The neutralizing effect of heparin on blood-derived antimicrobial compounds: impact on antibacterial activity and inflammatory response.

Acting through a combination of direct and indirect pathogen clearance mechanisms, blood-derived antimicrobial compounds (AMCs) play a pivotal role in innate immunity, safeguarding the host against invading microorganisms. Besides their antimicrobial activity, some AMCs can neutralize endotoxins, preventing their interaction with immune cells and avoiding an excessive inflammatory response. In this study, we aimed to investigate the influence of unfractionated heparin, a polyanionic drug clinically used as anticoagulant, on the endotoxin-neutralizing and antibacterial activity of blood-derived AMCs. Serum samples from healthy donors were pre-incubated with increasing concentrations of heparin for different time periods and tested against pathogenic bacteria (Acinetobacter baumannii, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus) and endotoxins from E. coli, K. pneumoniae, and P. aeruginosa. Heparin dose-dependently decreased the activity of blood-derived AMCs. Consequently, pre-incubation with heparin led to increased activity of LPS and higher values of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Accordingly, higher concentrations of A. baumannii, E. coli, K. pneumoniae, and P. aeruginosa were observed as well. These findings underscore the neutralizing effect of unfractionated heparin on blood-derived AMCs in vitro and may lead to alternative affinity techniques for isolating and characterizing novel AMCs with the potential for clinical translation.

Pulsed-field versus cryoballoon ablation for atrial fibrillation-Impact of energy source on sedation and analgesia requirement.

INTRODUCTION: Pulsed field ablation (PFA) represents a novel, nonthermal energy modality that can be applied for single-shot pulmonary vein isolation (PVI) in atrial fibrillation (AF). Comparative data with regard to deep sedation to established single-shot modalities such as cryoballoon (CB) ablation are scarce. The aim of this study was to compare a deep sedation protocol in patients receiving PVI with either PFA or CB. METHODS: Prospective, consecutive AF patients undergoing PVI with a pentaspline PFA catheter were compared to a retrospective CB-PVI cohort of the same timeframe. Study endpoints were the requirements of analgesics, cardiorespiratory stability, and sedation-associated complications. RESULTS: A total of 100 PVI patients were included (PFA n = 50, CB n = 50, mean age 66 ± 10.6, 61% male patients, 65% paroxysmal AF). Requirement of propofol, midazolam, and sufentanyl was significantly higher in the PFA group compared to CB [propofol 0.14 ± 0.04 mg/kg/min in PFA vs. 0.11 ± 0.04 mg/kg/min in CB (p = .001); midazolam 0.00086 ± 0.0004 mg/kg/min in PFA vs. 0.0006295 ± 0.0003 mg/kg/min in CB (p = .002) and sufentanyl 0.0013 ± 0.0007 µg/kg/min in PFA vs. 0.0008 ± 0.0004 µg/kg/min in CB (p < .0001)]. Sedation-associated complications did not differ between both groups (PFA n = 1/50 mild aspiration pneumonia, CB n = 0/50, p > .99). Nonsedation-associated complications (PFA: n = 2/50, 4%, CB: n = 1/50, 2%, p > .99) and procedure times (PFA 75 ± 31, CB 84 ± 32 min, p = .18) did not differ between groups. CONCLUSIONS: PFA is associated with higher sedation and especially analgesia requirements. However, the safety of deep sedation does not differ to CB ablation.

A Simplified Approach to Pulmonary Vein Visualization during Cryoballoon Ablation of Atrial Fibrillation.

