Meropenem–nacubactam activity against AmpC-overproducing and KPC-expressing Pseudomonas aeruginosa in a neutropenic murine lung infection model

Nacubactam is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor under development for the treatment of serious Gram-negative infections. This study assessed the efficacy of human-simulated epithelial lining fluid (ELF) exposure of nacubactam in combination with meropenem against AmpC-overproducing (n=4) and Klebsiella pneumoniae carbapenemase (KPC)-expressing (n=3) Pseudomonas aeruginosa isolates in the neutropenic murine lung infection model. Meropenem, nacubactam and meropenem–nacubactam (1:1 concentration ratio) minimum inhibitory concentrations (MICs) were determined in triplicate using broth microdilution. Regimens that provided ELF profiles mimicking those observed in humans given nacubactam 2 g q8h (1.5-h infusion) alone and in combination with a subtherapeutic ELF exposure of meropenem were administered 2 h after inoculation. Efficacy was assessed as the change in log₁₀ colony-forming units (CFU)/lung at 24 h compared with 24-h meropenem monotherapy. Meropenem, nacubactam and meropenem–nacubactam MICs were 8–>64, 128–>256 and 2–16 mg/L, respectively. Meropenem and nacubactam monotherapy groups demonstrated bacterial growth over 24 h for each isolate. Against AmpC-overproducing and KPC-expressing P. aeruginosa isolates, meropenem–nacubactam resulted in −2.73±0.93 and −4.35±1.90 log₁₀CFU/lung reduction, respectively, relative to meropenem monotherapy. Meropenem–nacubactam showed promising in-vivo activity against meropenem-resistant P. aeruginosa, indicative of a potential role for the treatment of infections caused by these challenging pathogens.     

Management of non-small cell lung cancer in the elderly

Most developed countries accepted the chronological age of 70 years as the definition of “elderly” and there is a general consensus in clinical practice to consider this age as the threshold in risk assessment. This has a strong impact in the choice of treatment of these lung cancer patients. Indeed, more than 50% of these patients are over 70 and nearly 30% are over 75 years old. Because of the increasing number of elderly patients that are generally fitter than in the past, the treatment options should rather be based on individual fitness, taking into account risks and benefits of the diagnostic and therapeutic procedures. This means considering biological rather than chronological age to make decisions.For these reasons, we developed a simplified short comprehensive geriatric assessment (sCGA), including a standardised evaluation of activity of daily living, depression, cognitive status, comorbidities and geriatric syndromes. This allowed us the classification of these patients into 3 categories: frail, vulnerable and fit.Through the emblematic case of a fit elderly man affected by NSLCC, we present the multidisciplinary assessment and discussions to identify the best treatment options for this patient.     

Effect of insulin secretagogues on major cardiovascular events and all-cause mortality: A meta-analysis of randomized controlled trials

Background and aimIn 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs) and all-cause mortality as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin secretagogues (sulfonylureas and glinides) with this respect.Methods and resultsA MEDLINE database search was performed to identify all RCTs, up to January 1st, 2020, with duration≥52 weeks, in which insulin secretagogues (glibenclamide, gliclazide, glimepiride, glipizide, chlorpropamide, repaglinide, nateglinide) were compared with either placebo or active comparators. The principal endpoints were MACE (restricted for RCT reporting MACEs within their outcomes) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH–OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Fourteen RCTs were included in the analysis for MACEs (919 in insulin secretagogues and 1,087 in control group). Insulin secretagogues were not significantly associated with an increased risk of MACEs in comparison with controls (MH–OR 1.08 [95% CI 0.96, 1.22], p = 0.20). When considering the 48 RCTs fulfilling criteria for inclusion in the analysis on all-cause mortality, insulin secretagogues were associated with a significantly increased risk of all-cause mortality (MH–OR 1.11 [1.00, 1.23], p = 0.04).ConclusionsThis meta-analysis suggests that insulin secretagogues are associated with an increased risk of all-cause mortality when compared with placebo or other anti-hyperglycaemic drugs.     

Performance of the Steno type 1 risk engine for cardiovascular disease prediction in Italian patients with type 1 diabetes

Background and aimsPremature cardiovascular disease cause excess mortality in type 1 diabetes (T1D). The Steno T1D Risk Engine was developed and validated in northern European countries but its validity in other populations is unknown. We evaluated the performance of the Steno T1D Risk Engine in Italian patients with T1D.Materials and methodsWe included patients with T1D with a baseline visit between July 2013 and April 2014, who were free of cardiovascular disease and had complete information to estimate risk. The estimated cardiovascular risk score was compared with the 5-year rate of cardiovascular events by means of logistic regression.ResultsAmong 223 patients (mean age 43 ± 13 years, 34.5% male, mean duration of diabetes 22 ± 12 years) the mean estimated cardiovascular risk at 5 years was 5.9% (95% C.I. 5.2–6.5%). At baseline, high estimated risk discriminated the presence of asymptomatic atherosclerosis better than microangiopathy, and was not associated with markers of inflammation or endothelial activation. After a mean follow-up of 4.7 ± 0.5 years, only 3 cardiovascular events were observed and nonetheless the risk score was significantly associated with their incidence (OR 1.22; 95% C.I. 1.08–1.39, p = 0.001). However, the observed event rate was significantly lower than the estimated one (3 vs 13; 95% C.I. 12–14; p < 0.001).ConclusionThe Steno T1D Risk Score identified subjects with subclinical atherosclerosis and high cardiovascular risk in an Italian T1D population. However, the absolute risk was significantly overestimated. Further studies in larger population are needed to confirm these results.     

A new der(1;7)(q10;p10) leading to a singular 1p loss in a case of glioblastoma with oligodendroglioma component

The combined 1p‐/19q‐ deletions in oligodendrogliomas originate from translocation between both chromosomes. In the few cases of oligoastrocytomas and glioblastomas with an oligodendroglioma component (GBMO) where only 1p deletion was described, the origin remains unknown. We report the first case of GBMO, in which a single 1p deletion was detected and was linked to a translocation between chromosomes 1 and 7. Fresh surgical specimens were collected during surgery and the samples were used for cell culture, touch preparation smear slides (TP slides) and DNA extraction. Peripheral venous blood was also collected from the patient. G‐banding using Trypsin and stained with Giemsa (GTG) banding and karyotyping were performed and 1p‐/19q‐, TP53, PTEN and c‐MYC were analyzed by fluorescent in situ hybridization (FISH). Multicolor FISH (mFISH) and microsatellites analyses were also performed to complete the investigation. Three‐dimensional quantitative FISH (3D‐QFISH) of telomeres was performed on nuclei from TP slides and analyzed using TeloView^TM to determine whether the 3D telomere profile as an assessment of telomere dysfunction and a characterization of genomic instability could predict the disease aggressiveness. An unbalanced chromosomal translocation was found in all metaphases and confirmed by mFISH. The karyotype of the case is: 50～99,XXX, +der(1;7)(q10;p10),inc[47] The derivative chromosome was found in all 47 analyzed cells, but the number of derivatives varied from one to four. There was neither imbalance in copy number for genes TP53 and PTEN, nor amplification of c‐MYC gene. We did not find loss of heterozygosity with analysis of microsatellite markers for chromosomes 1p and 19q in tumor cells. The 3D‐telomere profile predicted a very poor prognostic and short‐term survival of the patient and highlights the potential clinical power of telomere signatures as a solid biomarker of GBMO. Furthermore, this translocation between chromosomes 1 and 7 led to a singular 1p deletion in this GBMO and may generate the 1p and 7q deletions.