From early risk to one-year mortality: a comprehensive assessment of postoperative venous thromboembolism in upper gastrointestinal cancer patients - a nationwide cohort study.

BACKGROUND: Venous thromboembolism (VTE) is a well-recognized complication following gastrointestinal cancer surgery, particularly early postoperatively. The incidence and risk factors of VTE within one year after esophageal (including esophago-gastric junction) (ECS) and gastric (GCS) cancer surgeries, and especially its impact on one-year global mortality, are yet under-explored. METHODS: This nationwide observational population-based cohort study used data extracted from all patients undergoing ECS and GCS in France between 1 January 2015 and 31 December 2017. Multivariate logistic regression was used to identify risk factors for 90 post-operative days (POD) VTE (OR 95% CI). Cox proportional hazards models investigated the impact of one-year postoperative VTE on one-year global mortality (HR (95% CI)). RESULTS: During the study period, 8,005 patients underwent ECS (N=3,429) or GCS (N=4,576) (31.8% female; 66.7±12.1 years old). Majority (N=4,951) of patients had preoperative treatment (Chemotherapy or radiochemotherapy). Ninety POD incidence of VTE were 4.7% (ECS=6.2%) (GCS=3.6%) (44.7% during first hospitalization, 19.0% needing readmission and 36.3% ambulatory management). Main risk factors were 3 and 2 field esophagectomy (3.6 (2.20-5.83) and 2.2 (1.68-3.0)), obesity (1.9 (1.40-2.58)) and history of VTE (5.1 (2.72-9.45)). Late-onset VTE rates (occurring between the 6th and 12th month) represented 1.80% and 1.46% of the overall ECS and GCS groups. Patients with VTE within one year had higher risks of one-year global mortality: 2.04 1.52; 2.73) and 2.71 (2.09; 3.51), respectively. CONCLUSION: Our extensive analysis of a nationwide database highlights the significant risk of postoperative VTE after ECS and GCS, persisting within 90 POD and up to one year. Crucially, a higher risk of global mortality within one year for patients experiencing early or late VTE was found. These findings could advocate for further research into extended prophylactic regimens, particularly for those most at risk.

Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations.

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population.

Complication rates of proximal hypospadias: meta-analyses of four surgical repairs.

INTRODUCTION: Proximal hypospadias surgery is impacted by a high complication rate. The goal of this work was to assess the overall composite complication rate, fistula rate and stenosis rate following proximal hypospadias surgery realized according to onlay urethroplasty, Duckett, Koyanagi and Bracka techniques. METHODS: The databases MEDLINE, EMBASE, SCOPUS, Cochrane Library, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL) and Sciencedirect were searched. Studies had to report data about the mean age of population, the average duration of patient follow-up and the number of procedures required for surgical treatment of primary and proximal hypospadias. Two independent including one urologist reviewers screened all the articles and selected the articles to be included. RESULTS: Overall composite complication rates were 32%, 34%, 49%, and 43%, for Onlay urethroplasty, Duckett's tubularized flaps urethroplasty, Koyanagi repair and Bracka 2 stages repair, respectively. Fistula rates were 13%, 18%, 21% and 23% respectively. The heterogeneity of complication rates reported in the different studies was not moderated by age, country, or patient's continent origin. DISCUSSION: The classifications of complications used in articles were disparate and make comparisons between techniques difficult. The report of post-surgical complications in the literature is often poorly coded and follow-up times were often too short. CONCLUSION: This meta-analysis attempts to determine to the extent possible, given the serious weaknesses in the hypospadias literature, plausible estimates of complication rates after skin flap urethroplasty. The patched onlay skin flap, the Duckett's tubularized skin flap technique, the Koyanagi's technique, and the Bracka's two-stage urethroplasty procedure lead to very high complication rates. Reported complication rates are comparable across techniques.

Free and Open-Source Posologyr Software for Bayesian Dose Individualization: An Extensive Validation on Simulated Data.

