RESUMO
Metagenomic sequencing has emerged as a transformative tool in infectious disease diagnosis, offering a comprehensive and unbiased approach to pathogen detection. Leveraging international standards and guidelines is essential for ensuring the quality and reliability of metagenomic sequencing in clinical practice. This review explores the implications of international standards and guidelines for the application of metagenomic sequencing in infectious disease diagnosis. By adhering to established standards, such as those outlined by regulatory bodies and expert consensus, healthcare providers can enhance the accuracy and clinical utility of metagenomic sequencing. The integration of international standards and guidelines into metagenomic sequencing workflows can streamline diagnostic processes, improve pathogen identification, and optimize patient care. Strategies in implementing these standards for infectious disease diagnosis using metagenomic sequencing are discussed, highlighting the importance of standardized approaches in advancing precision infectious disease diagnosis initiatives.
Assuntos
Doenças Transmissíveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Reprodutibilidade dos Testes , Metagenoma , Padrões de Referência , Metagenômica , Doenças Transmissíveis/diagnósticoRESUMO
OBJECTIVES: The COVID-19 pandemic has raised concerns on whether colonoscopies (CS) carry a transmission risk. The aim was to determine whether CS are aerosol-generating procedures. METHODS: This was a prospective observational trial including all patients undergoing CS at the Prince of Wales Hospital from 1 June to 31 July 2020. Three particle counters were placed 10 cm from each patient's anus and near the mouth of endoscopists and nurses. The particle counter recorded the number of particles of size 0.3, 0.5, 0.7, 1, 5, and 10 µm. Patient demographics, seniority of endoscopists, use of CO2 and water immersion technique, and air particle count (particles/cubic foot, dCF) were recorded. Multilevel modeling was used to test all the hypotheses with a post-hoc analysis. RESULTS: A total of 117 patients were recruited. During CS, the level of 5 µm and 10 µm were significantly higher than the baseline period (P = 0.002). Procedures performed by trainees had a higher level of aerosols when compared to specialists (0.3 µm, P < 0.001; 0.5 µm and 0.7 µm, P < 0.001). The use of CO2 and water immersion techniques had significantly lower aerosols generated when compared to air (CO2 : 0.3, 0.5, and 0.7 µm: P < 0.001; water immersion: 0.3 µm: P = 0.048; 0.7 µm: P = 0.03). There were no significant increases in any particle sizes during the procedure at the endoscopists' and nurses' mouth. However, 8/117 (6.83%) particle count tracings showed a simultaneous surge of all particle sizes at the patient's anus and endoscopists' and nurses' level during rectal extubation. CONCLUSION: Colonoscopy generates droplet nuclei especially during rectal extubation. The use of CO2 and water immersion techniques may mitigate these risks.
Assuntos
COVID-19 , Humanos , COVID-19/prevenção & controle , Dióxido de Carbono , Partículas e Gotas Aerossolizadas , Água , Pandemias , Imersão , Aerossóis e Gotículas Respiratórios , Colonoscopia/métodosRESUMO
Circulating tumor RNA (ctRNA) has recently emerged as a novel and attractive liquid biomarker. CtRNA is capable of providing important information about the expression of a variety of target genes noninvasively, without the need for biopsies, through the use of circulating RNA sequencing. The overexpression of cancer-specific transcripts increases the tumor-derived RNA signal, which overcomes limitations due to low quantities of circulating tumor DNA (ctDNA). The purpose of this work is to present an up-to-date review of current knowledge regarding ctRNAs and their status as biomarkers to address the diagnosis, prognosis, prediction, and drug resistance of colorectal cancer. The final section of the article discusses the practical aspects involved in analyzing plasma ctRNA, including storage and isolation, detection technologies, and their limitations in clinical applications.
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Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Colorretais , Humanos , Biópsia Líquida , Ácidos Nucleicos Livres/genética , Biomarcadores Tumorais/genética , RNA/genética , Neoplasias Colorretais/patologiaRESUMO
BACKGROUND & AIMS: Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. METHODS: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by ß-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. RESULTS: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. ß-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and ß-galactosidase activity assay. ß-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional ß-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via ß-galactosidase. ß-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. CONCLUSION: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of ß-galactosidase.
