Risk factors for recurrence in patients with Clostridium difficile infection due to 027 and non-027 ribotypes

Objectives: Our objective was to evaluate factors associated with recurrence in patients with 027+ and 027– Clostridium difficile infection (CDI). Methods: Patients with CDI observed between January and December 2014 in six hospitals were consecutively included in the study. The 027 ribotype was deduced by the presence of tcdB, tcdB, cdt genes and the deletion Δ117 in tcdC (Xpert® C. difficile/Epi). Recurrence was defined as a positive laboratory test result for C. difficile more than 14 days but within 8 weeks after the initial diagnosis date with reappearance of symptoms. To identify factors associated with recurrence in 027+ and 027– CDI, a multivariate analysis was performed in each patient group. Subdistributional hazard ratios (sHRs) and 95% confidence intervals (95%CIs) were calculated. Results: Overall, 238 patients with 027+ CDI and 267 with 027– CDI were analysed. On multivariate analysis metronidazole monotherapy (sHR 2.380, 95%CI 1.549–3.60, p <0.001) and immunosuppressive treatment (sHR 3.116, 95%CI 1.906–5.090, p <0.001) were factors associated with recurrence in patients with 027+ CDI. In this patient group, metronidazole monotherapy was independently associated with recurrence in both mild/moderate (sHR 1.894, 95%CI 1.051–3.410, p 0.033) and severe CDI (sHR 2.476, 95%CI 1.281–4.790, p 0.007). Conversely, non-severe disease (sHR 3.704, 95%CI 1.437–9.524, p 0.007) and absence of chronic renal failure (sHR 16.129, 95%CI 2.155–125.000, p 0.007) were associated with recurrence in 027– CDI. Conclusions: Compared to vancomycin, metronidazole monotherapy appears less effective in curing CDI without relapse in the 027+ patient group, independently of disease severity

Early experience with targeted therapy and dendritic cell vaccine in metastatic renal cell carcinoma after nephrectomy

PURPOSE: Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant malignancies and nephrectomy, isolated or combined with systemic chemotherapy typically has limited or no effectiveness. We report our initial results in patients treated with the association of molecular targeted therapy, nephrectomy, and hybrid dendritic-tumor cell (DC) vaccine. MATERIALS AND METHODS: Two male patients diagnosed with metastatic RCC were selected for the study. They were treated with the triple strategy, in which sunitinib (50 mg per day) was given for 4 weeks, followed by radical nephrectomy after two weeks. DC vaccine was initiated immediately after surgery and repeated monthly. Sunitinib was restarted daily after 2 to 3 weeks of surgery with a 7-day interval every 4 weeks. RESULTS: Both patients had complete adherence to the proposed treatment with DC vaccine therapy combined with sunitinib. Follow-up in these patients at 9 and 10 months demonstrated a stable disease in both, as shown by imaging and clinical findings, with no further treatment required. CONCLUSION: The immune response obtained with DC vaccine combined with the antiangiogenic effect of sunitinib and the potential benefits of cytoreductive nephrectomy in advanced disease could represent a new option in the treatment of metastatic RCC. Further prospective trials are needed not only to elucidate the ideal dosing and schedule, but also to better define the proof-of-concept proposed in this report and its role in clinical practice

Sex-related differences in risk factors, type of treatment received and outcomes in patients with atrial fibrillation and acute stroke: Results from the RAF-study (Early Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation)

Introduction: Atrial fibrillation is an independent risk factor of thromboembolism. Women with atrial fibrillation are at a higher overall risk for stroke compared to men with atrial fibrillation. The aim of this study was to evaluate for sex differences in patients with acute stroke and atrial fibrillation, regarding risk factors, treatments received and outcomes. Methods Data were analyzed from the “Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation” (RAF-study), a prospective, multicenter, international study including only patients with acute stroke and atrial fibrillation. Patients were followed up for 90 days. Disability was measured by the modified Rankin Scale (0–2 favorable outcome, 3–6 unfavorable outcome). Results: Of the 1029 patients enrolled, 561 were women (54.5%) (p &lt; 0.001) and younger (p &lt; 0.001) compared to men. In patients with known atrial fibrillation, women were less likely to receive oral anticoagulants before index stroke (p = 0.026) and were less likely to receive anticoagulants after stroke (71.3% versus 78.4%, p = 0.01). There was no observed sex difference regarding the time of starting anticoagulant therapy between the two groups (6.4 ± 11.7 days for men versus 6.5 ± 12.4 days for women, p = 0.902). Men presented with more severe strokes at onset (mean NIHSS 9.2 ± 6.9 versus 8.1 ± 7.5, p &lt; 0.001). Within 90 days, 46 (8.2%) recurrent ischemic events (stroke/TIA/systemic embolism) and 19 (3.4%) symptomatic cerebral bleedings were found in women compared to 30 (6.4%) and 18 (3.8%) in men (p = 0.28 and p = 0.74). At 90 days, 57.7% of women were disabled or deceased, compared to 41.1% of the men (p &lt; 0.001). Multivariate analysis did not confirm this significance. Conclusions: Women with atrial fibrillation were less likely to receive oral anticoagulants prior to and after stroke compared to men with atrial fibrillation, and when stroke occurred, regardless of the fact that in our study women were younger and with less severe stroke, outcomes did not differ between the sexes

Immunoglobulin G; structure and functional implications of different subclass modifications in initiation and resolution of allergy.