Model-informed precision dosing is being increasingly used to improve therapeutic drug monitoring. To meet this need, several tools have been developed, but open-source software remains uncommon. Posologyr is a free and open-source R package developed to enable Bayesian individual parameter estimation and dose individualization. Before using it for clinical practice, performance validation is mandatory. The estimation functions implemented in posologyr were benchmarked against reference software products on a wide variety of models and pharmacokinetic profiles: 35 population pharmacokinetic models, with 4.000 simulated subjects by model. Maximum A Posteriori (MAP) estimates were compared to NONMEM post hoc estimates, and full posterior distributions were compared to Monolix conditional distribution estimates. The performance of MAP estimation was excellent in 98.7% of the cases. Considering the full posterior distributions of individual parameters, the bias on dosage adjustment proposals was acceptable in 97% of cases with a median bias of 0.65%. These results confirmed the ability of posologyr to serve as a basis for the development of future Bayesian dose individualization tools.

Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa, a randomized, placebo-controlled study.

BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.

Chronic itch: emerging treatments following new research concepts.

Until recently, itch pathophysiology was poorly understood and treatments were poorly effective in relieving itch. Current progress in our knowledge of the itch processing, the numerous mediators and receptors involved has led to a large variety of possible therapeutic pathways. Currently, inhibitors of IL-31, IL-4/13, NK1 receptors, opioids and cannabinoids, JAK, PDE4 or TRP are the main compounds involved in clinical trials. However, many new targets, such as Mas-related GPCRs and unexpected new pathways need to be also explored.

Sensitivity of Capillary Electrophoresis to Detect Monoclonal Immunoglobulins: a Report of Two Cases and a Systematic Review.

BACKGROUND: The detection of monoclonal immunoglobulins (MIg) is a key element in the diagnosis of monoclonal gammopathies. METHODS: Here we report two cases of high concentration serum IgM-kappa MIgs (6.4 g/L and 6.8 g/L) not detected with capillary electrophoresis (CE). A systematic literature search was conducted to assess the sensitivity of CE to detect MIgs. RESULTS: The CE sensitivity to detect MIgs did not exceed 0.9 to 0.95 compared to immunofixation as standard. On the one hand, MIgs with blood concentrations below 1 g/L may be hidden by other serum proteins. On the other hand, some MIgs of high concentrations are not detected due to their insolubility in the electrophoresis buffer. CONCLUSIONS: Performing a second SPE with agarose gel electrophoresis method or modifying buffer properties may reveal some MIgs not detected by a first SPE alone.

Detection of monoclonal protein by capillary zone electrophoresis can be challenged by iodinated contrast agent interference: a case report.

The detection of monoclonal immunoglobulins is a key element in the diagnosis of monoclonal gammopathy. In clinical practice, screening and measurement of monoclonal proteins are commonly performed using capillary zone electrophoresis (CZE). Some exogenous substances, such as iodinated contrast agents, absorb incident UV light at the same wavelengths as the peptide bonds and may therefore interfere with the detection of proteins in CZE. We herein use the description of a case to illustrate that iodinated contrast agents can mask the presence of monoclonal immunoglobulins in CZE and we discuss the strategy needed to confirm this interference. Performing immunofixation, immunosubtraction, or a second CZE at a distance from the first blood sample is not only necessary to confirm the presence of an iodinated contrast media interference but also to ensure the absence of monoclonal proteins.

Is hypophosphataemia an independent predictor of mortality in critically ill patients with bloodstream infection? A multicenter retrospective cohort study.

BACKGROUND: Hypophosphataemia affects up to one-third of patients in the intensive care unit (ICU) and is particularly common during sepsis. Experimental data suggest that hypophosphataemia leads to an acquired dysfunction of leukocytes, thus promoting infections and increasing the risk of death during sepsis. OBJECTIVES: The aim of our study was to investigate the association between hypophosphataemia and mortality in critically ill patients with a bloodstream infection (BSI). METHODS: We performed a retrospective study in three ICUs during an 18-month period. All adults with a BSI diagnosed in the ICU were eligible. Patients with and without hypophosphataemia, defined as phosphataemia below 0.8 mmol/L, were compared. A multivariate survival analysis using a Cox proportional hazard regression model was conducted to study the association between hypophosphataemia and 90-d mortality. RESULTS/FINDINGS: Among the 3783 patients admitted to the three participating ICUs within the 18-month study period, 203 met the inclusion criteria and 193 were analysed. Fifty-four patients had hypophosphataemia. After adjusting for confounders, hypophosphataemia was significantly associated with a twofold increased risk of 90-d mortality (hazard ratio = 2.10 [1.177-3.80], p = 0.013). This association is particularly strong in patients without shock. CONCLUSIONS: Hypophosphataemia was independently associated with a twofold increase in 90-d mortality in ICU patients with a BSI. These results suggest that investigators and physicians should include phosphataemia as a predictor of the severity of BSIs. Further research is warranted to better understand this association and to determine the potential benefits of systematic monitoring of phosphataemia and phosphorus supplementation. CLINICAL TRIAL REGISTRATION: NCT03529058.

