Choice of Frontline Tyrosine-Kinase Inhibitor and Early Events in Very Elderly Patients With Chronic Myeloid Leukemia in Chronic Phase: A "Campus CML" Study.

OBJECTIVES: The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP-CML patients. METHODS: A retrospective analysis was conducted on 332 CP-CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the "Campus CML" project. RESULTS: Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second-generation TKIs (2G-TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G-TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra-hematologic toxicity (9.5%), with no significant difference between IM and 2G-TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G-TKIs. CONCLUSIONS: IM was in our Centers the preferred frontline therapy for older CP-CML patients, with increasing utilization after the introduction of generic formulations. However, 2G-TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population.

The impact of comorbidity on health-related quality of life in elderly patients with chronic myeloid leukemia.

The primary objective of this study was to investigate whether the presence of comorbidities was associated with a lower health-related quality of life (HRQOL) in elderly patients with chronic myeloid leukemia (CML). A sample of 174 CML patients aged 60 years or above was analyzed. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). A number of pre-selected sociodemographic and disease-related factors were considered as potential confounding factors for the association between comorbidity and HRQOL. Mean age of the 174 patients analyzed was 70 years (range 60-87 years) and 55 % were male. Overall, 111 patients (64 %) reported at least one comorbidity. Analysis stratified by age group category showed a greater proportion of patients with comorbidities in the older sub-group population (≥70 years) compared to younger patients (60 to 69 years). Differences in HRQOL outcomes between patients with no comorbidity at all and those with two or more comorbid conditions were at least twice the magnitude of a clinically meaningful difference in all the physical and mental health scales of the SF-36. In multivariate analysis, after adjusting for key confounding factors, the following scales were significantly lower in those with comorbidity: general health (p < 0.001), bodily pain (p < 0.001), physical functioning (p = 0.002), and vitality (p = 0.002). Assessing comorbidity in elderly patients with CML is important to facilitate identification of those most in need of HRQOL improvements.

Effects of magnesium supplements on blood pressure, endothelial function and metabolic parameters in healthy young men with a family history of metabolic syndrome.

BACKGROUND AND AIMS: Magnesium plays an important role in the modulation of vascular tone and endothelial function and can regulate glucose and lipid metabolism. Patients with hypertension, metabolic syndrome (MetS) and diabetes mellitus (T2DM) have low body magnesium content; indeed, magnesium supplementation has been shown to have a positive effect on blood pressure (BP) and gluco-metabolic parameters. The aim of our study was to evaluate the effect of magnesium supplements on hemodynamic and metabolic parameters in healthy men with a positive family history of MetS or T2DM. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled 8-week crossover trial with a 4 week wash-out period, oral supplements of 8.1 mmol of magnesium-pidolate or placebo were administered twice a day to 14 healthy normomagnesemic participants, aged 23-33 years. The primary endpoint was office BP, measured with a semiautomatic oscillometric device. Secondary endpoints included characteristics of the MetS, namely endothelial function, arterial stiffness and inflammation. Plasma and urinary magnesium were measured in all participants while free intracellular magnesium was measured only in a subsample. There was no significant difference in either systolic and diastolic BP in participants post-magnesium supplementation and post-placebo treatment when compared to baseline BP measurements. Further, the metabolic, inflammatory and hemodynamic parameters did not vary significantly during the study. CONCLUSIONS: Our study showed no beneficial effect of magnesium supplements on BP, vascular function and glycolipid profile in young men with a family history of MetS/T2DM (trial registration at clinicaltrial.gov ID: NCT01181830; 12th of Aug 2010).

Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes.

BACKGROUND AND AIMS: Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of red-ox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events. METHODS AND RESULTS: The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmö Diet and Cancer" (MDC-CVA) study and successively in 17874 participants of the "Malmö Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP. Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females. However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in the MDC-CVA was not significantly different in carriers of different genotypes. CONCLUSIONS: Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events.

