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BACKGROUND: Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. METHODS: Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. RESULTS: When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26-0.75, P = 0.003 and HR 0.12, 95% CI 0.04-0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04-0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36-0.96, P = 0.034). CONCLUSIONS: The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Irinotecano/uso terapêutico , Oxaliplatina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/classificação , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Irinotecano/farmacologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/farmacologia , Panitumumabe/farmacologia , Panitumumabe/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Proteínas ras/genéticaRESUMO
Intravenous fluid therapy (IV-FT) is routinely used in the treatment of vaso-occlusive crises (VOCs), as dehydration possibly promotes and sustains erythrocyte sickling. Patients with sickle cell disease (SCD) are at risk of developing diastolic dysfunction and fluid overload due to IV-FT. However, data on the adverse effects of IV-FT for VOC is sparse. We aimed to evaluate the incidence and risk factors of fluid overload due to IV-FT in patients with SCD. Consecutive hospitalisations for VOC treated with IV-FT between September 2016 and September 2018 were retrospectively analysed. The median (interquartile range) age was 25·0 (18·3-33·8) years and 65% had a severe genotype (HbSS/HbSß0 -thal). Fluid overload occurred in 21% of 100 patients. Hospital stay was longer in patients with fluid overload (6·0 vs. 4·0 days, P = 0·037). A positive history of fluid overload (P = 0·017), lactate dehydrogenase level (P = 0·011), and top-up transfusion during admission (P = 0·005) were independently associated with fluid overload occurrence. IV-FT was not reduced in 86% of patients despite a previous history of fluid overload. Fluid overload is frequently encountered during IV-FT for VOC. IV-FT is often not adjusted despite a positive history of fluid overload or when top-up transfusion is indicated, emphasising the need for more awareness of this complication and a personalised approach.
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Anemia Falciforme/terapia , Hidratação/efeitos adversos , Administração Intravenosa , Adolescente , Adulto , Anemia Falciforme/complicações , Feminino , Hidratação/métodos , Hospitalização , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
Gastrointestinal (GI) cancers are highly heterogeneous at multiple levels. Tumor heterogeneity can be captured by molecular profiling, such as genetic, epigenetic, proteomic, and transcriptomic classification. Transcriptomic subtyping has the advantage of combining genetic and epigenetic information, cancer cell-intrinsic properties, and the tumor microenvironment (TME). Unsupervised transcriptomic subtyping systems of different GI malignancies have gained interest because they reveal shared biological features across cancers and bear prognostic and predictive value. Importantly, transcriptomic subtypes accurately reflect complex phenotypic states varying not only per tumor region, but also throughout disease progression, with consequences for clinical management. Here, we discuss methodologies of transcriptomic subtyping, proposed taxonomies for GI malignancies, and the challenges posed to clinical implementation, highlighting opportunities for future transcriptomic profiling efforts to optimize clinical impact.
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BACKGROUND: Small intestinal adenocarcinomas (SIAs) are rare. Hence, randomized controlled trials are lacking and understanding of the disease features is limited. This nationwide cohort investigates incidence, treatment and prognosis of SIA patients, to improve disease outcome. PATIENTS AND METHODS: Data of 2697 SIA patients diagnosed from January 1999 through December 2019 were retrieved from the Netherlands Cancer Registry and Pathology Archive. Incidence was calculated using the revised European Standardized Rate. The influence of patient and tumor characteristics on overall survival (OS) was studied using survival analyses. RESULTS: The age-standardized incidence rate almost doubled from 0.58 to 1.06 per 100,000 person-years, exclusively caused by an increase in duodenal adenocarcinomas. OS did not improve over time. Independent factors for a better OS were a younger age, jejunal tumors, Lynch syndrome and systemic therapy. Only 13.8% of resected patients was treated with adjuvant chemotherapy, which improved OS compared to surgery alone in stage III disease (HR 0.47 (0.35-0.61)), but not in the limited group of deficient mismatch repair (MMR) patients (n = 53, HR 0.93 (0.25-3.47)). In the first-line setting, CAPOX was associated with improved OS compared to FOLFOX (HR 0.51 (0.36-0.72)). For oligometastatic patients, a metastasectomy significantly improved OS (HR 0.54 (0.36-0.80)). CONCLUSIONS: The incidence of SIAs almost doubled in the past 20 years, with no improvement in OS. This retrospective non-randomized study suggests the use of adjuvant chemotherapy for stage III disease and first-line CAPOX for metastatic patients. For selected oligometastatic patients, a metastasectomy may be considered. MMR-status testing could aid in clinical decision-making.