Background and Objectives: Selective pulmonary vein (PV) angiography has been established as the gold standard for PV visualization in cryoballoon (CB)-based pulmonary vein isolation (PVI). We sought to simplify this approach to reduce procedural complexity and radiation exposure. Materials and Methods: Patients with paroxysmal and recently diagnosed persistent AF undergoing CB-based PVI from January 2015 to December 2017 were retrospectively analyzed. Patients underwent either selective PV angiography or conventional left atrial (LA) angiography for PV visualization. Results: A total of 336 patients were analyzed. A total of 87 patients (26%) received PV angiography and 249 (74%) LA angiography. LA angiography required fewer cine-sequences for PV visualization, translating into a significant reduction in procedure duration, fluoroscopy time and dose area product. Additionally, less contrast medium was utilized. PV occlusion by the CB, CB temperature and time to isolation showed no significant differences. The number of CB applications and total application time (LA angiography: 1.4 ± 0.02 vs. PV Angiography: 1.6 ± 0.05; p < 0.0001; LA angiography: 297.9 ± 4.62 vs. PV-Angiography: 348.9 ± 11.03; p < 0.001, respectively) per vein were slightly but significantly higher in the PV angiography group. We observed no difference in late AF recurrence (24.7% LA angiography vs. 21.3% PV angiography; p = 0.2657). Conclusions: A simplified protocol, using LA angiography for PV visualization, entails a reduction in procedure time and radiation exposure while equally maintaining procedural efficiency and safety in both groups.

Outcome after tailored catheter ablation of atrial tachycardia using ultra-high-density mapping.

INTRODUCTION: Tailored catheter ablation of atrial tachycardias (ATs) is increasingly recommended as a potentially easy treatment strategy in the era of high-density mapping (HDM). As follow-up data are sparse, we here report outcomes after HDM-guided ablation of ATs in patients with prior catheter ablation or cardiac surgery. METHODS AND RESULTS: In 250 consecutive patients (age 66.5 ± 0.7 years, 58% male) with ATs (98% prior catheter ablation, 13% prior cardiac surgery) an HDM-guided catheter ablation was performed with the support of a 64-electrode mini-basket catheter. A total of 354 ATs (1.4 ± 0.1 ATs per patient; mean cycle length 304 ± 4.3 ms; 64% macroreentry, 27% localized reentry, and 9% focal) with acute termination of 95% were targeted in the index procedure. A similar AT as in the index procedure recurred in five patients (2%) after a median follow-up time of 535 days (interquartile range (IQR) 25th-75th percentile: 217-841). Tailored ablation of reentry ATs with freedom from any arrhythmia was obtained in 53% after a single procedure and in 73% after 1.4 ± 0.4 ablation procedures (range: 1-4). A total of 228 patients (91%) were free from any arrhythmia recurrence after 210 days (IQR: 152-494) when including optimal usual care. CONCLUSIONS: Tailored catheter ablation of ATs guided by HDM has a high acute success rate. The recurrence rate of the index AT is low. In patients with extensive atrial scaring further ablation procedures need to be considered to achieve freedom from any arrhythmia.

Radiation protection modelling for 2.5 Petawatt-laser production of ultrashort x-ray, proton and ion bunches: Monte Carlo model of the Munich CALA facility.

The 'Centre for Advanced Laser Applications' (CALA) is a new research institute for laser-based acceleration of electron beams for brilliant x-ray generation, laser-driven sub-nanosecond bunches of protons and heavy ions for biomedical applications like imaging and tumour therapy as well as for nuclear and high-field physics.The radiation sources emerging from experiments using the up to 2.5 petawatt laser pulses with 25 femtosecond duration will be mixed particle-species of high intensity, high energy and pulsed, thus posing new challenges compared to conventional radiation protection. Such worldwide pioneering laser experiments result in source characteristics that require careful a-priori radiation safety simulations.The FLUKA Monte-Carlo code was used to model the five CALA experimental caves, including the corridors, halls and air spaces surrounding the caves. Beams of electrons (<5 GeV), protons (<200 MeV),12C (<400MeV/u) and197Au (<10MeV/u) ions were simulated using spectra, divergences and bunch-charges based on expectations from recent scientific progress.Simulated dose rates locally can exceed 1.5 kSv h-1inside beam dumps. Vacuum pipes in the cave walls for laser transport and extraction channels for the generated x-rays result in small dose leakage to neighboring areas. Secondary neutrons contribute to most of the prompt dose rate outside caves into which the beam is delivered. This secondary radiation component causes non-negligible dose rates to occur behind walls to which large fluences of secondary particles are directed.By employing adequate beam dumps matched to beam-divergence, magnets, passive shielding and laser pulse repetition limits, average dose rates in- and outside the experimental building stay below design specifications (<0.5µSv h-1) for unclassified areas,<2.5µSv h-1for supervised areas,<7.5µSv h-1maximum local dose rate) and regulatory limits (<1mSv a-1for unclassified areas).