Assuntos
Proteínas de Bactérias/metabolismo , Neoplasias Colorretais/prevenção & controle , Probióticos/administração & dosagem , Streptococcus thermophilus/enzimologia , beta-Galactosidase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Proteínas de Bactérias/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Colo/microbiologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/microbiologia , Neoplasias Experimentais/prevenção & controle , Probióticos/metabolismo , Streptococcus thermophilus/genética , beta-Galactosidase/genéticaRESUMO
Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Neoplasias do Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores Proteína Tirosina Quinases/genética , Adenoma/genética , Adenoma/patologia , Animais , Neoplasias do Colo/genética , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Camundongos , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
BACKGROUND: Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown. METHODS: Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. RESULTS: Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis. CONCLUSIONS: Our findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Fosfoproteínas/metabolismo , Transdução de Sinais , Animais , Células CACO-2 , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Hibridização Genômica Comparativa , Proteínas Ativadoras de GTPase , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Via de Sinalização Hippo , Humanos , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Análise de Sobrevida , Fatores de Transcrição , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Proteínas de Sinalização YAPRESUMO
BACKGROUND: Granulin epithelin precursor (GEP) is reported to function as a growth factor stimulating proliferation and migration, and conferring chemoresistance in many cancer types. However, the expression and functional roles of GEP in colorectal cancer (CRC) remain elusive. The aim of this study was thus to investigate the clinical significance of GEP in CRC and reveal the molecular mechanism of GEP in CRC initiation and progression. METHODS: The mRNA expression of GEP in CRC cell lines were detected by qRT-PCR. The GEP protein expression was validated by immunohistochemistry in tissue microarray (TMA) including 190 CRC patient samples. The clinicopathological correlation analysis were achieved by GEP expression on TMA. Functional roles of GEP were determined by MTT proliferation, monolayer colony formation, cell invasion and migration and in vivo studies through siRNA/shRNA mediated knockdown assays. The cancer signaling pathway identification was acquired by flow cytometry, western blot and luciferase activity assays. RESULTS: The mRNA expression of GEP in CRC was significantly higher than it in normal colon tissues. GEP protein was predominantly localized in the cytoplasm and most of the CRC cases demonstrated abundant GEP protein compared with non-tumorous tissues. GEP overexpression was associated with non-rectal location, advanced AJCC stage, regional lymph node and distant metastasis. By Kaplan-Meier survival analysis, GEP abundance served as a prognostic marker for worse survival in CRC patients. GEP knockdown exhibited anti-cancer effect such as inhibiting cell proliferation, monolayer colony formation, cell invasion and migration in DLD-1 and HCT 116 cells and decelerating xenograft formation in nude mice. siGEP also induced G1 cell cycle arrest and apoptosis. Luciferase activity assays further demonstrated GEP activation was involved in MAPK/ERK signaling pathway. CONCLUSION: In summary, we compressively delineate the oncogenic role of GEP in colorectal tumorigenesis by activating MAPK/ERK signaling pathway. GEP might serve as a useful prognostic biomarker and therapeutic target for CRC.
Assuntos
Carcinogênese/patologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Granulinas/metabolismo , Sistema de Sinalização das MAP Quinases , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Granulinas/genética , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de SobrevidaRESUMO
Metastasis is the main cause of cancer death. As the tumor progresses, cells from the primary tumor site are shed into the bloodstream as circulating tumor cells (CTCs). Eventually, these cells colonize other organs and form distant metastases. It is therefore imperative that we gain a better understanding of the biological characteristics of CTCs for development of novel treatment modalities to minimize metastasis-associated cancer deaths. In recent years, rapid developments in technologies for the study of CTCs have taken place. We now have a variety of tools for the isolation and examination of CTCs which were not available before. This review introduces some commonly used protein markers in CTC investigations and summarizes a few advanced technologies which have been successfully applied for studying CTC biology at the protein level.
