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Funder: New York Stem Cell Foundation; Id: http://dx.doi.org/10.13039/100003194, 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.

Contains fulltext : 290951.pdf (Publisher’s version ) (Open Access) 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.

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 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.

Summary 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/HbSβ0‐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.

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.

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.

Introduction: As longevity of sickle cell disease (SCD) patients increases, chronic organ damage becomes more prevalent. Tricuspid regurgitation velocity (TRV) ≥2.5 m/sec) has long been considered a reliable indicator of pulmonary hypertension (PH). However, studies using right heart catherization confirmed PH in only 25% of patients with TRV elevation, despite the independent association of an elevated TRV with mortality. Since TRV elevation is also associated with anemia and cardiac remodeling on trans-thoracic echocardiography (TTE), we hypothesized that an elevated TRV may also identify SCD patients with a hyperdynamic circulation due to severe anemia, putting them at higher risk for anemia-related organ damage and early mortality. We aimed to determine the associations between TRV elevation and other high output parameters on TTE with anemia-related organ damage and to assess what echocardiographic parameters predict anemia-related organ damage and mortality. Methods: In this retrospective, longitudinal study, SCD patients were followed from the oldest TTE onwards. At baseline and after follow-up, TTE parameters of cardiac function (including TRV and signs of volume and pressure overload), anemia-related organ damage (microalbuminuria, renal failure, stroke, leg ulcers, priapism, diastolic dysfunction) and mortality were assessed. Logistic and cox regression analyses were applied to analyze associations between baseline echocardiographic findings and laboratory results with development of anemia-related organ damage during follow-up to identify predictors of organ damage. Results: In total 254 patients were included in the study cohort. The mean follow-up was 6.0 years (4.0-8.0 yr). Elevated TRV was found at baseline in 58/254 (22.8%) patients versus 196/254 (77.2%) patients with a normal TRV. Patients with an elevated TRV had an increased cardiac output (59 dL/min vs. 52 dL/min; P Conclusion: A high output state in SCD patients is associated with an elevated TRV and anemia-related organ damage, in particular nephropathy, mainly as a consequence of severe anemia and increasing age. These associations may better explain early mortality in these patients despite the fact that only a limited part of these patients do have pulmonary hypertension. Patients with an elevated TRV or other signs of a high output state are at risk of anemia-related organ damage (in particular nephropathy) and should be monitored closely. Early administration of available treatment modalities should be considered. Disclosures No relevant conflicts of interest to declare.

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.