Cancer care for people with dementia: Literature overview and recommendations for practice and research.

As many countries experience population aging, patients with cancer are becoming older and have more preexisting comorbidities, which include prevalent, age-related, chronic conditions such as dementia. People living with dementia (PLWD) are vulnerable to health disparities, and dementia has high potential to complicate and adversely affect care and outcomes across the cancer trajectory. This report offers an overview of dementia and its prevalence among patients with cancer and a summary of the research literature examining cancer care for PLWD. The reviewed research indicates that PLWD are more likely to have cancer diagnosed at an advanced stage, receive no or less extensive cancer treatment, and have poorer survival after a cancer diagnosis. These cancer disparities do not necessarily signify inappropriately later diagnosis or lower treatment of people with dementia as a group, and they are arguably less feasible and appropriate targets for care optimization. The reviewed research indicates that PLWD also have an increased risk of cancer-related emergency presentations, lower quality processes of cancer-related decision making, accessibility-related barriers to cancer investigations and treatment, higher experienced treatment burden and higher caregiver burden for families, and undertreated cancer-related pain. The authors propose that optimal cancer care for PLWD should focus on proactively minimizing these risk areas and thus must be highly person-centered, with holistic decision making, individualized reasonable adjustments to practice, and strong inclusion and support of family carers. Comprehensive recommendations are made for clinical practice and future research to help clinicians and providers deliver best and equitable cancer care for PLWD and their families.

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.

An update on the management and outcomes of cancer patients with severe aortic stenosis.

OBJECTIVES: We compared the outcomes of aortic valve replacement (AVR) by transcatheter (TAVR) and surgical (SAVR) routes with those of optimal medical management in patients with cancer and severe aortic stenosis (AS). BACKGROUND: Cancer therapy requires optimal cardiac output; however, the treatment of AS in cancer patients is not established. METHODS: Cancer patients with severe AS during January 2009 through February 2018 at a large cancer center were identified. Demographic and clinical characteristics including previous or active cancer diagnosis, history of chest radiotherapy, AS treatment, and survival were collected. Univariate Cox proportional hazards regression, the Kaplan-Meier analysis, and log-rank tests were used to compare overall survival (OS) between AS treatment groups. RESULTS: Sixty-five cancer patients with severe AS were identified; 28 received optimal medical treatment alone, 30 received TAVR, and seven received SAVR. The patients were predominantly male (n = 44, 68%) with a mean age of 71.17 years. The median OS was 9.87 months, and the most common cause of death was cancer (n = 29, 94% of deaths). AVR was associated with a lower risk of death than no AVR (hazard ratio [HR] 0.38, P = 0.007), and patients who underwent TAVR (HR 0.36, P = 0.01) had better survival than those with no AVR. Malignancy type, stage, and treatment were not associated with OS. CONCLUSIONS: Patients with cancer and severe AS who underwent AVR, predominantly TAVR, experienced better survival than those who had no AVR regardless of cancer type or cancer treatment. TAVR may be considered in patients with cancer and AS.

"Bringing on the light" in a complex clinical scenario: Optical coherence tomography-guided discontinuation of antiplatelet therapy in cancer patients with coronary artery disease (PROTECT-OCT registry).

BACKGROUND: Cancer patients with recently placed drug-eluting stents (DESs) often require premature dual antiplatelet therapy (DAPT) discontinuation for cancer-related procedures. Optical coherence tomography (OCT) can identify risk factors for stent thrombosis such as stent malapposition, incomplete strut coverage and in-stent restenosis and may help guide discontinuation of DAPT. METHODS: We conducted a single-center prospective study in cancer patients with recently placed (1-12 months) DES who required premature DAPT discontinuation. Patients were evaluated with diagnostic coronary angiogram and OCT. Individuals with appropriate stent strut coverage, expansion, apposition, and absence of in-stent restenosis or intraluminal masses were considered low risk and transiently discontinued DAPT to allow optimal cancer therapy. Patients who did not meet all these criteria were considered high risk and underwent further endovascular treatment when appropriate and bridging with low-molecular weight heparin. The incidence of adverse cardiovascular events was assessed after the procedure and at 12 months. RESULTS: A total of 40 patients were included. Twenty-seven patients (68%) were considered low risk by OCT criteria and DAPT was transiently discontinued. Thirteen patients (32%) were considered high risk with one or more OCT findings: uncovered stent struts (4 patients, 10%); stent underexpansion (3 patients, 8%); malapposition (8 patients, 20%); in-stent restenosis (2 patients, 5%). The high-risk patients with uncovered stent struts and malapposition underwent additional stent dilatation. There were no cardiovascular events in the low-risk group. One myocardial infarction occurred in the high-risk group. Fourteen non-cardiac deaths were registered before 12 months due to cancer progression or cancer therapy. CONCLUSION: OCT imaging allows identification of low-risk cancer patients with DES placed who may safely discontinue DAPT and proceed with cancer-related surgery or procedures.