Assuntos
Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , Células Neoplásicas Circulantes , Proteômica/métodos , Humanos , Separação Imunomagnética/métodos , Neoplasias/sangue , Neoplasias/patologia , Kit de Reagentes para DiagnósticoRESUMO
Endoscopic submucosal dissection (SD) has emerged as one of the treatment strategies for submucosal rectal cancers. The present study reviewed the clinical outcomes of patients with rectal submucosal cancer treated by ESD. This was a retrospective review of four patients who had rectal tumor treated by ESD from 2010 to 2012 with histopathology showing T1 submucosal adenocarcinoma. The mean age (SD) was 69.5 (7.33) and the male to female ratio was 3:1. There were no post-ESD complications. The mean (SD) size of the tumors was 2.93 (0.87) cm. One patient with deep resection margin involvement received laparoscopic low anterior resection. Another with deep margin involvement of <1 mm refused surgery and was treated by chemoradiotherapy.There was no recurrence in all the cases with a mean follow-up duration of 461.3 (209.0) days. ESD was one of the important treatment strategies for T1sm-s rectal cancer especially when the risk of nodal metastasis was low. ESD spared the patient from colostomy when the T1 cancer was located in the lower third of the rectum. The role of adjuvant and neoadjuvant chemoradiotherapy remains controversial.
Assuntos
Adenocarcinoma/cirurgia , Colonoscopia/métodos , Dissecação/métodos , Mucosa Intestinal/cirurgia , Neoplasias Retais/cirurgia , Adenocarcinoma/diagnóstico , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Retais/diagnóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM: To determine the factors affecting survival of patients with unresectable stage IV colon cancer with Primary tumour resection (PTR) as first treatment compared with those with conventional palliative chemotherapy. METHODOLOGY: Patient with minimally or asymptomatic stage IV colon cancer at diagnosis were identified from prospectively managed database in included centers from 2015 to 2020. Patient with and without PTR performed were followed up. Primary end point was overall survival. Risk factors affecting survival will be analysis by Kaplan Meier statistics and Cox regression analysis. Secondary outcome will be stoma formation, complication rate and reoperation. RESULTS: 162 patients were included in analysis. 68 patients treated with systemic therapy PTR and 94 patients with tumour in-situ before systemic therapy. Baseline demographics including sex, age, functional status, tumour location, site of metastasis, RAS status were similar except there was slightly more liver metastasis on non-resection group (63.2% vs 79.8%). Cox regression analysis found PTR (HR 0.485, 0.302-0.778, p = 0.003)), bone metastasis (HR 3.163, 1.146-6.918, p = 0.004) commencement (HR 0.579, 0.345-0.971, p = 0.038) and completion of systemic therapy (HR 0.310, 0.178-0.539, p = 0.000) are independent factors predicting survival. The median overall survival after PTR vs tumour in-situ is 28 (IQR: 16-47) vs 12 (IQR:6-31) months (p<0.001). CONCLUSION: Resection of primary tumour is an independent good prognostic factor in relatively asymptomatic stage IV CA colon patients with unresectable metastasis. Resection should be considered as long as the procedure is straight forward and do not impose significant morbidities with careful patient selection.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias do Colo/cirurgia , Prognóstico , Neoplasias Retais/patologia , Neoplasias Colorretais/cirurgiaRESUMO
AIM: To evaluate the operative and oncological results after colonic stent bridging for left-sided malignant large bowel intestinal obstruction and the risk factors for survival and recurrence after definitive surgery. METHODOLOGY: Consecutive patients who underwent colonic stenting for malignant left-sided colonic obstruction were included. Patients for palliative stenting or emergency surgery, patient with low rectal tumour or peritoneal metastasis were excluded. The primary outcome was overall survival. Secondary outcomes included stent success rate, stenting related complications, rate of stoma formation and long-term oncological outcome including recurrence rate and recurrence free survival rate. RESULTS: From June 2011 to June 2021, a total of 222 patients underwent colonic stenting. 112 patients were bridged to surgery after initial stenting, but 7 patients dropped out. Overall survival was 35 months (IQR = 17.75-75.25 months) in the early operation group, 30 months (IQR = 17.5-49.5 months) in the delayed surgery group HR 0.981 (95%CI 0.70-1.395, p = 0.907). Sensitivity analysis performed by excluding stent complications and emergency surgery yielded the same conclusion. Overall stenting complications rate was 17.1%. 