Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

EFAST: The evolution of FAST in politrauma

EFAST (Extended Focused Assessment with Sono - graphy for Trauma) is a bedside US examination, performed in patients victims of trauma directly from intensivist. The examen duration should be <5 minutes without interference with resuscitation manoeuvres. It should answer to precise questions (is there air? is there fluid?). EFAST examen consists of 6 US windows, 2 thoracic and 4 abdominal, by researching on 2 simple and reliable US signs: 1) the pleural “gliding sign” for the diagnosis of PNX; 2) the presence of an “anechoic area” suggesting a blood effusion. EFAST finds its particular employ in unstable patients, while for hemodinamically stable patients CT scan must be performed to detect lesions of abdominal organs and retroperitoneal injuries. In stable patients with normal CT scan, the EFAST exam could be employed in the follow-up. The EFAST can be performed in pregnancy, providing even the possibility to evaluate foetus

The ultrasonographic deep sulcus sign in traumatic pneumothorax

A series of 186 patients with blunt chest trauma was studied with transthoracic ultrasonography to diagnose pneumothorax and to evaluate its size and location. The results were compared with bedside chest radiography and spiral CT scan. The prevalence of pneumothorax on CT scan was 56/186 (30.1%). Pneumothorax was proven on radiography in 30/56 cases without false positive results: "radiographic deep sulcus sign" was evident in 3/29 cases, 26/29 cases being occult. The ultrasound study demonstrated the presence of pneumothorax in 55/56 patients: one occult pneumothorax was missed and no false positive results were observed. The CT scan differed of +/-2.3 cm (range 1-5 cm) from the US study in evaluating size and location of pneumothorax. In conclusion, ultrasound study may detect occult pneumothorax undiagnosed by standard plain radiography. It reflects accurately the extent of pneumothorax if compared with CT scan, outlining the "ultrasonographic deep sulcus sign" on anterior chest wall

Lung ultrasound in COVID-19: clinical correlates and comparison with chest computed tomography

Lung ultrasound (LUS) and chest computed tomography (chest CT) are largely employed to evaluate coronavirus disease 2019 (COVID-19) pneumonia. We investigated semi-quantitative LUS and CT scoring in hospitalized COVID-19 patients. LUS and chest CT were performed within 24 h upon admission. Both were analyzed according to semi-quantitative scoring systems. Subgroups were identified according to median LUS score. Patients within higher LUS score group were older (79 vs 60 years, p<0.001), had higher C-reactive protein (CRP) (7.2 mg/dl vs 1.3 mg/dl, p<0.001) and chest CT score (10 vs 4, p=0.027) as well as lower PaO2/FiO2 (286 vs 356, p=0.029) as compared to patients within lower scores. We found a significant correlation between scores (r=0.390, p=0.023). Both LUS and CT scores correlated directly with patients age (r=0.586, p<0.001 and r=0.399, p=0.021 respectively) and CRP (r=0.472, p=0.002 and r=0.518, p=0.002 respectively), inversely with PaO2/FiO2 (r=-0.485, p=0.003 and r=-0.440, p=0.017 respectively). LUS score only showed significant correlation with hs-troponin T, NT-pro-BNP, and creatinine (r=0.433, p=0.019; r=0.411, p=0.027, and r=0.497, p=0.001, respectively). Semi-quantitative bedside LUS is related to the severity of COVID-19 pneumonia similarly to chest CT. Correlation of LUS score with markers of cardiac and renal injury suggests that LUS might contribute to a more comprehensive evaluation of this heterogeneous population

ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells

B-cell precursor-acute lymphoblastic leukemia modulates the bone marrow (BM) niche to become leukemia-supporting and chemo-protective by reprogramming the stromal microenvironment. New therapies targeting the interplay between leukemia and stroma can help improve disease outcome. We identified ActivinA, a TGF-\u3b2 family member with a well-described role in promoting several solid malignancies, as a factor favoring leukemia that could represent a new potential target for therapy. ActivinA resulted over-expressed in the leukemic BM and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells. Moreover, MSCs isolated from BM of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA compared to their normal counterparts. The pro-inflammatory leukemic BM microenvironment synergized with leukemic cells to induce stromal-derived ActivinA. Gene expression analysis of ActivinA-treated leukemic cells showed that this protein was able to significantly influence motility-associated pathways. Interestingly, ActivinA promoted random motility and CXCL12-driven migration of leukemic cells, even at suboptimal chemokine concentrations, characterizing the leukemic niche. Conversely, ActivinA severely impaired CXCL12-induced migration of healthy CD34+ cells. This opposite effect can be explained by the ability of ActivinA to increase intracellular calcium only in leukemic cells, boosting cytoskeleton dynamics through a higher rate of actin polymerization. Moreover, by stimulating the invasiveness of the leukemic cells, ActivinA was found to be a leukemia-promoting factor. Importantly, the ability of ActivinA to enhance BM engraftment and the metastatic potential of leukemic cells was confirmed in a xenograft mouse model of the disease. Overall, ActivinA was seen to be a key factor in conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche

