A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.

OBJECTIVE: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. METHODS: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. RESULTS: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. CONCLUSIONS: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.

[Histological changes in intraperitoneal onlay mesh (IPOM) with synthetic and biological meshes. Results of the chronic experiment]. / Gistologicheskie izmeneniya pri intraperitoneal'noi plastike (IPOM) sinteticheskimi i biologicheskimi endoprotezami. Rezul'taty khronicheskogo eksperimenta.

OBJECTIVE: The objective of the study was to analyze histological changes in the site of the meshes FTOREX, FTOREX coated with carboxymethylcellulose, Ventralight ST, Symbotex, REPEREN-16-2 and decellularized porcine peritoneum on the parietal peritoneum of the pig. MATERIAL AND METHODS: At laparoscopy, 6 different meshes were placed intraperitoneally in each of the 3 pigs. After 90 days, the animals were taken out of the experiment. After staining with hematoxylin and eosin, quantitative morphometry and counting the number of vessels and cells in the interstitium in the areas of the mesh and peritoneum were performed. An immunohistochemical study with an antibody to pancytokeratins assessed the state of the initial peritoneum and neoperitoneum. RESULTS: According to morphological characteristics, the meshes were divided into 3 groups: 1) with fluoropolymer coating FTOREX, 2) Ventralight ST and Symbotex, 3) REPEREN and decellularized peritoneum. In group 1, the surface area of the mesh threads was optimal in terms of the arrangement and arrangement of the threads relative to each other. This contributed to the formation of a relatively dense fibrous framework and a place to preserve the underlying peritoneum involved in the formation of the neoperitoneum. Despite the smallest surface area of the threads, in group 3, the greatest fibroblastic reaction was noted. Inflammatory changes were the least pronounced in group 1. They were the greatest in group 3, where there was a pronounced leukocyte reaction, combined with the processes of metaplasia, the development of fibrinoid necrosis, and the progression of the secondary inflammatory process. In group 1, the optimal ratio of newly formed vessels was noted, in group 2 - veins prevailed over arteries, in group 3 - the number of vessels was minimal. Immunohistochemical study showed that in group 1, mesothelial cells covered almost the entire surface of the implant, and there were also areas of preserved basic peritoneum. In group 2, mesothelium also covered most of the surface of the meshes, but the underlying peritoneum was absent. In group 3, on the contrary, a significant number of extended areas not covered with mesothelium were revealed. CONCLUSION: The conducted morphological and morphometric study showed that the most balanced ratio of the components of the newly formed fibrous tissue and blood vessels is observed when using implants with a fluoropolymer coating FTOREX. At the same time, the remaining basic peritoneum actively participated in the formation of the neoperitoneum. The Ventralight ST and Symbotex meshes also contributed to the formation of a full-fledged fibrous tissue and adequate vascular proliferation, however, they prevented the preservation of the underlying peritoneum, which practically excluded its participation in the formation of the neoperitoneum. The REPEREN mesh and decellularized porcine peritoneum led to the least balanced cell and vascular proliferation and the greatest fibroplastic reaction, which could further negatively affect the state of the formed scar.

Behaviour at the peritoneal interface of next-generation prosthetic materials for hernia repair.

