Raquel Hernández

Exosomal microRNAs isolated from plasma of mesenteric veins linked to liver metastases in resected patients with colon cancer

Before reaching a peripheral vein (PV), miRNAs released by the tumor are diluted and dispersed throughout the body or even retained in a specific organ. We hypothesized that blood drawn from the tumor-draining vein could provide more homogeneous information than blood drawn from the PV as that blood would contain all the biomarkers released by the tumor before they reach a potential metastatic site. We have profiled 754 miRNAs in 15 colon cancer plasma samples from the tumor-draining vein, the mesenteric vein (MV), identifying 13 microRNAs associated with relapse. The prognostic impact of these miRNAs were validated in 50 MV and 50 paired PV plasma samples of stage I-III colon cancer patients. Four miRNAs, let-7g, miR-15b, miR-155 and miR-328, were found overexpressed in MV compared to PV, and patients with high levels of those miRNAs in MV plasma had shorter time to relapse. Interestingly, in patients developing liver metastases, the exosomal cargo of miR-328 was much greater in MV than in PV plasma indicating a possible role of miR-328 in the development of liver metastases. Our results indicate that in colon cancer, the primary tumor releases high concentrations of miRNAs through the MV, and some of them are contained in tumor derived exosomes.

Differential MIR-21 expression in plasma from mesenteric versus peripheral veins: an observational study of disease-free survival in surgically resected colon cancer patients.

AbstractFindings on the role of plasma miR-21 expression in colorectal cancer are contradictory. Before reaching a peripheral vein (PV), microRNAs released by the tumor are dispersed throughout the body. We hypothesized that blood drawn from the mesenteric vein (MV) near the site of the primary tumor could provide more homogeneous information than blood drawn from the PV.We have analyzed miR-21 expression in matched samples of tumor tissue, normal tissue, MV plasma, and PV plasma in 57 surgically resected patients with colon cancer and correlated our findings with clinical characteristics and disease-free survival (DFS).miR-21 expression was higher in MV than PV plasma (Pu200a=u200a0.014) and in tumor than in normal tissue (Pu200a<u200a0.001). Patients with high levels of miR-21 in MV plasma had shorter DFS (Pu200a=u200a0.05) than those with low levels, and those with high levels in both MV and PV plasma had shorter DFS than all other patients (Pu200a=u200a0.01).Our findings suggest that the primary tumor in colon cancer releases high concentrations of miR-21 in the MV but that these concentrations are later diluted in the circulatory system. MV expression of miR-21 may be a stronger prognostic marker than PV expression.

Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer

BackgroundTrastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC.MethodsThis Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression.ResultsThe rate of HER2 testing increased steadily over time, from 58.3xa0% in 2008 to 92.9xa0% in 2016. HER2 was positive in 194 tumors (21.3xa0%). In the stratified Cox PH regression, each 1xa0% increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3xa0% increase in the risk of death: hazard ratio, 1.0035 (CI 95xa0%, 1.001–1.005), Pxa0=xa00.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2.ConclusionPatients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

Anthracycline-based triplets do not improve the efficacy of platinum-fluoropyrimidine doublets in first-line treatment of advanced gastric cancer: real-world data from the AGAMEMON National Cancer Registry

BackgroundAlthough anthracycline-based triplets are one of the most widely used schedules to treat advanced gastric cancer (AGC), the benefit of including epirubicin in these therapeutic combinations remains unknown. This study aims to evaluate both the efficacy and tolerance of triplets with epirubicin vs. doublets with platinum-fluoropyrimidine in a national AGC registry.MethodsPatients with AGC treated with polychemotherapy without trastuzumab at 28 hospitals in Spain between 2008 and 2016 were included. The effect of anthracycline-based triplets against doublets was evaluated by propensity score matching (PSM) and Cox proportional hazards (PH) regression.ResultA total of 1002 patients were included (doublets, nxa0=xa0653; anthracycline-based triplets, nxa0=xa0349). The multivariable Cox PH regression failed to detect significantly increased OS in favor of triplets with anthracyclines: HR 0.90 (95% CI, 0.78–1.05), pxa0=xa00.20035. After PSM, the sample contained 325 pairs with similar baseline characteristics. This method was also unable to reveal an increase in OS: 10.5 (95% CI, 9.7–12.3) vs. 9.9 (95% CI, 9.2–11.4) months, HR 0.91 (CI 95%, 0.76–1.083), and (log-rank test, pxa0=xa00.226). Response rates (42.1 vs. 33.1%, pxa0=xa00.12) and PFS (HR 0.95, CI 95%, 0.80–1.13, log-rank test, pxa0=xa00.873) were not significantly higher with epirubicin-based regimens. The triplets were associated with greater grade 3–4 hematological toxicity, and increased hospitalization due to toxicity by 68%. The addition of epirubicin is viable, but 23.7% discontinued treatment because of adverse effects or patient decision.ConclusionAnthracyclines added to platinum-fluoropyrimidine doublets did not improve the response rate or survival outcomes in patients with AGC but entailed greater toxicity.

