Large Multicenter Clinical Trials Research Articles

The silent killer: myocardial injury after non-cardiac surgery (MINS)

Introduction: Recent work into the causes of death after non-cardiac surgery has identified a new clinical concept, namely myocardial injury after non-cardiac surgery (MINS). The pathophysiology is related to a supply-and-demand mismatch in the peri-operative period and differs from the traditional model of myocardial ischaemia and infarction. Methods: Literature review of current body of knowledge and recent large multicentre clinical trials. Results: MINS is associated with increased morbidity and mortality at 30 days’ post-surgery. A large international multicentre trial found that a troponin T level of greater than 0.3 ng/ml was associated with a mortality rate of 16.9%. Moreover, 84.2% of MINS would probably go undetected if systematic troponin monitoring after surgery was not performed. Conclusion: This review examines the current body of knowledge and provides practical guidelines on how to identify and manage patients with MINS. Level of evidence: Level 5

Rationale and design of the SAIL trial for intramuscular injection of allogeneic mesenchymal stromal cells in no-option critical limb ischemia

BackgroundCritical limb ischemia (CLI) represents the most severe form of peripheral artery disease and has an immense impact on quality of life, morbidity, and mortality. A considerable proportion of CLI patients are ineligible for revascularization, leaving amputation as the only option. Mesenchymal stromal cells (MSCs), because of their vasculoregenerative and immunomodulatory characteristics, have emerged as a potential new treatment. MethodsThe primary objective of this trial is to investigate whether intramuscular administration of allogeneic bone marrow (BM)-derived MSCs is safe and potentially effective. The SAIL (allogeneic mesenchymal Stromal cells for Angiogenesis and neovascularization in no-option Ischemic Limbs) trial is a double-blind, placebo-controlled randomized clinical trial to investigate the effect of allogeneic BM-MSCs in patients with CLI who are not eligible for conventional revascularization. A total of 66 patients will be included and randomized (1:1) to undergo 30 intramuscular injections with either BM-MSCs (5 × 106 MSCs per injection) or placebo in the ischemic lower extremity. Primary outcome, that is, therapy success, a composite outcome consisting of mortality, limb status, clinical status, and changes in pain score, will be assessed at 6 months. All study-related procedures will take place in the University Medical Center Utrecht in The Netherlands. ConclusionsIf our results indicate that intramuscular allogeneic BM-MSC therapy for CLI is safe and potentially effective, this will have important consequences for treatment of patients with CLI. A large multicenter clinical trial with longer follow-up focusing on hard end points should then be initiated to confirm these findings.

Impact of Next-Generation Flow (NGF) Minimal Residual Disease (MRD) Monitoring in Multiple Myeloma (MM): Results from the Pethema/GEM2012 Trial

Background: MRD is an established biomarker to evaluate treatment efficacy, define patients at risk based on persistent MRD, and eventually, act as surrogate for prolonged survival based on sensitive MRD-negative definitions. Accordingly, the IMWG has developed criteria for MRD-negativity defined by next-generation sequencing, NGF or PET/CT, and has recommended their inclusion in clinical trials. Notwithstanding, most flow cytometry results have been obtained using less sensitive methods and in fact, there is no data about the impact of NGF-based MRD assessment in clinical trials. Aim: To define the feasibility, sensitivity and clinical impact of NGF-based MRD assessment in the phase III PETHEMA/GEM2012 trial. Methods: A total of 458 patients were enrolled into the PETHEMA/GEM2012 trial. MRD was predefined to be prospectively assessed at three time-points: after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), after HDT/ASCT, and after two courses of consolidation with VRD. MRD monitoring was performed blinded for clinical outcomes in four PETHEMA/GEM laboratory cores, and data was centralized for MRD analyses. MRD assessment was performed following EuroFlow SOPs in a total of 1,134 bone marrow (BM) samples from 419 patients. The 39 cases without MRD assessment had suboptimal response to induction and were thus considered as MRD+ for intention-to-treat analyses. Noteworthy, in 14 BM samples with undetectable MRD, B-cell precursors, erythroblasts and mast cells represented Results: Overall, 225/458 (49%) patients had undetectable MRD at the latest time-point in which MRD was assessed and were thus classified as MRD-. Conversely, 233/458 (51%) cases remained MRD+: 28% with ≥10-4 MRD, 12% with 10-5 MRD, and 11% with 10-6 MRD. Detailed analyses of MRD kinetics in 320 patients with available MRD results at all three time-points, showed that the percentage of MRD- patients increased from 35% into 54% and 58% after induction, HDT/ASCT and consolidation, respectively. Furthermore, a restricted analysis among MRD+ patients showed that whereas after induction only 8% of them had MRD levels as low as 10-6, subsequent intensification with HDT/ASCT and consolidation could reduce MRD levels down to 10-6 in 32% of MRD+ cases. Progression-free survival (PFS) rates at 3-years were of 92%, 70%, 54% and 44% for patients being MRD-negative, MRD+ 10-6, 10-5 and ≥10-4, respectively (P Conclusions: This is the largest study of MRD monitoring in MM based on the total number of samples analyzed (n=1,134). Our results show that NGF-based MRD assessment is feasible in large multicenter clinical trials, is highly-sensitive, and allows the identification of hemodiluted BM samples inadequate for MRD assessment. Risk of relapse among MRD-negative patients was remarkably reduced (3%), and was particularly related to the reappearance of extramedullary plasmacytomas, which urges the need for combined cellular and imaging MRD monitoring in these patients; by contrast, even MRD levels as low as 10-5 and 10-6 conferred significantly inferior PFS. Overall, this study defines MRD-negativity as the most relevant clinical endpoint for both standard- and high-risk transplant-eligible MM patients. Disclosures Paiva: Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Merck: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; EngMab: Research Funding. Oriol: Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: sponsored symposia; Celgene: Speakers Bureau. de la Rubia: Janssen: Other: Honoraria; Amgen: Other: Honoraria; Celgene: Other: Honoraria. Rosinol: Celgene: Honoraria; Janssen: Honoraria. Mateos: Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees. Lahuerta: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. San Miguel: Roche: Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity9s Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity9s Board of Directors or advisory committees.

