The non-coding RNome after splenectomy.

Splenectomy is a common surgical procedure performed in millions of people worldwide. Epidemiologic data show that splenectomy is followed by infectious (sepsis) and non-infectious complications, with unknown mechanisms. In order to explore the role of the non-coding transcripts involved in these complications, we analysed a panel of circulating microRNAs (miRNAs), which were previously reported to be deregulated in sepsis, in the plasma of splenectomized patients. MiR-223 was overexpressed immediately and late after splenectomy, while miR-146a was overexpressed immediately after splenectomy, returning latter to basal levels; and miR-16, miR-93, miR-26a and miR-26b were overexpressed only late after splenectomy, suggesting similarities with sepsis. We also explored the non-coding (nc)RNome of circulating peripheral blood leucocytes by performing a ncRNA full genome profiling. We observed a reorganization of the ncRNoma after splenectomy, characterized by up-regulation of miRNAs and down-regulation of transcribed pyknons (T-PYKs). Pathway analysis revealed that deregulated miRNAs control pathways involved in immunity, cancer and endothelial growth. We checked the expression of the ncRNAs in 15 immune cell types from healthy donors and observed that plasma miRNAs, cellular miRNAs and T-PYKs have a cell-specific expression pattern and are abundant in different types of immune cells. These findings suggest that the ncRNAs potentially regulate the immune changes observed after splenectomy.

Cancer as a Risk Factor for Cardiovascular Disease.

Improvements in early diagnosis and cancer treatments have contributed to high survival rates for many cancer patients. However, these patients often die of cardiovascular disease rather than recurrence of their cancer. Heart disease manifesting after cancer may be due to several mechanisms: shared cardiovascular risks between cancer and cardiovascular disease, inflammatory states associated with malignancies, and/or cardiotoxic effects of cancer therapy. Cancer treatment increases the risk of cardiovascular diseases directly by damaging critical structures of the heart or indirectly by promoting accelerated atherosclerosis. Estimating cardiovascular risk by using advanced imaging and monitoring of the cardiac biomarkers can be used for early detection and treatment of subclinical cardiac injury. Better knowledge of these early and late cardiac effects in cancer patients will enable adoption of both primary and secondary prevention measures of long-term treatment complications in cancer survivors.

Management of CAD in Patients with Active Cancer: the Interventional Cardiologists' Perspective.

PURPOSE OF REVIEW: Coronary artery disease in patients with active cancer presents particular challenges for clinicians, as optimum management is required in order to treat the underlying malignancy and to reduce morbidity and mortality associated with cardiovascular diseases. Special considerations must be made in respect to either primary or secondary thrombocytopenia, the presence of coagulopathies and the propensity of bleeding, vascular access complications, and increased risk of stent thrombosis. RECENT FINDINGS: In presence of acute coronary symptoms, the cardio-oncology team has to make a complex decision between conservative medical management or early angiography (within 24 h) and revascularization. There is a lack of reliable data on the outcomes of patients with active cancer who undergo invasive procedures for the diagnostic and treatment of coronary artery disease. Cardiac catheterization recommendations in cancer patients are being currently elaborated by cardio-oncologists in order to improve the overall survival in cancer patients with coronary artery disease.

microRNA and Chronic Lymphocytic Leukemia.

Expression profiling of microRNAs identified important differences in microRNA expression between CLL samples and normal CD5+ B-cells. Researchers have first discussed the dual role of miRNAs working as tumor suppressors (inhibiting malignant potential) or as oncogenes (activating malignant potential) in CLL pathogenesis. Understanding the roles of miRNAs in leukemic cells brings information on a new layer of gene regulation and also provides new markers for improved diagnosis and prognosis, as well as novel therapeutic options for CLL patients. Herein we will focus on the roles of miRNAs in CLL, highlighting what is already known about their function, proposing a novel model of CLL predisposition and progression, and describing the challenges for the near future.

Robotic splenectomy: what is the real benefit?

