Use of a prospective risk analysis method to improve the safety of the cancer chemotherapy process

Objective. To perform a risk analysis of the cancer chemotherapy process, by comparing five different organizations. To quantitatively demonstrate the usefulness of centralization and information technologies, to identify residual risks that may be the target of additional actions. Study design. A reengineering of the process started in 1999 and was planned to be finished in 2006. The analysis was performed after the centralization and at the beginning of information technologies integration. Setting. Two thousand two hundred beds university hospital, with medical, surgical, haematological, gynaecological, geriatric, paediatric oncological departments. Twelve thousand cancer chemotherapies each year. Methods. According to the failure modes, effects and criticality analysis (FMECA) method, the failure modes were defined and their criticality indexes were calculated on the basis of the likelihood of occurrence, the potential severity for the patients, and the detection probability. Criticality indexes were compared and the acceptability of residual risks was evaluated. Results. The sum of criticality indexes of 27 identified failure modes was 3596 for the decentralized phase, 2682 for centralization, 2385 for electronic prescription, 2081 for electronic production control, and 1824 for bedside scanning (49% global reduction). The greatest improvements concerned the risk of errors in the production protocols (by a factor of 48), followed by readability problems during transmission (14) and product/dose errors during the production (8). Among the six criticality indexes remaining superior to 100 in the final process, two were judged to be acceptable, whereas further improvements were planned for the four others. Conclusions. Centralization to the pharmacy was associated with a strong improvement but additional developments involving information technologies also contributed to a major risk reduction. A cost-effect analysis confirmed the pertinence of all developments, as the cost per gained criticality point remained stable all over the different phase

Intestinal Colonization of IL-2 Deficient Mice with Non-Colitogenic B. vulgatus Prevents DC Maturation and T-Cell Polarization

BACKGROUND: IL-2 deficient (IL-2(-/-)) mice mono-colonized with E. coli mpk develop colitis whereas IL-2(-/-)-mice mono-colonized with B. vulgatus mpk do not and are even protected from E. coli mpk induced colitis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated if mono-colonization with E. coli mpk or B. vulgatus mpk differentially modulates distribution, activation and maturation of intestinal lamina propria (LP) dendritic cells (DC). LP DC in mice mono-colonized with protective B. vulgatus mpk or co-colonized with E. coli mpk/B. vulgatus mpk featured a semi-mature LP DC phenotype (CD40(lo)CD80(lo)MHC-II(hi)) whereas mono-colonization with colitogenic E. coli mpk induced LP DC activation and maturation prior to onset of colitis. Accordingly, chemokine receptor (CCR) 7 surface expression was more strikingly enhanced in mesenteric lymph node DC from E. coli mpk than B. vulgatus mpk mono- or co-colonized mice. Mature but not semi-mature LP DC promoted Th1 polarization. As B. vulgatus mpk promotes differentiation of semi-mature DC presumably by IL-6, mRNA and protein expression of IL-6 was investigated in LP DC. The data demonstrated that IL-6 mRNA and protein was increased in LP DC of B. vulgatus mpk as compared to E. coli mpk mono-colonized IL-2(-/-)-mice. The B. vulgatus mpk mediated suppression of CCR7 expression and DC migration was abolished in IL-6(-/-)-DC in vitro. CONCLUSIONS/SIGNIFICANCE: From this data we conclude that the B. vulgatus triggered IL-6 secretion by LP DC in absence of proinflammatory cytokines such as IL-12 or TNF-alpha induces a semi-mature LP DC phenotype, which might prevent T-cell activation and thereby the induction of colitis in IL-2(-/-)-mice. The data provide new evidence that IL-6 might act as an immune regulatory cytokine in the mucosa by targeting intestinal DC

Relationship between HDL Cholesterol Efflux Capacity, Calcium Coronary Artery Content, and Antibodies against ApolipoproteinA-1 in Obese and Healthy Subjects