UK-Cubic Complete Randomized Design of Experiment: A Complete Three Way Layout for Large Multi-Center Clinical Trials

UK-Cubic Complete Randomized Design of Experiment: A Complete Three Way Layout for Large Multi-Center Clinical Trials

Chip-based digital PCR as a novel detection method for quantifying microRNAs in acute myocardial infarction patients.

miRNAs have shown promise as potential biomarkers for acute myocardial infarction (AMI). However, the current used quantitative real-time PCR (qRT-PCR) allows solely for relative expression of nucleic acids and it is susceptible to day-to-day variability, which has limited the validity of using the miRNAs as biomarkers. In this study we explored the technical qualities and diagnostic potential of a new technique, chip-based digital PCR, in quantifying the miRNAs in patients with AMI and ischaemia-reperfusion injury (I/R). In a dilution series of synthetic C.elegans-miR-39, chip-based digital PCR displayed a lower coefficient of variation (8.9% vs 46.3%) and a lower limit of detection (0.2 copies/μL vs 1.1 copies/μL) compared with qRT-PCR. In the serum collected from 24 patients with ST-elevation myocardial infarction (STEMI) and 20 patients with stable coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI), we used qRT-PCR and multiplexed chip-based digital PCR to quantify the serum levels of miRNA-21 and miRNA-499 as they have been validated in AMI in prior studies. In STEMI, I/R injury was assessed via measurement of ST-segment resolution (ST-R). Chip-based digital PCR revealed a statistical significance in the difference of miR-21 levels between stable CAD and STEMI groups (118.8 copies/μL vs 59 copies/μL; P=0.0300), whereas qRT-PCR was unable to reach significance (136.4 copies/μL vs 122.8 copies/μL; P=0.2273). For miR-499 levels, both chip-based digital PCR and qRT-PCR revealed statistically significant differences between stable CAD and STEMI groups (2 copies/μL vs 8.5 copies/μL, P=0.0011; 0 copies/μL vs 19.4 copies/μL; P<0.0001). There was no association between miR-21/499 levels and ST-R post-PCI. Our results show that the chip-based digital PCR exhibits superior technical qualities and promises to be a superior method for quantifying miRNA levels in the circulation, which may become a more accurate and reproducible method for directly quantifying miRNAs, particularly for use in large multi-centre clinical trials.

A systematic review of perioperative seizure prophylaxis during brain tumor resection: the case for a multicenter randomized clinical trial.