BACKGROUND: When using a prosthetic material in hernia repair, the behaviour of the mesh at the peritoneal interface is especially important for implant success. Biomaterials developed for their intraperitoneal placement are known as composites and are made up of two different-structure materials, one is responsible for good integration within host tissue and the other is responsible to make contact with the viscera. This study examines the behaviour at the peritoneal level of two composites, the fully degradable Phasix-ST® and the partially degradable Symbotex®. A polypropylene mesh (Optilene®) served as control. METHODS: Sequential laparoscopy from 3 to 90 days, in a preclinical model in the New Zealand white rabbit, allowed monitoring adhesion formation. Morphological studies were performed to analyse the neoperitoneum formed in the repair process. Total macrophages were identified by immunohistochemical labelling. To identify the different macrophage phenotypes, complementary DNAs were amplified by qRT-PCR using specific primers for M1 (TNF-α/CXCL9) and M2 (MRC1/IL-10) macrophages. RESULTS: The percentage of firm and integrated adhesions remained very high in the control group over time. Both composites showed a significant decrease in adhesions at all study times and in qualitative terms were mainly loose. Significant differences were also observed from 7 days onwards between the two composites, increasing the values in Phasix over time. Neoperitoneum thickness for Phasix was significantly greater than those of the other meshes, showing mature and organized neoformed connective tissue. Immunohistochemically, a significantly higher percentage of macrophages was observed in Symbotex. mRNA expression levels for the M2 repair-type macrophages were highest for Phasix but significant differences only emerged for IL-10. CONCLUSIONS: Fewer adhesions formed to the Symbotex than Phasix implants. Ninety days after implant, total macrophage counts were significantly higher for Symbotex, yet Phasix showed the greater expression of M2 markers related to the tissue repair process.

Feasibility of pressurized intra peritoneal aerosol chemotherapy using an ultrasound aerosol generator (usPIPAC).

BACKGROUND: We tested the feasibility of ultrasound technology for generating pressurized intraperitoneal aerosol chemotherapy (usPIPAC) and compared its performance vs. comparator (PIPAC). MATERIAL AND METHODS: A piezoelectric ultrasound aerosolizer (NextGen, Sinaptec) was compared with the available technology (Capnopen, Capnomed). Granulometry was measured for water, Glc 5%, and silicone oil using laser diffraction spectrometry. Two- and three-dimensional (2D and 3D) spraying patterns were determined with methylene blue. Tissue penetration of doxorubicin (DOX) was measured by fluorescence microscopy in the enhanced inverted Bovine Urinary Bladder model (eIBUB). Tissue DOX concentration was measured by high-performance liquid chromatography (HPLC). RESULTS: The droplets median aerodynamic diameter was (usPIPAC vs. PIPAC): H20: 40.4 (CI 10-90%: 19.0-102.3) vs. 34.8 (22.8-52.7) µm; Glc 5%: 52.8 (22.2-132.1) vs. 39.0 (23.7-65.2) µm; Silicone oil: 178.7 (55.7-501.8) vs. 43.0 (20.2-78.5) µm. 2D and 3D blue ink distribution pattern of usPIPAC was largely equivalent with PIPAC, as was DOX tissue concentration (usPIPAC: 0.65 (CI 5-95%: 0.44-0.86) vs. PIPAC: 0.88 (0.59-1.17) ng/ml, p = 0.29). DOX tissue penetration with usPIPAC was inferior to PIPAC: usPIPAC: 60.1 (CI 5.95%: 58.8-61.5) µm vs. PIPAC: 1172 (1157-1198) µm, p < 0.001). The homogeneity of spatial distribution (top, middle and bottom of the eIBUB) was comparable between modalities. DISCUSSION: usPIPAC is feasible, but its performance as a drug delivery system remains currently inferior to PIPAC, in particular for lipophilic solutions.

Intraperitoneal Administration of a Cisplatin-Loaded Nanogel through a Hybrid System Containing an Alginic Acid-Based Nanogel and an In Situ Cross-Linkable Hydrogel for Peritoneal Dissemination of Ovarian Cancer.

Intraperitoneal chemotherapy demonstrates potential applicability in the treatment of peritoneally disseminated ovarian cancer because the disseminated tumors can directly receive exposure to high concentrations of anticancer drugs. However, a considerable proportion of drugs, particularly micromolecular and hydrophilic drugs, such as cisplatin (CDDP), are often excreted through glomerular filtration for a short period. To effectively deliver CDDP into peritoneally disseminated ovarian cancer tissues, we developed an alginate (AL)-based hybrid system in which a CDDP-loaded AL nanogel (AL/CDDP-nanogel) was encapsulated in an injectable AL-hydrogel cross-linked with calcium ions. This system enabled the sustained release of CDDP from the AL/CDDP-nanogel/AL-hydrogel hybrid for over a week. Herein, we constructed a peritoneally disseminated ovarian cancer mouse model using ovarian cancer cell lines with KRAS mutations (ID8-KRAS: KRASG12V). The AL/CDDP-nanogel/AL-hydrogel hybrid system showed significant antitumor activity in vivo. This therapy may be considered a novel strategy for the treatment of advanced-stage ovarian cancer with KRAS mutations.