Ultra-high-density mapping of conduction gaps and atrial tachycardias: Distinctive patterns following pulmonary vein isolation with cryoballoon or contact-force-guided radiofrequency current.

INTRODUCTION: The aim of this study was to investigate electrophysiological findings in patients with arrhythmia recurrence undergoing a repeat ablation procedure using ultra-high-density (UHDx) mapping following an index procedure using either contact-force (CF)-guided radiofrequency current (RFC) pulmonary vein isolation (PVI) or second-generation cryoballoon (CB) PVI for treatment of atrial fibrillation (AF). METHODS AND RESULTS: Fifty consecutive patients with recurrence of AF and/or atrial tachycardia (AT) following index CF-RFC PVI (n = 21) or CB PVI (n = 29) were included. A 64-pole mini-basket mapping catheter in combination with an UHDx-mapping system-guided ablation was used. RFC was applied using a catheter tip with three incorporated mini-electrodes. PV reconnection rates were higher after CF-RFC PVI (CF-RFC: 2.5 ± 1.3 PVs vs CB: 1.4 ± 0.9 PVs; P = .0025) and left PVs were more frequently reconnected (CF-RFC: 64% PVs vs CB: 35% PVs; P = .0077). Fractionated signals along the antral index ablation line (FS) were found in 30% of CB-PVI patients (CF-RFC: 9.5% vs CB:30%; P = .098) targeted for ablation. In five cases, FS were a critical part of maintaining consecutive AT. The main AT mechanism found during reablation (n = 45 ATs) was macroreentry (80% [36/45], CF-RFC: 78.9% vs CB: 80.8%; P = 1.0) with a variety of circuits throughout both atria. CONCLUSION: UHDx mapping is sensitive in detecting conduction gaps along the index ablation line. Left PVs are more frequently reconnected after initial CF-RFC PVI. FS are a common finding after CB PVI and can maintain certain forms of ATs. ATs after index PVI are mostly macroreentries with a broad spectrum of entities.

Cytokine Removal in Extracorporeal Blood Purification: An in vitro Study.

BACKGROUND/AIMS: Cytokines are among the main target substances that have to be removed effectively in order to improve the patient's health status in the treatment of sepsis, septic shock, and liver diseases. Although there are various medical devices commercially available, the success of their clinical use is limited. The aim of this in vitro study was to compare 3 different medical devices with respect to their clearance for the cytokines interleukin-6 (IL-6), IL-8, IL-1ß, and tumor necrosis factor alpha. The medical devices that were tested are the whole blood adsorbent CytoSorb, the high cutoff filter EMiC2, and the hemofilter HemofeelCH 1.8. METHODS: The study was carried out on the multiFiltrate machine with 1 L human plasma for 8 h. Samples for cytokine quantification were taken at defined time points from the plasma pool. Each experiment was conducted in triplicates, and clearance was calculated for all tested cytokines. RESULTS: All 3 medical devices showed good cytokine removal. The highest clearance for all cytokines was achieved by hemoperfusion with Cytosorb. IL-8 and IL-6 clearance were higher with Hemofeel (continuous venovenous hemodiafiltration) than with EMiC2 (continuous venovenous hemodialysis) because the polymethyl methacrylate (PMMA)-based membrane Hemofeel is able to remove these 2 cytokines by adsorption. Protein and albumin loss was highest withCytosorb and lowest with EMiC2. CONCLUSION: The mechanisms of cytokine removal by blood purification include convection, diffusion, and adsorption. PMMA-based filters are able to combine all 3 mechanisms for certain cytokines. Cytosorb showed the best adsorption kinetics, while dialysis with polystyrene-based membranes offers the best biocompatibility because they do not show any unspecific adsorption of other plasma components.

