Infliximab biosimilar GP1111: a review of 5 years' post-approval experience.

INTRODUCTION: Infliximab is a chimeric monoclonal antibody against tumor necrosis factor alpha, and GP1111 (Zessly®, Sandoz) is the most recently approved infliximab biosimilar in Europe. We reviewed the approval process and key evidence for GP1111, focusing primarily on the indications of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). AREAS COVERED: This narrative review discusses preclinical, clinical, and real-world data for GP1111. EXPERT OPINION: Results from the Phase III REFLECTIONS trial in patients with moderate-to-severe active RA despite methotrexate therapy confirmed the similarity in efficacy and safety between GP1111 and reference infliximab. Switching from reference infliximab to GP1111 in REFLECTIONS had no impact on efficacy or safety. Since the European approval of GP1111 in March 2018, real-world data have also confirmed the efficacy and safety of switching from another infliximab biosimilar to GP1111 in patients with RA and IBD. In addition, budget impact analysis of various sequential targeted treatments in patients with RA found that GP1111 was cost-effective when used early after failure of conventional synthetic disease-modifying antirheumatic drugs. Therefore, 5 years' post-approval experience with GP1111 in RA and IBD, and key clinical and real-world evidence, support the safety and efficacy of continued use of GP1111 in all infliximab-approved indications.

A review of the totality of evidence supporting the development and approval of a pegfilgrastim biosimilar (LA-EP2006).

OBJECTIVE: The totality-of-evidence approach requires that similarity between a proposed biosimilar and a reference biologic is demonstrated across a range of analytical, preclinical, and clinical parameters to establish biosimilarity. We describe the totality of evidence for Sandoz biosimilar pegfilgrastim (LA-EP2006 [marketed as Ziextenzo]) that supported its regulatory approval in Europe and the United States. METHODS: Analytical similarity to the reference biologic [marketed by Amgen as Neulasta] was first investigated with regard to physiochemical quality attributes such as primary structure, pegylation, higher-order structures, variants and impurities, molecular size variants, and formulation (protein content, pH, excipients, etc.). In vitro biological activity studies were performed to examine the primary mechanism of action of pegfilgrastim. Bioequivalence (clinical pharmacokinetics [PK] and pharmacodynamics [PD]) of Sandoz biosimilar pegfilgrastim to the reference biologic was studied in healthy volunteers; efficacy, safety, and immunogenicity were assessed during confirmatory clinical efficacy studies in patients undergoing treatment for breast cancer. RESULTS: No meaningful or relevant differences were identified between Sandoz biosimilar pegfilgrastim and the reference biologic during analytical testing. Similar receptor binding and induction of cellular proliferation in vitro confirmed no functional differences between the biologics. Clinical studies in healthy adult participants demonstrated PK/PD biosimilarity and a similar safety profile between biosimilar and reference pegfilgrastim. Clinical studies in a sensitive patient population also demonstrated similar efficacy, safety, and immunogenicity between Sandoz biosimilar pegfilgrastim and the reference biologic. CONCLUSIONS: The totality of evidence confirms that Sandoz biosimilar pegfilgrastim matches the reference biologic and will therefore provide equivalent efficacy and safety in all eligible indications.

EuroScore and IL-6 predict the course in ICU after cardiac surgery.

BACKGROUND: Despite modern advances in intensive care medicine and surgical techniques, mortality rates in cardiac surgical patients are still about 3%. Considerable efforts were made to predict morbidity and mortality after cardiac surgery. In this study, we analysed the predictive properties of EuroScore and IL-6 for mortality in ICU, prolonged postoperative mechanical ventilation, and prolonged stay in ICU. METHODS: We enrolled 2972 patients undergoing cardiac surgery. The patients either underwent aortic valve surgery (AV), mitral valve surgery (MV), coronary artery bypass grafting (CABG), and combined operations of aortic valve and coronary artery bypass grafting (AV + CABG) or of mitral and tricuspid valve (MV + TV). Different laboratory and clinical parameters were analysed. RESULTS: EuroScore as well as IL-6 were associated with increased mortality after cardiac surgery. Furthermore, a higher EuroScore and elevated levels of IL-6 were predictors for prolonged mechanical ventilation and a longer stay in ICU. Especially, highly significant elevated IL-6 levels and an increased EuroScore showed a strong association. Statistics suggested superiority when both parameters were combined in a single model. CONCLUSION: Our results suggest that EuroScore and IL-6 are helpful in predicting the course in ICU after cardiac surgery, and therefore, the use of intensive care resources. Especially, the combination of highly elevated levels of IL-6 and EuroScore may prove to be excellent predictors for an unfortunate postoperative course in ICU.