BACKGROUND: The laparoscopic approach to a difficult splenectomy requires a longer total operative time and is frequently associated with an increased risk of bleeding and a high conversion rate. METHODS: A total of 418 elective splenectomies were registered in the Department of General Surgery and Liver Transplantation of Fundeni Clinical Institute between January 1995 and June 2012, of which 299 splenectomies (212 laparoscopic and 77 robotic) were performed by a single surgical team and retrospectively documented. The effect of the learning curve and the relative complexity of each type of procedure were analyzed using the Minimally Invasive Splenectomy Score, which further allowed categorizing the splenectomies as simple or difficult. Statistical analyses using the CUSUM algorithm of the intra- and postoperative parameters of the laparoscopic and robotic approaches, for both the simple and the difficult splenectomies, were performed. RESULTS: The results of the statistical analyses clearly indicated that there was a learning curve effect for laparoscopic splenectomy but not for robotic splenectomy. When compared with the laparoscopic approach in difficult splenectomies, the robotic approach had a shorter total operative time (84.13 vs. 97.2 min), less blood loss (30.88 vs. 156.9 ml), and decreased risk of hemorrhagic complications during surgery. CONCLUSIONS: Laparoscopic splenectomy remains the approach of choice for simple splenectomies in the surgical treatment for common indications. The robotic system is particularly beneficial in difficult splenectomies (i.e., partial splenectomy, splenectomy in liver cirrhosis, splenic tumors, or malignant hemopathies).

Morphometrical differences between resectable and non-resectable pancreatic cancer: a fractal analysis.

BACKGROUND/AIMS: Pancreatic cancer is a highly aggressive cancer with a rising incidence and poor prognosis despite active surgical treatment. Candidates for surgical resection should be carefully selected. In order to avoid unnecessary laparotomy it is useful to identify reliable factors that may predict resectability. Nuclear morphometry and fractal dimension of pancreatic nuclear features could provide important preoperative information in assessing pancreas resectability. METHODOLOGY: Sixty-one patients diagnosed with pancreatic cancer were enrolled in this retrospective study between 2003 and 2005. Patients were divided into two groups: one resectable cancer group and one with non-resectable pancreatic cancer. Morphometric parameters measured were: nuclear area, length of minor axis and length of major axis. Nuclear shape and chromatin distribution of the pancreatic tumor cells were both estimated using fractal dimension. RESULTS: Morphometric measurements have shown significant differences between the nuclear area of the resectable group and the non-resectable group (61.9 ± 19.8µm vs. 42.2 ± 15.6µm). Fractal dimension of the nuclear outlines and chromatin distribution was found to have a higher value in the non-resectable group (p<0.05). CONCLUSIONS: Objective measurements should be performed to improve risk assessment and therapeutic decisions in pancreatic cancer. Nuclear morphometry of the pancreatic nuclear features can provide important pre-operative information in resectability assessment. The fractal dimension of the nuclear shape and chromatin distribution may be considered a new promising adjunctive tool for conventional pathological analysis.

Association between ibrutinib and mid-cavitary Takotsubo cardiomyopathy: a case report and a review of chemotherapy-induced Takostubo's cardiomyopathy.

Takotsubo cardiomyopathy (TC) is a rare but increasingly recognized phenomenon, which can occur as a side effect of cancer treatment. We report an interesting case of a 53-year-old woman with non-small-cell lung cancer, who developed TC after chemotherapy with ibrutinib. Echocardiography revealed marked left ventricular dysfunction with apical hyperkinesis and mid-ventricular hypokinesia. Coronary angiogram was normal but did show mid-cavitary akinesis. To our knowledge, this is the first case of TC with ibrutinib. Therefore, TC remains a rare entity, and we present an elegant case of ibrutinib-mediated mid-cavitary Takotsubo cardiomyopathy with a literature review.

Ischemic Heart Disease: Special Considerations in Cardio-Oncology.

OPINION STATEMENT: The interplay and balance between the competing morbidity and mortality of cardiovascular diseases and cancer have a significant impact on both short- and long-term health outcomes of patients who survived cancer or are being treated for cancer. Ischemic heart disease in patients with cancer or caused by cancer therapy is a clinical problem of emerging importance. Prompt recognition and optimum management of ischemic heart disease mean that patients with cancer can successfully receive therapies to treat their malignancy and reduce morbidity and mortality due to cardiovascular disease. In this sense, the presence of cancer and cancer-related comorbidities (e.g., thrombocytopenia, propensity to bleed, thrombotic status) substantially complicates the management of cardiovascular diseases in cancer patients. In this review, we will summarize the current state of knowledge on the management strategies for ischemic disease in patients with cancer, focusing on the challenges encountered when addressing these complexities.

Stress-Induced Cardiomyopathy in Cancer Patients.