Retroperitoneal Hematoma after Bone Marrow Biopsy: The First Cut Should Not Be the Deepest.

Bone marrow biopsies are standard hematology procedures. We report the case of a patient with acute myeloid leukemia who developed retroperitoneal hematoma after the procedure. The bleeding was stopped with endovascular embolization and coiling. This case raises several issues about the standards for bone marrow biopsies and discusses the approach to patients with bleeding risk factors. We also provide a literature review.

MicroRNA-143 targets ERK5 in granulopoiesis and predicts outcome of patients with acute myeloid leukemia.

Hematopoiesis, the formation of blood cells from hematopoietic stem cells (HSC), is a highly regulated process. Since the discovery of microRNAs (miRNAs), several studies have shown their significant role in the regulation of the hematopoietic system. Impaired expression of miRNAs leads to disrupted cellular pathways and in particular causes loss of hematopoietic ability. Here, we report a previously unrecognized function of miR-143 in granulopoiesis. Hematopoietic cells undergoing granulocytic differentiation exhibited increased miR-143 expression. Overexpression or ablation of miR-143 expression resulted in accelerated granulocytic differentiation or block of differentiation, respectively. The absence of miR-143 in mice resulted in a reduced number of mature granulocytes in blood and bone marrow. Additionally, we observed an association of high miR-143 expression levels with a higher probability of survival in two different cohorts of patients with acute myeloid leukemia (AML). Overexpression of miR-143 in AML cells impaired cell growth, partially induced differentiation, and caused apoptosis. Argonaute2-RNA-Immunoprecipitation assay revealed ERK5, a member of the MAPK-family, as a target of miR-143 in myeloid cells. Further, we observed an inverse correlation of miR-143 and ERK5 in primary AML patient samples, and in CD34+ HSPCs undergoing granulocytic differentiation and we confirmed functional relevance of ERK5 in myeloid cells. In conclusion, our data describe miR-143 as a relevant factor in granulocyte differentiation, whose expression may be useful as a prognostic and therapeutic factor in AML therapy.

ABR, a novel inducer of transcription factor C/EBPα, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia.

Active BCR related (ABR) gene deactivates ras-related C3 botulinum toxin substrate 1 (RAC1), which plays an essential role in regulating normal hematopoiesis and in leukemia. BCR gene, closely related to ABR, acts as a tumor suppressor in chronic myeloid leukemia and has overlapping functions with ABR. Evidence for a putative tumor suppressor role of ABR has been shown in several solid tumors, in which deletion of ABR is present. Our results show downregulation of ABR in AML. A block of ABR prevents myeloid differentiation and leads to repression of the myeloid transcription factor C/EBPα, a major regulator of myeloid differentiation and functionally impaired in leukemia. Conversely, stable overexpression of ABR enhances myeloid differentiation. Inactivation of the known ABR target RAC1 by treatment with the RAC1 inhibitor NSC23766 resulted in an increased expression of C/EBPα in primary AML samples and in AML cell lines U937 and MV4;11. Finally, AML patients with high ABR expression at diagnosis showed a significant longer overall survival and patients who respond to azacitidine therapy showed a significant higher ABR expression. This is the first report showing that ABR expression plays a critical role in both myelopoiesis and AML. Our data indicate the tumor suppressor potential of ABR and underline its potential role in leukemia therapeutic strategies.

Clearance of Selected Plasma Cytokines with Continuous Veno-Venous Hemodialysis Using Ultraflux EMiC2 versus Ultraflux AV1000S.