Experimental Extracellular Matrix of the Xenoperitoneum: Comprehensive Assessment of a New Biological Material for Plastic Surgery of Anterior Abdominal Wall Defects.

A new biological implant, extracellular matrix of bovine peritoneum, was developed and obtained for plastic surgery of the anterior abdominal wall defects. The material was implanted to rats into the anterior abdominal wall. The content of rejection markers (TNF, IL-2, C-reactive protein) and the morphological picture of the implantation zone at the early stages (30 days) after surgery were evaluated. The studied material at this stage demonstrated adequate biocompatibility; the formation of mature, consistent contact with the tissues of the anterior abdominal wall and minimum tissue inflammatory reactions were observed.

A Novel Formulation of Glucose-Sparing Peritoneal Dialysis Solutions with l-Carnitine Improves Biocompatibility on Human Mesothelial Cells.

The main reason why peritoneal dialysis (PD) still has limited use in the management of patients with end-stage renal disease (ESRD) lies in the fact that the currently used glucose-based PD solutions are not completely biocompatible and determine, over time, the degeneration of the peritoneal membrane (PM) and consequent loss of ultrafiltration (UF). Here we evaluated the biocompatibility of a novel formulation of dialytic solutions, in which a substantial amount of glucose is replaced by two osmometabolic agents, xylitol and l-carnitine. The effect of this novel formulation on cell viability, the integrity of the mesothelial barrier and secretion of pro-inflammatory cytokines was evaluated on human mesothelial cells grown on cell culture inserts and exposed to the PD solution only at the apical side, mimicking the condition of a PD dwell. The results were compared to those obtained after exposure to a panel of dialytic solutions commonly used in clinical practice. We report here compelling evidence that this novel formulation shows better performance in terms of higher cell viability, better preservation of the integrity of the mesothelial layer and reduced release of pro-inflammatory cytokines. This new formulation could represent a step forward towards obtaining PD solutions with high biocompatibility.

[Influence of unmodified and modified sutures on experimental abdominal adhesive process]. / Éksperimental'naia otsenka spaechnogo protsessa v briushnoi polosti pri ispol'zovanii nemodifitsirovannogo shovnogo materiala i modifitsirovannogo geparinom.

OBJECTIVE: Experimental assessment of the effect of modified and unmodified surgical suture material on abdominal adhesive process. MATERIAL AND METHODS: The study was performed on male rats of the Wistar subpopulation. There were 5 animals in each group. In all animals, midline abdominal incision was followed by suturing the parietal peritoneum with modified and unmodified suture material. All animals were euthanized with carbon dioxide vapors in 14 days after surgery. Macro- and microscopic assessment of severity of abdominal adhesive process was carried out. Two types of preparation of excised complexes 'peritoneum-suture material-adhesion' were applied for histological examination: paraffin sections and embedding in epoxy resin. Specimens were stained by Van Gieson and with methylene blue solution. Histological specimens were examined using Axio Imager A1 light microscope (Zeiss, Germany). RESULTS: Polypropylene filaments result extensive adhesions occupying about 75% of the area. Adhesions have a dense structure with signs of vascularization. Modification of suture material with solution of polyhydroxybutyrate/hydroxyvalerate and heparin reduce severity of adhesions. The use of modified suture material was followed by adhesions with more loose structure, no signs of vascularization. Adhesions occupied less than 25% of the area. Histological examination of excised complexes 'peritoneum-suture material-adhesion' revealed accumulation of inflammatory cells around the unmodified suture material, while there were no signs of tissue inflammatory process around the modified sutures. CONCLUSION: Application of polyhydroxybutyrate/hydroxyvalerate and heparin on the surface of surgical sutures is an effective method for prevention of abdominal adhesions.