Diffuse neoplasms of the pleural serosa.

This study describes the diffuse neoplastic conditions that may affect pleural membranes. These include mesothelioma, the most important and common malignancy of pleural origin, and metastatic involvement by carcinomas, lymphomas and thymomas. On the basis of diagnostic imaging, we identify the distinctive features of pleural involvement by each of these conditions and provide elements enabling accurate differential diagnosis. Finally, we discuss the best diagnostic approach in the case of suspected primary or secondary neoplastic involvement of pleural membranes.

Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure.

Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1,000,000, in Sweden, suggesting that approximately 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.

Conjugated linoleic acid improves airway hyper-reactivity in overweight mild asthmatics.

BACKGROUND: Conjugated linoleic acids (CLA) are naturally occurring fatty acids that have multiple biological properties including the regulation of metabolic, proliferative and immune processes. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of CLA as a dietary supplement in mild asthma. METHODS: This was a prospective, randomized, double-blind, placebo-controlled study. Twenty-eight adult subjects (aged 19-40 years) with mild asthma (FEV(1)>70% predicted) were randomized to CLA 4.5 g/day or placebo for 12 weeks in addition to usual treatment. On average, subjects were overweight with a mean body mass index (BMI) of 27.9 kg/m(2). RESULTS: Subjects in the CLA group had a significant improvement in airway hyperresponsiveness (AHR) at week 12 compared with week 0 [PC(20) 6.6 (2.1) mg/mL vs. 2.2 (0.7) mg/mL; P<0.05]. The CLA group had a significant reduction in weight and BMI compared with placebo and this was associated with a reduction in leptin/adiponectin ratio. There were no differences in systemic cytokine levels, induced sputum cell counts, quality-of-life scores or adverse events. CONCLUSIONS: CLA treatment as an adjunct to usual care in overweight mild asthmatics was well tolerated and was associated with improvements in AHR and BMI.

Computed tomography and thymoma: distinctive findings in invasive and noninvasive thymoma and predictive features of recurrence.

PURPOSE: Our goal was to assess the computed tomography (CT) imaging findings of thymoma and to correlate these features with Masaoka staging system and prognosis. MATERIALS AND METHODS: CT findings of thymoma were analysed in 58 patients who had undergone surgery between January 2002 and September 2007. All cases were classified according to the Masaoka staging system. The presence of various CT findings was correlated with tumour invasiveness and recurrence. In statistical analysis, a p value <0.05 was interpreted as significant. RESULTS: The study found 26 noninvasive thymomas and 32 invasive thymomas. Invasive thymomas were more likely to be greater in size (p<0.01), with lobulated or irregular contours (p<0.02), a necrotic or cystic component (p<0.04), foci of calcification (p<0.05) and heterogeneous contrast enhancement (p<0.01) than were noninvasive thymomas. Disease progression developed in nine of 58 patients. Tumour recurrence and metastasis correlated with greater size (p<0.04), lobulated or irregular contours (p<0.01), complete mediastinal fat obliteration (p<0.01), great vessel invasion (p<0.01) and pleural implants (p<0.02). CONCLUSIONS: CT is useful in differentiating invasive from noninvasive thymomas and plays an important role in evaluating and treating these patients for multimodal therapy with neoadjuvant approaches. Moreover, CT findings may serve as predictors of postoperative recurrence or metastasis.

Solitary fibrous tumor of the lung: three rare cases of intraparenchymal nodules.

Solitary fibrous tumor (SFT) of the pleura usually presents as a peripheral mass, in contact with the surface of the pleura. However, on occasion, it can occur separately from the pleura, in the lung parenchyma. We describe the radiological and imaging features of three SFTs of the lung, diagnosed in our department, with relevant clinical data. The diagnosis of SFT of the lung, although rare, should be considered in a slow-growing solitary lung parenchymal nodule.

The pulmonary nodule: clinical and radiological characteristics affecting a diagnosis of malignancy.