OBJECTIVE The majority of neurosurgeons administer antiepileptic drugs (AEDs) prophylactically for supratentorial tumor resection without clear evidence to support this practice. The putative benefit of perioperative seizure prophylaxis must be weighed against the risks of adverse effects and drug interactions in patients without a history of seizures. Consequently, the authors conducted a systematic review of prospective randomized controlled trials (RCTs) that have evaluated the efficacy of perioperative seizure prophylaxis among patients without a history of seizures. METHODS Five databases (PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL/Academic Search Complete, Web of Science, and ScienceDirect) were searched for RCTs published before May 2017 and investigating perioperative seizure prophylaxis in brain tumor resection. Of the 496 unique research articles identified, 4 were selected for inclusion in this review. RESULTS This systematic review revealed a weighted average seizure rate of 10.65% for the control groups. There was no significant difference in seizure rates among the groups that received seizure prophylaxis and those that did not. Further, this expected incidence of new-onset postoperative seizures would require a total of 1258 patients to enroll in a RCT, as determined by a Farrington-Manning noninferiority test performed at the 0.05 level using a noninferiority difference of 5%. CONCLUSIONS According to a systematic review of major RCTs, the administration of prophylactic AEDs after brain tumor resection shows no significant reduction in the incidence of seizures compared with that in controls. A large multicenter randomized clinical trial would be required to assess whether perioperative seizure prophylaxis provides benefit for patients undergoing brain tumor resection.

Challenges for Quality Assurance of Target Volume Delineation in Clinical Trials.

In recent years, new radiotherapy techniques have emerged that aim to improve treatment outcome and reduce toxicity. The standard method of evaluating such techniques is to conduct large scale multicenter clinical trials, often across continents. A major challenge for such trials is quality assurance to ensure consistency of treatment across all participating centers. Analyses from previous studies have shown that poor compliance and protocol violation have a significant adverse effect on treatment outcomes. The results of the clinical trials may, therefore, be confounded by poor quality radiotherapy. Target volume delineation (TVD) is one of the most critical steps in the radiotherapy process. Many studies have shown large inter-observer variations in contouring, both within and outside of clinical trials. High precision techniques, such as intensity-modulated radiotherapy, image-guided brachytherapy, and stereotactic radiotherapy have steep dose gradients, and errors in contouring may lead to inadequate dose to the tumor and consequently, reduce the chance of cure. Similarly, variation in organ at risk delineation will make it difficult to evaluate dose response for toxicity. This article reviews the literature on TVD variability and its impact on dosimetry and clinical outcomes. The implications for quality assurance in clinical trials are discussed.

Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis.

Large multicenter clinical trials have led to two recently approved drugs for patients with idiopathic pulmonary fibrosis (IPF); yet, both of these therapies only slow disease progression and do not provide a definitive cure. Traditionally, preclinical trials have utilized mouse models of bleomycin (BLM)-induced pulmonary fibrosis—though several limitations prevent direct translation to human IPF. Spontaneous pulmonary fibrosis occurs in other animal species, including dogs, horses, donkeys, and cats. While the fibrotic lungs of these animals share many characteristics with lungs of patients with IPF, current veterinary classifications of fibrotic lung disease are not entirely equivalent. Additional studies that profile these examples of spontaneous fibroses in animals for similarities to human IPF should prove useful for both human and animal investigators. In the meantime, studies of BLM-induced fibrosis in aged male mice remain the most clinically relevant model for preclinical study for human IPF. Addressing issues such as time course of treatment, animal size and characteristics, clinically irrelevant treatment endpoints, and reproducibility of therapeutic outcomes will improve the current status of preclinical studies. Elucidating the mechanisms responsible for the development of fibrosis and disrepair associated with aging through a collaborative approach between researchers will promote the development of models that more accurately represent the realm of interstitial lung diseases in humans.

Phantom-based standardization of CT angiography images for spot sign detection.

The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p<0.001). All spot signs identified in the non-calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images. Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion.

Advances in the management of malignant pleural effusion.

The current review describes the latest evidence in the management of malignant pleural effusions (MPE). Daily drainage of indwelling pleural catheters achieved auto-pleurodesis at a higher rate compared with every-other-day drainage [0.47 vs. 0.24; difference in proportion of 0.23; 95% confidence interval (CI) 0.08-0.38; P = 0.003]. In patients with MPE undergoing talc pleurodesis, a large multicenter randomized clinical trial found that pain control with opiates vs. nonsteroidal anti-inflammatory drugs (NSAID) group were not significantly different (mean visual analog scale of 23.8 vs. 22.1 mm, respectively, adjusted difference -1.5 mm; 95% CI 1.3-3.4; P = 0.40). NSAID use was found to be noninferior to opiates with respect to the rate of pleurodesis failure at 3-month follow-up (prespecified noninferiority margin 15%, failure rates 20% opiates vs. 23% NSAIDS, respectively, difference -3%, 95% CI -10% to ∞; P = 0.004 for noninferiority). Talc remains the most effective sclerosing agent based on multiple systematic reviews and meta-analyses. More prospective studies are needed to determine the optimal frequency of indwelling pleural catheters drainage. NSAIDS can be used for pain control and do not adversely impact the chance of successful pleurodesis.