Bilirubin and lactate: easy to determine and valuable to predict outcome in cardiac surgery.

BACKGROUND: Cardiopulmonary bypass during cardiac surgery is associated with metabolic changes after operation and results inter alia in increased levels of lactate and bilirubin. Since prediction of the course after operation has become very important for the management of an ICU and the patients themselves, we evaluated easily assessable markers (lactate and bilirubin), regarding their potential to predict mortality 90 days after surgery and the length of stay in ICU. METHODS: All patients within a period of five years undergoing cardiac surgery were enrolled in the study. Among others peak levels of lactate and bilirubin within 48 hours after operation were recorded. A Cox proportional hazard model as well as a logistic regression model were used to predict mortality or rather length of stay in ICU. RESULTS: Increased levels of bilirubin and lactate were associated with a significantly increase in mortality and length of stay in ICU (in a concentration-related manner). Interestingly, creatinine serum levels before operation showed a similar performance. CONCLUSIONS: Three easily assessable and cheap laboratory parameters (bilirubin, lactate, and creatinine) are useful to predict 90-day mortality and length of stay in ICU. These findings might be helpful to give patients a reliable prediction about short and mid-term-survival and to improve the management of an ICU.

Smoking and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients: a substudy from the randomized TROPICAL-ACS trial.

AIMS: Prior analyses disclosed variations in antiplatelet drug response and clinical outcomes between smokers and non-smokers, thus the safety and efficacy of any dual antiplatelet therapy (DAPT) de-escalation strategy may differ in relation to smoking status. Hence, we assessed the impact of smoking on clinical outcomes and adenosine diphosphate-induced platelet aggregation following guided de-escalation of DAPT in invasively managed acute coronary syndrome (ACS) patients. METHODS AND RESULTS: The multicentre TROPICAL-ACS trial randomized 2610 biomarker-positive ACS patients 1:1 to standard treatment with prasugrel for 12 months (control group) or a platelet function testing guided de-escalation of DAPT. Current smokers (n = 1182) showed comparable event rates between study groups [6.6% vs. 6.6%; hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.64-1.56, P > 0.99]. In non-smokers (n = 1428), a guided DAPT de-escalation was associated with a lower 1-year incidence of the primary endpoint [cardiovascular death, myocardial infarction, stroke, or bleeding ≥ Grade 2 according to Bleeding Academic Research Consortium (BARC) criteria] compared with control group patients (7.9% vs. 11.0%; HR 0.71, 95% CI 0.50-0.99, P = 0.048). This reduction was mainly driven by a lower rate of BARC ≥ Grade 2 bleedings (5.2% vs. 7.7%; HR 0.68, 95% CI 0.45-1.03, P = 0.066). There was no significant interaction of smoking status with treatment effects of guided DAPT de-escalation (Pint = 0.23). Adenosine diphosphate-induced platelet aggregation values were higher in current smokers [median 28 U, interquartile range (IQR: 20-40)] vs. non-smoker [median 24 U (16-25), P < 0.0001] in the control group and in current smokers [median 42 U, IQR (27-68)] vs. non-smoker [median 37 U, IQR (25-55), P < 0.001] in the monitoring group. CONCLUSION: Guided DAPT de-escalation appears to be equally safe and effective in smokers and non-smokers. Regardless of smoking status and especially for those patients deemed unsuitable for 1 year of potent platelet inhibition this DAPT strategy might be used as an alternative antiplatelet treatment regimen.

Remifentanil for abdominal surgery is associated with unexpectedly unfavorable outcomes.