The role of computed tomography (CT) in the diagnosis of the solitary pulmonary nodule (SPN) is constantly expanding. CT helps to detect a growing number of increasingly small lesions, but, as with chest radiography, the primary goal in the evaluation of small pulmonary nodules is to exclude malignancy. Despite the availability of numerous, variously invasive, diagnostic tests, diagnostic accuracy tends to decline as the size of the nodule decreases. The role of the radiologist is therefore to help the clinician determine the most appropriate management strategy by using all available modalities [CT, magnetic resonance (MR) imaging, positron emission tomography (PET)] and evaluating the patient's clinical history and the imaging features leading to a diagnosis of benignity or malignancy. Imaging features include nodule size, margins, calcifications and fatty component, internal features (cavitations, pseudocavitations, air bronchogram, halo sign), as well as advanced techniques for characterisation (growth rate, contrast enhancement) and management (computer-aided diagnosis, Bayesian analysis, neural networks). The aim of this paper is to summarise the approach to pulmonary nodules from the point of view of the radiologist, oncologist and thoracic surgeon.

Clinical application of lung ultrasound in patients with acute dyspnea: differential diagnosis between cardiogenic and pulmonary causes.

This review discusses the usefulness of bedside lung ultrasound in the diagnostic distinction between the various causes of acute dyspnoea in the emergency department, with special attention to the differential diagnosis of pulmonary oedema and exacerbation of chronic obstructive pulmonary disease (COPD). This is made possible by using mid- to low-end scanners and simple acquisition techniques accessible to both radiologists and clinicians. Major advantages include ready availability at the bedside, the absence of ionising radiation, high reproducibility and cost efficiency. The technique is based on the recognition and analysis of sonographic artefacts rather than direct visualisation of the pulmonary structures. These artefacts are caused by the interaction of water-rich structures and air, called comet tails or B-lines. When such artefacts are widely detected on anterolateral transthoracic lung scans, diffuse alveolar-interstitial syndrome can be diagnosed, which is often a sign of acute pulmonary oedema. This condition rules out exacerbation of COPD as the main cause of acute dyspnoea.

[Validation of a screening method for occupational bladder cancer]. / Neoplasie transizionali della vescica di origine professionale: valutazione della accuratezza di un metodo di screening basato su intervista strutturata.

BACKGROUND: Transitional bladder cancer is the most frequent malignant urinary neoplasm. Occupational exposure to aromatic amines and to polycyclic aromatic hydrocarbons are the main risk factors, in addition to cigarette smoking, recurrent inflammatory diseases of the urinary tract, consumption of certain drugs and a positive family history. Nevertheless cases of work-related bladder cancer are poorly identified in Italy. OBJECTIVE: The aim of this study is to assess the screening accuracy of a short structured interview to detect suspected cases of occupational bladder cancer, which may be confirmed in a second step assessment by an occupational physician. METHODS: The study sample consisted of 94 transitional bladder cancer patients, first hospitalised in 2004 and 2005 at the Department of Urology of the Ospedale di Circolo - Fondazione Macchi, in Varese, Italy. Based on data collected through a simple structured interview, it was possible to estimate two occupational exposure indices: one taking into account only the length of employment in industrial settings (DS Index) and the other considering job title in addition (DSM Index). For all cases a second-step assessment by an occupational physician (gold standard) made it possible to establish the occupational origin of cancer and to assess accuracy. RESULTS: Satisfactory values of the area under the ROC curve were found for both indices (AUC 0,81 for DS and 0,87 for DSM). In particular at the same level of sensitivity (90%), the DSM Index showed a better specificity (72%) in comparison to the DS Index (64%). CONCLUSIONS: The short structured interview proposed here proved to be a valuable tool for general practitioners and urologists to detect cases of bladder cancer of suspected occupational aetiology, which can be referred to an occupational physician for further investigations.

A genetic risk score for hypertension is associated with risk of thoracic aortic aneurysm.