11 patients (10.4%) required emergency surgery. CONCLUSION: There was no difference between early and delayed surgery groups (>4weeks) in the overall survival and recurrence in patients who had stent-bridge to surgery for malignant left colonic obstruction. It is safe to defer definitive surgery to optimize patients and allow better recovery from initial obstruction after colonic stenting before definitive surgery without adversely affecting the oncological outcomes.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Obstrução Intestinal , Neoplasias Retais , Humanos , Neoplasias do Colo/complicações , Neoplasias do Colo/cirurgia , Neoplasias do Colo/patologia , Stents/efeitos adversos , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Obstrução Intestinal/patologia , Análise Fatorial , Neoplasias Colorretais/complicações , Neoplasias Colorretais/cirurgia , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Colorectal cancer (CRC) threatens human health seriously. Early diagnosis of CRC is critical to improving patient survival. Meanwhile, non-invasive detection through tumor-circulating markers can be an important auxiliary diagnosis. In this study, we performed targeted RNA sequencing in paired tumor and adjacent normal fresh frozen tissues from 68 patients, and we also measured circulating mRNA levels in 4 time-point plasma samples collected before and after operation or chemotherapy. Our results showed that SOX9 (6.73-fold with adjusted p value < 1 × 10-45), MYC (20.59-fold with adjusted p value < 1 × 10-57), and MMP7 (131.94-fold with adjusted p value < 1 × 10-78) highly expressed in tumor compared with adjacent normal tissues. Besides, the circulating mRNA of SOX9 (41.14-fold with adjusted p value < 1 × 10-13) in CRC was significantly higher than in the normal control as well. Moreover, a SOX9-based 9-gene panel (SOX9, GSK3A, FZD4, LEF1, DVL1, FZD7, NFATC1, KRT19, and RUVBL1) showed the non-invasive diagnostic value of CRC (AUC: 0.863 (0.766-0.960), TPR: 0.92, TNR: 0.87). In summary, SOX9 expression consistently increases in tumor and plasma samples from CRC patients, which indicates the important role of SOX9 in CRC progression and its potential in non-invasive diagnosis of CRC.
Assuntos
Neoplasias Colorretais , Humanos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Biomarcadores Tumorais , Detecção Precoce de Câncer/métodos , RNA Mensageiro , Regulação Neoplásica da Expressão Gênica , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismoRESUMO
INTRODUCTION: Fear of cancer recurrence (FCR) is a prevalent and frequently debilitating response to a cancer diagnosis, affecting a substantial proportion of cancer survivors. Approximately 30% of local Hong Kong Chinese cancer survivors in a recent survey reportedly experienced persistent high FCR over the first-year post-surgery. This was associated with lower levels of psychological well-being and quality of life. A manualised intervention (ConquerFear) developed primarily based on the Self-Regulatory Executive Function Model and the Rational Frame Theory, has been found to reduce FCR effectively among Caucasian cancer survivors. The intervention now has been adapted to a Chinese context; ConquerFear-HK. The primary aim of this study is to evaluate its efficacy vs a standard-survivorship-care control (BasicCancerCare) in FCR improvement in a randomised control trial (RCT). METHODS AND ANALYSIS: In this RCT, using the sealed envelope method, 174 eligible Chinese cancer survivors will be randomised to either the ConquerFear-HK or BasicCancerCare intervention. Both interventions include six sessions over 10 weeks, which will be delivered via face to face or online by trained therapists. The ConquerFear-HK intervention incorporates value classification, metacognitive therapy, attentional training, detached mindfulness and psychoeducation; BasicCancerCare includes relaxation training, dietary and physical activity consultations. Participants will be assessed at prior randomisation (baseline; T0), immediately postintervention (T1), 3 months (T2) and 6 months postintervention (T3) on the measures of FCR (Fear of Cancer Recurrence Inventory) as a primary outcome; metacognition (30-item Metacognitions Quesionnaire) and cognitive attentional syndrome (Cognitive-attentional Syndrome Questionnaire) as process outcomes; psychological distress (Hospital Anxiety and Depression Scale), cancer-related distress (Chinese Impact of Events Scale), quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire) and treatment satisfaction are secondary outcomes. ETHICS AND DISSEMINATION: Ethics approval has been obtained from HKU/HA HKW Institutional Review Board (ref: UW19-183). The patients/participants provide their written informed consent to participate in this study. The study results will be disseminated through international peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04568226.