FF-10832 enables long survival via effective gemcitabine accumulation in a lethal murine peritoneal dissemination model.

Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF-10832 as liposome-encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF-10832 with those of gemcitabine. Despite the single intravenous administration, FF-10832 treatment enabled long-term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF-10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome-encapsulated gemcitabine FF-10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors.

Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties.

Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness.

Long-term drug delivery using implantable electrospun woven polymeric nanotextiles.

A woven nanotextile implant was developed and optimized for long-term continuous drug delivery for potential oncological applications. Electrospun polydioxanone (PDS) nanoyarns, which are twisted bundles of PDS nanofibres, were loaded with paclitaxel (PTX) and woven into nanotextiles of different packing densities. A mechanistic modeling of in vitro drug release proved that a combination of diffusion and matrix degradation controlled the slow PTX-release from a nanoyarn, emphasizing the role of nanostructure in modulating release kinetics. Woven nanotextiles, through variations in its packing density and thereby architecture, demonstrated tuneable PTX-release. In vivo PTX-release, pharmacokinetics and biodistribution were evaluated in healthy BALB/c mice by suturing the nanotextile to peritoneal wall. The slow and metronomic PTX-release for 60 days from the loosely woven implant was extremely effective in enhancing its residence in peritoneum, in contrast to intraperitoneal injections. Such an implantable matrix offers a novel platform for therapy of solid tumors over prolonged durations.

Liposome supported peritoneal dialysis in rat amitriptyline exposure with and without intravenous lipid emulsion.

Liposome supported peritoneal dialysis is a recently described technique which may eventually be applicable in the clinical scenario of the intoxicated patient. We evaluated the hypothesis that intravenous injection of lipid emulsion (ILE) would augment acidic pH gradient liposome supported peritoneal dialysis (LSPD). Orogastrically amitriptyline dosed rats were treated with either Sodium bicarbonate (NaHCO3) intravenously and standard intraperitoneal dialysate (Group A); NaHCO3 intravenously and LSPD (Group B); or ILE and LSPD (Group C). The primary endpoint was dialysate amitriptyline concentration after a 60 min dwell. Secondary analysis included an estimate of extraction ratio for peritoneal blood flow (ERs). There were significantly higher intraperitoneal concentrations of amitriptyline and ERs in the two groups treated with LSPD (Group B, p = 0.02, Group C, p < 0.01 vs. Group A). There was no observed effect for ILE on intraperitoneal amitriptyline concentration or ERs (p > 0.20). LSPD increased the amitriptyline concentration in peritoneal dialysate. No further increase was demonstrated with ILE. This may be either because such an effect is absent, or type II error. Exploratory analysis suggests LSPD may be driven by total rather than free drug concentrations.

Retromuscular Approach in Ventral Hernia Repair - Endoscopic Rives-Stoppa Procedure.

Introduction: In 1993 Leblanc published his laparoscopic technique in ventral hernia repair. The procedure has been improved due to deeply change of the paradigm in abdominal wall reconstruction. Placing the mesh into the retrorectus space was initially a big challenge but now the Rives-Stoppa procedure by endoscopic approach extended total extra-peritoneal approach (eTEP) become a well known technique. Method: The total extraperitoneal (TEP) approach used in inguinal hernia repair, is extended cranially into the rectus sheath. Crossover the midline toward the contralateral retrorectus space, being outside the peritoneal cavity, allows bilateral retrorectus dissection, reducing the hernia, restoring the linea alba and placing a polypropylene mesh under the rectus muscles. Results: I applied this technique between 2016 June 2017 December in 63 cases in ventral (primary or incisional) hernia repair having median area 60 sqcm (6 - 300). To close the defect and restore linea alba it was necessary to perform TAR in 19 cases. Median hospitalisation was 1day (1 9). Follow up at 2, 6, 12 months: 1 case with chronic pain and no recurrences until now. Conclusions: Combining the advantages of the Rives-Stoppa procedure with the the advantages of minimally invasive surgery (MIS), the eTEP approach tends to occupy an important place in ventral hernia repair.

