Long-term outcome after pulmonary embolism in patients who continue or stop secondary prophylaxis

Background: Pulmonary embolism (PE) is potentially lethal acutely and prone to recur. After anticoagulant therapy discontinuation, the rate of recurrences increases with time and therefore decide when and how to stop secondary prophylaxis may be difficult in several patients. Objective: to investigate the incidence of mortality and recurrence of PE and the time course of these events during a 5 year-follow-up in patients who discontinue and in those who continue secondary prophylaxis only according to 2001 ACCP Guide-lines. Secondary purposes were to evaluate the risk factors for recurrences and mortality of PE in patients who continue and in those who discontinue therapy and the incidence of bleeding in the former group of patients. Design and methods: we evaluated consecutive patients with acute PE enrolled in a single University centre during a 5 year-period (2001-2005), and followed for 5 further years (2006-2011) after the decision to continue or stop anticoagulant treatment on the basis of 2001 ACCP Guide-lines. Results: we considered 471 patients with PE that were followed for 5 year follow-up period. Among them, 361 (76.6 %) continued anticoagulant therapy, the remaining 110 (23.4 %) patients stopped it. Among all patients, 263 (55.8%) completed the 5 year-follow-up period while 122 (25.9%) patients died before completing it and 86 (18.3%) were lost to follow-up. Patients who continued anticoagulant therapy experienced 34 (72.3%) recurrences (incidence recurrence rate 2.58 events for 100 person-years), while patients who discontinued therapy developed 13 (27.7 %) recurrences (incidence recurrence rate 2.92 events for 100 person-years). In the group of patients who continued anticoagulant therapy, 109 (89.3 %) deaths (mortality rate 8 events for 100 person-years) occurred, while in the group who discontinued it 13 (10.7 %) deaths (mortality rate 2.84 events for 100 person-years) occurred; the difference between the two groups was statistically significant (RR 2.81, 95% CI 1.58-5.46). The group of patients who continued anticoagulant therapy experienced 13 fatal recurrences (incidence recurrence rate 0.95 events for 100 person-years) while patients who discontinued it had 4 fatal recurrences (incidence recurrence rate 0.8 events for 100 person-years). Among patients who continued anticoagulant therapy, those with unprovoked or recurrent PE show more than 3 times grater probability of dying for fatal recurrence than those who continued treatment since affected by uncontrolled cancer or disabling chronic illness (RR 3.60, 95% CI 001-1.84). Recurrence was significantly associated with age greater than 61 years and with the presence of DVT at the diagnosis of PE. Conditions independently associated with all-cause mortality, were age greater than 70 years, presence of cancer, and continuation of anticoagulant therapy. Fatal recurrences, were significantly associated with age greater than 78 years. Conclusion: our findings suggest that, according to Guide-lines, most patients (80%) should be anticoagulated for long period of time; that prolonging anticoagulation markedly reduce the risk for fatal recurrence in all patients and, mostly, in those with unprovoked PE, while it does not decrease total recurrences or all-cause mortality. This, indeed, is influenced greatly by the presence of cancer, both in patients who continue and in those who stop anticoagulant prophylaxis. Whether or not the strategy of adhering to Guide-lines is correct remains not demonstrated

Characterization of Skin Interfollicular Stem Cells and Early Transit Amplifying Cells during the Transition from Infants to Young Children

In the interfollicular epidermis, keratinocyte stem cells (KSC) generate a short-lived population of transit amplifying (TA) cells that undergo terminal differentiation after several cell divisions. Recently, we isolated and characterized a highly proliferative keratinocyte cell population, named “early” TA (ETA) cell, representing the first KSC progenitor with exclusive features. This work aims to evaluate epidermis, with a focus on KSC and ETA cells, during transition from infancy to childhood. Reconstructed human epidermis (RHE) generated from infant keratinocytes is more damaged by UV irradiation, as compared to RHE from young children. Moreover, the expression of several differentiation and barrier genes increases with age, while the expression of genes related to stemness is reduced from infancy to childhood. The proliferation rate of KSC and ETA cells is higher in cells derived from infants’ skin samples than of those derived from young children, as well as the capacity of forming colonies is more pronounced in KSC derived from infants than from young children’s skin samples. Finally, infants-KSC show the greatest regenerative capacity in skin equivalents, while young children ETA cells express higher levels of differentiation markers, as compared to infants-ETA. KSC and ETA cells undergo substantial changes during transition from infancy to childhood. The study presents a novel insight into pediatric skin, and sheds light on the correlation between age and structural maturation of the skin