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Adenocarcinoma , Neoplasias do Jejuno , Humanos , Adenocarcinoma/terapia , Adenocarcinoma/tratamento farmacológico , Estudos de Coortes , Incidência , Neoplasias do Jejuno/terapia , Neoplasias do Jejuno/tratamento farmacológico , Prognóstico , Estudos RetrospectivosRESUMO
Consensus Molecular Subtype (CMS) classification of colorectal cancer (CRC) tissues is complicated by RNA degradation upon formalin-fixed paraffin-embedded (FFPE) preservation. Here, we present an FFPE-curated CMS classifier. The CMSFFPE classifier was developed using genes with a high transcript integrity in FFPE-derived RNA. We evaluated the classification accuracy in two FFPE-RNA datasets with matched fresh-frozen (FF) RNA data, and an FF-derived RNA set. An FFPE-RNA application cohort of metastatic CRC patients was established, partly treated with anti-EGFR therapy. Key characteristics per CMS were assessed. Cross-referenced with matched benchmark FF CMS calls, the CMSFFPE classifier strongly improved classification accuracy in two FFPE datasets compared with the original CMSClassifier (63.6% versus 40.9% and 83.3% versus 66.7%, respectively). We recovered CMS-specific recurrence-free survival patterns (CMS4 versus CMS2: hazard ratio 1.75, 95% CI 1.24-2.46). Key molecular and clinical associations of the CMSs were confirmed. In particular, we demonstrated the predictive value of CMS2 and CMS3 for anti-EGFR therapy response (CMS2&3: odds ratio 5.48, 95% CI 1.10-27.27). The CMSFFPE classifier is an optimized FFPE-curated research tool for CMS classification of clinical CRC samples.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/classificação , Neoplasias Colorretais/patologia , Inclusão em Parafina , Biomarcadores Tumorais/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Consenso , Fixação de Tecidos/métodos , Masculino , Perfilação da Expressão Gênica/métodos , Idoso , Pessoa de Meia-Idade , Prognóstico , Regulação Neoplásica da Expressão Gênica , FormaldeídoRESUMO
BACKGROUND: Here we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: Retrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC. RESULTS: Updated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months). CONCLUSION: Adding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Cetuximab , Bevacizumab , Capecitabina , Oxaliplatina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Intervalo Livre de Doença , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: The consensus molecular subtypes (CMSs) of colorectal cancer (CRC) capture tumor heterogeneity at the gene-expression level. Currently, a restricted number of molecular features are used to guide treatment for CRC. We summarize the evidence on the clinical value of the CMSs. METHODS: We systematically identified studies in Medline and Embase that evaluated the prognostic and predictive value of CMSs in CRC patients. A random-effect meta-analysis was performed on prognostic data. Predictive data were summarized. RESULTS: In local disease, CMS4 tumors were associated with worse overall survival (OS) compared with CMS1 (hazard ratio [HR] = 3.28, 95% confidence interval = 1.27 to 8.47) and CMS2 cancers (HR = 2.60, 95% confidence interval = 1.93 to 3.50). In metastatic disease, CMS1 consistently had worse survival than CMS2-4 (OS HR range = 0.33-0.55; progression-free survival HR range = 0.53-0.89). Adjuvant chemotherapy in stage II and III CRC was most beneficial for OS in CMS2 and CMS3 (HR range = 0.16-0.45) and not effective in CMS4 tumors. In metastatic CMS4 cancers, an irinotecan-based regimen improved outcome compared with oxaliplatin (HR range = 0.31-0.72). The addition of bevacizumab seemed beneficial in CMS1, and anti-epidermal growth factor receptor therapy improved outcome for KRAS wild-type CMS2 patients. CONCLUSIONS: The CMS classification holds clear potential for clinical use in predicting both prognosis and response to systemic therapy, which seems to be independent of the classifier used. Prospective studies are warranted to support implementation of the CMS taxonomy in clinical practice.