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.

Trigger related outcomes of takotsubo syndrome in a cancer population.

Background: Takotsubo syndrome (TTS) occurs more frequently in cancer patients than in the general population, but the effect of specific TTS triggers on outcomes in cancer patients is not well studied. Objectives: The study sought to determine whether triggering event (chemotherapy, immune-modulators vs. procedural or emotional stress) modifies outcomes in a cancer patient population with TTS. Methods: All cancer patients presenting with acute coronary syndrome (ACS) between December 2008 and December 2020 at our institution were enrolled in the catheterization laboratory registry. Demographic and clinical data of the identified patients with TTS were retrospective collected and further classified according to the TTS trigger. The groups were compared with regards to major adverse cardiac events, overall survival and recovery of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) after TTS presentation. Results: Eighty one of the 373 cancer patients who presented with ACS met the Mayo criteria for TTS. The triggering event was determined to be "cancer specific triggers" (use of chemotherapy in 23, immunomodulators use in 7, and radiation in 4), and "traditional triggers" (medical triggers 22, and procedural 18 and emotional stress in 7). Of the 81 patients, 47 died, all from cancer-related causes (no cardiovascular mortality). Median survival was 11.9 months. Immunomodulator (IM) related TTS and radiation related TTS were associated with higher mortality during the follow-up. Patients with medical triggers showed the least recovery in LVEF and GLS while patients with emotional and chemotherapy triggers, showed the most improvement in LVEF and GLS, respectively. Conclusion: Cancer patients presenting with ACS picture have a high prevalence of TTS due to presence of traditional and cancer specific triggers. Survival and improvement in left ventricular systolic function seem to be related to the initial trigger for TTS.

Hospital readmissions after stroke in patients with and without dementia and undergone gastrostomy tube placement.

INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) in stroke patients is associated with high hospital readmission rates. The impact of dementia on hospital readmission rates in stroke patients who underwent PEG is unknown. We aimed to assess if stroke patients with dementia who undergo PEG are at risk for readmission. METHODS: We conducted a retrospective, observational study using the National Readmission Database from Healthcare Cost and Utilization Project (HCUP) from 2013 to 2014. Patients 65 years or older admitted with stroke and who had gastrostomy in the same hospital admission were included. We compared readmission rates at 30 and 60 days between patients with and without dementia and assessed the five most common readmission diagnosis. The association of dementia and hospital readmission was analyzed. RESULTS: Out of 492,727 patients over 65 who had stroke/PEG, 45,477 (9 %) had dementia. Patients with dementia underwent PEG placement more frequently than those without dementia (4.3% vs. 3.3%, respectively). There was no significant difference in the 30 and 60 days readmission rates between those with dementia and those without. Septicemia, aspiration pneumonitis and complications from the procedure were among top five readmission diagnosis. Dementia was not significantly associated with 30-day (odds ratio (OR) 0.99, 95% CI 0.87-1.13) or 60-day (OR 1, 95% CI 0.89-1.12) readmissions. CONCLUSIONS: Risks and benefits of gastrostomy in older adults with stroke and dementia should be honestly discussed with patients and their families since it exposes them to a higher risk of hospital readmission due to aspiration pneumonitis and complications from PEG.

How Does a Tumor Get Its Shape? MicroRNAs Act as Morphogens at the Cancer Invasion Front.

The generation and organization of the invasion front shape of neoplasms is an intriguing problem. The intimate mechanism is not yet understood, but the prevailing theory is that it represents an example of morphogenesis. Morphogenesis requires the presence of specific molecules, known as morphogens (activators and inhibitors), which can diffuse and elicit dose-dependent responses in their target cells. Due to their ability to modulate most of the coding transcriptome, their well-established role in embryogenesis, and their capacity to rapidly move between neighboring and distant cells, we propose microRNAs as inhibitors that could shape the cancer invasion front. In order to explain the genesis of the tumor border, we use Alan Turing's reaction diffusion model, refined by Meinhardt and Gierer. This assumes the existence of an activator called a, and an inhibitor called h, which we hypothesize could be a freely moving microRNA. We used the fractal dimension as a measure of tumor border irregularity. We observed that the change in fractal dimension associates with variations in the diffusion coefficient of the activator (Da) or the inhibitor (Dh). We determined that the fractal dimension remains constant (i.e., the irregularity of the tumor border does not change) across a Dh interval, which becomes narrower as Da rises. We therefore conclude that a change in fractal dimension occurs when the balance between Da and Dh is disrupted. Biologically, this could be explained by a faulty distribution of the inhibitor caused by an abnormal density of the intercellular connection network. From a translational perspective, if experimentally confirmed, our observations can be used for a better diagnosis of cancer aggressiveness.