Impact of bariatric surgery on oral anticoagulants pharmacology, and consequences for clinical practice: a narrative review.

The prevalence of obesity has been steadily increasing in recent years worldwide. At the same time bariatric surgery, the best therapeutic strategy to date in terms of sustainable weight loss and improvement of associated comorbidities has been also increasing. However, these surgeries, whether primarily restrictive or malabsorptive, raise questions about the pharmacology of oral drugs. Among widely used drugs, anticoagulants are the referent therapy to treat some cardiovascular diseases such as atrial fibrillation and venous thromboembolism. How bariatric surgery may impact pharmacological properties of oral anticoagulants, and more specifically, direct oral anticoagulants (DOACs) are difficult to anticipate. In this review, we describe available data concerning the potential impact of bariatric surgery on the pharmacology of oral anticoagulants. The vitamin K antagonists (VKAs) requirements for the same international normalized ratio target are reduced after bariatric surgery. Limited data available for dabigatran 150 mg twice daily indicate a risk of insufficient efficacy in atrial fibrillation after gastric bypass due to probable impaired absorption. Data for rivaroxaban at the prophylactic dose of 10 mg per day suggest no impact of bariatric surgery from 3 days to 8 months post-surgery. However, no conclusive data are available for other anticoagulants or the use of DOACs at therapeutic doses. To date, DOACs are not recommended in patients who have undergone bariatric surgery, because of limited available data. Pending new studies to confirm the predictable pharmacokinetics and safety of DOACs in this population, especially at therapeutic doses, VKAs remain the first option for chronic anticoagulation.

Non-Linear Pharmacokinetics of Oral Roscovitine (Seliciclib) in Cystic Fibrosis Patients Chronically Infected with Pseudomonas aeruginosa: A Study on Population Pharmacokinetics with Monte Carlo Simulations.

Roscovitine (Seliciclib), a new protein kinase inhibitor, was administered orally to adult patients with cystic fibrosis for the first time in the ROSCO-CF trial, a dose-escalation, phase IIa, randomized, controlled trial. Extensive pharmacokinetic sampling was performed up to 12 h after the first oral dose. Roscovitine and its main metabolite M3 were quantified by liquid chromatography coupled with tandem mass spectrometry. The pharmacokinetics analyses were performed by non-linear mixed effects modelling. Monte Carlo simulations were performed to assess the impact of dose on the pharmacokinetics of oral roscovitine. Twenty-three patients received oral doses ranging from 200 to 800 mg of roscovitine and 138 data points were available for both roscovitine and M3 concentrations. The pharmacokinetics was best described by a two-compartment parent-metabolite model, with a complex saturable absorption process modelled as the sum of Gaussian inverse density functions. The Monte Carlo simulations showed a dose-dependent and saturable first-pass effect leading to pre-systemic formation of M3. The treatment with proton-pump inhibitors reduced the rate of absorption of oral roscovitine. The pharmacokinetics of oral roscovitine in adult patients with cystic fibrosis was non-linear and showed significant inter-individual variability. A repeat-dose study will be required to assess the inter-occasional variability of its pharmacokinetics.

A case of IgE myeloma transformed into IgE-producing plasma cell leukaemia.