Takotsubo syndrome, also known as stress-induced cardiomyopathy (SC), is underrecognized in cancer patients. This study aims to investigate the incidence, natural history, and triggers of SC in cancer patients and its impact on cancer therapy and overall survival. A total of 30 subjects fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6-year period. Clinical presentation, electrocardiogram, laboratory data, and transthoracic echocardiogram results registered during the acute phase and follow-up were collected. All patients underwent coronary angiography. The most frequent presenting symptoms were chest pain in 63.3% of the patients and shortness of breath/dyspnea on exertion in 27% of the patients. T-wave inversion was a more common electrocardiographic presentation (60%) than ST elevation (13.3%). The median and interquartile range of peak creatine kinase MB fraction, troponin I, and brain natriuretic peptide were creatine kinase MB fraction 8.9, 4.6 to 21.1; troponin I 1.31, 0.7 to 3.3; and brain natriuretic peptide 1,124, 453.5 to 2,369.5. The most common complication of SC was cardiogenic shock requiring inotropic agents (20%). Of the 21 patients who required ongoing cancer treatment, 16 were able to resume chemotherapy, 5 underwent surgery, and 4 received radiation treatment. Median time to resume cancer treatment was 20 days after SC. None of the patients experienced recurrence of SC and other cardiac events. In conclusion, SC should be considered in the differential diagnosis of cancer patients who present with chest pain and ECG findings characteristic of acute coronary syndrome. Most of these patients normalize ejection fraction and may resume cancer therapy early.

Plasma Viral miRNAs Indicate a High Prevalence of Occult Viral Infections.

Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P<0.001). The prevalence of KSHV infection based on miRNAs qPCR is significantly higher than the prevalence determined by seropositivity, and this is more obvious for immuno-depressed patients. Plasma viral miRNAs quantification proved that EBV infection is ubiquitous. Measurement of viral miRNAs by qPCR has the potential to become the "gold" standard method to detect certain viral infections in clinical practice.

Cellular and viral microRNAs in sepsis: mechanisms of action and clinical applications.

Regardless of its etiology, once septic shock is established, survival rates drop by 7.6% for every hour antibiotic therapy is delayed. The early identification of the cause of infection and prognostic stratification of patients with sepsis are therefore important clinical priorities. Biomarkers are potentially valuable clinical tools in this context, but to date, no single biomarker has been shown to perform adequately. Hence, in an effort to discover novel diagnostic and prognostic markers in sepsis, new genomic approaches have been employed. As a result, a number of small regulatory molecules called microRNAs (miRNAs) have been identified as key regulators of the inflammatory response. Although deregulated miRNA expression is increasingly well described, the pathophysiological roles of these molecules in sepsis have yet to be fully defined. Moreover, non-human miRNAs, including two Kaposi Sarcoma herpesvirus-encoded miRNAs, are implicated in sepsis and may drive enhanced secretion of pro-inflammatory and anti-inflammatory cytokines exacerbating sepsis. A better understanding of the mechanism of action of both cellular and viral miRNAs, and their interactions with immune and inflammatory cascades, may therefore identify novel therapeutic targets in sepsis and make biomarker-guided therapy a realistic prospect.

MicroRNAs and ceRNAs: therapeutic implications of RNA networks.

INTRODUCTION: A new concept of gene regulation, in which competitive endogenous RNAs (ceRNAs) compete for common microRNAs (miRNAs), suggests that mRNA targets have an active role as key elements in the regulation of miRNA availability within cells. ceRNAs are considered to be natural decoys of miRNA activity and can influence the expression of multiple miRNAs. AREAS COVERED: A new complex network of indirect interaction among the RNA transcripts competing for the same pool of miRNAs has been described; in this network, the nodes are the targets, and the links between the nodes are the miRNAs the targets have in common, which form smaller subnetworks. The incidence, state and severity of cancer can be evaluated on the basis of this network signature. The study of these new genome-scale regulatory networks involving miRNAs and ceRNAs may provide information that researchers can use to fine-tune these networks to improve responses to cancer therapy and/or develop new therapeutic interventions. EXPERT OPINION: Combinational approaches based on complex regulatory ceRNA networks (ceRNETs) may be one of the most promising strategies for silencing important mediators of cancer-promoting pathways. Targeting a single miRNA may in fact represent a combined intervention that acts on the feedback and compensatory pathways that can impair treatment response or cause treatment resistance.

Key principles of miRNA involvement in human diseases.

Although rapid progress in our understanding of the functions of miRNA has been made by experimentation and computational approach, a considerable effort still has to be done in determining the general principles that govern the miRNA's mode of action in human diseases. We will further discuss how these principles are being progressively approached by molecular studies, as well as the importance of miRNA in regulating different target genes and functions in specific biological contexts. There is a great demand to understand the principles of context - specific miRNA target recognition in order to design future experiments and models of normal developmental and disease states.