Proteomic Analysis of Liquid Biopsy from Tumor-Draining Vein Indicates that High Expression of Exosomal ECM1 Is Associated with Relapse in Stage I-III Colon Cancer

BACKGROUND: The analysis of exosomes in blood obtained from the tumor-draining mesenteric vein (MV) can identify tumor biomarkers before they reach target organs and form the premetastatic niche where circulating tumor cells can anchor. Our group has recently shown that microRNAs in plasma from the MV—but not the peripheral vein (PV)—have been related to liver metastases in colon cancer (CC) patients. Here we examine the exosomal protein cargo in plasma from the MV and paired PV in 31 CC patients. PATIENTS AND METHODS: The study included patients who were initially diagnosed with stage I-III CC and 10 healthy controls. Exosomes from the MV and PV of all patients and controls were isolated by ultracentrifugation and confirmed by cryogenic transmission electron microscopy. High-throughput proteomic analysis by mass spectrometry was used to identify expression levels of exosomal proteins. Findings were confirmed by Western blot. RESULTS: Exosomal ECM1 protein was more highly expressed in patients than in controls and was 13.55 times higher in MV from relapsed than relapse-free patients. High exosomal ECM1 expression was associated with liver metastases. Patients with high exosomal ECM1 expression in MV—but not PV—plasma had shorter time to relapse than those with low ECM1 expression (P = .04). CONCLUSION: High levels of exosomal ECM1 protein can identify CC patients with a higher risk of relapse. The analysis of exosomes isolated from the tumor-draining MV is a promising method for the identification of biomarkers before they reach the target organ.

miR-328 mediates a metabolic shift in colon cancer cells by targeting SLC2A1/GLUT1

PurposeIncreasing evidence shows that altered metabolism is a critical hallmark in colon cancer. There is a strong need to explore the molecular mechanisms underlying cancer metabolism. Whether the aberrant expression of microRNAs contributes to cancer metabolism is not fully understood. miR-328 is a putative potential target of SLC2A1, but the regulating mechanism between them remains unknown. We have examined whether miR-328 directly regulates SLC2A1/GLUT1 expression in colon cancer cells.MethodsWe performed in silico bioinformatic analyses to identify miR-328-mediated molecular pathways and targets. We also performed luciferase assays and western blot analyses in LOVO and SW480 colon cancer cell lines. In addition, we assessed miR-328 expression in 47 paired tumor and normal tissue specimens from resected colon cancer patients.ResultsLuciferase reporter assays showed that miR-328 directly targeted SLC2A1 3′-untranslated region (UTR), with a significant decrease in luciferase activity in both LOVO and SW480 cell lines. These results were validated by western blot. miR-328 expression was significantly downregulated in tumor tissue compared with paired normal tissue.ConclusionsOur results show that miR-328 targets SLC2A1/GLUT1. We suggest that miR-328 may be involved in the orchestration of the Warburg effect in colon cancer cells. Furthermore, miR‐328 expression is reduced in colon cancer patients and thus inversely correlates with the classically reported upregulated SLC2A1/GLUT1 expression in tumors.

Factors associated with anxiety and depression in cancer patients prior to initiating adjuvant therapy

ObjectiveAnxiety and depression affect cancer patients’ quality of life. Our objectives were to determine the prevalence of anxiety and depression and analyze the association between positive psychological factors, sociodemographic factors, and clinical factors in oncological patients initiating adjuvant treatment.MethodsA prospective, multicenter cohort of 600 consecutive patients completed the Brief Symptom Inventory, Mini-Mental Adjustment to Cancer, Life Orientation Scale-Revised, and Multidimensional Scale of Perceived Social Support questionnaires.ResultsPrevalence of anxiety and depression was 49.8 and 36.6%, respectively. Women and younger individuals were more anxious and depressed than men and seniors. Employed participants suffered more anxiety than retirees, and singles exhibited more depression than married or partnered subjects. Logistic regression analysis showed that hope, optimism, social support, being male, and older were significantly associated with a lower risk of anxiety and depression (pu2009<u20090.001).ConclusionsThe high prevalence of anxiety and depression among Spaniards with cancer starting adjuvant chemotherapy suggests that more attention should be paid to mental health in these individuals. These findings are important for cancer patients because they can benefit from interventions that increase positive psychological factors such as hope, optimism, and social support to reduce anxiety and depression.