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Neoplasias Colorretais , Perfilação da Expressão Gênica , Bevacizumab/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Oxaliplatina/uso terapêutico , PrognósticoRESUMO
Previously, colorectal cancer (CRC) has been classified into four distinct molecular subtypes based on transcriptome data. These consensus molecular subtypes (CMSs) have implications for our understanding of tumor heterogeneity and the prognosis of patients. So far, this classification has been based on the use of messenger RNAs (mRNAs), although microRNAs (miRNAs) have also been shown to play a role in tumor heterogeneity and biological differences between CMSs. In contrast to mRNAs, miRNAs have a smaller size and increased stability, facilitating their detection. Therefore, we built a miRNA-based CMS classifier by converting the existing mRNA-based CMS classification using machine learning (training dataset of n = 271). The performance of this miRNA-assigned CMS classifier (CMS-miRaCl) was evaluated in several datasets, achieving an overall accuracy of ~ 0.72 (0.6329-0.7987) in the largest dataset (n = 158). To gain insight into the biological relevance of CMS-miRaCl, we evaluated the most important features in the classifier. We found that miRNAs previously reported to be relevant in microsatellite-instable CRCs or Wnt signaling were important features for CMS-miRaCl. Following further studies to validate its robustness, this miRNA-based alternative might simplify the implementation of CMS classification in clinical workflows.
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Neoplasias Colorretais , MicroRNAs , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética , Instabilidade de Microssatélites , RNA Mensageiro/genética , TranscriptomaRESUMO
INTRODUCTION: Chronic lymphocytic leukemia (CLL) is frequently complicated by cytopenias, either due to bone marrow infiltration or autoimmunity, resulting in autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), pure red cell aplasia (PRCA), or autoimmune neutropenia (AIN). Morbidity due to autoimmune cytopenias (AIC) can be substantial; in addition, infection risk increases and pre-existing infections might deteriorate due to immunosuppressive medication. In the aging population, CLL occurs more frequently and AIC related to CLL represent a growing clinical challenge. Areas covered: This review summarizes current knowledge on pathophysiological mechanisms involved in AIC development and their prognostic significance. It provides diagnostic criteria and a treatment guideline for daily clinical practice, which includes the role of novel targeted agents. Expert commentary: The pathophysiology of AIC involves loss of self-tolerance, antigen presentation by malignant CLL cells, and autoantibody production through aberrant T- and B-cell function. The value of detecting autoantibodies via the direct antiglobulin test (DAT) is disputable, since a positive test does not imply overt hemolysis. Importantly, AIC should be distinguished from infiltrative cytopenias, because of prognostic and therapeutic consequences. Compared to chemotherapy, triggering AIC by targeted therapies is less common and, hence, these agents may be valuable as treatment for CLL-related immune cytopenias.
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Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Leucemia Linfocítica Crônica de Células B/complicações , Pancitopenia/diagnóstico , Pancitopenia/etiologia , Doenças Autoimunes/terapia , Biomarcadores , Diagnóstico Diferencial , Gerenciamento Clínico , Humanos , Pancitopenia/terapia , Fenótipo , PrognósticoRESUMO
OBJECTIVE: Studies regularly show a higher incidence, prevalence and mortality of cardiovascular disease among immigrant groups from low-income countries. Despite residing in the Netherlands for over 60 years, the Moluccan-Dutch cardiovascular disease profile and health care use are still unknown. We aimed to compare (a) the clinical prevalence of cardiovascular diseases and (b) the use of health care services by cardiovascular disease patients of 5,532 Moluccan-Dutch to an age-sex matched control group of 55,320 native Dutch. METHODS: We performed a cross-sectional analysis of data of the Achmea health insurance company for the period of 1 January 2009 to 31 December 2010. We collected information on health care use, including diagnostic information. Linear and logistic regression models were used for comparison. RESULTS: Moluccans had a higher clinical prevalence of ischemic heart diseases (odds ratio 1.26; 95% confidence interval 1.03-1.56), but tended to have a lower prevalence of cerebrovascular accidents (0.79; 0.56-1.11) and cardiac failure (0.67; 0.44-1.03). The clinical prevalence of cardiovascular diseases together tended to be lower among Moluccans (0.90; 0.80-1.00). Consultation of medical specialists did not differ. Angiotensin II inhibitors (1.42; 1.09-1.84), antiplatelet agents (1.27; 1.01-1.59) and statins (1.27; 1.00-1.60) were prescribed more frequently to Moluccans, as were cardiovascular agents in general (1.27; 0.94-1.71). CONCLUSION: The experience of Moluccans in the Netherlands suggests that, in the long run, cardiovascular risk and related health care use of ethnic minority groups may converge towards that of the majority population.