Laparoscopic lens fogging: solving a common surgical problem in standard and robotic laparoscopes via a scientific model.

BACKGROUND: Laparoscopic lens fogging (LLF) hampers vision and impedes operative efficiency. Attempts to reduce LLF have led to the development of various anti-fogging fluids and warming devices. Limited literature exists directly comparing these techniques. We constructed a model peritoneum to simulate LLF and to compare the efficacy of various anti-fogging techniques. MATERIALS AND METHODS: Intraperitoneal space was simulated using a suction bag suspended within an 8 L container of water. LLF was induced by varying the temperature and humidity within the model peritoneum. Various anti-fogging techniques were assessed including scope warmers, FREDTM, ResoclearTM, chlorhexidine, betadine and immersion in heated saline. These products were trialled with and without the use of a disposable scope warmer. Vision scores were evaluated by the same investigator for all tests and rated according to a predetermined scale. Fogging was assessed for each product or technique 30 times and a mean vision rating was recorded. RESULTS: All products tested imparted some benefit, but FREDTM performed better than all other techniques. Betadine and ResoclearTM performed no better than the use of a scope warmer alone. Immersion in saline prior to insertion resulted in decreased vision ratings. The robotic scope did not result in LLF within the model. CONCLUSIONS: In standard laparoscopes, the most superior preventative measure was FREDTM utilised on a pre-warmed scope. Despite improvements in LLF with other products FREDTM was better than all other techniques. The robotic laparoscope performed superiorly regarding LLF compared to standard laparoscope.

Prospective cohort study on mesh shrinkage measured with MRI after laparoscopic ventral hernia repair with an intraperitoneal iron oxide-loaded PVDF mesh.

BACKGROUND: Current data on shrinkage of intraperitoneal meshes come mainly from animal studies. High-quality human data in prospective studies are scarce. METHODS: We used the ability to visualize intraperitoneal PVDF meshes enhanced with iron particles (DynaMesh IPOM visible) with magnetic resonance imaging (MRI) to determine the amount of shrinkage between 1 and 13 months postoperatively. All measurements of the width, length, and surface area of the mesh were performed with a standardized methodology independently by four radiologists blinded for the timing of the MRI. RESULTS: Of the 15 patients undergoing laparoscopic ventral hernia repair, 13 patients received an MRI both at 1 and at 13 months. Evaluation of inter-rater reliability between the radiologists showed intra-class correlations of 0.95 (95% CI 0.92-0.98) for the width, 0.96 (95% CI 0.93-0.98) for the length, and 0.99 (90% CI 0.99-1.00) for the surface area of the mesh. The change between measurement at implantation and 1-month MRI was - 0.7 cm (P = 0.023; - 3.6%) for the width and - 1.9 cm (P = 0.001; - 7.2%) for the length. The change between 1 and 13 months was - 0.06 cm (P = 0.74; shrinkage = 0.3%) for the width, - 0.12 cm (P = 0.56; shrinkage = 0.5%) for the length, and - 4.0 cm2 (P = 0.20; shrinkage = 1.0%) for the surface area of the mesh. CONCLUSION: There is excellent inter-rater reliability between radiologists when measuring width, length, and surface area of visible intraperitoneal PVDF mesh with MRI. There is no significant shrinkage between 1 and 13 months of intraperitoneal PVDF mesh after laparoscopic ventral hernia repair.

Thermosensitive Injectable Hydrogel for Simultaneous Intraperitoneal Delivery of Doxorubicin and Prevention of Peritoneal Adhesion.