This is a case report of a challenging diagnosis of IgE monoclonal gammopathy of undetermined significance, which transformed into myeloma, then transformed into IgE-producing plasma cell leukaemia in a 71-year-old male who was followed in Brest, France, from 2015 to 2019. The IgE-producing variant is the rarest sub-type of multiple myeloma, and plasma cell leukaemia is considered to be the rarest and the most aggressive of human monoclonal gammopathies. In November 2015, hypogammaglobulinemia was detected during a systematic check-up. A kappa light chain monoclonal gammopathy was first diagnosed due to an increase of the free kappa/lambda light chains ratio. No monoclonal immunoglobulin was detected by either serum protein electrophoresis (Capillarys 2, Sebia, Issy-les-Moulineaux, France) or immunofixation (Hydrasys 2, Sebia, Issy-les-Moulineaux, France). In June 2018, a blood smear led to the diagnosis of plasma cell leukaemia. A monoclonal peak was detected and identified as IgE-kappa. Analysis of an archival sample taken three years earlier, revealed the presence of a monoclonal IgE, which had been missed at diagnosis. Chemotherapy with bortezomib and dexamethasone was introduced. The patient survived 10 months after the diagnosis of leukaemia. This case shows that an abnormal free light chain ratio should be considered as a possible marker of IgE monoclonal gammopathy even in the absence of a solitary light chain revealed by immunofixation. In addition, the use of an undiluted serum may increase the sensitivity of the immunofixation for the detection of IgE monoclonal gammopathies compared to the 1:3 dilution recommended by the manufacturer.

Comparison of the New, Rapid, and Fully Automated Kryptor TSH receptor Antibodies Assay (B.R.A.H.M.S.) with the Radioimmunological Assay (B.R.A.H.M.S.).

BACKGROUND: Radioimmunoassays, which are often not automated and time-consuming, are gradually being re-placed in medical laboratories by non-radioactive methods that need to be evaluated. The purpose was to compare the measurement of thyroid-stimulating hormone receptor antibodies (TRAb) by the new Brahms' kit using Kryptor TRACE technology and the Brahms' radioimmunoassay. METHODS: We prospectively collected all samples from patients who received thyroid-stimulating hormone receptor antibodies testing in July 2018 at the University Hospital of Brest. The radioimmunoassay used was the Dynotest TRAK human by BRAHMS Diagnostica (Berlin, Germany). The Kryptor method used the BRAHMS TRAK human Kryptor kit performed with the Kryptor Compact Plus system. RESULTS: The inter-assay coefficient variations for the radioimmunological and Kryptor methods were 11.07% and 8.36%, respectively, with the low level quality control and 8.36% and 4.38%, respectively, with the high level quality control. Forty-four patients were included in the study including thirty-two Graves' disease patients in follow-up. The sensitivity of the radioimmunological method for the detection of Graves' disease was 0.94 and the specificity was 0.73. The sensitivity of the Kryptor method was 0.91 and the specificity was 0.91. A non-proportional systematic bias in favor of higher values of TRAb concentrations with the radioimmunological method was observed: slope of 0.93 (0.74 - 1.07, 95% confidence interval) and an intercept of -0.69 IU/L (-1.58 to -0.30, 95% confidence interval). Compared to the Kryptor method, the radioimmunological method tends to overestimate TRAb concentrations by up to 120%. CONCLUSIONS: The fully automated Brahms Kryptor kit using TRACE technology to measure TRAb reduces sampling time and intra- as well as inter-assay variations. The Kryptor kit underestimates the results of TRAb leading to a lower sensitivity and higher specificity compared to the radioimmunoassay. Thus, the new Brahms Kryptor kit has good laboratory performances but the interpretation of the results must still be performed with caution.

Immune Checkpoint Inhibitors in Melanoma: A Review of Pharmacokinetics and Exposure-Response Relationships.

Immune checkpoint inhibitors are a new class of monoclonal antibodies that amplify T-cell-mediated immune responses against cancer cells. The introduction of these new drugs, first anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and then anti-programmed death-1 (anti-PD1), was a major improvement in the treatment of advanced or metastatic melanoma, a highly immunogenic tumour. The development strategy for immune checkpoint immunotherapies differed from that traditionally used for cytotoxic therapies in oncology. The choices of doses at which to conduct clinical trials, and subsequently the choice of doses at which to use these new therapies, were not based on the identification of a maximum tolerated dose from dose-escalation studies; thus, pharmacokinetic and pharmacokinetic-pharmacodynamic modelling was essential. The studies conducted have shown that the pharmacokinetics of ipilimumab were linear and not time-dependent. In addition, there was a correlation between the trough concentrations of ipilimumab and its therapeutic efficacy. On the contrary, the anti-PD1 immunotherapies nivolumab and pembrolizumab had time-dependent pharmacokinetics. Their therapeutic efficacy was not related to their trough concentration, but there was a correlation between the clearance of anti-PD1 and the survival of melanoma patients. This review highlights the complexity of interpreting the exposure-response relationships of these agents. Further studies are needed to assess the value of therapeutic drug monitoring of immune checkpoint inhibitors in the treatment of melanoma.