Insufficient perioperative pain treatment is known as a highly predictive risk factor for the development of chronic postoperative pain. Remifentanil is an ultrashort-acting opioid that provides quick and efficient analgesia but is associated with the induction of opioid-induced hyperalgesia. Despite these well-known characteristics, this substance is being increasingly used in anesthesia and in a variety of medical fields, such as intensive-care medicine and obstetrics. The aim of our study was to reveal whether remifentanil influences postoperative pain, the requirement for postoperative analgesics, and requirement of antiemetics (as indirect indicator of postoperative nausea and vomiting), as well as the effects on time to extubation and length of stay in the postanesthesia care unit in daily clinical routine. From an electronic medical records database of 55,693 anesthesias, we analyzed data from all patients receiving intraabdominal surgery (visceral, gynecological, and urological) under general anesthesia or combined general-epidural anesthesia by propensity score matching. The administration of remifentanil was associated with higher postoperative pain scores despite a higher requirement of postoperative analgesics. Additional epidural analgesia was not able to avoid this finding. The intraoperative use of remifentanil is associated with a deterioration of pain levels and postoperative analgesic requirement, wherefore the potential benefit of this substance seems to be outweighed by its potential disadvantages. Especially in operative procedures in which high postoperative pain scores are expected, the unreflective use should be critically questioned.

Smoking Associated T-Cell Imbalance in Patients With Chronic Pain.

INTRODUCTION: Smoking is associated with several diseases and affects the immune system. Recently, published data demonstrate an involvement of T helper 17 cells (Th17) and regulatory T cells (Tregs) in the pathogenesis of chronic pain and pain intensity. The role of these T-cell subsets in smoking patients with chronic pain is nebulous so far. We therefore analyzed Th17 cells and Tregs in smokers and nonsmokers with chronic pain. METHODS: Analyses of T-cell subsets, mRNA expression and T-cell related cytokine profiles were done in 44 patients with chronic pain. Twenty-two of these patients were smokers. Numbers of T-cell subsets were quantified by flow cytometry. mRNA expression of the Th17- (RAR-related orphan receptor gamma) and Treg (forkhead box protein P3)-specific transcription factors was determined by quantitative real-time PCR, and levels of cytokines were measured by Human Cytokine Multiplex Immunoassay. RESULTS: Compared to nonsmokers, smokers showed significantly enhanced pain levels. On cellular basis, the number of pro-inflammatory Th17 cells (smokers: 2.2 ± 2.5% vs. nonsmokers: 0.5 ± 0.4%; p = .04) was increased, whereas the number of anti-inflammatory Tregs (smokers: 2.5 ± 0.9% vs. nonsmokers: 3.1 ± 1.1%; p = .02) was significantly decreased, resulting in an altered Th17/Treg ratio (Th17/Treg ratio: 0.9 ± 1.0 in smokers vs. 0.2 ± 0.1 in nonsmokers; p < .01). These findings were confirmed by quantitative real-time PCR. Analyses of cytokines revealed only marginal changes. CONCLUSIONS: In patients with chronic pain, smoking is associated with enhanced pain levels together with an imbalance of the Th17/Treg ratio. The shift of the Th17/Treg ratio toward inflammation may explain in part the increased pain intensity in these patients. IMPLICATIONS: Smoking is associated with increased pain levels and a pro-inflammatory Th17/Treg shift. The altered Th17/Treg ratio in smoking patients with chronic pain may partly explain their increased pain intensity. GERMAN CLINICAL TRIAL REGISTER (DRKS): Registration Trial DRKS00005954.

Eighty years of Medication-Overuse Headache: what about Medication-Overuse Backpain?

INTRODUCTION: Although chronic low back pain (CLBP) is one of the most common pain syndromes, up to now, clear pathophysiological causes or specific treatment options are missing. Medication-overuse has been associated with chronic headache, but never with CLBP. HYPOTHESIS: Based on several similarities between CLBP and Medication-Overuse Headache (MOH), we hypothesized that medication-overuse might contribute to CLBP as well, maybe even as an own entity. Might there be something like Medication-Overuse Backpain (MOB)? METHODS: We substantiate our hypothesis with a preliminary case-series analyzing five patients suffering from CLBP with a marked medication-overuse. In these patients, a stepwise analgesic withdrawal was recommended. RESULTS: Within 6 months of recruitment, five patients fulfilled the inclusion criteria and successfully completed discontinuation of their medication. All patients reported noticeable pain relief, despite the discontinuation of their analgesics. Withdrawal was well tolerated in all cases. CONCLUSIONS: Considering our results, the described withdrawal method seems to be a simple and safe method to achieve pain reduction while simultaneously preventing organ damage. Despite the preliminary character of our results, our hypothesis might stimulate a new understanding of CLBP's pathophysiology.

Altered regulation of the T-cell system in patients with CRPS.