IgE and not IgG is usually associated with allergy. IgE lodged on mast cells in skin or gut and basophils in the blood allows for the prolonged duration of allergy through the persistent expression of high affinity IgE receptors. However, many allergic reactions are not dependent on IgE and are generated in the absence of allergen specific and even total IgE. Instead, IgG plasma cells are involved in induction of, and for much of the pathogenesis of, allergic diseases. The pattern of IgG producing plasma cells in atopic children and the tendency for direct or further class switching to IgE are the principle factors responsible for long-lasting sensitization of mast cells in allergic children. Indirect class switching from IgG producing plasma cells has been shown to be the predominant pathway for production of IgE while a Th2 microenvironment, genetic predisposition, and the concentration and nature of allergens together act on IgG plasma cells in the atopic tendency to undergo further immunoglobulin gene recombination. The seminal involvement of IgG in allergy is further indicated by the principal role of IgG4 in the natural resolution of allergy and as the favourable immunological response to immunotherapy. This paper will look at allergy through the role of different antibodies than IgE and give current knowledge of the nature and role of IgG antibodies in the start, maintenance and resolution of allergy

Lipoxin A4 and interleukin-8 levels in cystic fibrosis sputum after antibiotherapy

AbstractAntibiotics are largely prescribed for cystic fibrosis (CF) respiratory exacerbations. Effects of antibiotics on the inflammatory profile of the patients have been shown but remain controversial. Lipoxin A4 (LXA4) is a lipid mediator, reported to play a central role in resolving airway inflammation. The aim of the study was to investigate the consequences of antibiotherapy on LXA4 and IL-8 levels in CF patients' airways.MethodsEighteen CF patients (7 females, median age 20, range 8 to 47 years) consecutively admitted at the CF center of Montpellier for antibiotics during pulmonary exacerbation, were enrolled. Before and after antibiotics, all patients underwent spirometry (FEV1 and FVC), bacterial cultures and cell counts in sputa. IL-8 and LXA4 concentrations were determined in sputum samples by the median of immunometric assays.ResultsAs previously reported, after antibiotics therapy, FEV1 and FVC significantly improved. While neutrophil cell counts and IL-8 levels decreased, the LXA4 levels significantly increased after antibiotics therapy and were inversely correlated with IL-8 levels.In conclusion, we reported a correlation between antibiotics treatments and inflammatory markers in CF sputum. Our data provide evidences for a novel effect of antibiotics increasing the concentration of the anti-inflammatory lipid mediator LXA4

Cost-effectiveness analysis of alectinib versus crizotinib in first-line treatment of anaplastic lymphoma kinase-positive advanced non-small cell lung cancer:

In the randomized, active-controlled, multicenter Phase III open-label ALEX trial, alectinib showed superior efficacy and lower toxicity compared with crizotinib in the primary treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK-positive NSCLC). The aim of this economic evaluation was to assess the cost-utility of alectinib versus crizotinib from the perspective of the Italian National Health Service (INHS). A partitioned survival model with three health states (progression-free, post-progression, and death) was used. The clinical data (progression-free survival, overall survival and time to progression) was based on the ALEX trial. Utility values were derived from EQ-5D scores evaluated in the ALEX trial and literature. Costs included drug treatments, progression-free, post-progression and supportive care. Direct medical costs and benefits (quality-adjusted life-years, QALYs) were discounted at a 3.0% annual rate. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses. Treatment with alectinib versus crizotinib led to a gain of 2.82 life-years, 1.86 QALYs, and incremental costs of €58,276, resulting in an incremental cost-utility ratio of €31,353 per QALY. The deterministic analysis showed that the most critical parameters in the model were the cost of post-progression and utility scores. From the probabilistic sensitivity analysis, alectinib had a 64.5% probability of being cost-effective at a willingness-to-pay threshold of €40,000 per QALY. Compared with crizotinib, alectinib increased the length of the progression-free state and the QALYs. The incremental overall cost increase was reflective of longer treatment durations in the progression-free state. Compared with crizotinib, alectinib can be considered a valid cost-utility option in the treatment of naive patients with ALK-positive NSCLC

Modulating Tumor Microenvironment: A Review on STK11 Immune Properties and Predictive vs Prognostic Role for Non-small-cell Lung Cancer Immunotherapy

