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

La ricostituzione immunologica post trapianto allogenico di cellule staminali ematopoietiche: un modello di studio integrato clinico-laboratoristico su popolazioni linfocitarie T circolanti

Il trapianto di cellule staminali ematopoietiche è un’importante opzione terapeutica. Sviluppatosi a partire dal secolo scorso, ha subito una progressiva estensione delle indicazioni, fino a diventare un trattamento di prima linea per numerose patologie ematologiche. La chiave del trapianto sta nella possibilità di poter somministrare chemio-radioterapie a dosi sovramassimali, o comunque in grado di indurre aplasia midollare, utilizzando il potenziale rigenerativo delle cellule staminali reinfuse per poter ricostituire in tempi relativamente rapidi un’emopoiesi efficace. Le cellule staminali emopoietiche ricostituiscono un repertorio B, T, e NK attraversando le fasi della genesi del sistema immunitario a partire da precursori. Questo processo, conosciuto come ricostituzione immunologica, si svolge nel midollo osseo per i progenitori B, e nel residuo timico e in altri tessuti per le cellule della linea T, e si sviluppa nell’arco di mesi o anni. Scopo di questo studio è approfondire le modalità della ricostituzione nel primo anno post-trapianto, con attenzione particolare alla ripresa timica e alla ricostituzione del repertorio linfocitario T. I pazienti in esame sono stati seguiti con visite ambulatoriali e prelievi seriati a intervalli definiti, e la ricostituzione è stata studiata mediante l’uso di parametri laboratoristici (dosaggio delle concentrazioni cellulari mediante citofluorimetria, analisi dei TRECs mediante digital PCR) e clinici (insorgenza di GvHD, riattivazione di CMV) per studiare le modalità con cui questi fattori agiscono e interagiscono tra di loro

Impatto sul danno mucosale di diversi regimi chemioterapici valutato con ecografia bedside: uno studio su 213 casi di Leucemia Mieloide Acuta

Introduzione: L’enterocolite del paziente neutropenico(NEC) è una complicanza potenzialmente letale riportata nei pazienti affetti da leucemia mieloide acuta (AML)sottoposti a chemioterapia (CHT).La terapia intensiva di induzione e consolidamento può danneggiare la mucosa intestinale portando a un episodio di NEC (NECe). La mortalità riportata per NEC può arrivare fino al 30-60%. Una diagnosi precoce guidata da ecografia e un trattamento tempestivo possono migliorare sostanzialmente la sopravvivenza. Una preoccupazione emergente a livello mondiale è la colonizzazione intestinale da parte di batteri multiresistenti, specialmente quando i pazienti sono esposti a regimi di chemioterapia potenzialmente correlati al danno mucosale. Metodi: Nel nostro studio abbiamo reclutato prospetticamente tutti i pazienti con AML ricoverati nel nostro reparto di Ematologia per ricevere chemioterapia intensiva di induzione e consolidamento e che hanno sviluppato neutropenia da chemioterapia(CHTN).Risultati e discussione: Complessivamente, abbiamo reclutato N=213 pazienti dal 2007a marzo 2023. Abbiamo registrato N=465 episodi di neutropenia (CHTN)e N=42NECe(incidenza del 9,0%). Lo scopo del nostro studio era valutare quali regimi di chemioterapia fossero più associati a NEC. Abbiamo riscontrato che ALM1310, seguito da 7 + 3 (daunorubicina), 7 + 3 (idarubicina), 5 + 3 + 3 (citarabina, etoposide,idarubicina) e AML1310 (consolidamento) erano associati a un'incidenza statisticamente più alta di NEC. Non abbiamo riscontrato episodi di NEC in pazienti trattati con CPX-351, 5 + 2 (citarabina, idarubicina) e citarabina ad alte dosi. Abbiamo quindi ipotizzatoche la citarabina potrebbe determinare danni mucosali quando associata a un'antracicilina ma non se somministrata da sola o come formulazione liposomiale della combinazione daunorubicina/citarabina. Descriviamo anche la mortalità da NEC, i sintomi alla diagnosi, i siti intestinali coinvolti e il significatoprognostico dell'ispessimento della parete intestinale

Relapsed/Refractory Chronic Lymphocytic Leukemia Patients Treated with Fixed Duration Venetoclax-Rituximab: Assessment of Response with Ultrasound, and Relationship with Minimal Residual Disease

A fixed duration of venetoclax-rituximab (VenR) resulted in a significant benefit of both PFS and in the attainment of an undetectable minimal residual disease (uMRD) compared with bendamustine-rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. The 2018 International Workshop on CLL guidelines, outside the context of clinical trials, suggested ultrasonography (US) as a possible imaging technique to evaluate visceral involvement, and palpation to evaluate superficial lymph nodes (SupLNs). In this real-life study we prospectively enrolled N = 22 patients. Patients were assessed by US, to determine nodal and splenic response in R/R CLL patients treated with a fixed duration VenR. We found an overall response rate, complete remission, partial remission, and stable disease, of 95.4%, 68%, 27.3%, and 4.5%, respectively. Responses were also correlated with risk categories. The time to response, and the time to clearance of the disease in the spleen, in abdominal LN (AbdLNs), and in SupLNs were discussed. Responses were independent from LN size. The correlation between response rate with MRD were also investigated. US allowed to detect a substantial CR rate correlated with uMRD

Prospective study on the impact of BEAM versus FEAM conditioning on occurrence of neutropenic enterocolitis and on transplant outcome in lymphoma patients