The aim of this study was to investigate T-cell subsets and immunomodulatory factors in patients with complex regional pain syndrome (CRPS). We found decreased numbers of pro-inflammatory Th17 cells in patients with CRPS as compared to healthy volunteers. The expression of Th17 related RORγT mRNA was also significantly decreased. Patients with CRPS showed an increased proportion of CD39+ Tregs. CD39 is a known inhibitor of Th17 cell differentiation. Systemic cytokine levels were almost unchanged in patients with CRPS. These findings suggest that the decrease in Th17 cells in CRPS is regulated by an increase in CD39+ Tregs and that this anti-inflammatory T-cell shift may be a mechanism to control inflammation in CRPS. GERMAN CLINICAL TRIAL REGISTER: Registration Trial DRKS00005954.

Intronic miRNA-641 controls its host Gene's pathway PI3K/AKT and this relationship is dysfunctional in glioblastoma multiforme.

MicroRNAs have established their role as important regulators of the epigenome. A considerable number of human miRNA genes are found in intronic regions of protein-coding host genes, in many cases adopting their regulatory circuitry. However, emerging evidence foreshadows an unprecedented importance for this relationship: Intronic miRNAs may protect the cell from overactivation of the respective host pathway, a setting that may trigger tumor development. AKT2 is a well-known proto-oncogene central to the PI3K/AKT pathway. This pathway is known to promote tumor growth and survival, especially in glioblastoma. Its intronic miRNA, hsa-miR-641, is scarcely investigated, however. We hypothesized that miR-641 regulates its host AKT2 and that this regulation may become dysfunctional in glioblastoma. We found that indeed miR-641 expression differs significantly between GBM tissue and normal brain samples, and that transfection of glioma cells with miR-641 antagonizes the PI3K/AKT pathway. Combining clinical samples, cell cultures, and biomolecular methods, we could show that miR-641 doesn't affect AKT2's expression levels, but down-regulates kinases that are necessary for AKT2-activation, thereby affecting its functional state. We also identified NFAT5 as a miR-641 regulated central factor to trigger the expression of these kinases and subsequently activate AKT2. In summary, our study is the first that draws a connecting line between the proto-oncogene AKT2 and its intronic miRNA miR-641 with implication for glioblastoma development.

Challenging equipotency calculation for hydromorphone after long-term intravenous application.

In advanced stages, most cancer patients suffer from pain which can usually be well controlled following the World Health Organization (WHO) level scheme. While the majority of patients report adequate pain relief by strong opioids (WHO III), some require an opioid rotation. Despite the existence of conversion tables, these rotations mea lead to inadequate pain control or life threatening events. Here, we report about a patient with urothelial cell carcinoma presenting in our Department of Pain Medicine with massive pain aggravation up to NRS values of 10/10 despite administration of the highest dose of intravenously applied hydromorphone. After a small single dose of the far less potent opioid piritramide with exceptionally good response, we conducted a stepwise opioid rotation from hydromorphone to piritramide within one week without any signs of abstinence or withdrawal. After the opioid rotation, we discharged the patient nearly free of pain with piritramide doses far less than equianalgesic dose tables would have recommended. Our report impressively points out that even after long-term intravenous application of highly potent opioids, new titrations are necessary for rotation to avoid overdosage and discusses several mechanisms underlying individual response to different opioids.

Altered renal functions in patients with occlusion of an accessory renal artery after endovascular stenting of an infrarenal aneurysm.

OBJECTIVE: Coverage of an accessory renal artery (ARA) during endovascular aneurysm repair (EVAR) may result in renal infarction (RI) or decline in renal function. Until now, it remains vague which patients are at risk to develop these complications. We therefore analyzed the effect of ARA sealing by EVAR with respect to the occurrence of RI and renal function. METHODS: A retrospective analysis of the medical records and computed tomographic scans of patients who underwent EVAR within a period of 5 years was performed. Particular attention was paid to the presence or absence of accessory renal arteries and renal function before EVAR. Thirty-four patients with ARA were matched 1:3 to 102 patients without ARA. The results after EVAR were analyzed in patients with and without ARA. In patients with ARA, we further examined the results after EVAR in patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min and eGFR < 60 mL/min before EVAR. RESULTS: Before EVAR, the median eGFR was 74 mL/min (25th/75th percentiles, 57/89) in patients with ARA and 72 mL/min (25th/75th percentiles, 63/87) in patients without ARA. Alterations in eGFR were significantly pronounced in patients with ARA when compared with patients without ARA 1 week after EVAR (ARA, -10.7 ± 16.9 mL/min vs without ARA, 1.2 ± 13.3 mL/min; P = .002) and after 6 months (ARA, -10.8 ± 17.4 mL/min vs without ARA, 1.2 ± 13.3 mL/min; P = .001). RI only occurred in patients with ARA. Within the group of patients with ARA, patients with normal renal function (NF) showed a more pronounced decline in eGFR preoperatively when compared with patients with impaired renal function (IF) 1 week after EVAR (NF, -14.3 ± 18.0 mL/min vs IF, -1.3 ± 10.8 mL/min; P = .02) and after 6 months (NF, -15.8 ± 17.9 mL/min vs IF, 0.1 ± 15.2 mL/min; P = .007). CONCLUSIONS: The decrease in renal function was more pronounced in patients with ARA after EVAR when compared with patients without ARA undergoing EVAR. In patients with ARA, the observed decline in renal function was significantly distinct in patients presenting NF preoperatively. Consequently, the risk of IF after EVAR seems to be increased in patients with ARA and normal preoperative renal function.

