Impact of different chemotherapy regimens on intestinal mucosal injury assessed with bedside ultrasound: a study in 213 AML patients

IntroductionNeutropenic enterocolitis (NEC) is a life-threatening complication reported in patients with acute myeloid leukemia (AML) following chemotherapy (CHT). Intensive induction and consolidation CHT may damage intestinal mucosa leading to a NEC episode (NECe). NEC reported mortality may be up to 30-60%. Early US-guided bed-side diagnosis and prompt treatment may substantially improve the survival. An emerging worldwide concern is the intestinal colonization by multi-drug-resistant bacteria especially when patients are exposed to chemotherapy regimens potentially correlated to mucosal damage. MethodsIn our study we prospectively enrolled all AML patients admitted in our leukemia unit to receive intensive induction and consolidation chemotherapy and experiencing chemotherapy-induced-neutropenia (CHTN). Results and discussionOverall, we enrolled N=213 patients from 2007 to March 2023. We recorded N=465 CHTN, and N=42 NECe (9.0% incidence). The aim of our study was to assess which chemotherapy regimens are more associated with NEC. We found that ALM1310, followed by 7 + 3 (daunorubicin), 7 + 3 (idarubicin), 5 + 3 + 3 (cytarabine, etoposide, idarubicin), and AML1310 (consolidation) were associated with a statistically higher incidence of NEC. We did not detect NEC episodes in patients treated with CPX-351, 5 + 2 (cytarabine, idarubicine), and high-dose cytarabine. Thus, we found that cytarabine could determine mucosal damage when associated with an anthracycline but not if delivered either alone or as dual-drug liposomal encapsulation of daunorubicin/cytarabine. We also describe NEC mortality, symptoms at diagnosis, intestinal sites involvement, and prognostic significance of bowel wall thickening

Marine phycotoxin levels in shellfish-14 years of data gathered along the Italian coast

Along the Italian coasts, toxins of algal origin in wild and cultivated shellfish have been reported since the 1970s. In this study, we used data gathered by the Veterinary Public Health Institutes (IZS) and the Italian Environmental Health Protection Agencies (ARPA) from 2006 to 2019 to investigate toxicity events along the Italian coasts and relate them to the distribution of potentially toxic species. Among the detected toxins (OA and analogs, YTXs, PTXs, STXs, DAs, AZAs), OA and YTX were those most frequently reported. Levels exceeding regulatory limits in the case of OA (≤2,448 μg equivalent kg-1) were associated with high abundances of Dinophysis spp., and in the case of YTXs (≤22 mg equivalent kg-1) with blooms of Gonyaulax spinifera, Lingulodinium polyedra, and Protoceratium reticulatum. Seasonal blooms of Pseudo-nitzschia spp. occur all along the Italian coast, but DA has only occasionally been detected in shellfish at concentrations always below the regulatory limit (≤18 mg kg-1). Alexandrium spp. were recorded in several areas, although STXs (≤13,782 μg equivalent kg-1) rarely and only in few sites exceeded the regulatory limit in shellfish. Azadinium spp. have been sporadically recorded, and AZAs have been sometimes detected but always in low concentrations (≤7 μg equivalent kg-1). Among the emerging toxins, PLTX-like toxins (≤971 μg kg-1 OVTX-a) have often been detected mainly in wild mussels and sea urchins from rocky shores due to the presence of Ostreopsis cf. ovata. Overall, Italian coastal waters harbour a high number of potentially toxic species, with a few HAB hotspots mainly related to DSP toxins. Nevertheless, rare cases of intoxications have occurred so far, reflecting the whole Mediterranean Sea conditions

Stool Xpert MTB/RIF as a possible diagnostic alternative to sputum in Africa: a systematic review and meta-analysis