AIMS: To explore the associations between cholesterol efflux capacity (CEC), coronary artery calcium (CAC) score, Framingham risk score (FRS), and antibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in healthy and obese subjects (OS). METHODS AND RESULTS: ABCA1-, ABCG1-, passive diffusion (PD)-CEC and anti-apoA-1 IgG were measured in sera from 34 controls and 35 OS who underwent CAC score determination by chest computed tomography. Anti-apoA-1 IgG ability to modulate CEC and macrophage cholesterol content (MCC) was tested in vitro. Controls and OS displayed similar ABCG1-, ABCA1-, PD-CEC, CAC and FRS scores. Logistic regression analyses indicated that FRS was the only significant predictor of CAC lesion. Overall, anti-apoA-1 IgG were significantly correlated with ABCA1-CEC (r = 0.48, p < 0.0001), PD-CEC (r = -0.33, p = 0.004), and the CAC score (r = 0.37, p = 0.03). ABCA1-CEC was correlated with CAC score (r = 0.47, p = 0.004) and FRS (r = 0.18, p = 0.29), while PD-CEC was inversely associated with the same parameters (CAC: r = -0.46, p = 0.006; FRS: score r = -0.40, p = 0.01). None of these associations was replicated in healthy controls or after excluding anti-apoA-1 IgG seropositive subjects. In vitro, anti-apoA-1 IgG inhibited PD-CEC (p < 0.0001), increased ABCA1-CEC (p < 0.0001), and increased MCC (p < 0.0001). CONCLUSIONS: We report a paradoxical positive association between ABCA1-CEC and the CAC score, with the latter being inversely associated with PD in OS. Corroborating our clinical observations, anti-apoA-1 IgG enhanced ABCA1 while repressing PD-CEC, leading to MCC increase in vitro. These results indicate that anti-apoA-1 IgG have the potential to interfere with CEC and macrophage lipid metabolism, and may underpin paradoxical associations between ABCA1-CEC and cardiovascular risk

CC chemokine CCL5 plays a central role impacting infarct size and post-infarction heart failure in mice

Aims The chemokine CCL5 plays a critical role as neutrophil and macrophage activator do in atherosclerosis and myocardial infarction. Thus, we investigated whether the treatment with a neutralizing monoclonal antibody (mAb) to mouse CCL5 would provide therapeutic benefit when provoking a coronary-associated ischaemic event. Methods and Results C57Bl/6 mice were submitted to left coronary artery permanent ligature. Then, various parameters were monitored for up to 21 days. At5 min and 3days after coronary occlusion, mice received one intravenous injection of the rat anti-mouse CCL5 mAb or isotype IgG control. Infarct size was assessed histologically and by measuring serum cardiac troponin I levels. Kinetics of CCL5 tissue expression, leucocyte infiltration, matrix metalloproteinase (MMP) levels, and collagen deposition were histologically assessed. Serum chemokine levels were measured by enzyme-linked immunosorbent assay. Cardiac function and dimensions were assessed by magnetic resonance imaging (MRI). Chronic ischaemia increased both circulating and intracardiac levels of CCL5. At 24 h, treatment with the anti-CCL5 mAb resulted in a smaller infarct size and reduced circulating levels of chemokines. This effect was associated with reduction of neutrophil and macrophage infiltration within the infarcted myocardium. After 3 days of chronic ischaemia, anti-CCL5 mAb treatment reduced cardiac MMP-9. At 7 days, collagen content was significantly lower. At 21 days, neutralizing CCL5 improved mouse survival, cardiac myocyte size, and cardiac function. Conclusion Treatment with anti-CCL5 mAb significantly reduced both infarct size and post-infarction heart failure in a mouse model of chronic cardiac ischaemia. Cardioprotective effects were associated with the reduction of leucocyte recruitment within infarcted heart

Anti-apolipoprotein A-1 IgG as an independent cardiovascular prognostic marker affecting basal heart rate in myocardial infarction

Aims To assess the prognostic value of anti-apolipoprotein A-1 (anti-apoA-1) IgG after myocardial infarction (MI) and its association with major cardiovascular events (MACEs) at 12 months and to determine their association with resting heart rate (RHR), a well-established prognostic feature after MI. Anti-apoA-1 IgG have been reported in MI without autoimmune disease, but their clinical significance remains undetermined. Methods and results A total of 221 consecutive patients with MI were prospectively included, and all completed a 12-month follow-up. Major cardiovascular events consisted in death, MI, stroke, or hospitalization either for an acute coronary syndrome or heart failure. Resting heart rate was obtained on Holter the day before discharge under the same medical treatment. Neonate rat ventricular cardiomyocytes (NRVC) were used in vitro to assess the direct anti-apoA-1 IgG effect on RHR. During follow-up, 13% of patients presented a MACE. Anti-apoA-1 IgG positivity was 9% and was associated with a higher RHR (P = 0.0005) and higher MACE rate (adjusted OR, 4.3; 95% CI, 1.46-12.6; P = 0.007). Survival models confirmed the significant nature of this association. Patients with MACE had higher median anti-apoA-1 IgG values at admission than patients without (P = 0.007). On NRVC, plasma from MI patients and monoclonal anti-apoA-1 IgG induced an aldosterone and dose-dependent positive chronotropic effect, abrogated by apoA-1 and therapeutic immunoglobulin (IVIG) pre-incubation. Conclusions In MI patients, anti-apoA-1 IgG is independently associated with MACE at 1-year, interfering with a currently unknown aldosterone-dependent RHR determinant. Knowing whether anti-apoA-1 IgG assessment could be of interest to identify an MI patient subset susceptible to benefit from apoA-1/IVIG therapy remains to be demonstrate