A genetic risk score (GRS) based on 29 single nucleotide polymorpysms (SNPs) associated with high blood pressure (BP) was prospectively associated with development of hypertension, stroke and cardiovascular events. The aim of the present study was to evaluate the impact of this GRS on the incidence of aortic disease, including aortic dissection (AD), rupture or surgery of a thoracic (TAA) or abdominal (AAA) aortic aneurysm. More than 25,000 people from the Swedish Malmo Diet and Cancer Study had information on at least 24 SNPs and were followed up for a median ≥ 18 years. The number of BP elevating alleles of each SNPs, weighted by their effect size in the discovery studies, was summed into a BP-GRS. In Cox regression models, adjusted for traditional cardiovascular risk factors including hypertension, we found significant associations of the BP-GRS, prospectively, with incident TAA (hazard ratio (HR) 1.64 (95% confidence interval (CI) 1.081-2.475 comparing the third vs. the first tertile; p = 0.020) but not with either AAA or aortic dissection. Calibration, discrimination and reclassification analyses show modest improvement in prediction using the BP-GRS in addition to the model which used only traditional risk factors. A GRS for hypertension associates with TAA suggesting a link between genetic determinants of BP and aortic disease. The effect size is small but the addition of more SNPs to the GRS might improve its discriminatory capability.

The Pro12Ala polymorphism of the PPARG gene is not associated with the metabolic syndrome in an urban population of middle-aged Swedish individuals.

BACKGROUND: To determine if the common Pro12Ala polymorphism (rs1801282) of the peroxisome proliferator-activated receptor (PPARG) gene is associated with the metabolic syndrome (MetS) or with its individual components in middle-aged Swedish individuals. METHODS: MetS was defined according to the National Cholesterol Education Program/Adult Panel III (NCEP/ATP III), the International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance (EGIR) criteria in a population-based sample of nearly 5000 subjects participating in the Malmö Diet and Cancer-cardiovascular arm. RESULTS: Of the subjects included in the analysis, 21.8, 29.4 and 20.4% had MetS according to the NCEP/ATP III, IDF and EGIR (only in subjects without diabetes) definitions, respectively. The Pro12Ala was not associated with MetS or with its individual components. These results were similar when patients with diabetes were excluded. Hypertensive and obese ala-carriers had lower fasting glucose and hypertensive ala-carriers also had lower level triglycerides (P < 0.05). CONCLUSIONS: Our data do not support a major role for the Pro12Ala variant of the PPARG gene in MetS and its individual components. The modest difference in triglyceride and glucose levels, restricted to hypertensive and obese subjects in our cohort, suggests that the polymorphism has a minor effect on glucose and lipid metabolism, particularly in individuals at risk for gluco-metabolic disturbances.

[Transitional bladder cancer and occupational exposure. Accuracy assessment of a screening method based on structured interview]. / Neoplasie transizionali della vescica ed esposizione professionale. Valutazione della accuratezza di un metodo di screening basato su intervista strutturata.

The transitional bladder cancer is the most frequent urinary malignant neoplasm. The main risk factors are cigarette smoking, recurrent inflammatory diseases of the urinary tract, assumption of some drugs, familiarity and occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons. The aim of this study is to assess the screening efficacy of a short structured interview to detect the possible occupational bladder cancer, to submit to the specialists evaluation. The sample of the study is represented by 100 subjects, hospitalized for transitional bladder cancer in the years 2004 and 2005 at the Department of Urology of the Ospedale di Circolo - Fondazione Macchi in Varese. Through the structured interview was possible to estimate two occupational exposure indexes: Length-Field Index (DS) and Length-Field-Job Index (DSM). The specialist's evaluation allowed to establish the occupational cancer origin. The analysis of the indexes' accuracy showed good operating characteristics with higher specificity and equal sensitivity for DSM in comparison to DS. Therefore the short structured interview should be considered as a valuable tool to identify urothelial carcinomas worthy of further evaluation of occupational specialist.