Safety of Diagnostic and Therapeutic Cardiac Catheterization in Cancer Patients With Acute Coronary Syndrome and Chronic Thrombocytopenia.

Little data is available on the bleeding risk and outcomes of cancer patients with chronic thrombocytopenia who underwent cardiac catheterization. We sought to assess the safety of coronary angiography, percutaneous coronary intervention, and antiplatelet therapy in cancer patients with acute coronary syndrome (ACS) and chronic thrombocytopenia. We performed a retrospective study of patients with chronic thrombocytopenia who underwent cardiac catheterization for ACS between November 2009 and November 2015. Preprocedural platelet counts were classified into 3 groups: mild thrombocytopenia (50,000 to 100,000/µL), moderate thrombocytopenia (30,000 to 50,000/µL), and severe thrombocytopenia (<30,000/µL). Postprocedural bleeding complications and overall survival (OS) were recorded. A total of 98 patients were included. Mean platelet count on admission was 47.63 ± 29.85 K/µL. Severe thrombocytopenia was identified in 36 patients (36.7%), moderate thrombocytopenia in 20 patients (20.4%), and mild thrombocytopenia in 42 patients (42.9%). Aspirin therapy (alone or in combination with clopidogrel) was used in 66 patients (67.3%), whereas 27 patients (27.6%) were on dual antiplatelet therapy. One procedure-related retroperitoneal hematoma and 3 procedure-related small hematomas were identified. No cerebrovascular events related to the procedure or the antiplatelet therapy were noted. Moderate thrombocytopenia was associated with decreased OS, whereas aspirin, dual antiplatelet therapy, and statin use showed a trend of improved OS. In conclusion, we suggest that coronary angiography and percutaneous coronary intervention can be performed safely in cancer patients with chronic thrombocytopenia. Aspirin therapy and dual antiplatelet therapy should be considered in cancer patients with chronic thrombocytopenia and ACS.

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.

Progressive and Reversible Conduction Disease With Checkpoint Inhibitors.

Novel antineoplastic therapies are focused on harnessing our own immune system to fight cancer. To that end, cytotoxic T-lymphocyte-associated antigen 4 and programmed death ligand 1 are 2 coinhibitory signals that play central roles in decreasing T-cell response and represent a class of medications termed "checkpoint inhibitors." We present an unusual case of progressive conduction abnormalities induced by checkpoint inhibitors. Prompt medical intervention resulted in full recovery. Despite the anticancer efficacy, the newer antineoplastic agents pose a significant and often life-threatening risk of cardiotoxicity.

Circulating miRNAs in sepsis-A network under attack: An in-silico prediction of the potential existence of miRNA sponges in sepsis.

Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and treatment. A large panel of small non-coding microRNAs was reported to modulate the immune response in sepsis but have not been tested in clinical practice. Large-scale identification of microRNA networks in sepsis might reveal a new biological mechanism that can be also targeted by gene therapy. Therefore, the main objective of this study is to perform a comparison of the miRNA network between septic patients and healthy controls. We used the previously measured levels of expression of 16 different circulating human and viral microRNAs in plasma from 99 septic patients and 53 healthy controls. We used three different computational methods to find correlations between the expressions of microRNAs and to build microRNA networks for the two categories, septic patients and healthy controls. We found that the microRNA network of the septic patients is significantly less connected when compared to miRNA network of the healthy controls (21 edges vs 52 edges, P < 0.0001). We hypothesize that several microRNAs (miR-16, miR-29a, miR-146, miR-155, and miR-182) are being sponged in sepsis explaining the loss of connection in the septic patient miRNA network. This was specific for sepsis, as it did not occur in other conditions characterized by an increased inflammatory response such as in post-surgery patients. Using several target prediction instruments, we predicted potential common sponges for the miRNA network in sepsis from several signaling pathways. Understanding the dynamics of miRNA network in sepsis is useful to explain the molecular pathophysiology of sepsis and for designing therapeutic strategies that target essential components of the immune response pathways.

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.