The application of remote ischemic conditioning in cardiac surgery.

Perioperative myocardial ischemia and infarction are the leading causes of morbidity and mortality following anesthesia and surgery. The discovery of endogenous cardioprotective mechanisms has led to testing of new methods to protect the human heart. These approaches have included ischemic pre-conditioning, per-conditioning, post-conditioning, and remote conditioning of the myocardium. Pre-conditioning and per-conditioning include brief and repetitive periods of sub-lethal ischemia before and during prolonged ischemia, respectively; and post-conditioning is applied at the onset of reperfusion. Remote ischemic conditioning involves transient, repetitive, non-lethal ischemia and reperfusion in one organ or tissue (remote from the heart) that renders myocardium more resistant to lethal ischemia/reperfusion injury. In healthy, young hearts, many conditioning maneuvers can significantly increase the resistance of the heart against ischemia/reperfusion injury. The large multicenter clinical trials with ischemic remote conditioning have not been proven successful in cardiac surgery thus far. The lack of clinical success is due to underlying risk factors that interfere with remote ischemic conditioning and the use of cardioprotective agents that have activated the endogenous cardioprotective mechanisms prior to remote ischemic conditioning. Future preclinical research using remote ischemic conditioning will need to be conducted using comorbid models.

Hydroxyurea therapy in adult Nigerian sickle cell disease: a monocentric survey on pattern of use, clinical effects and patient's compliance.

The clinical prospects of hydroxyurea therapy in the management of sickle cell disease (SCD) require evaluation in the Nigerian setting to develop indigenous guidelines. This survey examines the pattern of hydroxyurea therapy, its clinico-haematologic benefits and safety profile in Nigerian SCD subjects. A cross sectional pilot survey was carried out among 60 adult SCD subjects over 3 months. Data on clinical phenotypes, relevant haematological parameters and details of hydroxyurea therapy were obtained using a structured questionnaire through an interview process and case file review. The median age was 30 years. Thirty-four (56.7%) of the subjects are aware of hydroxyurea therapy in SCD. Twenty-four (40%) SCD patients had previously used hydroxyurea. Only 4 subjects were fully compliant. Reasons for non-compliance included poor knowledge and lack of funds. In particular, hydroxyurea reduced leucocyte count and increased mean red cell volume (MCV) in compliant subjects. Hydroxyurea use is low among Nigerian SCD subjects despite its proven efficacy/clinical prospects in the developed nations. Large scale multicenter studies and clinical trials are needed to form a basis for developing standard local treatment protocol for its use.

Empty polyetheretherketone (PEEK) cages in anterior cervical diskectomy and fusion (ACDF) show slow radiographic fusion that reduces clinical improvement: results from the prospective multicenter \u201cPIERCE-PEEK\u201d study

BackgroundAnterior cervical diskectomy and fusion (ACDF) is a well-established surgical treatment for radiculopathy and myelopathy. Previous studies showed that empty PEEK cages have lower radiographic fusion rates, but the clinical relevance remains unclear. This paper’s aim is to provide high-quality evidence on the outcomes of ACDF with empty PEEK cages and on the relevance of radiographic fusion for clinical outcomes.MethodsThis large prospective multicenter clinical trial performed single-level ACDF with empty PEEK cages on patients with cervical radiculopathy or myelopathy. The main clinical outcomes were VAS (0–10) for pain and NDI (0–100) for functioning. Radiographic fusion was evaluated by two investigators for three different aspects.ResultsThe median (range) improvement of the VAS pain score was: 3 (1–6) at 6 months, 3 (2–8) at 12 months, and 4 (2–8) at 18 months. The median (range) improvement of the NDI score was: 12 (2–34) at 6 months, 18 (4–46) at 12 months, and 22 (2–44) at 18 months. Complete radiographic fusion was reached by 126 patients (43%) at 6 months, 214 patients (73%) at 12 months, and 241 patients (83%) at 18 months. Radiographic fusion was a highly significant (p < 0.001) predictor of the improvement of VAS and NDI scores.ConclusionThis study provides strong evidence that ACDF is effective treatment, but the overall rate of radiographic fusion with empty PEEK cages is slow and insufficient. Lack of complete radiographic fusion leads to less improvement of pain and disability. We recommend against using empty uncoated pure PEEK cages in ACDF.Trial registrationISRCTN42774128. Retrospectively registered 14 April 2009.