Nab-PIPAC: a phase IB study protocol of intraperitoneal cisplatin and nab-paclitaxel administered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of advanced malignancies confined to the peritoneal cavity

Introduction: Intraperitoneal dissemination is a major problem resulting in very poor prognosis and a rapid marked deterioration in the quality of life of patients. Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is an emergent laparoscopic procedure aiming to maximise local efficacy and to reduce systemic side effects. Methods and analysis: Nab-PIPAC, a bicentre open-label phase IB, aims to evaluate safety of nab-paclitaxel and cisplatin association using in patients with peritoneal carcinomatosis (PC) of gastric, pancreatic or ovarian origin as ≥1 prior line of systemic therapy. Using a 3+3 design, sequential intraperitoneal laparoscopic application of nab-paclitaxel (7.5, 15, 25, 37.5, 52.5 and 70 mg/m2) and cisplatin (10.5 mg/m2) through a nebuliser to a high-pressure injector at ambient temperature with a maximal upstream pressure of 300 psi. Treatment maintained for 30 min at a pressure of 12 mm Hg and repeated4-6 weeks intervals for three courses total.A total of 6-36 patients are expected, accrual is ongoing. Results are expected in 2024.The primary objective of Nab-PIPAC trial is to assess tolerability and safety of nab-paclitaxel and cisplatin combination administered intraperitoneally by PIPAC in patients with PC of gastric, pancreatic or ovarian origin. This study will determine maximum tolerated dose and provide pharmacokinetic data. Ethic and dissemination: Ethical approval was obtained from the ethical committees of Geneva and Vaud (CCER-2018-01327). The study findings will be published in an open-access, peer-reviewed journal and presented at relevant conferences and research meetings. Trial registration number: NCT04000906.</p

Inferior vena cava parameters predict re-admission in ischaemic heart failure

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Association Between Patient Sex and Familial Hypercholesterolemia and Long-Term Cardiovascular Risk Factor Management 5 Years After Acute Coronary Syndrome.

BACKGROUND Long-term control of cardiovascular risk factors after acute coronary syndrome (ACS) is the cornerstone for preventing recurrence. We investigated the extent of cardiovascular risk factor management in males and females with and without familial hypercholesterolemia (FH) 5 years after ACS. METHODS We studied patients hospitalized for ACS between 2009 and 2017 in a Swiss multicenter prospective cohort study. FH was defined based on clinical criteria from the Dutch Lipid Clinic Network and Simon Broome definitions. Five years post-ACS, we assessed low-density lipoprotein-cholesterol (LDL-c) levels, lipid-lowering therapy (LLT), and other cardiovascular risk factors, comparing males to females with and without FH using generalized estimating equations. RESULTS A total of 3139 patients were included; mean age was 61.4 years (SD, 12.1), 620 (19.8%) were female, and 747 (23.5%) had possible FH. Compared with males at 5-years post-ACS, females were more likely to not use statins (odds ratio, 1.61 [95% CI, 1.28-2.03]) and less likely to have combination LLT (odds ratio, 0.72 [95% CI, 0.55-0.93]), without difference between patients with FH and without FH. Females in both FH and non-FH groups less frequently reached LDL-c values ≤1.8 mmol/L (odds ratio, 0.78 [95% CI, 0.78-0.93]). Overall, patients with FH were more frequently on high-dose statins compared with patients without FH (51.0% versus 42.9%; P=0.001) and presented more frequently with a combination of 2 or more LLT compared with patients without FH (33.8% versus 17.7%; P<0.001), but less frequently reached LDL-c targets of ≤1.8 mmol/L (33.5% versus 44.3%; P<0.001) or ≤2.6 mmol/L (70.2% versus 78.1%; P=0.001). CONCLUSIONS Five years after ACS, females had less intensive LLT and were less likely to reach target LDL-c levels than males, regardless of FH status. Males and females with FH had less optimal control of LDL-c despite more frequently taking high-dose statins or combination LLT compared with patients without FH. Long-term management of patients with ACS and FH, especially females, warrants optimization

Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation

Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5-15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, and studied their in vitro effects on foam cell formation, gene regulation, and their functional impact on cholesterol passive diffusion (PD)