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BACKGROUND: Esophageal cancer is a common type of cancer and serious bleeding from esophageal tumors can occur in routine clinical practice. The arrest of bleeding from esophageal tumor is not a trivial task, which can sometimes require nonstandard solutions. We report a case of successful hemostasis of massive bleeding from esophageal tumor performed by a novel two-balloon catheter inserted endoscopically, with a local hemostatic treatment applied. CASE SUMMARY: A 36-years old male patient with advanced esophageal cancer developed bleeding from the tumor following endoscopic stenting with a self-expanding metal stent. Due to the ineffectiveness of standard approaches, after a medical conference, the patient was treated with a novel method based on the use of a two-balloon catheter creating an isolated area in esophagus and locally dispersing hemostatic polysaccharide powder inside the isolated interior. Hemostasis was successful and subsequent endoscopic examination revealed the presence of organized clot and localized defect, which was coagulated in a planned manner. CONCLUSION: The authors present a new catheter-based method of hemostasis of esophageal tumor bleeding.
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Early detection of cancer will improve survival rates. The blood biomarker 5-hydroxymethylcytosine has been shown to discriminate cancer. In a large covariate-controlled study of over two thousand individual blood samples, we created, tested and explored the properties of a 5-hydroxymethylcytosine-based classifier to detect colorectal cancer (CRC). In an independent validation sample set, the classifier discriminated CRC samples from controls with an area under the receiver operating characteristic curve (AUC) of 90% (95% CI [87, 93]). Sensitivity was 55% at 95% specificity. Performance was similar for early stage 1 (AUC 89%; 95% CI [83, 94]) and late stage 4 CRC (AUC 94%; 95% CI [89, 98]). The classifier could detect CRC even when the proportion of tumor DNA in blood was undetectable by other methods. Expanding the classifier to include information about cell-free DNA fragment size and abundance across the genome led to gains in sensitivity (63% at 95% specificity), with similar overall performance (AUC 91%; 95% CI [89, 94]). We confirm that 5-hydroxymethylcytosine can be used to detect CRC, even in early-stage disease. Therefore, the inclusion of 5-hydroxymethylcytosine in multianalyte testing could improve sensitivity for the detection of early-stage cancer.
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Ácidos Nucleicos Livres , Neoplasias Colorretais , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA/genética , Detecção Precoce de Câncer/métodos , Humanos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: There is no method routinely used to predict response to anthracycline and cyclophosphamide-based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection. METHODS: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided. RESULTS: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population. CONCLUSIONS: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Dano ao DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Anemia de Fanconi/metabolismo , Adulto , Idoso , Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Epirubicina/administração & dosagem , Anemia de Fanconi/genética , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Estudos ProspectivosRESUMO
Model selection between competing models is a key consideration in the discovery of prognostic multigene signatures. The use of appropriate statistical performance measures as well as verification of biological significance of the signatures is imperative to maximise the chance of external validation of the generated signatures. Current approaches in time-to-event studies often use only a single measure of performance in model selection, such as logrank test p-values, or dichotomise the follow-up times at some phase of the study to facilitate signature discovery. In this study we improve the prognostic signature discovery process through the application of the multivariate partial Cox model combined with the concordance index, hazard ratio of predictions, independence from available clinical covariates and biological enrichment as measures of signature performance. The proposed framework was applied to discover prognostic multigene signatures from early breast cancer data. The partial Cox model combined with the multiple performance measures were used in both guiding the selection of the optimal panel of prognostic genes and prediction of risk within cross validation without dichotomising the follow-up times at any stage. The signatures were successfully externally cross validated in independent breast cancer datasets, yielding a hazard ratio of 2.55 [1.44, 4.51] for the top ranking signature.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Transcriptoma , Algoritmos , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Modelos Biológicos , Modelos Estatísticos , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Modelos de Riscos Proporcionais , RiscoRESUMO
This study examined variations in gene expression between FFPE blocks within tumors of individual patients. Microarray data were used to measure tumor heterogeneity within and between patients and disease states. Data were used to determine the number of samples needed to power biomarker discovery studies. Bias and variation in gene expression were assessed at the intrapatient and interpatient levels and between adenocarcinoma and squamous samples. A mixed-model analysis of variance was fitted to gene expression data and model signatures to assess the statistical significance of observed variations within and between samples and disease states. Sample size analysis, adjusted for sample heterogeneity, was used to determine the number of samples required to support biomarker discovery studies. Variation in gene expression was observed between blocks taken from a single patient. However, this variation was considerably less than differences between histological characteristics. This degree of block-to-block variation still permits biomarker discovery using either macrodissected tumors or whole FFPE sections, provided that intratumor heterogeneity is taken into account. Failure to consider intratumor heterogeneity may result in underpowered biomarker studies that may result in either the generation of longer gene signatures or the inability to identify a viable biomarker. Moreover, the results of this study indicate that a single biopsy sample is suitable for applying a biomarker in non-small-cell lung cancer.
