Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06.

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).

Baseline PET as prognostic index in diffuse large B-cell lymphoma and grade IIIb follicular lymphoma: a retrospective study of a single-center experience.

BACKGROUND: International guidelines support performing baseline positron emission tomography (PET) in lymphoma. Metabolic tumor volume (MTV) measurement has been proposed as a good measurement of disease burden. We investigated if MTV at baseline PET can be predictive of complete response (CR) to first line standard chemotherapy in diffuse large B-cell lymphoma (DLBCL) and in follicular lymphoma (FL) grade IIIb. METHODS: We retrospectively analyzed data on 54 consecutive patients with DLBCL and FL grade IIIb treated in our institution. Dedicated software automatically estimated the SUVmax of the most active lesion and the MTV of the entire lesion burden using an isocontour threshold method set at 42% (MTV42) and 28% (MTV28) of the SUVmax. In addition, the ratio value (MTV28/MTV42) was calculated. Every group of lesions was evaluated separately. All patients were treated with R-CHOP-21. We performed a univariate and a multivariate logistic regression analysis to explore any possible association between PET parameters and CR. RESULTS: At the univariate logistic regression analysis, patients with a MTV28 lower than the median value (173.1) had an odds ratio (OR) of 4 (95% CI: 0.94-16.9) of obtaining a CR in comparison to patients with a MTV 28 higher than the median value; patients with a MTV42 lower than the median value (i.e. 85.6) had an OR of 3.63 (95% CI: 0.85-15.34) of obtaining a CR in comparison to patients with a MTV 42 equal or higher than the median value. Using MTV28/MTV42 value with median as cut-off instead of MTV28, patients with a MTV28/MTV42 lower than the median value (i.e. 1.81) had an OR of 4.26 (95% CI: 0.72-25.07) and of 7.54 (95% CI: 0.70-80.91) of obtaining a CR in comparison to patients with a MTV28/MTV42 equal or higher than the median value in the two models, respectively. CONCLUSIONS: The results of our study suggest that MTV could be a useful tool to predict response to R-CHOP in patients affected with DLBCL and FL grade IIIb and that a multi-parameters evaluation should be considered.

sRAGE and early signs of cardiac target organ damage in mild hypertensives.

BACKGROUND: Soluble Receptor for Advanced Glycation End Products (sRAGE) may be considered a marker inversely related to inflammation and its participation has been established in patients with advanced atherosclerotic vascular diseases. However, it is still unknown whether sRAGE reduction could be early metabolic change in the first stage of hypertension and initial hypertension-associated cardiac damage. We sought to determine the sRAGE values in otherwise healthy, untreated and recently diagnosed mild hypertensives and evaluate their association with blood pressure (BP) values, metabolic parameters, and with subclinical initial signs of cardiac target organ damage (TOD). METHODS: sRAGE were measured in 100 hypertensive and 100 normotensive subjects matched for age, gender and body mass index (BMI), submitted to a clinic visit and both ambulatory BP monitoring and echocardiography to determine the presence of initial cardiac TOD (presence of signs of left ventricular hypertrophy: left ventricular mass indexed for height2.7 (LVMi) > 48 g/m2.7 for men and > 44 g/m2.7 for women and/or increased left atrial volume 4-chamber indexed for body surface area (LAVi) > 34 ml/m2). RESULTS: sRAGE levels were similar between hypertensive and normotensive subjects and were not significantly correlated with office and 24-h BPs values. However, when subgrouping the hypertensive patients in Hyp-TOD and Hyp-withoutTOD, sRAGE was found to be different among the three groups (p = 0.030), being lower in the Hyp-TOD group than the values of both Hyp-withoutTOD (p = 0.038) and normotensives (p = 0.038). In hypertensive patients sRAGE was negatively related with both LVMi (r = - 0.239, p = 0.034) and LAVi (r = - 0.315, p = 0.005) and was independently related to cardiac TOD also in multivariable analysis. CONCLUSIONS: In this population of mild hypertensives, low circulating sRAGE may be a very early marker of initial TOD, suggesting the possible participation of oxidative stress in initial cardiac changes in human hypertension.

Recurrent ETNK1 mutations in atypical chronic myeloid leukemia.

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.

Relationship between regulatory T cells subsets and lipid profile in dyslipidemic patients: a longitudinal study during atorvastatin treatment.