Monocyte–macrophage polarization and recruitment pathways in the tumour microenvironment of B‐cell acute lymphoblastic leukaemia

Summary B‐cell acute lymphoblastic leukaemia (B‐ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia‐supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B‐ALL development. Immunohistochemistry analyses showed that CD68‐expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2‐like markers CD163 and CD206. Furthermore, the "non‐classical" CD14 CD16 monocyte subset, expressing high CX3CR1 levels, was significantly increased in B‐ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia‐related inflammatory mediators. C5a, a macrophage chemoattractant and M2‐polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B‐ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy

Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer

Tumor-associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa). The mechanistic basis of this correlation and therapeutic strategies to target TAMs in PCa remain poorly defined. Here, single-cell RNA sequencing was used to profile the transcriptional landscape of TAMs in human PCa, leading to identification of a subset of macrophages characterized by dysregulation in transcriptional pathways associated with lipid metabolism. This subset of TAMs correlates positively with PCa progression and shorter disease-free survival and is characterized by an accumulation of lipids that is dependent on Marco. Mechanistically, cancer cell-derived IL-1β enhances Marco expression on macrophages, and reciprocally, cancer cell migration is promoted by CCL6 released by lipid-loaded TAMs.Moreover, administration of a highfat diet to tumor-bearing mice raises the abundance of lipid-loaded TAMs. Finally, targeting lipid accumulation by Marco blockade hinders tumor growth and invasiveness and improves the efficacy of chemotherapy in models of PCa, pointing to combinatorial strategies that may influence patient outcomes

Abstracts from the 23rd Italian congress of Cystic Fibrosis and the 13th National congress of Cystic Fibrosis Italian Society

Cystic Fibrosis (CF) occurs most frequently in caucasian populations. Although less common, this disorder have been reported in all the ethnicities. Currently, there are more than 2000 described sequence variations in CFTR gene, uniformly distributed and including variants pathogenic and benign (CFTR1:www.genet.sickkids.on.ca/). To date,only a subset have been firmily established as variants annotated as disease-causing (CFTR2: www.cftr2.org). The spectrum and the frequency of individual CFTR variants, however, vary among specific ethnic groups and geographic areas. Genetic screening for CF with standard panels of CFTR mutations is widely used for the diagnosis of CF in newborns and symptomatic patients, and to diagnose CF carrier status. These screening panels have an high diagnostic sensitivity (around 85%) for CFTR mutations in caucasians populations but very low for non caucasians. Developed in the last decade, Next-Generation Sequencing (NGS) has been the last breakthrough technology in genetic studies with a substantial reduction in cost per sequenced base and a considerable enhancement of the sequence generation capabilities. Extended CFTR gene sequencing in NGS includes all the coding regions, the splicing sites and their flankig intronic regions, deep intronic regions where are localized known mutations,the promoter and the 5'-3' UTR regions. NGS allows the analysis of many samples concurrently in a shorter period of time compared to Sanger method . Moreover, NGS platforms are able to identify CFTR copy number variation (CNVs), not detected by Sanger sequencing. This technology has provided new and reliable approaches to molecular diagnosis of CF and CFTR-Related Disorders. It also allows to improve the diagnostic sensitivity of newborn and carrier screeningmolecular tests. In fact, bioinformatics tools suitable for all the NGS platforms can filter data generated from the gene sequencing, and analyze only mutations with well-established disease liability. This approach allows the development of targeted mutations panels with a higher number of frequent CF mutations for the target populationcompared to the standard panels and a consequent enhancement of the diagnostic sensitivity. Moreover, in the emerging challenge of diagnosing CF in non caucasians patients, the possibility of customize a NGS targeted mutations panel should increase the diagnostic sensitivity when the target population has different ethnicities