IntroductionWorldwide, COVID-19 pandemic lead to a large fall in the number of newly reported TB cases. In sub-Saharan Africa, microbiological diagnosis of TB is generally based on smear microscopy and Xpert MTB/RIF on sputum samples, but good quality sputum samples are often difficult to obtain, leading clinicians to rely on more invasive procedures for diagnosis. Aim of this study was to investigate pooled sensitivity and specificity of Xpert MTB/RIF on stool samples compared to respiratory microbiological reference standards in African countries.MethodsFour investigators independently searched PubMed, SCOPUS, and Web of Science until 12th October 2022, then screened titles and abstracts of all potentially eligible articles. The authors applied the eligibility criteria, considered the full texts. All the studies reported the data regarding true positive (TP), true negative (TN), false positive (FP) and false negative (FN). Risk of bias and applicability concerns were assessed with the Quadas-2 tool.Resultsoverall, among 130 papers initially screened, we evaluated 47 works, finally including 13 papers for a total of 2,352 participants, mainly children. The mean percentage of females was 49.6%, whilst the mean percentage of patients reporting HIV was 27.7%. Pooled sensitivity for Xpert MTB/RIF assay for detecting pulmonary tuberculosis was 68.2% (95%CI: 61.1–74.7%) even if characterized by a high heterogeneity (I2=53.7%). Specificity was almost 100% (99%, 95%CI: 97–100%; I2 = 45.7%). When divided for reference standard, in the six studies using sputum and nasogastric aspirate the accuracy was optimal (AUC = 0.99, SE = 0.02), whilst in the studies using only sputum for tuberculosis detection the AUC was 0.85 (with a SE = 0.16). The most common source of bias was exclusion of enrolled patients in the analysis.ConclusionsOur study confirms that, in Africa, stool Xpert MTB/RIF may be a useful rule-in test for children above and below 5 years of age under evaluation for pulmonary tuberculosis. Sensitivity increased substantially when using both sputum and nasogastric aspirate as reference samples

Studio prospettico della Enterocolite Necrotizzante su 228 pazienti affetti da leucemia mieloblastica acuta: incidenza, diagnosi precoce, terapia, sopravvivenza ed impatto di diversi regimi di chemioterapia sulla mucosa intestinale

L’Enterocolite necrotizzante del neutropenico (NEC) è una sindrome clinica potenzialmente fatale che può svilupparsi come complicanza nei pazienti neutropenici sottoposti a chemioterapie intensive. È un’entità clinica caratterizzata da un’alta incidenza nel paziente neutropenico, rappresenta infatti la complicanza gastro-intestinale più frequente in questi pazienti ed ha una prognosi infausta. A partire da Gennaio 2007 a Giugno 2018, abbiamo condotto uno studio prospettico su 228 pazienti neutropenici post-chemioterapia per leucemia mieloblastica acuta. L’intento dello studio è stato di esaminare alcuni aspetti dell’enterocolite necrotizzante nel paziente neutropenico, in particolare: calcolarne l’incidenza e la mortalità, individuare i principali micro-organismi responsabili, capire se un primo episodio di NEC (NECe) predisponga il paziente allo sviluppo di un secondo NECe, ricercare una correlazione fra tipo di ciclo chemioterapico ed insorgenza di un NECe e dimostrare l’utilità di una diagnosi precoce mediante ecografia bed-side. Tutti i pazienti inclusi nello studio sono stati sottoposti ad un’ecografia bed-side prima dell’inizio della chemioterapia ed una seconda eco entro 12 h dall’insorgenza di eventuali segni/sintomi di NEC: diarrea, dolore addominale, febbre. All’esame ecografico sono stati associati un accurato esame obbiettivo e una ricerca microbiologica mirata. In caso di diagnosi di un NECe (secondo i criteri di Gorschluter) è stata intrapresa una tempestiva terapia medica (N=22/25 pazienti), secondo il protocollo del reparto, o chirurgica (N=3/25 pazienti). L’incidenza di NEC è stata del 5,1% per episodio di neutropenia (NTe), la mortalità per NEC è stata del 25%. Nel 32,1% dei casi la ricerca microbiologica ha permesso l’isolamento di un microorganismo; N=7 NECe/28NECe avevano un’emocoltura positiva, N=2/28 avevano una coprocoltura positiva. I microorganismi isolati sono stati soprattutto batteri gram-negativi (Escherichia Coli, Klebsiella Pneumoniae, Pseudomonas Aeruginosa, Enterococco Faecalis) e funghi della specie Candida. Data l’alta concentrazione dei decessi nel gruppo con emocoltura positiva (5 su 7 decessi totali per NEC) abbiamo calcolato il rischio relativo di morte per NEC con emo+ che è risultato essere RR=7,5. La sede e il tipo di presentazione clinica (con febbre, diarrea e dolore addominale, variabilmente associati) non risultano essere correlati con una diversa mortalità. Il tipo di ciclo chemioterapico che correla con una maggiore incidenza di NECe è, nella nostra casistica, l’AML1310, con un’incidenza, intesa come NECe/NTe del 25,9%, diversa, in maniera statisticamente significativa, dall’incidenza riscontrata con tutti gli altri tipi di schemi chemioterapici a cui sono stati sottoposti i pazienti in studio. Dal nostro studio possiamo concludere che: i) L’incidenza di NEC è del 5,1% (NECe/NTe) ii) Una diagnosi precoce con eco bed-side permette di iniziare in maniera tempestiva un’adeguata terapia, medica o chirurgica, con una diminuzione della mortalità, rispetto alle percentuali riportate da altri autori: nella nostra casistica abbiamo infatti registrato una mortalità del 25% rispetto alle percentuali maggiori, 50-100%, che si ritrovano in letteratura. iii) Un NECe in cui si ha un’emocoltura positiva correla con un RR=7,5 di mortalità rispetto ad un NECe con emocoltura negativa. iv) Lo schema chemioterapico maggiormente predisponente allo sviluppo di un NECe è l’AML1310