Assuntos
Sobreviventes de Câncer , Metacognição , Humanos , Sobreviventes de Câncer/psicologia , Recidiva Local de Neoplasia/psicologia , Medo/psicologia , Sobreviventes/psicologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer deaths in Hong Kong. We tested the hypothesis that circulating tumor cell (CTC) analysis by ARB101 antibody could be used as a tool for CRC detection, progression, and therapy response. RESEARCH METHODS: ARB101 antibody was used for investigation of CDH17 expression in formalin-fixed, paraffin-embedded (FFPE) tissue sections and circulating tumor cells (CTCs) of CRC patients. RESULTS: Using ARB101, highest sensitivity was observed in 98/100 (98%) colorectal cancer tissue compared to 72/100 gastric cancer (72%) and 27/32 pancreatic cancer (84%). Immunoreactivity of CDH17 was significantly higher in distant metastatic (tumor-node-metastasis [TNM] stage IV) than non-distant metastatic (TNM stage I to III) CRC. ARB101 antibody also manifested the higher sensitivity than c-erbB2 (8%) and epidermal growth factor receptor (EGFR)-targeting antibodies (37%) with the significance (p < 0.0001). ARB101 positive CTCs were detected in 64/83 (77%) TNM stage I to IV CRC patients. Furthermore, ARB101 positive CTCs detected in TNM stage I to III CRC patients before and after surgical operation are statistically significant (p < 0.0001). CONCLUSIONS: CTC detection by ARB101 antibody could serve as a potential non-invasive approach for CRC detection, progression, and monitoring of treatment response.
Assuntos
Neoplasias Colorretais , Células Neoplásicas Circulantes , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Células Neoplásicas Circulantes/patologia , Neoplasias Colorretais/metabolismo , Hong Kong , Biomarcadores Tumorais/metabolismo , CaderinasRESUMO
Background: Cell free RNA (cfRNA) contains transcript fragments from multiple cell types, making it useful for cancer detection in clinical settings. However, the pathophysiological origins of cfRNAs in plasma from colorectal cancer (CRC) patients remain unclear. Methods: To identify the tissue-specific contributions of cfRNAs transcriptomic profile, we used a published single-cell transcriptomics profile to deconvolute cell type abundance among paired plasma samples from CRC patients who underwent tumor-ablative surgery. We further validated the differentially expressed cfRNAs in 5 pairs of CRC tumor samples and adjacent tissue samples as well as 3 additional CRC tumor samples using RNA-sequencing. Results: The transcriptomic component from intestinal secretory cells was significantly decreased in the in-house post-surgical cfRNA. The HPGD, PACS1, and TDP2 expression was consistent across cfRNA and tissue samples. Using the Cancer Genome Atlas (TCGA) CRC datasets, we were able to classify the patients into two groups with significantly different survival outcomes. Conclusions: The three-gene signature holds promise in applying minimal residual disease (MRD) testing, which involves profiling remnants of cancer cells after or during treatment. Biomarkers identified in the present study need to be validated in a larger cohort of samples in order to ascertain their possible use in early diagnosis of CRC.
RESUMO
OBJECTIVE: The purpose of this study was to examine the hypothesis that angiotensin II (Ang II) induced endothelial cyclooxygenase-2 (COX-2) expression, which in turn mediated the generation of proinflammatory cytokines. METHODS AND RESULTS: Western blot analysis on primary rat endothelial cells showed Ang II induced COX-2 expression, which was abolished by cotreatment of p38 mitogen-activated protein kinase (SB 202190) and extracellular signal-regulated kinase 1/2 (PD 98059) inhibitors. Protein kinase Cδ (PKCδ) inhibitor (rottlerin) prevented extracellular signal-regulated kinase 1/2 phosphorylation and COX-2 expression. The pivotal role of PKCδ was further supported by a similar stimulatory effect of the PKC activator on COX-2 expression, signified by Ang II-stimulated translocation of PKCδ to the plasma membrane, and confirmed by PKCδ phosphorylation at Tyr311. Small interfering RNA targeting PKCδ diminished COX-2 expression, which was further abrogated by SB 202190. Human mesenteric arteries incubated with Ang II showed increased levels of endothelial COX-2 and monocyte chemoattractant protein-1; the former was inhibited by SB 202190 plus rottlerin, whereas the latter was prevented by COX-2 inhibitor. CONCLUSIONS: The present study pinpoints a novel role of PKCδ in Ang II-induced endothelial COX-2 upregulation and identifies a COX-2-dependent proatherosclerotic cytokine monocyte chemoattractant protein-1. The findings raise the possibility of curtailing endothelial COX-2 expression as a means of limiting or preventing vascular inflammation.