Traditional cardiovascular risk factors or inflammation: Which factors accelerate atherosclerosis in arthritis patients?

Patients with chronic inflammatory arthritis experience an increased incidence of cardiovascular (CV) events. In addition to visualizing atherosclerotic plaques, ultrasound examinations (USs) of the carotid arteries permit the measurement of subclinical markers of atherosclerosis, such as intima-media thickness (cIMT) and carotid segmental distensibility (cDC). The aims of the study were to identify the determinants of atherosclerosis acceleration (plaques, cIMT and cDC) in a sample of patients suffering from chronic arthritis and to compare these patients with a control group of people with ≤1 traditional risk factor (TRF) for CV disease. METHODS: We recruited 137 patients with rheumatoid arthritis (RA), 43 patients with psoriatic arthritis (PsA), 28 patients with ankylosing spondylitis (AS) and 48 healthy volunteers without histories of previous CV events. These patients underwent carotid artery US examinations using dedicated hardware. RESULTS: Regression and multivariate analyses demonstrated that only age (p<0.001) was consistently associated with cDC, cIMT and atherosclerotic plaques, both in the entire sample of patients with arthritis and in the subgroup of patients with RA. Among modifiable TRFs for cardiovascular disease, only hypertension, diabetes mellitus and smoking exhibited associations with some carotid phenotypes, with borderline significance. When patients with RA carrying ≤1 TRF were compared with control subjects carrying ≤1 TRF, only cDC was slightly lower in the RA group than in the control group. CONCLUSIONS: Age is the major determinant of subclinical atherosclerosis in patients with different types of arthritis, as the contributions of other TRFs and disease activity and duration indices to the disease seem to be limited.

Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator-stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry.

UNLABELLED: ESSENTIALS: The reliability of platelet tests as markers of the variable bioavailability of clopidogrel is not yet defined. Kinetics of clopidogrel active metabolite (CAM) and platelet response were studied in ischemic heart disease. CAM plasma maximum concentration (Cmax ) predicted vasodilator-stimulated phosphoprotein (VASP-P). Timely performed VASP-P, not an aggregation-based test, may be a surrogate for clopidogrel bioavailability. BACKGROUND: The high inter-individual variability in the inhibition of platelet function by clopidogrel is mostly explained by high variability in its transformation to an active metabolite (CAM). Objective We investigated the relations between pharmacokinetics and pharmacodynamics of CAM by comparing two methods of platelet function. METHODS: We enrolled 14 patients undergoing percutaneous coronary interventions for non-ST-segment elevation acute coronary syndrome or inducible myocardial ischemia. Plasma concentrations of clopidogrel and CAM, phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P), expressed as a platelet reactivity index (PRI) and whole-blood platelet aggregation (multiple electrode aggregometer, MEA) were measured before and after a 600-mg clopidogrel loading dose (nine time-points) and before and after 75-mg maintenance doses on days 2, 7 and 30. RESULTS: Plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax ) (median, 110.8 nm; range, 41.9-484.8) 0.5-2 h after the loading dose. A sigmoid dose-response curve defined the relations between CAMCmax and PRI after 3 to 24 h (IC50 , 459.6 nm; 95% confidence interval, 453.4-465.7; R(2) = 0.82). PRI was unchanged from baseline in patients with the lowest CAMCmax (< 83 nm, n = 7), indicating low sensitivity of VASP-P. PRI values were also predicted by CAMCmax at days 2, 7 and 30. Platelet aggregation measured by MEA did not show significant relations with either PRI or with CAM pharmacokinetics at any time-point. CONCLUSIONS: After 600 mg clopidogrel, VASP-P, but not whole-blood platelet aggregation measured by MEA, is almost entirely predicted by CAMCmax . VASP-P could be useful in studies aimed at investigating relations between CAM bioavailability and clinical events.