To improve intraperitoneal chemotherapy and to prevent postsurgical peritoneal adhesion, we aimed to develop a drug delivery strategy for controlled release of a chemotherapeutic drug from the intraperitoneally injected thermosensitive poly(N-isopropylacrylamide)-based hydrogel (HACPN), which is also endowed with peritoneal anti-adhesion properties. Anticancer drug doxorubicin (DOX) was loaded into the hydrogel (HACPN-DOX) to investigate the chemotherapeutic and adhesion barrier effects in vivo. A burst release followed by sustained release of DOX from HACPN-DOX was found due to gradual degradation of the hydrogel. Cell culture studies demonstrated the cytotoxicity of released DOX toward CT-26 mouse colon carcinoma cells in vitro. Using peritoneal carcinomatosis animal model in BALB/c mice with intraperitoneally injected CT-26 cells, animals treated with HACPN-DOX revealed the best antitumor efficacy judging from tumor weight and volume, survival rate, and bioluminescence signal intensity when compared with treatment with free DOX at the same drug dosage. HACPN (or HACPN-DOX) also significantly reduced the risk of postoperative peritoneal adhesion, which was generated by sidewall defect-cecum abrasion in tumor-bearing BALB/c mice, from gross and histology analyses. This study could create a paradigm to combine controlled drug release with barrier function in a single drug-loaded injectable hydrogel to enhance the intraperitoneal chemotherapeutic efficacy while simultaneously preventing postsurgical adhesion.

Caesarean section surgical techniques: 3 year follow-up of the CORONIS fractional, factorial, unmasked, randomised controlled trial.

BACKGROUND: The CORONIS trial reported differences in short-term maternal morbidity when comparing five pairs of alternative surgical techniques for caesarean section. Here we report outcomes at 3 years follow-up. METHODS: The CORONIS trial was a pragmatic international 2 × 2 × 2 × 2× 2 non-regular fractional, factorial, unmasked, randomised controlled trial done at 19 sites in Argentina, Chile, Ghana, India, Kenya, Pakistan, and Sudan. Pregnant women were eligible if they were to undergo their first or second caesarean section through a planned transverse abdominal incision. Women were randomly assigned by a secure web-based allocation system to one intervention from each of the three assigned pairs. All investigators, surgeons, and participants were unmasked to treatment allocation. In this follow-up study, we compared outcomes at 3 years following blunt versus sharp abdominal entry, exteriorisation of the uterus for repair versus intra-abdominal repair, single versus double layer closure of the uterus, closure versus non-closure of the peritoneum, and chromic catgut versus polyglactin-910 for uterine repair. Outcomes included pelvic pain; deep dyspareunia; hysterectomy and outcomes of subsequent pregnancies. Outcomes were assessed masked to the original trial allocation. This trial is registered with the Current Controlled Trials registry, number ISRCTN31089967. FINDINGS: Between Sept 1, 2011, and Sept 30, 2014, 13,153 (84%) women were followed-up for a mean duration of 3·8 years (SD 0·86). For blunt versus sharp abdominal entry there was no evidence of a difference in risk of abdominal hernias (adjusted RR 0·66; 95% CI 0·39-1·11). We also recorded no evidence of a difference in risk of death or serious morbidity of the children born at the time of trial entry (0·99, 0·83-1·17). For exteriorisation of the uterus versus intra-abdominal repair there was no evidence of a difference in risk of infertility (0·91, 0·71-1·18) or of ectopic pregnancy (0·50, 0·15-1·66). For single versus double layer closure of the uterus there was no evidence of a difference in maternal death (0·78, 0·46-1·32) or a composite of pregnancy complications (1·20, 0·75-1·90). For closure versus non-closure of the peritoneum there was no evidence of a difference in any outcomes relating to symptoms associated with pelvic adhesions such as infertility (0·80, 0·61-1·06). For chromic catgut versus polyglactin-910 sutures there was no evidence of a difference in the main comparisons for adverse pregnancy outcomes in a subsequent pregnancy, such as uterine rupture (3·05, 0·32-29·29). Overall, severe adverse outcomes were uncommon in these settings. INTERPRETATION: Although our study was not powered to detect modest differences in rare but serious events, there was no evidence to favour one technique over another. Other considerations will probably affect clinical practice, such as the time and cost saving of different approaches. FUNDING: UK Medical Research Council and the Department for International Development.

Is there such a thing as biocompatible peritoneal dialysis fluid?