BACKGROUND: The CD4+ T-lymphocytes and their subtype CD4 + CD25(high)FoxP3+ regulatory T cells are receiving growing interest as major regulators of atherogenesis. We sought to investigate 1) whether the CD4 + cell subsets were expressed differently in dyslipidemic patients (Pts) and healthy subjects (HS) and 2) whether atorvastatin treatment could be associated in-vivo and in-vitro with cell changes in expression and functional response. METHODS: CD4+ subsets frequency (CD4 + CD25(high)FoxP3+, CD4 + CD25-FoxP3+) and mRNA expression for FoxP3, IL-10 and TGF-ß were evaluated in 30 consecutive Pts at baseline and after a 3-month atorvastatin therapy, and in 17 HS. RESULTS: The % of CD4 + cells did not differ between HS and Pts. The % of CD4 + CD25(high)FoxP3+ was higher in Pts than HS and did not change during treatment. The CD4 + CD25-FoxP3+ cells were similar between the two groups and were lower in Pts at visit 2. Cytokine expression and FoxP3 did not differ in HS and Pts and no substantial change was observed during treatment. At visit 1, CD4 + CD25(high)FoxP3+ cells were significantly correlated with both total-cholesterol (r = 0.570, P = 0.0002), LDL-cholesterol (r = 0.715, P = 0.0001), Apolipoprotein B (r = 0.590, P = 0.0001). In-vitro atorvastatin (up to 5 µM) failed to induce any significant modulation of cell functions. CONCLUSION: CD4 + CD25(high)FoxP3+ regulatory cells seem to be over-stimulated in the early pre-clinical phase of atherosclerosis and a relationship exists between their frequency and circulating lipids. A potential immuno-modulation by statin treatment is not achieved through a normalization in peripheral CD4 + cell subsets.

Direct oral anticoagulants in patients with a left-sided bioprosthetic heart valve: a systematic review and meta-analysis.

To compare the efficacy/effectiveness and safety of DOACs versus VKAs in patients with a previously and newly surgically implanted BHV with or without AF. A systematic search on MEDLINE and EMBASE was performed till November 2022. Treatment effects were estimated with relative risk (RR) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed with the I2 statistic. Four randomized controlled trials (RCTs), 2 subgroup analysis from ARISTOTLE and ENGAGE-AF-TIMI 48 and 4 observational studies were included for a total of 5808 patients, 1893 on DOACs and 3915 on VKAs. AF prevalence was 98.28%. In the overall analysis, DOACs vs VKAs were associated with a RR for stroke/transient ischemic attack (TIA)/systemic embolism (SE) of 0.63 (95% CI 0.51-0.79; I2 = 0%) and a RR of major bleeding of 0.50 (95% CI 0.39-0.63; I2 = 0%) in a median follow-up of 19 months (IQR 4.5-33.4). In the 3 RCTs (DAWA, RIVER, ENAVLE), DOACs vs VKAs were associated with a RR of stroke/TIA/SE and major bleeding of 0.38 (95% CI 0.13-1.58, I2 = 0%) and of 0.68 (95% CI 0.32-1.44; I2 = 5%) respectively. In patients randomized during the first three months from valve surgery, DOACs vs VKAs were associated with a RR of stroke/TIA/SE and major bleeding of 0.54 (95% CI 0.14-2.08; I2 = 0%) and of 0.76 (95% CI 0.05-10.72; I2 = 66%). In previously implanted BHV patients with AF, DOACs showed a risk-benefit profile at least comparable to VKAs. DOACs showed a similar, even if underpowered, risk-benefit profile during the first three months after BHV implantation prevalently in patients with AF.

Body mass index (BMI) influence on Cetuximab-induced antibody-dependent cellular cytotoxicity in advanced colon cancer.

To date, we do not know if the excess of the body mass index (BMI) improves or worsens the outcomes in colorectal cancer treatment, and the correlation between BMI and prognosis remains unclear. A recent study in vitro showed a significant negative correlation between BMI and Cetuximab-induced antibody-dependent cellular cytotoxicity. On these bases, we tried to analyze the potential correlation between BMI and survival in patients affected by metastatic colorectal cancer (mCRC) and treated with Cetuximab. Retrospective data were collected from 132 patients affected by mCRC treated with Cetuximab in monotherapy or association with chemotherapy between January 2007 and October 2019. The cohort of patients was divided into different groups according to the World Health Organization (WHO) BMI classification: underweight (BMI < 18.59), normal weight (BMI 18.5-24.9,) overweight (BMI 25-29.9), and obese (BMI > 30), and we observed the influence of BMI on survival and treatment response. Patients with BMI ≥ 25 had statistically significantly better survival than patients BMI < 25 (19 vs 10 months, p = 0.025). Dividing the sample into the four WHO BMI categories, the best survival rates were seen in the overweight and obese subgroups (18 and 26 months respectively, p < 0.01). The multivariate analysis confirmed BMI as the only parameter able to influence survival. No correlation between BMI and treatment response was seen between BMI ≥ 25 and BMI ≤ 24 groups (p = 0.14). Our experience suggests that mild obese and overweight patients treated with Cetuximab could experience a better survival. We also observed that among normal weight, overweight, and mild obese patients, there is a better response to immunochemotherapy in comparison with underweight patients, but this difference does not reach a significative statistical value.