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Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/genética , Adenocarcinoma/classificação , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Inclusão em Parafina , Análise de Componente Principal , Tamanho da AmostraRESUMO
PURPOSE: Current prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray-based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples. PATIENTS AND METHODS: A gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery. RESULTS: The 634-probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P < .001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P < .001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P < .001). CONCLUSION: This gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples.
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Neoplasias do Colo/patologia , Recidiva Local de Neoplasia/patologia , Inclusão em Parafina/métodos , Idoso , Neoplasias do Colo/genética , Feminino , Formaldeído , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Inclusão em Parafina/normas , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fixação de TecidosRESUMO
BACKGROUND: To date, there are no clinically reliable predictive markers of response to the current treatment regimens for advanced colorectal cancer. The aim of the current study was to compare and assess the power of transcriptional profiling using a generic microarray and a disease-specific transcriptome-based microarray. We also examined the biological and clinical relevance of the disease-specific transcriptome. METHODS: DNA microarray profiling was carried out on isogenic sensitive and 5-FU-resistant HCT116 colorectal cancer cell lines using the Affymetrix HG-U133 Plus2.0 array and the Almac Diagnostics Colorectal cancer disease specific Research tool. In addition, DNA microarray profiling was also carried out on pre-treatment metastatic colorectal cancer biopsies using the colorectal cancer disease specific Research tool. The two microarray platforms were compared based on detection of probesets and biological information. RESULTS: The results demonstrated that the disease-specific transcriptome-based microarray was able to out-perform the generic genomic-based microarray on a number of levels including detection of transcripts and pathway analysis. In addition, the disease-specific microarray contains a high percentage of antisense transcripts and further analysis demonstrated that a number of these exist in sense:antisense pairs. Comparison between cell line models and metastatic CRC patient biopsies further demonstrated that a number of the identified sense:antisense pairs were also detected in CRC patient biopsies, suggesting potential clinical relevance. CONCLUSIONS: Analysis from our in vitro and clinical experiments has demonstrated that many transcripts exist in sense:antisense pairs including IGF2BP2, which may have a direct regulatory function in the context of colorectal cancer. While the functional relevance of the antisense transcripts has been established by many studies, their functional role is currently unclear; however, the numbers that have been detected by the disease-specific microarray would suggest that they may be important regulatory transcripts. This study has demonstrated the power of a disease-specific transcriptome-based approach and highlighted the potential novel biologically and clinically relevant information that is gained when using such a methodology.
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Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Biópsia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Fluoruracila/farmacologia , Genótipo , Células HCT116 , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fenótipo , Prognóstico , RNA Antissenso/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.
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Biomarcadores Tumorais , Neoplasias Colorretais/genética , Genômica , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Genes p53/genética , Instabilidade Genômica , Humanos , Instabilidade de Microssatélites , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaRESUMO
BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. At present no reliable biomarkers are available to guide the management of this condition. Microarray technology may allow appropriate biomarkers to be identified but present platforms are lacking disease focus and are thus likely to miss potentially vital information contained in patient tissue samples. METHODS: A combination of large-scale in-house sequencing, gene expression profiling and public sequence and gene expression data mining were used to characterise the transcriptome of NSCLC and the data used to generate a disease-focused microarray - the Lung Cancer DSA research tool. RESULTS: Built on the Affymetrix GeneChip platform, the Lung Cancer DSA research tool allows for interrogation of ~60,000 transcripts relevant to Lung Cancer, tens of thousands of which are unavailable on leading commercial microarrays. CONCLUSION: We have developed the first high-density disease specific transcriptome microarray. We present the array design process and the results of experiments carried out to demonstrate the array's utility. This approach serves as a template for the development of other disease transcriptome microarrays, including non-neoplastic diseases.