Combined Carotid Endarterectomy and Retrograde Stenting of the Supra-Aortic Trunk: Does Cervical Block Offer Advantages?

BACKGROUND: Atherosclerosis of the carotid artery is a major source of stroke. In some cases, atherosclerosis occurs at several positions within the carotid artery. Carotid endarterectomy (CEA) in combination with retrograde balloon angioplasty and stenting of a brachiocephalic or common carotid artery stenosis has been described as efficacious and safe procedure to prevent stroke in these cases. The aim of this study was to analyze the impact of anesthetic techniques on hemodynamic factors, operation time, duration of clamping, and postoperative pain. METHODS: A retrospective analysis of patients undergoing CEA in combination with retrograde stenting under either general anesthesia (GA) or cervical block (CB) was carried out. Preoperative risk factors were analyzed as well as operating and cross-clamping time, hemodynamic factors, perioperative complications, postoperative pain, application of pain killers, and duration of intensive care unit (ICU) and hospital stay. RESULTS: Operating (GA: 193 ± 91 min vs. CB: 125 ± 52 min, P = 0.029) and cross-clamping time (GA: 34 ± 12 min vs. CB: 26 ± 9 min, P < 0.001) were shorter under CB. Patients under CB were hemodynamically more stable and required less norepinephrine (GA: 1.1 ± 0.6 mg vs. CB: 0.1 ± 0.1 mg, P < 0.001) and crystalloids (GA: 2,813 ± 1,173 mL vs. CB: 1,088 ± 472 mL, P < 0.001). Postoperative pain levels (GA: numeric rating scale 4.3/10 vs. 2.0/10; P = 0.004) and requirement of pain killers were also lower within the CB group. CONCLUSIONS: Synchronous CEA and retrograde balloon angioplasty and stenting of a brachiocephalic or common carotid artery stenosis under CB is associated with reduction of operating and cross-clamping time, improved hemodynamical stability, lower postoperative pain, shorter ICU and hospital stay, and it offers the advantage of a continuous neurological monitoring.

Anti-inflammatory T-cell shift in neuropathic pain.

BACKGROUND: The classification of pain into nociceptive and neuropathic pain is based on characteristic symptoms and different pathophysiological mechanisms. In a recent investigation, we found a disrupted TH17/Treg balance in patients suffering from chronic unspecific low back pain (CLBP). These patients did not show any signs of neuropathy. There is evidence for a considerable impact of the immune system also in neuropathic pain. However, the role of the adaptive immune system is still unclear. In the present study, we investigated systemic T-cell subset responses and T-cell related cytokine profiles in patients with chronic neuropathic pain. METHODS: We analyzed T-cell subsets, mRNA expression and T-cell-related cytokine profiles in 26 patients suffering from neuropathic pain in comparison to 26 healthy controls. Using multicolor flow cytometry (FACS), we quantified the number of T helper cells 1 (TH1), TH2, TH17 and regulatory T-cells (Tregs). Forkhead-Box-Protein 3 (FoxP3), Transforming growth factor-ß (TGF-ß) and RAR-related orphan receptor-γT (ROR-γT) mRNA expression was determined by quantitative real-time PCR (qPCR) and levels of pain-related cytokines were measured by Human Cytokine Multiplex Immunoassay (Macrophage inflammatory protein-1α (MIP-1α), Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), Interleukin (IL) -4, IL-6, IL-10, IL-17, and IL-23). RESULTS: We found a TH17/Treg imbalance with significantly increased anti-inflammatory Tregs and decreased pro-inflammatory TH17 cells in patients with neuropathic pain as compared to healthy controls. These results were confirmed on mRNA level: Treg-related FoxP3 and TGF-ß mRNA expression was elevated, whereas expression of TH17-related RORγT was reduced. Cytokine analyses revealed only marginal changes. CONCLUSIONS: Our investigation revealed a clear shift of T-cell subsets towards anti-inflammation in patients with neuropathic pain. Interestingly, this is quite similar to our previous findings in CLBP patients, but even more pronounced. Therefore, it remains to be elucidated in future investigations whether the immune changes represent an underlying pathophysiological mechanism or an epiphenomenon induced by ongoing pain and stress. GERMAN CLINICAL TRIAL REGISTER (DRKS): Trial registration number: DRKS00005954.