High frequency of BCL2 gene rearrangement-negative follicular lymphoma in northwestern Italy.

BCL2 rearrangement is reported to be an early pathogenetic event in follicular lymphoma (FL) and it is considered as a reliable marker in the follow up of the disease. We aimed to investigate the frequency of BCL2 rearrangement in FLs from northwestern Italy, to evaluate their clinicopathological features, and to investigate alternative genetic aberrations in BCL2-negative FLs. We collected a series of 76 consecutive FLs diagnosed between 2013 and 2016. All lymphomas underwent histopathological review. Interphasic fluorescent in situ hybridization (FISH) was performed with break apart probes targeting BCL2, IGH, BCL6 and MYC on paraffin embedded (PE) and fresh frozen (FF) specimens. 1p36 region and p53 locus in BLC2-negative cases were investigated using dual color probes. Karyotype analysis was available in a subset of cases. BCL2 rearrangements were detected in 39 cases (51,3%). Of the remaining 37, 6 showed IGH rearrangement, and were further tested: 1 showed variant BCL2 translocation, 1 had BCL6 rearrangement, and the other 4 were negative for further gene rearrangements. FISH on FF specimens detected small BCL2+ clones in cases otherwise categorized as BCL2-. 1p36 and p53 deletion were observed in 1 and 8 BCL2- FLs, respectively. Karyotype analysis documented 3q, 1p and BCL6 alternative abnormalities in 3 cases. In conclusion, BCL2 rearrangement is not a constant finding in FL, its frequency being probably affected by geographical factors. Thus, it should not be considered as a reliable molecular marker in the follow up of the disease, unless it is found to be present at the initial diagnosis of FL. Alternative genetic aberrations exist in BCL2-negative cases.

Current management of cancer-associated venous thromboembolism in patients with thrombocytopenia: a retrospective cohort study.

Optimal management of venous thromboembolism (VTE) in cancer patients with thrombocytopenia is uncertain. We described current management and clinical outcomes of these patients. We retrospectively included a cohort of cancer patients with acute VTE and concomitant mild (platelet count 100,000-150,000/mm3), moderate (50,000-99,000/mm3), or severe thrombocytopenia (< 50,000/mm3). Univariate and multivariate logistic regression analyses explored the association between different therapeutic strategies and thrombocytopenia. The incidence of VTE and bleeding complications was collected at a 3-month follow-up. A total of 194 patients of whom 122 (62.89%) had mild, 51 (26.29%) moderate, and 22 (11.34%) severe thrombocytopenia were involved. At VTE diagnosis, a full therapeutic dose of LMWH was administered in 79.3, 62.8 and 4.6% of patients, respectively. Moderate (OR 0.30; 95% CI 0.12-0.75), severe thrombocytopenia (OR 0.01; 95% CI 0.00-0.08), and the presence of cerebral metastasis (OR 0.06; 95% CI 0.01-0.30) were independently associated with the prescription of subtherapeutic LMWH doses. Symptomatic VTE (OR 4.46; 95% CI 1.85-10.80) and pulmonary embolism (OR 2.76; 95% CI 1.09-6.94) were associated with the prescription of full therapeutic LMWH doses. Three-month incidence of VTE was 3.9% (95% CI 1.3-10.1), 8.5% (95% CI 2.8-21.3), 0% (95% CI 0.0-20.0) in patients with mild, moderate, and severe thrombocytopenia, respectively. The corresponding values for major bleeding and mortality were 1.9% (95% CI 0.3-7.4), 6.4% (95% CI 1.7-18.6), 0% (95% CI 0.0-20.0) and 9.6% (95% CI 5.0-17.4), 48.2% (95% CI 16.1-42.9), 20% (95% CI 6.6-44.3). In the absence of sound evidence, anticoagulation strategy of VTE in cancer patients with thrombocytopenia was tailored on an individual basis, taking into account not only the platelet count but also VTE presentation and the presence of cerebral metastasis.

A randomized comparison of caspofungin versus antifungal prophylaxis according to investigator policy in acute leukaemia patients undergoing induction chemotherapy (PROFIL-C study).