Introduction of the so-called biocompatible peritoneal dialysis (PD) fluids was based on a large body of experimental evidence and various clinical trials suggesting important clinical benefits. Of these, until now, only preservation of residual renal function-likely due to lower glucose degradation product load and, in case of icodextrin, improved fluid and blood pressure control-have consistently been proven, whereas the impact on important clinical endpoints such as infectious complications, preservation of PD membrane transport function, and patient outcome, are still debated. In view of the high morbidity and mortality rates of PD patients, novel approaches are warranted and comprise the search for alternative osmotic agents and enrichment of PD fluids with specific pharmacologic agents, such as alanyl-glutamine, potentially counteracting local but also systemic sequelae of uremia and PD.

A novel procedure for introducing large sheet-type surgical material with a self-expanding origami structure using a slim trocar (chevron pleats procedure).

BACKGROUND: Large sheet-type surgical materials (e.g., absorbable hemostat, adhesion barrier membranes, and flat surgical mesh) are difficult to introduce into a corporeal cavity using a 5-mm trocar; however, laparoscopic surgeries that use mainly 5-mm trocars are increasing. Furthermore, it is necessary not only to introduce but also to secure the applied surgical material and expand it from the original surgical site. To address these challenges, we developed a novel procedure for introducing such surgical materials into a corporeal cavity using a 5-mm trocar and a self-expanding origami structure, called the "chevron pleats procedure (CPP)". METHODS: We used CPP in 114 cases of laparoscopic surgery for gastrointestinal diseases. The chevron folding pattern is an excellent origami structure and compactly folds a large sheet of material for use with a slim trocar. Surgical materials were folded using a chevron pleats pattern and inserted into a novel, slim, long syringe-type device, which was made from a specially ordered precision polypropylene tube, for introduction into a corporeal cavity. When the surgical material was used, the end of the device was placed above the surgical site and the inner rod was pushed. The surgical material was securely injected and expanded over the surgical site. RESULTS: Surgical materials were introduced smoothly and securely using a 5-mm trocar to a site of intraoperative bleeding, the incisional surface of the liver, and defects of the abdominal wall or peritoneum. Efficient hemostasis was attained, the introduction and expansion of surgical mesh was made simpler, and the covering of defects of the peritoneum with adhesion barrier membranes, which is typically difficult during laparoscopic surgery, was easily performed. CONCLUSIONS: CPP is a basic utility procedure for introducing several sheet-type surgical materials into a corporeal cavity with a 5-mm trocar and might help ensure efficient and safe laparoscopic surgery.

Fibrin glue versus staple for mesh fixation in laparoscopic transabdominal preperitoneal repair of inguinal hernia: a meta-analysis and systematic review.

BACKGROUND: The aim of this study was to compare outcomes of mesh fixation using fibrin glue versus staple in laparoscopic transabdominal preperitoneal (TAPP) repair of inguinal hernia. METHODS AND PROCEDURES: Database searches were carried out in PubMed, Embase, Cochrane Library, Web of Science and Cochrane databases until February 2016 using specific search terms. Studies which compared fibrin glue and staple for mesh fixation in laparoscopic transabdominal preperitoneal repair of inguinal hernia were enrolled. Outcomes, including inguinal hernia recurrence, chronic inguinal pain, seroma or hematoma formation and operating time, were measured. RESULTS: Four randomized controlled trials (RCTs, 430 patients) and six non-randomized controlled trials (non-RCTs, 8637 patients) were analyzed. Meta-analysis of the four RCTs showed no significant difference in hernia recurrence (OR 2.10, 95 % CI 0.61, 7.22), seroma or hematoma formation (OR 0.55, 95 % CI 0.27, 1.14) and operating time (SMD 0.80, 95 % CI -0.34, 1.94). Similarly, there was no significant difference in most of the outcomes of the six non-RCTs. CONCLUSIONS: Our meta-analysis and systematic review shows that the use of fibrin glue fixation may provide an alternative approach to staple fixation in TAPP inguinal hernia repair without increasing the postoperative morbidity. Large-scale RCTs with long-term follow-up are still needed to further assess postoperative outcomes such as chronic pain and disease recurrence.