Daptomycin as supportive treatment option in patients developing mediastinitis after open cardiac surgery.

BACKGROUND: Mediastinitis is a severe complication after cardiac surgery. While improvement of prophylaxis and of medical and surgical therapy has reduced its incidence, the treatment of mediastinitis continues to be a challenging problem. Within this study, we report the successful use of daptomycin as supportive therapy in patients developing mediastinitis after open cardiac surgery. METHODS: The records of 21 consecutive patients who developed mediastinitis after cardiac surgery were retrospectively reviewed. After diagnosis, all patients received surgical debridement and antibiotic therapy with daptomycin. All patients were followed up to death or discharge. RESULTS: Clinical improvement after combined surgical and antibiotic therapy with daptomycin was found in 90.5% of the patients. The median time until clinical improvement occurred was 5 [4/6] days. Daptomycin was well-tolerated and no major adverse events during therapy were observed observed. CONCLUSIONS: This study provides new and helpful information regarding the beneficial use of daptomycin as supportive treatment option in patients developing mediastinitis after cardiac surgery.

Adenosine A2A receptor upregulation in human PMNs is controlled by miRNA-214, miRNA-15, and miRNA-16.

Immunosuppressive signaling via the adenosine A2A receptor (A2AR) is an important pathway to control inflammation. In immune cells, expression levels of A2ARs influence responsiveness to inflammatory stimuli. However, mechanisms driving expressional changes of A2ARs are still largely elusive. In the current study, we have investigated the impact of microRNAs (miRNAs) on A2AR expression in human polymorphonuclear leukocytes (PMNs) and T cells. Bioinformatic analyses and reporter gene assays revealed that A2AR expression is controlled by miRNA-214, miRNA-15, and miRNA-16. We detected all three miRNAs in both human PMNs and T cells. However, in PMNs, up to 10-fold higher levels of miRNA-16 and miRNA-214 were detected as compared with T cells. Upon in vitro stimulation, no significant expressional changes occurred. Expression levels of all three miRNAs strongly differed between individuals. A2AR expression also exhibited significant differences between PMNs and T cells: In PMNs, more than a 60-fold increase was seen upon LPS stimulation, whereas in T cells only a 2-fold increase was observed upon anti-CD3/CD28 activation. The extent of A2AR upregulation in PMNs strongly differed between individuals (from less than 10-fold to more than 100-fold). In PMNs, the increase in A2AR mRNA expression upon stimulation was inversely correlated with the expression levels of miRNA-214, miRNA-15, and miRNA-16 (R = -0.87, P < 0.0001); no correlation was found in human T cells. These results indicate that individual miRNA profiles gain important influence on A2AR expression regulation in PMNs upon stimulation. Determination of miRNA expression levels may help to identify patients with an increased risk for severe inflammation.

Medical suppression of hypercortisolemia in Cushing's syndrome with particular consideration of etomidate.