BACKGROUND: Invasive fungal infections (IFIs) are considered a major problem among patients undergoing acute leukaemia (AL) induction treatment. PROphylaxis of Fungal invasive Infections in Leukaemia-Caspofungin (PROFIL-C) is a multicentre study aiming to assess the comparative yield of using caspofungin versus standard policy (SP) regimens and the overall impact of IFI in routine clinical care conditions. METHODS: All AL patients receiving IFI prophylaxis according to local SP were prospectively included in the study by Northern Italy Leukaemia Group (NILG) centres. To allow the comparison of caspofungin versus SP regimens as prophylaxis strategies, caspofungin treatment was assigned via a centralized randomized procedure. The study was registered at http://www.clinicaltrial.gov (NCT00501098). RESULTS: Over a 2 year period, 175 patients were included. The overall incidence of IFI was 32/175 (18.3%) [10/175 (5.7%) probable/proven and 22/175 (12.6%) possible], with no statistically significant differences between caspofungin-based versus SP-based regimens [overall: 15/93 (16.1%) versus 17/82 (20.7%), relative risk (RR) 0.78, 95% confidence interval (CI) 0.42-1.46; probable/proven: 7/93 (7.5%) versus 3/82 (3.7%), RR 2.06, 95% CI 0.55-7.7; possible: 8/93 (8.6%) versus 14/82 (17.1%), RR 0.5, 95% CI 0.22-1.14]. Only one IFI-related death was recorded (10%). CONCLUSIONS: The incidence and mortality of IFI were lower than expected in this strictly sequential cohort representative of the routine care in the NILG network. The efficacy and safety of caspofungin were similar to other prophylactic regimens.

JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis.

Recent studies suggested that JAK2V617F mutation is frequent in patients with splanchnic vein thrombosis (SVT) but not in patients with other venous thromboembolic events (VTE). However, whether screening for the JAK2V617F mutation in VTE patients is justified remains unclear. Therefore, we performed a systematic review to assess the frequency of JAK2 mutation in VTE patients and the role of JAK2V617F mutation in the diagnosis of myeloproliferative neoplasms. MEDLINE and EMBASE databases were searched. Two reviewers independently performed study selection and extracted study characteristics. Pooled odds ratios of case-control studies and weighted mean proportion of the prevalence of JAK2V617F mutation of uncontrolled series were calculated. Twenty-four studies involving 3123 patients were included. Mean prevalence of JAK2 mutation was 32.7% (95% confidence interval, 25.5%-35.9%) in SVT patients. JAK2 mutation was associated with increased risk of SVT (odds ratio, 53.98; 95% confidence interval, 13.10-222.45). Mean prevalence of JAK2 mutation in other VTE patients was low (range, 0.88%-2.57%). Presence of JAK2V617F mutation in SVT patients was associated with a subsequent diagnosis of myeloproliferative neoplasm in many patients. JAK2 mutation is strongly associated with SVT, and routine screening of JAK2 mutation appears to be indicated in these patients.

Prevention of anthracycline-induced cardiotoxicity: a systematic review and meta-analysis.

Anthracyclines are extensively used in oncologic patients, in particular for breast cancer and hematological malignancies. Cardiac injury is a potentially dangerous side effect of these drugs. In this systematic review, we analyzed published randomized controlled trials (RCTs) to assess if potential cardioprotective drugs (i.e., renin-angiotensin-aldosterone system [RAAS] blockers and ß-blockers) may prevent heart damage by anthracyclines. Studies were identified by electronic search of MEDLINE and EMBASE database until August 2020. The impact of cardioprotective drugs to prevent anthracyclines-induced cardiac injury was expressed as mean difference (MD) or odds ratio (OR) and 95% confidence intervals (95% CI). Statistical heterogeneity was assessed with the I2 statistic. Twelve RCTs for a total of 1.035 cancer patients treated with anthracyclines were included. RAAS blockers, ß-blockers, and aldosterone antagonists showed a statistically significant benefit in preventing left ventricular ejection fraction (LVEF) reduction (MD 3.57, 95% CI 1.04, 6.09) in 11 studies. A non-statistically significant difference was observed in preventing E/A velocity decrease (MD 0.09, 95% CI 0.00, 0.17; 9 studies), left ventricular end-systolic diameter (LVESD) increase (MD - 0.88, 95% CI, - 2.75,0.99; 6 studies), left ventricular end-diastolic diameter (LVEDD) increase (MD -0.95, 95% CI - 2.67,0.76; 6 studies), and mitral A velocity decrease (MD - 1.42, 95% CI - 3.01,0.17; 4 studies). Heart failure was non-significantly reduced in the cardioprotective arm (OR 0.31, 95% CI 0.06, 1.59; 5 studies). Hypotension was non-significantly increased in the cardioprotective arm (OR 3.91, 95% CI 0.42, 36.46, 3 studies). Cardioprotective drugs reduce anthracycline-induced cardiac damage as assessed by echocardiographic parameters. The clinical relevance of this positive effect is still to be defined.