Is there a role for ischaemic conditioning in cardiac surgery?

Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Coronary artery bypass graft (CABG) surgery is the revascularisation strategy of choice in patients with diabetes mellitus and complex CAD. Owing to a number of factors, including the ageing population, the increased complexity of CAD being treated, concomitant valve and aortic surgery, and multiple comorbidities, higher-risk patients are being operated on, the result of which is an increased risk of sustaining perioperative myocardial injury (PMI) and poorer clinical outcomes. As such, new treatment strategies are required to protect the heart against PMI and improve clinical outcomes following cardiac surgery. In this regard, the heart can be endogenously protected from PMI by subjecting the myocardium to one or more brief cycles of ischaemia and reperfusion, a strategy called “ischaemic conditioning”. However, this requires an intervention applied directly to the heart, which may be challenging to apply in the clinical setting. In this regard, the strategy of remote ischaemic conditioning (RIC) may be more attractive, as it allows the endogenous cardioprotective strategy to be applied away from the heart to the arm or leg by simply inflating and deflating a cuff on the upper arm or thigh to induce one or more brief cycles of ischaemia and reperfusion (termed “limb RIC”). Although a number of small clinical studies have demonstrated less PMI with limb RIC following cardiac surgery, three recently published large multicentre randomised clinical trials found no beneficial effects on short-term or long-term clinical outcomes, questioning the role of limb RIC in the setting of cardiac surgery. In this article, we review ischaemic conditioning as a therapeutic strategy for endogenous cardioprotection in patients undergoing cardiac surgery and discuss the potential reasons for the failure of limb RIC to improve clinical outcomes in this setting. Crucially, limb RIC still has the therapeutic potential to protect the heart in other clinical settings, such as acute myocardial infarction, and it may also protect other organs against acute ischaemia/reperfusion injury (such as the brain, kidney, and liver).

Safety and effectiveness of colistin compared with non-colistin combinations in the treatment of multi drug resistant bacterial infections

Background: Multi drug resistant (MDR) bacteria are usually defined as when it is resistant to three or more group of antibiotics. The objective of this study was to determine the efficacy and safety of colistin when compared with other antibiotics for the treatment of infections caused by MDR Acinetobacter baumannii and Pseudomonas aeruginosa.Methods: A single centre, prospective cohort study was conducted at Krishna Institute of medical Sciences, Hyderabad, India between September 2016 to March 2017. Seventy-four patients (74) were included in the study. Primary outcome were good clinical response and thirty days’ mortality, secondary outcome were microbiological response and adverse drug reactions of the drug.Results: A total of 74 patients were enrolled into the study. Forty patients (40) were received intravenous colistin dose of 2.5mg-5mg/kg/day. Remaining thirty-four patients (34) received other antibiotics which includes carbapenem, aminoglycosides. etc. The mean age, gender, underlying conditions and severity of illness of the patients in both groups were significantly same. In colistin group 27 (67.5%) patients and 11 (32.3%) patients had good clinical response. The overall mortality of the patients in the colistin group was 17.5% and that in the non-colistin group was 38.2%. The incidence of nephrotoxicity in colistin was 15% and 35.2% in non colistin group. No neurotoxicity was observed in present study.Conclusions: Our study concludes treatment with colistin decreases patient mortality and increase the clinical response in multidrug-resistant A. baumannii and P. aeruginosa infected patients. However large multicentric clinical trials are needed to demonstrate the safety and efficacy of colistin.