BACKGROUND: High cutoff hemofilters might support the restoration of immune homeostasis in systemic inflammation by depleting inflammatory mediators from the circulation. METHODS: Interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha depletion was assessed in 30 sepsis patients with acute renal failure using continuous veno-venous hemodialysis with high cutoff versus standard filters (CVVHD-HCO vs. CVVHD-STD) over 48 h. RESULTS: The transfer of IL-6 and IL-8 was significantly higher for CVVHD-HCO, as shown by increased IL-6 and IL-8 effluent concentrations. The mean plasma cytokine concentrations decreased over time for all cytokines without detectable differences for the treatment modalities. No transfer of albumin was observed for either of the filters. C-reactive protein remained stable over time and did not differ between CVVHD-HCO and CVVHD-STD, while procalcitonin decreased significantly over 48 h for both treatment modalities. CONCLUSION: CVVHD-HCO achieved enhanced removal of IL-6 and IL-8 as compared to CVVHD-STD, without differentially reducing plasma cytokine levels.

[Approval of clinical trials with biological medicinal products]. / Genehmigung klinischer Prüfungen mit biologischen Arzneimitteln.

Biological medicinal products can be distinguished from chemically characterized medicines. Their active substance is either extracted or manufactured from organic source materials. Monoclonal antibodies are currently the fastest growing product class in the pharmaceutical sector. The Paul Ehrlich Institute (PEI), an independent federal authority, has the task of assessing the benefits and risks for the purposes of clinical development and approval and after launch onto the market.To ensure the credibility of the results of clinical trials, there are internationally accepted quality requirements for the planning, execution and recording of the trials. The rights, safety and well-being of all participants in clinical trials are to be ensured in the Member States of the European Union (EU). To achieve a common basis for the evaluation at a European level, the goal was to harmonise the regulatory requirements for clinical trials of human drugs. With full entry into force of EU regulation 536/2014 by the fourth quarter of 2018, this objective is being pursued. It is expected that this will result in procedural changes in the course of processes leading to the approval of clinical trials. The content and technical specifications that should ensure that the investigational products are safe and compatible for the subjects or patients should not be influenced by this.

Disruption of the C/EBPα-miR-182 balance impairs granulocytic differentiation.

Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPα by microRNAs during granulopoiesis or acute myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPα. Moreover, we identify a regulatory loop between C/EBPα and miR-182. While C/EBPα blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPα protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPα and miR-182 for the maintenance of healthy granulopoiesis.C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.

Phytosulfokine Regulates Growth in Arabidopsis through a Response Module at the Plasma Membrane That Includes CYCLIC NUCLEOTIDE-GATED CHANNEL17, H+-ATPase, and BAK1.

Phytosulfokine (PSK) is perceived by the leucine-rich repeat receptor kinase PSKR1 and promotes growth in Arabidopsis thaliana. PSKR1 is coexpressed with the CYCLIC NUCLEOTIDE-GATED CHANNEL gene CNGC17. PSK promotes protoplast expansion in the wild type but not in cngc17. Protoplast expansion is likewise promoted by cGMP in a CNGC17-dependent manner. Furthermore, PSKR1-deficient protoplasts do not expand in response to PSK but are still responsive to cGMP, suggesting that cGMP acts downstream of PSKR1. Mutating the guanylate cyclase center of PSKR1 impairs seedling growth, supporting a role for PSKR1 signaling via cGMP in planta. While PSKR1 does not interact directly with CNGC17, it interacts with the plasma membrane-localized H(+)-ATPases AHA1 and AHA2 and with the BRI-associated receptor kinase 1 (BAK1). CNGC17 likewise interacts with AHA1, AHA2, and BAK1, suggesting that PSKR1, BAK1, CNGC17, and AHA assemble in a functional complex. Roots of deetiolated bak1-3 and bak1-4 seedlings were unresponsive to PSK, and bak1-3 and bak1-4 protoplasts expanded less in response to PSK but were fully responsive to cGMP, indicating that BAK1 acts in the PSK signal pathway upstream of cGMP. We hypothesize that CNGC17 and AHAs form a functional cation-translocating unit that is activated by PSKR1/BAK1 and possibly other BAK1/RLK complexes.

PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia.

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL.

Characterization of Adsorbents for Cytokine Removal from Blood in an In Vitro Model.

INTRODUCTION: Cytokines are basic targets that have to be removed effectively in order to improve the patient's health status in treating severe inflammation, sepsis, and septic shock. Although there are different adsorbents commercially available, the success of their clinical use is limited. Here, we tested different adsorbents for their effective removal of cytokines from plasma and the resulting effect on endothelial cell activation. METHODS: The three polystyrene divinylbenzene (PS-DVB) based adsorbents Amberchrom CG161c and CG300m and a clinically approved haemoperfusion adsorbent (HAC) were studied with regard to cytokine removal in human blood. To induce cytokine release from leucocytes, human blood cells were stimulated with 1 ng/ml LPS for 4 hours. Plasma was separated and adsorption experiments in a dynamic model were performed. The effect of cytokine removal on endothelial cell activation was evaluated using a HUVEC-based cell culture model. The beneficial outcome was assessed by measuring ICAM-1, E-selectin, and secreted cytokines IL-8 and IL-6. Additionally the threshold concentration for HUVEC activation by TNF-α and IL-1ß was determined using this cell culture model. RESULTS: CG161c showed promising results in removing the investigated cytokines. Due to its pore size the adsorbent efficiently removed the key factor TNF-α, outperforming the commercially available adsorbents. The CG161c treatment reduced cytokine secretion and expression of cell adhesion molecules by HUVEC which underlines the importance of effective removal of TNF-α in inflammatory diseases. CONCLUSION: These results confirm the hypothesis that cytokine removal from the blood should approach physiological levels in order to reduce endothelial cell activation.

Transcription factor C/EBPα-induced microRNA-30c inactivates Notch1 during granulopoiesis and is downregulated in acute myeloid leukemia.

The transcription factor CCAAT enhancer binding protein α (C/EBPα) is a master regulator in granulopoiesis and is frequently disrupted in acute myeloid leukemia (AML). We have previously shown that C/EBPα exerts its effects by regulating microRNAs (miRs) such as miR-223 and miR-34a. Here, we confirm miR-30c as a novel important target of C/EBPα during granulopoiesis. Thus, wild-type C/EBPα-p42 directly upregulates miR-30c expression, whereas C/EBPα-p30, found in AML, does not. miR-30c is downregulated in AML, especially in normal karyotype AML patients with CEBPA mutations. An induced C/EBPα knockout in mice leads to a significant downregulation of miR-30c expression in bone marrow cells. We identified NOTCH1 as a direct target of miR-30c. Finally, a block of miR-30c prevents C/EBPα-induced downregulation of Notch1 protein and leads to a reduced CD11b expression in myeloid differentiation. Our study presents the first evidence that C/EBPα, miR-30c, and Notch1 together play a critical role in granulocytic differentiation and AML, and particularly in AML with CEBPA mutations. These data reveal the importance of deregulated miRNA expression in leukemia and may provide novel biomarkers and therapeutic targets in AML.

Laparoscopic anterior 180-degree versus nissen fundoplication for gastroesophageal reflux disease: systematic review and meta-analysis of randomized clinical trials.