Negative impact of high body mass index on cetuximab-mediated cellular cytotoxicity against human colon carcinoma cells.

This study assessed the relationship between the ability of Natural Killer (NK) cells to activate antibody-dependent cellular cytotoxicity against human HT29 colorectal cancer cells exposed to cetuximab and the body mass index of the human subjects from whom the NK cells had been obtained. NK cells obtained from 73 human donors were co-incubated with HT-29 human colon cancer cells in the presence or absence of cetuximab. Antibody-dependent cellular cytotoxicity was assessed by measuring LDH release. A significant negative correlation was observed between body mass index and cetuximab-induced antibody-dependent cellular cytotoxicity. NK cells obtained from subjects who were overweight or with obesity were less efficient in killing cetuximab-treated HT29 cells than those derived from normal weight donors. Our results suggest that the success of cetuximab-containing regimens might be impaired in overweight and obese patients with colorectal cancer.

Composite follicular lymphoma and "early" (in situ and mantle zone growth pattern) mantle cell neoplasia: A rare entity with peculiar cytogenetic and clinical features.

Composite follicular lymphoma (FL) and mantle cell lymphoma (MCL) is rare and not fully characterized from a genetic and clinicopathological point of view. We report a composite lymphoma (CL) in which a G1-2 FL was associated with an in situ mantle cell neoplasia (ISMCN) and a mantle zone growth pattern (MZGP) MCL, followed-up for six years after the first diagnosis, until the exitus of the patient. We performed a comprehensive immunohistochemical study and a detailed cytogenetic analysis, including conventional karyotyping, SKY FISH, FISH on metaphases and interphasic separated nuclei, and FISH on histological sections. The study was completed by the review of the 13 published composite FL and MCL. Our results show that this entity generally behaves like an indolent lymphoma, with the outcome of patients driven by the progression of the FL component. The MCL component generally does not evolve in an aggressive disease. Indeed, half of the cases present exclusively ISMCN. In our case, mantle cell neoplasia at diagnosis was represented by ISMCN and MZGP MCL and it was characterized by a simple karyotype, with t(11;14) as the sole cytogenetic abnormality. This cytogenetic aspect well correlates with the indolent behavior of the mantle cell component. Conversely, the complex karyotype of the FL component was associated with disseminated disease that influenced patient's outcome. Finally, we suggest that not only ISMCN, but also isolated MZGP MCL, may be considered as lesions with low potential of transformation in an aggressive MCL.

Right ventricular remodelling in mild hypertensive patients: role of left ventricular morpho-functional parameters.

Previous studies suggested that hypertensive patients with left ventricular (LV) hypertrophy display right ventricular (RV) remodelling. Few data are available about RV remodelling in naive hypertensives without severe cardiac organ damage. Our aim was to evaluate the relationship between RV and LV morpho-functional parameters in never-treated patients with grade 1 hypertension and whether central blood pressure (CBP), inflammatory and metabolic parameters are potentially associated with RV remodelling. 150 never-treated subjects without evidence of diabetes or other cardiovascular diseases were enrolled in our study. We recruited 100 patients with mild hypertension (twenty-four hours blood pressure (24 h BP) ≥ 130/80 mmHg) and 50 normotensive subjects matched for gender, age and body mass index. To estimate the LV/RV parameters, we performed echography as well as arterial tonometry to assess pulse wave analysis/velocity (PWA/PWV). We found 24 h BP, CBP and PWV were higher in hypertensive patients than in normotensives. In addition, LV mass index was higher in hypertensives, and greater RV free wall thickness was observed (5.3 ± 1.4 vs 4.6 ± 1.2 mm, P = 0.02). RV thickness correlated with interventricular septum (IVS), systolic CBP and RV E' (r = 0.50, P = 0.0001, r = 0.30, P = 0.003, r = -0.24, P = 0.015); linear regression analysis showed a correlation with only IVS (ß = 0.39, P = 0.001). RV E' was correlated with IVS, LV E' and systolic CBP (r = -0.35, P = 0.0001, r = 0.25, P = 0.012, r = -0.24, P = 0.019); the correlation with IVS and LV E' (ß = -0.310, P = 0.001; ß = 0.27, P = 0.004) was confirmed by linear regression analysis. Our study shows RV remodelling is mostly correlated with IVS thickness, supporting the ventricular interdependence hypothesis.

High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG).

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.