Validation and Application of an HPLC-DAD Method for Routine Therapeutic Drug Monitoring of Ceftobiprole.

Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of pneumonia, with a broad antibacterial spectrum, including potent activity against methicillin-resistant Staphylococcus aureus As for the other cephalosporins, high pharmacokinetic variability and concentration-dependent neurotoxicity are expected. We describe here the first simple and rapid analytical method intended for ceftobiprole serum concentration monitoring. We report the data of 5 patients treated with ceftobiprole, among who 2 developed reversible neurological disorders with high ceftobiprole serum concentration.

Systematic overestimation of human serum albumin by capillary zone electrophoresis method due to monoclonal immunoglobulin interferences.

BACKGROUND: The capillary zone electrophoresis method of albumin measurement is frequently used in monoclonal gammopathy patients but some studies suggest poor performances of the method in this population. The aim of this study was to analyse the impact of serum monoclonal immunoglobulins on human serum albumin determination by capillary zone electrophoresis method compared to other available methods. METHOD: We prospectively measured albumin in 100 freshly collected non-frozen serum samples in a monoclonal gammopathy patients population, by using four different methods: the capillary zone electrophoresis method, the bromocresol purple dye method, the nephelometric method and the turbidimetric method. Differences in albumin values between the different methods were analysed with respect to serum monoclonal immunoglobulin concentration. These differences were further investigated by measuring albumin levels in human serum samples spiked with exogenous monoclonal immunoglobulins. RESULTS: Human serum albumin difference values between capillary zone electrophoresis compared to immunonephelometry method are significantly correlated with increasing monoclonal immunoglobulins concentrations: regression analyses revealed a correlation coefficient r2 = 0.60 and a slope of 0.14 (0.12-0.17, 95% confidence interval). The capillary zone electrophoresis method overestimated serum albumin levels by up to 67% (12 g/L) when monoclonal immunoglobulin level was 63 g/L. The determination of albumin levels in human serum samples spiked with exogenous monoclonal immunoglobulins showed an overestimation of human serum albumin measurement by the capillary zone electrophoresis method proportional to the amount of monoclonal immunoglobulin added in the serum with a slope of 0.19 (0.18-0.20, 95% confidence interval). CONCLUSION: Monoclonal immunoglobulins directly interfere with serum albumin measurement by the capillary zone electrophoresis method leading to a systematic overestimation of serum albumin concentrations proportional to the serum monoclonal immunoglobulin level.

Is capillary zone electrophoresis a suitable method for estimating serum albumin: A comparison of four methods.

BACKGROUND: The capillary zone electrophoresis method of albumin measurement is frequently used for oncologic and haematologic patients but few data exist about the agreement between the albumin measurements performed by capillary zone electrophoresis and other methods. The aim of this study was to analyse the agreement between human serum albumin measurements by capillary zone electrophoresis and by the nephelometry, bromocresol purple and turbidimetry methods. METHOD: We prospectively measured 100 freshly collected non-frozen patient serum samples, by using four different methods: the capillary zone electrophoresis method performed with a CAPILLARYS 2 instrument, the bromocresol purple dye method performed with an Advia XPT analyser, the nephelometric method performed with a BN ProSpec analyser and the turbidimetric method with reagents from DiAgam and performed with the Advia XPT analyser. RESULTS: A bias towards higher values in the lower range of albumin concentrations was observed with capillary zone electrophoresis compared to immunonephelometry: correlation coefficient r2 = 0.925; slope of 0.86 (0.82-0.89, 95% confidence interval), which is significantly different from 1; and an intercept of 4.94 g/L (3.67-6.16, 95% confidence interval). Similar results were observed when comparing capillary zone electrophoresis to the bromocresol purple and immunoturbidimetry methods. The capillary electrophoresis method overestimated low albumin levels by up to 25% (5 g/L). CONCLUSION: Compared to the nephelometry, turbidimetry and bromocresol purple methods, the capillary zone electrophoresis method tends to overestimate human serum albumin concentrations for levels below 30 g/L. This discrepancy could lead to an overestimation of the nutritional status, an inappropriate scoring of the disease and a delay in nutritional treatment.