OBJECTIVE: To compare short- and long-term outcome after 180-degree laparoscopic anterior fundoplication (180-degree LAF) with laparoscopic Nissen fundoplication (LNF). SUMMARY OF BACKGROUND DATA: LNF is currently the most frequently performed surgical therapy for gastroesophageal reflux disease. Alternatively, 180-degree LAF has been alleged to reduce troublesome dysphagia and gas-related symptoms, with similar reflux control. METHODS: MEDLINE, EMBASE, Cochrane Library, and web of Knowledge CPCI-S were searched for randomized clinical trials comparing primary 180-degree LAF with LNF. The methodological quality was evaluated to assess bias risk. Primary outcomes were esophageal acid exposure, esophagitis, heartburn score, dilatation for dysphagia, modified Dakkak dysphagia score (0-45), and reoperation rate. Meta-analysis was conducted at 1 and 5 years. RESULTS: Five distinct randomized clinical trials comparing 180-degree LAF (n = 227) with LNF (n = 231) were identified. At 1 year, the Dakkak dysphagia score [2.8 vs 4.8; weighted mean difference: -2.25; 95% confidence interval (CI): -2.66 to -1.83; P < 0.001], gas bloating [11% vs 18%; relative risk (RR) 0.59; 95% CI: 0.36-0.97; P = 0.04], flatulence (14% vs 25%; RR: 0.57; 95% CI: 0.35-0.91; P = 0.02), inability to belch (19% vs 31%; RR: 0.63; 95% CI: 0.40-0.99; P = 0.05), and inability to relieve bloating (34% vs 44%; RR: 0.74; 95% CI: 0.55-0.99; P = 0.04) were lower after 180-degree LAF. Esophageal acid exposure (standardized mean difference: 0.19; 95% CI: -0.07 to 0.46; P = 0.15), esophagitis (19% vs 13%; RR: 1.42; 95% CI: 0.69-2.91; P = 0.34), heartburn score (standardized mean difference: 1.27; 95% CI:-0.36 to 2.90; P = 0.13), dilatation rate (1.4% vs 2.8%; RR: 0.60; 95% CI: 0.19-1.91; P = 0.39), reoperation rate (5.7% vs 2.8%; RR: 2.08; 95% CI: 0.80-5.41; P = 0.13), perioperative outcome, regurgitation, proton pump inhibitor (PPI) use, lower esophageal sphincter pressure, and patient satisfaction were similar after 180-degree LAF and LNF. At 5 years, the Dakkak dysphagia score, flatulence, inability to belch, and inability to relieve bloating remained lower after 180-degree LAF. The 5-year heartburn score, dilatation rate, reoperation rate, PPI use, and patient satisfaction were similar. CONCLUSIONS: At 1 and 5 years, dysphagia and gas-related symptoms are lower after 180-degree LAF than after LNF, and esophageal acid exposure and esophagitis are similar, with no differences in heartburn scores, patient satisfaction, dilatations, and reoperation rate. These results lend level 1a support for the use of 180-degree LAF for the surgical treatment of gastroesophageal reflux disease.

Quality of life in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is it worth the risk?

OBJECTIVE: To investigate the course of health-related quality of life (HQL) over time in patients with peritoneal carcinomatosis (PC) after complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Prospective, single-center, nonrandomized cohort study using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. RESULTS: Ninety patients who underwent CRS and HIPEC for PC in our institution were enrolled in the study. Mean age was 56 years (range 27-77 years) (61% female). Primary tumor was colorectal in 21%, ovarian in 19%, pseudomyxoma peritonei in 16%, an appendix tumor in 16%, gastric cancer in 10%, and peritoneal mesothelioma in 13% of cases. Mean peritoneal carcinomatosis index was 22 (range 2-39). Mean global health status score was 69±25 preoperatively and 55±20, 66±22, 66±23, 71±23, and 78±21 at months 1, 6, 12, 24, and 36, respectively. Physical and role function recovered significantly at 6 months and were close to baseline at the 24-month measurement. Emotional function starting from a low baseline recovered to baseline by month 12. Cognitive and social function had slow recovery on follow-up. Fatigue, diarrhea, dyspnea, and sleep disturbance were symptoms persistent at 6-month follow-up, improving later on in survivors. CONCLUSIONS: Survivors after CRS and HIPEC have postoperative quality of life similar to preoperatively, with most of the reduced elements recovering after 6-12 months. We conclude that reduced quality of life of patients after CRS and HIPEC should not be used as an argument to deny surgical therapy to these patients.