoma Humano , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Análise em Microsséries , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Neoplásico/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Fatores de RiscoRESUMO
Insulinomas are the most common hormone-producing pancreatic neuroendocrine tumours (NETs), and patients usually present with symptoms secondary to hypoglycaemia. Octreotide has been widely used in the symptomatic treatment of patients with pancreatic NETs, including insulinomas. We describe a case of a patient with a metastatic NET, subsequently identified as a malignant insulinoma, who developed severe hypoglycaemia after treatment with long-acting octreotide.
Assuntos
Hipoglicemia/induzido quimicamente , Insulinoma/tratamento farmacológico , Octreotida/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Humanos , Hipoglicemia/diagnóstico , Insulinoma/diagnóstico , Masculino , Octreotida/administração & dosagem , Neoplasias Pancreáticas/diagnósticoRESUMO
BACKGROUND: The study's aim was to determine the maximum tolerated dose (MTD) of celecoxib combined with chemoradiotherapy (CRT) for locally advanced oesophageal cancer (OC). METHODS: CRT comprised of 5FU (1000 mg/m(2)/day, days 1-4, weeks 1 & 5), cisplatin (75 mg/m(2), days 1 & 29) and radiotherapy (50 Gy in 25 fractions or 50.4 Gy in 28 fractions). Celecoxib was given daily during CRT at one of five doses (200 mg bd to 600 mg bd). Three to six patients were assigned per dose. RESULTS: Thirteen patients were recruited before trial closure due to external safety concerns regarding celecoxib. Median follow up was 17 months (95% CI 9 - >39). The highest administered dose was 400 mg bd (n=4) with one dose-limiting toxicity at this level: grade 3 rash. Five (38%) and 8(62%) patients had grade 3 non-haematological and haematological toxicities respectively. No grade 4 toxicities occurred. Radiological response rate was 54% (n=7: all CR). Six patients had resection with one pathological CR. Median progression-free and overall survival were 8.8 (95% CI 5.1 - >24.8) and 19.6 months (95% CI 7.3 - >39) respectively. CONCLUSIONS: A MTD was not reached. The regimen was tolerable, indicating that celecoxib can be safely administered with CRT for locally advanced OC.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Celecoxib , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Terapia Combinada , Progressão da Doença , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/radioterapia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Análise de SobrevidaAssuntos
Testes Diagnósticos de Rotina , Resistência a Meticilina , Procedimentos Ortopédicos , Cuidados Pré-Operatórios , Staphylococcus aureus/isolamento & purificação , Infecção da Ferida Cirúrgica/prevenção & controle , Adulto , Portador Sadio , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Staphylococcus aureus/efeitos dos fármacos , País de GalesAssuntos
Antígenos HIV/imunologia , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Variação Antigênica , Antígeno B7-1/imunologia , Reações Cruzadas , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologiaRESUMO
The ability of the POU family transcription factor Brn-3a to stimulate neurite outgrowth and the expression of the genes encoding neuronal proteins such as the neurofilaments and SNAP-25 has previously been shown to be dependent upon the C-terminal POU domain which can mediate both DNA binding and transcriptional activation. We show here, however, that the ability of Brn-3a to activate Bcl-2 expression and protect neuronal cells from apoptosis (programmed cell death) requires a distinct N-terminal activation domain. Bcl-2 gene activation and protection from apoptosis are thus produced only by the long form of Brn-3a which contains this domain and not by a naturally occurring short form lacking this domain or by the isolated POU domain, although all these forms of Brn-3a can stimulate neurite outgrowth. Hence Brn-3a is a multi-functional transcription factor with different regions of the factor mediating its different effects and two distinct forms with different properties being generated by alternative splicing.
Assuntos
Apoptose , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Genes bcl-2 , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Transcrição/metabolismo , Animais , Ciclo Celular , Linhagem Celular , Proteínas de Ligação a DNA/genética , Humanos , Cinética , Neurônios/citologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/metabolismo , Fator de Transcrição Brn-3 , Fator de Transcrição Brn-3A , Fatores de Transcrição/genética , Ativação Transcricional , TransfecçãoRESUMO
The Brn-3a POU family transcription factor is expressed only in posmitotic neurons in the central nervous system and identifies the first differentiated neurons to appear in the midbrain, hindbrain, and spinal cord during development. This factor is also induced when undifferentiated proliferating ND7 cells cease dividing and differentiate to a mature neuronal-like phenotype bearing numerous neurite processes. We show that overexpression of Brn-3a in undifferentiated ND7 cells induces a mature neuronal phenotype characterized by process outgrowth and the induction of genes encoding synaptic proteins, although the cells continue to proliferate. In contrast, the closely related factors Brn-3b and Brn-3c do not have this effect. Although the N-terminal activation domain of Brn-3a is required for maximum induction of neurite outgrowth and gene expression, these effects are primarily dependent on the DNA binding POU domain, which also acts as an activation domain. Overexpression of the isolated POU domain of Brn-3a is sufficient to induce neurite outgrowth, while the ability of full-length Brn-3a to do so is abolished by mutating a single amino acid in the Brn-3a POU homeodomain to its equivalent in Brn-3b. Thus, Brn-3a appears to play a critical role in the specification of the mature neuronal phenotype, acting by stimulating the expression of genes whose products are required for process outgrowth and synapse formation.