The quest for immunotherapy (IT) biomarkers is an element of highest clinical interest in both solid and hematologic tumors. In non-small-cell lung cancer (NSCLC) patients, besides PD-L1 expression evaluation with its intrinsic limitations, tissue and circulating parameters, likely portraying the tumor and its stromal/immune counterparts, have been proposed as potential predictors of IT responsiveness. STK11 mutations have been globally labeled as markers of IT resistance. After a thorough literature review, STK11 mutations condition the prognosis of NSCLC patients receiving ICI-containing regimens, implying a relevant biological and clinical significance. On the other hand, waiting for prospective and solid data, the putative negative predictive value of STK11 inactivation towards IT is sustained by less evidence. The physiologic regulation of multiple cellular pathways performed by STK11 likely explains the multifaceted modifications in tumor cells, stroma, and tumor immune microenvironment (TIME) observed in STK11 mutant lung cancer, particularly explored in the molecular subgroup of KRAS co-mutation. IT approaches available thus far in NSCLC, mainly represented by anti-PD-1/PD-L1 inhibitors, are not promising in the case of STK11 inactivation. Perceptive strategies aimed at modulating the TIME, regardless of STK11 status or specifically addressed to STK11-mutated cases, will hopefully provide valid therapeutic options to be adopted in the clinical practice

The appropriate dosing of erenumab for migraine prevention after multiple preventive treatment failures: a critical appraisal

BACKGROUND: Erenumab, a fully human monoclonal antibody directed against the calcitonin gene-related peptide receptor, was approved for the prevention of episodic (EM) or chronic migraine (CM) at the monthly dose of 70 mg or 140 mg. We reviewed the available literature to understand if patients with prior preventive treatment failures benefit more from the 140 mg dose than the 70 mg. MAIN BODY: We searched papers indexed in PubMed and conference abstracts published in the last 2 years which assessed the safety and efficacy of erenumab in patients with prior preventive treatment failures. We reviewed the results of 3 randomized controlled trials and their subgroup analyses and open-label extensions. The 140 mg monthly dose of erenumab had a numerical advantage over the 70 mg monthly dose in patients with prior preventive treatment failures, both in EM and CM (with or without medication overuse) during the double blind phases of the trials and their open-label extensions. The numerical difference between the two doses increased with the increase in the number of prior preventive treatment failures. CONCLUSIONS: The available data suggest that erenumab 140 mg monthly might be preferred over the 70 mg monthly dose in patients with EM or CM and prior preventive treatment failures. Further data are needed to assess the long-term efficacy in clinical practice of the two doses of erenumab, while their safety profile is comparable

All-cause mortality and estimated renal function in type 2 diabetes mellitus outpatients: is there a relationship with the equation used?

BACKGROUND: We investigated the relationship between serum creatinine (SCr) and estimated glomerular filtration rate (eGFR), evaluated by different formulae, and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) outpatients. METHODS: This observational cohort study considered 1365 T2DM outpatients, who had been followed up for a period of up to 11 years. eGFR was estimated using several equations. RESULTS: Seventy subjects (5.1%) died after a follow-up of 9.8 ± 3 years. Univariate analysis showed that diagnosis of nephropathy (odds ratio (OR): 2.554, 95% confidence interval (CI): 1.616-4.038, p < 0.001) and microvascular complications (OR: 2.281, 95% CI: 1.449-3.593, p < 0.001) were associated with ACM. Receiving operating characteristic (ROC) curves showed that the areas under the curve for ACM were similar using the different eGFR equations. eGFR values were predictors of ACM, and the hazard ratios (HRs) of the different equations for eGFR estimation were similar. CONCLUSION: In our cohort of T2DM outpatients, different eGFR equations perform similarly in predicting ACM, whereas SCr did not

Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-positive NSCLC: ALNEO Trial

Background: Alectinib is a potent anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) which is currently used in the first-line setting of advanced ALK+ non-small cell lung cancer (NSCLC). Despite favorable results in the metastatic setting, the activity of alectinib in locally-advanced ALK+ NSCLC as a neoadjuvant treatment remains to be assessed. We report the case of a patient with stage IIIA ALK+ NSCLC (cT2aN2) who received alectinib as neoadjuvant treatment, achieving major pathological response (MPR) at pathologic examination. Hence we present the treatment rationale and study design of a phase II, open-label, single-arm, multicenter clinical trial (ALNEO study, EUDRACT number 2020-003432-25). Materials and Methods: Patients with potentially resectable stage III ALK+ NSCLC (any T with N2, T4N0-1) will be registered to receive oral alectinib 600 mg twice daily for 2 cycles of 4 weeks each (8 weeks totally) during the neoadjuvant phase. After definitive surgery, patients will enter in the adjuvant setting, during which they will receive alectinib 600 mg twice daily for 24 cycles (96 weeks). The primary endpoint is MPR, defined as ≤10% residual viable tumor cells histologically detected in the resected primary tumor and all resected lymph nodes after surgery. Secondary endpoints include pathological complete response, objective response, event-free survival, disease-free survival, overall survival, adverse events. Conclusions: Our case report supports the feasibility of alectinib as neoadjuvant treatment. ALNEO study will further explore the activity and safety of this novel treatment strategy