Assuntos
Angiotensina II/metabolismo , Aterosclerose/enzimologia , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/enzimologia , Inflamação/enzimologia , Artérias Mesentéricas/enzimologia , Proteína Quinase C-delta/metabolismo , Idoso , Idoso de 80 Anos ou mais , Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Western Blotting , Células Cultivadas , Quimiocina CCL2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Mediadores da Inflamação/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Pessoa de Meia-Idade , Fosforilação , Proteína Quinase C-delta/antagonistas & inibidores , Proteína Quinase C-delta/genética , Inibidores de Proteínas Quinases/farmacologia , Transporte Proteico , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Fatores de Tempo , Técnicas de Cultura de Tecidos , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
PURPOSES: This study aims to compare the perioperative outcomes and survival between laparoscopic-assisted right hemicolectomy (LARH) and open right hemicolectomy (ORH) for right-sided colon cancer. METHODS: Between July 1996 and October 2005, 145 patients were randomized to receive LARH (n = 71) or ORH (n = 74). RESULTS: The median follow-up of living patients was 99.7 months. The demographic data of the two groups were similar. The time to resume diet (4 vs. 5 days, p = 0.045) and the hospital stay (7.8 vs. 10 days, p = 0.033) were significantly shorter in LARH group, but these benefits were at the expense of longer operating time (198 vs. 129 min, p = 0.002) and higher direct cost (USD8745 vs. USD6293, p < 0.001). The morbidity and mortality were comparable between the two groups. After curative resection, the probabilities of survival at 5 years of the LARH and ORH groups were 74.2% (SE 7.4%) and 75% (SE 7.1%), respectively. The probabilities of being disease free at 5 years were 82.3% (SE 6.9%) and 84.1% (SE 6.2%), respectively. CONCLUSIONS: Laparoscopic-assisted resection of right-sided colonic cancer has the advantage over open surgery in allowing earlier recovery. However this is at the expense of a longer operating time and higher direct cost (registration number: NCT00485316 ( http://www.clinicaltrials.gov )).
Assuntos
Neoplasias do Colo/cirurgia , Laparoscopia , Idoso , Demografia , Intervalo Livre de Doença , Determinação de Ponto Final , Feminino , Humanos , Masculino , Assistência Perioperatória , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Recidiva , Resultado do TratamentoRESUMO
INTRODUCTION: To describe the experience of utilization of real time indocyanide green (ICG) fluorescent imaging for mapping out drainage lymph node and hence personalized lymphadenectomy in colorectal resection. METHODS: Perioperative injection of ICG before or during colon cancer resection by either intraluminal submucosal injection or laparoscopic peritumoural injection. The drainage lymph nodes were mapped out, and hence lymphadenectomy was performed enbloc with the main tumor. The effectiveness of mapping of drainage lymphatics and the procedure performed were recorded. RESULTS: A total of 21 patients (M:F = 14: 7) had perioperative ICG injection to map out the drainage lymphatics. The overall success rate was 86%. Seven patients (33%) had endoscopic submucosal injection, while 14 patients (67%) had intraoperative peritumoural injection. Three patients who had endoscopic submucosal injection had ICG extravasation, and hence failed lymph node mapping. Four patients (19%) had a change in extent of resection according to the lymph node mapping results. CONCLUSIONS: Personalized oncological colorectal resection and lymphadenectomy can be performed with the aid of ICG technology. Laparoscopic subserosal ICG injection may be the preferred route, as it minimize extravasation and aids to identify drainage lymph nodes without prolonging minimally invasive surgery. Further studies are required to determine the best route, strength, and timing of ICG injection and concordance with pathology to tailor the extent of resection for individual patients.