Cushing's syndrome is associated with excessive cortisol secretion by the adrenal gland or ectopic tumours and may result in diabetes, hypertension, and life-threatening infections with high mortality rates especially in the case of surgical resection. Although surgical resection is the treatment of choice, patients may benefit from preceding medical therapy. This may especially be useful as an adjunctive approach in emergency settings, if patients cannot undergo surgery, if surgery or radiotherapy fails, or if the tumour recurs. Medical therapy can be categorized in three different groups-inhibition of steroidogenesis, suppression of adrenocorticotropic hormone, and antagonism of the glucocorticoid receptor. However, the majority of common drugs are not available for parenteral administration, which may evoke a management problem in emergency settings or in patients unable to tolerate oral medication. The carboxylated imidazole etomidate is a well known parenteral induction agent for general anaesthesia. Besides its hypnotic properties, etomidate also has α-adrenergic characteristics and inhibits the enzyme 11-deoxycortisol ß-hydroxylase, which catalyzes the final step of the conversion of cholesterol to cortisol. Adverse outcomes have been reported when used for sedation in septic or trauma patients probably by its interference with steroid homeostasis. However, its capability of inhibition of the 11-deoxycortisol ß-hydroxylase leads to suppression of cortisol secretion which has been demonstrated to be a useful tool in severe and complicated hypercortisolemia. Within this article, we review the data concerning different pharmacological approaches with particular consideration of etomidate in order to suppress steroidogenesis in patients with Cushing's syndrome.

Endovascular treatment of abdominal aortic aneurysms combined with bilateral common and internal iliac aneurysms.

INTRODUCTION: Combined aneurysms of aortic and iliac arteries are rare with a prevalence of less than 0.1%. However, these combined aneurysms are associated with a high incidence of thrombosis, distal embolism, or rupture. Endovascular repair is a therapeutic option and includes embolization of the internal iliac artery in numerous cases. Embolization of the internal iliac artery may cause severe ischemia with hip and buttock complications in 2-5%. Therefore, preservation of internal iliac arteries is essential to reduce complications. PATIENT AND METHOD: We describe in detail an endovascular procedure for combined abdominal aortic (diameter of 8.6 cm) and bilateral common and internal iliac aneurysm (diameter of the left side: 6.4 cm; diameter of the right side: 4.3 cm) in a 44-year-old patient caused by media necrosis Erdheim-Gsell. The blood flow of both internal arteries was preserved in this patient. RESULT: Operation was done without any complications. Conversion to an open procedure was not necessary. During follow up (3, 6, and 12 months after operation) the patient did not develop any signs of severe hip and buttock complications. Furthermore, sonography and CT angiography revealed a good blood flow via the internal and external iliac arteries. CONCLUSION: Endovascular repair of abdominal aortic aneurysms combined with bilateral common and internal iliac aneurysms offers a promising minimal invasive procedure. Most importantly, this technique is less invasive than open operations and reduces complications by preserving the pelvic perfusion.

Penetrating aortic ulcer in the infrarenal stent-graft landing zone: treatment with coils and the ethylene vinyl alcohol copolymer onyx.

PURPOSE: To describe a technique to enable endovascular aneurysm repair in patients with penetrating aortic ulcer (PAU) in the infrarenal neck of an abdominal aortic aneurysm (AAA). TECHNIQUE: The technique is illustrated in a 76-year-old man with a 5.7-cm infrarenal AAA and a 2.3 × 1.8-cm PAU situated immediately distal to the right renal artery and covering 20% of the 28-mm-diameter proximal aortic neck. During the stent-graft repair, the PAU was successfully excluded by embolization with coils and the ethylene vinyl alcohol copolymer Onyx. The AAA and PAU were completely excluded without complications. At 6 months, there were no signs of endoleak, the AAA remained excluded, and there was no reperfusion of the Onyx cast in the PAU. CONCLUSION: This technique for treatment of a PAU in the proximal neck of an AAA is a reasonable alternative in cases involving severely diseased infrarenal necks that would otherwise require open surgery. The liquid embolic agent Onyx performed well, with fast embolization and excellent control of the growing cast maintained by the interventionist.

Inflammatory reactions and hydrocortisone in the setting of cardiac surgery: an overview.

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with activation of the complement system, platelets, neutrophils, monocytes, and macrophages which may lead to systemic inflammatory response syndrome in several cases. Despite modification of surgical techniques, biocompatibility of the bypass circuit and intensive care procedures after operation, CPB is still associated with post-operative morbidity including reduced cardiac function, capillary leak or multi-organ dysfunction. Corticosteroids are known for their anti-inflammatory effects and therefore, they are beneficial in selected trauma or septic patients. Prophylaxis with corticosteroids in cardiac surgery has been used since decades. The studies for methylprednisolone and hydrocortisone, the most commonly used corticosteroids, show conflicting results. For hydrocortisone, which is the mainstream of corticosteroid treatment in septic patients, the number of studies is low, but will increase in the next years. This article reviews the data concerning its use in patients undergoing cardiac surgery, its contraindications, adverse effects, risks, and benefits.