Prognostic Impact of miR-200 Family Members in Plasma and Exosomes from Tumor-Draining versus Peripheral Veins of Colon Cancer Patients

Objective: To evaluate the prognostic potential of expression levels of miR-200 family members (miR-200a, miR-200b, miR-200c, miR-429, miR-141) in plasma and exosomes from the tumor-draining vein (mesenteric vein [MV]) and peripheral vein (PV) of colon cancer (CC) patients. Methods: We analyzed the expression of miR-200 family members in matched samples of MV and PV plasma from 50 resected patients with CC and correlated our findings with overall survival (OS). We also examined the content of these microRNAs in MV and PV exosomes. Results: Expression levels were higher in MV than in PV (miR-200a, p < 0.001; miR-200b, p < 0.001; miR-429, p = 0.01; miR-200c, p = 0.05; miR-141, p = 0.05). Low levels of both miR-200c and miR-141 in MV plasma were associated with longer OS (p = 0.02). This association was maintained for the MV exosome cargo of miR-200c and miR-141 (p = 0.02). Conclusion: Our findings provide the first indication that expression levels of miR-200c and miR-141 in MV plasma can identify CC patients with poor prognosis. In addition, our results lend further support to the premise that tumor-draining veins constitute a better source of biomarkers than do PVs.

Comparison of Coping, Psychological Distress, and Level of Functioning in Patients With Gastric and Colorectal Cancer Before Adjuvant Chemotherapy

CONTEXTnPatients with gastrointestinal cancers are at high risk for functional problems that are generally accompanied by a decline in their overall status and intense psychological distress.nnnOBJECTIVESnThis study compares the level of functioning in individuals with gastric cancer (GC) and colorectal cancer (CRC) and analyzes whether improved functioning can be explained by patients psychological status and coping strategies.nnnMETHODSnThis is a prospective, transversal, multicenter study in patients with nonmetastatic GC and CRC before initiating adjuvant chemotherapy. Participants answered questionnaires evaluating quality of life, including functioning (European Organization for Research and Treatment of Cancer Quality of Life questionnaire), coping strategies (Mini-Mental Adjustment to Cancer), and psychological distress (Brief Symptom Inventory-18).nnnRESULTSnBetween December 2015 and July 2017, 266 patients with CRC and 69 patients with GC were consecutively recruited. A pathological level of functioning was more prevalent in people with GC than in those with CRC (20% vs. 5%). Individuals with GC presented worse functioning and more psychological distress and displayed more hopelessness, anxious preoccupation, and cognitive avoidance as coping strategies than those with CRC. Psychological distress and fighting spirit accounted for 40% of the functional status in GC patients, whereas psychological distress and hopelessness represented 58% of CRC patients functional status.nnnCONCLUSIONnOur findings suggest that level of functioning affects many subjects with GC and reveals the importance of developing interventions targeted at enhancing adaptive coping strategies before initiating adjuvant cancer treatment.

Surgery for metastases for esophageal-gastric cancer in the real world: Data from the AGAMENON national registry.

INTRODUCTIONnThe effect of surgery for metastases in patients with esophagogastric cancer is unknown, given the lack of randomized clinical trials; likewise, the criteria for selecting eligible patients remain to be determined.nnnMETHODSnThis registry evaluates the results of patients with advanced adenocarcinoma of the stomach, distal esophagus, or gastro-esophageal junction from 32 centers. To assess selection criteria and prognostic factors, a state arrival extended Markov proportional hazards (PH) model was used.nnnRESULTSn1792 subjects were analyzed, 5% of whom (nxa0=xa092) underwent surgery for metastasis. The most common surgeries were peritoneal (29%), hepatic (24%), and distant lymph nodes (11%). Subjects chosen for metastasectomy had higher survival rates, HR 0.34 (95% CI, 0.06-0.80, pxa0=xa00.021). Patients who underwent surgery had a mOS since metastasectomy of 16.7 months (95% CI, 12.5-22.4). The 1- and 3-year relapse rates following R0 resection were 58% and 65%, respectively. Median time since R0 metastasectomy until relapse was 8.4 months (95% CI, 7.6-23.7). The 3-year OS after surgery was 30.6% (95% CI, 19.3-40.4). Duration of chemotherapy prior to surgery (months) increased mortality (HR 1.04 [95% CI, 1.01-1.07]), pxa0=xa00.009. The only significant interaction involved the use of anti-HER2 therapy.nnnCONCLUSIONnThe AGAMENON registry suggests that subjects with limited metastatic disease, selected on a clinical basis, can benefit from early surgeries. Prospective trials are needed to confirm these data.