Introduction: Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant (ASCT) in lymphoid malignancies. During BCNU shortages, some centers switched to fotemustine-substituted BEAM (FEAM). Neutropenic enterocolitis (NEC) is a life-threatening complication occurring after intestinal mucosa damage related to intensive chemotherapy. NEC mortality may be up to 30%-50%. In our study, we compared NEC incidence, symptoms, mortality, and transplant outcome in terms of overall survival (OS) and progression-free survival (PFS) in the BEAM vs. FEAM groups. Furthermore, we compared the cost of hospitalization of patients who did vs. patients who did not experience a NEC episode (NECe). Methods: A total of 191 patients were enrolled in this study (N = 129 and N = 62 were conditioned with BEAM and FEAM, respectively). All patients received bed-side high-resolution ultrasound (US) for NEC diagnosis. Results and discussion: NEC incidence and NEC-related mortality were similar in the BEAM and FEAM groups (31% and 40.3%, p = 0.653, and 5% and 8%, p = 0.627, respectively). At a median follow-up of 116 months, no difference was noted between BEAM vs. FEAM groups in terms of OS and PFS (p = 0.181 and p = 0.978, respectively). BEAM appeared equivalent to FEAM in terms of NEC incidence and efficacy. The high incidence of NEC and the low mortality is related to a timely US diagnosis and prompt treatment. US knowledge in NEC diagnosis allows to have comparable days of hospitalization of patients NECpos vs. patients NECneg. The cost analysis of NECpos vs. NECneg has been also performed

Evaluation of Circulating Endothelial Cells (CECs) As Marker of Endothelial Damage in Allo-Transplanted Patients at High Risk of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS): The Cecinvod Study

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially fatal complication after allogeneic stem cell transplantation (alloSCT). Identifying a predictive biomarker for VOD has been challenging. Since endothelial injury is considered one of the main pathogenic factors for VOD onset, with the CECinVOD prospective study we aimed to evaluate Circulating Endothelial Cells (CEC) in allo-transplanted patients (pts) at higher risk to develop VOD. From October 2020 to November 2022, 150 pts have been enrolled in the CECinVOD study from 11 Italian Bone Marrow Transplantation Units. All pts must be older than 18 years and undergoing myeloablative alloSCT. CECs were detected using the CellSearch system, the FDA-approved immunomagnetic selection approach incorporating ferrofluid nanoparticles (anti CD146) and fluorophore-labelled antibodies (anti CD105, CD45 and DAPI). CEC were defined as CD146+, CD105+, DAPI+ and CD45-. CEC were collected at the following timepoints: before conditioning regimen (T0), at the end of conditioning regimen and before alloSCT (T1), at the time of neutrophils engraftment (T2), and 7-10 days after engraftment (T3). In pts who developed VOD, additional timepoints were collected as follows: at any time of suspected or proven VOD onset (T4), and then weekly during Defibrotide treatment (T5-T8). SOS/VOD was defined according to the 2016 European Group for Blood and Marrow Transplantation criteria. Pts' main characteristics are summarized in Table 1. Six out of 150 pts (4%) developed VOD during the follow up (4 “severe”, and 2 “very severe”). All pts were treated with Defibrotide, obtaining a complete remission in 5 of them, while 1 pt died due to VOD complications. Pts receiving TBI-based regimen were more likely to develop VOD compared to those receiving Treosulfan (10 to 14 g/m2) or Busulfan ev (9.6 to 12.8 mg/kg) (p 0.08). Similarly, higher baseline levels of bilirubin were associated with a higher incidence of VOD (p 0.08). Considering the CECs analysis, 615 samples were evaluated. At the enrollment, CECs levels were not related with any of clinical characteristics analyzed, except for the number of previous treatments. Indeed, those pts with 2 or more previous lines of treatments had higher levels of CECs (OR=0.53; p<0.001). Considering the different timepoints, conditioning regimen and alloSCT result in higher levels of CECs. Thus, CEC were higher at T1 than at T0 (p 0.02), as well as they were even higher at T2 than at T1 (p<0.0001) (Fig.1). Conversely, no significant differences have been observed between T3 and T2. No other clinical characteristic was correlated with CEC counts at the different timepoints. Pts who developed VOD had higher median levels of CEC at all the timepoints analyzed, but this difference has not achieved statistical significance, probably due to the low number of pts in the VOD group. At VOD onset, the pts always had an increase in CEC levels compared with the previous timepoint. After defibrotide treatment, the CEC levels increased in the first week, while they progressively decreased during the VOD treatment (T6 and T7, -50,7% and -71,5%, respectively). Recently, another endothelial activation marker has been considered: the Easix score. We didn't find any relationship between the Easix score at transplant and the VOD onset, even if a trend may be observed. We also investigated whether the CEC levels may be related with Easix score, but we didn't find any relationship at each timepoint. Interestingly, in a subgroup of pts CECs have been observed as a cluster of multiple cells. This data is firstly described in allo-SCT. Its functional significate remains unclear, but we found a relationship between CECs cluster and the number of CECs (p < 0.001). The incidence of VOD in our prospective study was low with respect to the one reported in the literature. This can be explained by the changes in alloSCT from the past (better selection of the pts, lower use of TBI, higher use of reduced intensity regimen) and the retrospective nature of most of the previous reports. We show that CECs can be considered reliable marker of endothelial damage in alloSCT pts, highlighting the impact of previous treatments, the conditioning regimen, and allo-SCT itself. Increased CEC level may be helpful to confirm VOD diagnosis, as well as their monitoring may be useful to evaluate the response to the treatment for VOD

Additional file 28 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 28: Table S18. Sex-participation association of the variants with significant sex-specific lipid results

Additional file 27 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 27: Table S17. Sex-stratified effect sizes in UK Biobank considering all individuals or only those not on cholesterol lowering medications