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Introduction Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However, little is known about its feasibility, safety, tolerability, efficacy, costs and pharmacokinetics in this setting. This study aims to explore these parameters in patients with isolated unresectable colorectal PM who receive repetitive ePIPAC-OX as a palliative monotherapy. Methods and analysis This multicentre, open-label, single-arm, phase II study is performed in two Dutch tertiary referral hospitals for the surgical treatment of colorectal PM. Eligible patients are adults who have histologically or cytologically proven isolated unresectable PM of a colorectal or appendiceal carcinoma, a good performance status, adequate organ functions and no symptoms of gastrointestinal obstruction. Instead of standard palliative treatment, enrolled patients receive laparoscopycontrolled ePIPAC-OX (92 mg/m2 body surface area (BSA)) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every 6 weeks. Four weeks after each procedure, patients undergo clinical, radiological and biochemical evaluation. ePIPAC-OX is repeated until disease progression, after which standard palliative treatment is (re)considered. The primary outcome is the number of patients with major toxicity (grade =3 according to the Common Terminology Criteria for Adverse Events v4.0) up to 4 weeks after the last ePIPAC-OX. Secondary outcomes are the environmental safety of ePIPAC-OX, procedure-related characteristics, minor toxicity, postoperative complications, hospital stay, readmissions, quality of life, costs, pharmacokinetics of oxaliplatin, progression-free survival, overall survival, and the radiological, histopathological, cytological, biochemical and macroscopic tumour response. Ethics and dissemination This study is approved by an ethics committee, the Dutch competent authority and the institutional review boards of both study centres. Results are intended for publication in peer-reviewed medical journals and for presentation to patients, healthcare professionals and other stakeholders. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2012; 42 (11): 1235-1243 Abstract Background Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel cardiovascular risk marker, which is predominantly complexed to apolipoprotein (apo) B-containing lipoproteins in human plasma. As increasing dietary sodium intake may decrease plasma apoB-containing lipoproteins, we tested whether a sodium challenge lowers plasma Lp-PLA2 mass, as well as the levels of apoB-containing lipoprotein particles carrying Lp-PLA2 (apoB-Lp-PLA2), employing a newly developed enzyme-linked immunosorbent assay. Materials and methods In 45 women and 31 men (mean age 44 ± 14 years), plasma Lp-PLA2 mass (turbidimetric immunoassay), the level of apoB-Lp-PLA2, expressed in apoB concentration and lipoproteins were measured in response to a 3-day challenge with 9 g sodium chloride tablets daily. Results Urinary sodium excretion increased from 165 ± 60 to 321 ± 70 mmol/24 h ( P < 0·001) after salt loading. Plasma Lp-PLA2 mass decreased from 618 (493-719) to 588 (465-698) μg/L ( P < 0·001), and apoB-Lp-PLA2 decreased from 0·276 (0·200-0·351) to 0·256 (0·189-0·328) g LDL protein/L ( P = 0·004) in response to the sodium challenge together with decreases in plasma total cholesterol, nonhigh-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and the total cholesterol/HDL cholesterol ratio ( P < 0·01 for all). Changes in plasma Lp-PLA2 mass were correlated positively with changes in total cholesterol, LDL cholesterol and non-HDL cholesterol ( r = 0·260-0·276, P < 0·05 to P < 0·02), whereas changes in apoB-Lp-PLA2 were correlated positively with changes in non-HDL cholesterol and in the total cholesterol/HDL cholesterol ratio ( r = 0·232-0·385, P < 0·05-0·01). Conclusion Both plasma Lp-PLA2 mass levels and apoB-Lp-PLA2 decrease in response to a short-term oral sodium challenge. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict incident cardiovascular disease, impacting Lp-PLA2 as an emerging therapeutic target. We determined Lp-PLA2 responses to statin and fibrate administration in type 2 diabetes mellitus, and assessed relationships of changes in Lp-PLA2 with subclinical inflammation and lipoprotein characteristics. Methods: A placebo-controlled cross-over study (three 8-week treatment periods with simvastatin (40mg daily), bezafibrate (400mg daily) and their combination) was carried out in 14 male type 2 diabetic patients. Plasma Lp-PLA2 mass was measured by turbidimetric immunoassay. Results: Plasma Lp-PLA2 decreased (−21±4%) in response to simvastatin (p <0.05 from baseline and placebo), but was unaffected by bezafibrate (1±5%). The drop in Lp-PLA2 during combined treatment (−17±3%, p <0.05) was similar compared to that during simvastatin alone. The Lp-PLA2 changes during the 3 active lipid lowering treatment periods were related positively to baseline levels of high sensitive C-reactive protein, non-HDL cholesterol, triglycerides, the total cholesterol/HDL cholesterol ratio and less LDL electronegativity (p <0.02 to p <0.01), and inversely to baseline Lp-PLA2 (p <0.01). LpPLA2 responses correlated inversely with changes in non-HDL cholesterol, triglycerides and the total cholesterol/HDL cholesterol ratio during treatment (p <0.05 to p <0.02). Conclusions: In type 2 diabetes mellitus, plasma Lp-PLA2 is likely to be lowered by statin treatment only. Enhanced subclinical inflammation and more severe dyslipidemia may predict diminished LpPLA2 responses during lipid lowering treatment, which in turn appear to be quantitatively dissociated from decreases in apolipoprotein B lipoproteins. Conventional lipid lowering treatment may be insufficient for optimal LpPLA2 lowering in diabetes mellitus. [Copyright &y& Elsevier]

Background and Aims: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a pro-atherogenic phospholipase A2, which is predominantly complexed to low-density lipoprotein (LDL) particles. Proprotein convertase subtilisin-kexin type 9 (PCSK9) provides a key step in LDL metabolism by stimulating LDL receptor degradation. We determined relationships between plasma PCSK9 and Lp-PLA2 mass. Methods: Lp-PLA2 mass (turbidimetric immunoassay), PCSK9 (enzyme-linked immunosorbent assay) and (apo) lipoproteins were measured in 53 nondiabetic subjects (27 women) with body mass index <30 kg/m2. Results: Lp-PLA2 and PCSK9 levels were both correlated positively with LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol (r = 0.330 to r = 0.382, p ≤0.02). Remarkably, Lp-PLA2 was inversely related to PCSK9 (r = −0.388, p = 0.004). The Lp-PLA2/apolipoprotein B ratio, as a measure of the Lp-PLA2 content in apolipoprotein B-containing lipoproteins, was also inversely correlated with PCSK9 (r = −0.575, p <0.001). The inverse relationships of Lp-PLA2 (p = 0.023) and the Lp-PLA2/apolipoprotein B ratio (p = 0.001) with PCSK9 levels remained significant after controlling for age, gender, triglycerides and HDL cholesterol. Conclusions: Despite increasing effects on LDL cholesterol, higher PCSK9 levels are unlikely to confer impaired Lp-PLA2 metabolism. We propose to evaluate the possible influence of PCSK9 inhibiting strategies on Lp-PLA2 regulation and vice versa to determine effects of Lp-PLA2 inhibitors on the PCSK9 pathway. [Copyright &y& Elsevier]

Introduction: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan., Methods and Analysis: This phase I, '3+3' dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult patients with extensive peritoneal metastases of colorectal origin who have a good performance status and no extra-abdominal metastases. According to standard work-up for CRS-HIPEC, patients will undergo a diagnostic laparoscopy to score the PCI. In case of a PCI >20, a peritoneal access port will be placed in the abdomen of the patient. Through this port we will administer intraperitoneal irinotecan, in combination with standard systemic treatment consisting of 5-fluorouracil/leucovorin with oxaliplatin and the targeted agent bevacizumab. Therapy consists of a maximum of 12 cycles 2-weekly., Ethics and Dissemination: This study protocol is approved by a research medical ethics committee (Rotterdam, Netherlands) and the Dutch Competent Authority (CCMO, The Hague, Netherlands). The results of this trial will be submitted for publication in a peer-reviewed scientific journal., Trail Registration Number: NL6988 and NL2018-000479-33; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)