Epidemiology of ACE Inhibitor Angioedema Utilizing a Large Electronic Health Record

Angiotensin-converting enzyme inhibitors (ACEIs) are a common cause of drug-induced angioedema in the United States. Most epidemiologic ACEI angioedema data are from large multicenter clinical trials. The objective of this study was to identify the incidence of and risk factors for ACEI angioedema using a large integrated electronic health record (EHR). We conducted a retrospective cohort study of all ACEI prescriptions in the outpatient setting of a large academic center between January 1, 2000, and September 30, 2008. We determined frequency, timing, and risk factors for ACEI angioedema within 5 years of prescription. All data were derived from EHR sources, with angioedema defined by EHR reactions of angioedema, swelling, edema, or lip, eye, face, tongue, throat or mouth swelling. Among 134,945 patients prescribed an ACEI, 0.7%(n= 888) developed angioedema during the subsequent 5 years. Sex was similar but patients who developed ACEI angioedema were younger (61.5 vs 62.7 years, P= .007). Patients with ACEI angioedema were more likely to have a history of nonsteroidal anti-inflammatory drug allergy compared with patients who did not develop angioedema (7.1% vs 4.2%, P < .001). We identified a 0.07% incidence of ACEI angioedema within 1 month of prescription and a 0.23% incidence during the first year. Incidence of angioedema was relatively constant annually over the subsequent 4 years (0.10%to 0.12%). The incidence of ACEI angioedema within a large EHR is consistent with large clinical trial data. We observed a persistent and relatively constant annual risk; however, angioedema risk factors and underlying genetic and pathophysiological mechanisms require further study.

Is there a role for immunosuppression in immunoglobulin A nephropathy?

The most common primary glomerular disease globally is IgA nephropathy (IgAN). It is often a slowly progressive disease, and ∼40% of patients will progress to kidney failure. Due to a lack of large clinical trial networks and a lack of surrogate markers of treatment efficacy, there are relatively few large multicenter clinical trials in IgAN. Given that both the pathogenesis and progression of IgAN are linked to defects in mucosal immune regulation and inflammation, use of immunosuppression to prevent kidney failure is well founded. However, recent clinical trials have supported improvement in disease parameters, but this has not always translated to parallel amelioration in longer-term outcome. In this review we summarize the most current clinical research examining the efficacy of immunosuppression in IgAN.

Cold dialysis and its impact on renal patients' health: An evidence-based mini review.

Chronic renal disease is associated with advanced age, diabetes, hypertension, obesity, musculoskeletal problems and cardiovascular disease, the latter being the main cause of mortality in patients receiving haemodialysis (HD). Cooled dialysate (35 °C-36 °C) is recently employed to reduce the incidence of intradialytic hypotension in patients on chronic HD. The studies to date that have evaluated cooled dialysate are limited, however, data suggest that cooled dialysate improves hemodynamic tolerability of dialysis, minimizes hypotension and exerts a protective effect over major organs including the heart and brain. The current evidence-based review is dealing with the protective effect of cold dialysis and the benefits of it in aspects affecting patients’ quality of care and life. There is evidence to suggest that cold dialysis can reduce cardiovascular mortality. However, large multicentre randomized clinical trials are urgently needed to provide further supporting evidence in order to incorporate cold dialysis in routine clinical practice.

Anti-VEGF Therapy for Neovascular AMD and Polypoidal Choroidal Vasculopathy.

Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of neovascular age-related macular degeneration (AMD). This review will summarize the current evidence of anti-VEGF therapy in neovascular AMD, including subtypes of retinal angiomatous proliferation and polypoidal choroidal vasculopathy (PCV). Importantly, 2 large multicenter randomized clinical trials evaluating the safety and efficacy of anti-VEGF monotherapy and combination with photodynamic therapy (PDT) have recently reported initial first-year outcomes. In this review, we summarize the latest updates in the efficacy and safety of anti-VEGF monotherapy and combination with PDT in common lesion subtypes. Remaining gaps in current understanding are highlighted where further research is needed.

A Rapid Cell Expansion Process for Production of Engineered Autologous CAR-T Cell Therapies.

The treatment of B-cell malignancies by adoptive cell transfer (ACT) of anti-CD19 chimeric antigen receptor T cells (CD19 CAR-T) has proven to be a highly successful therapeutic modality in several clinical trials.1-6 The anti-CD19 CAR-T cell production method used to support initial trials relied on numerous manual, open process steps, human serum, and 10 days of cell culture to achieve a clinical dose.7 This approach limited the ability to support large multicenter clinical trials, as well as scale up for commercial cell production. Therefore, studies were completed to streamline and optimize the original National Cancer Institute production process by removing human serum from the process in order to minimize the risk of viral contamination, moving process steps from an open system to functionally closed system operations in order to minimize the risk of microbial contamination, and standardizing additional process steps in order to maximize process consistency. This study reports a procedure for generating CD19 CAR-T cells in 6 days, using a functionally closed manufacturing process and defined, serum-free medium. This method is able to produce CD19 CAR-T cells that are phenotypically and functionally indistinguishable from cells produced for clinical trials by the previously described production process.