Binding of Gamma-Glutamyl Transferase to TLR4 Signalling Allows Tissue Factor Activation in Monocytes

Gamma-glutamyl transferase (GGT) is involved in the progression of atherosclerosis, since its enzymatic activity promotes the generation of reactive oxygen species (ROS). Besides, GGT may act as a prothrombotic factor by inducing tissue factor (TF) expression, independently of its enzymatic activity. The aim of this study was to assess whether GGT-induced TF stimulation was a consequence of binding to toll-like receptor 4 (TLR4) expressed on monocytes, the precursors of macrophages and foam cells which colocalize with GGT activity within atherosclerotic plaques. Experiments were performed in human peripheral blood mononuclear cells (PBMCs), THP-1 cells (a monocytic cellular model), and HEK293 cells, which were genetically modified to study the activation of TLR4. TF procoagulant activity was assessed by a one-stage clotting time test, and TF protein expression was estimated by western blot. Human recombinant (hr) GGT protein increased TF procoagulant activity and protein expression in both PBMCs and THP-1 cells. The GGT-induced TF stimulation was prevented by cellular pretreatment with TLR4/NF-κB inhibitors (LPS-Rs, CLI-095, and BAY-11-7082), and HEK293 cells lacking TLR4 confirmed that TLR4 is essential for GGT-induced activation of NF-κB. In conclusion, hrGGT induced TF expression in monocytes through a cytokine-like mechanism that involved the activation of TLR4/NF-κB signaling

The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism

Transthyretin (TTR) is a homotetrameric protein mainly synthesised by the liver and the choroid plexus whose function is to carry the thyroid hormone thyroxine and the retinol-binding protein bound to retinol in plasma and cerebrospinal fluid. When the stability of the tetrameric structure is lost, it breaks down, paving the way for the aggregation of TTR monomers into insoluble fibrils leading to transthyretin (ATTR) amyloidosis, a progressive disorder mainly affecting the heart and nervous system. Several TTR gene mutations have been characterised as destabilisers of TTR structure and are associated with hereditary forms of ATTR amyloidosis. The reason why also the wild-type TTR is intrinsically amyloidogenic in some subjects is largely unknown. The aim of the review is to give an overview of the TTR biological life cycle which is largely unknown. For this purpose, the current knowledge on TTR physiological metabolism, from its synthesis to its catabolism, is described. Furthermore, a large section of the review is dedicated to examining in depth the role of mutations and physiological ligands on the stability of TTR tetramers