Gly482Ser PGC-1α gene polymorphism and exercise-related oxidative stress in amyotrophic lateral sclerosis patients

The role of exercise in Amyotrophic lateral sclerosis (ALS) pathogenesis is controversial and unclear. Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator that regulates mitochondrial biogenesis and antioxidant defense mechanisms. It has been suggested that a Gly482Ser substitution in PGC-1α has functional relevance in human disorders and in athletic performance. To test this hypothesis, we examined the genotype distribution of PGC-1α Gly482Ser (1444 G > A) in ALS patients to evaluate whether or not the minor serine-encoding allele 482Ser is involved in oxidative stress responses during physical exercise. We genotyped 197 sporadic ALS patients and 197 healthy controls in order to detect differences in allelic frequencies and genotype distribution between the two groups. A total of 74 ALS patients and 65 controls were then comparatively assessed for plasmatic levels of the oxidative stress biomarkers, advanced oxidation protein products, ferric reducing ability and thiol groups. In addition a subgroup of 35 ALS patients were also assessed for total SOD and catalase plasmatic activity. Finally in 28 ALS patients we evaluated the plasmatic curve of the oxidative stress biomarkers and lactate during an incremental exercise test. No significant differences were observed in the genotype distribution and allelic frequency in ALS patients compared to the controls. We found significant increased advanced oxidation protein products (p A SNP, ALS patients with Gly482Ser allelic variant show increased exercise-related oxidative stress. This thus highlights the possible role of this antioxidant defense transcriptional coactivator in ALS

Diagnosis and treatment of pulmonary embolism: a multidisciplinary approach

The diagnosis of pulmonary embolism (PE) is frequently considered in patients presenting to the emergency department or when hospitalized. Although early treatment is highly effective, PE is underdiagnosed and, therefore, the disease remains a major health problem. Since symptoms and signs are non specific and the consequences of anticoagulant treatment are considerable, objective tests to either establish or refute the diagnosis have become a standard of care. Diagnostic strategy should be based on clinical evaluation of the probability of PE. The accuracy of diagnostic tests for PE are high when the results are concordant with the clinical assessment. Additional testing is necessary when the test results are inconsistent with clinical probability. The present review article represents the consensus-based recommendations of the Interdisciplinary Association for Research in Lung Disease (AIMAR) multidisciplinary Task Force for diagnosis and treatment of PE. The aim of this review is to provide clinicians a practical diagnostic and therapeutic management approach using evidence from the literature

Liver enlargement predicts obstructive sleep apnea–hypopnea syndrome in morbidly obese women

Obstructive sleep apnea–hypopnea syndrome (OSAHS) is frequently present in patients with severe obesity, but its prevalence especially in women is not well defined. OSAHS and non-alcoholic fatty liver disease are common conditions, frequently associated in patients with central obesity and metabolic syndrome and are both the result of the accumulation of ectopic fat mass. Identifying predictors of risk of OSAHS may be useful to select the subjects requiring instrumental sleep evaluation. In this cross-sectional study, we have investigated the potential role of hepatic left lobe volume (HLLV) in predicting the presence of OSAHS. OSAHS was quantified by the apnea/hypopnea index (AHI) and oxygen desaturation index in a cardiorespiratory inpatient sleep study of 97 obese women [age: 47 ± 11 years body mass index (BMI): 50 ± 8 kg/m2]. OSAHS was diagnosed when AHI was ≥5. HLLV, subcutaneous and intra-abdominal fat were measured by ultrasound. After adjustment for age and BMI, both HLLV and neck circumference (NC) were independent predictors of AHI. OSAHS was found in 72% of patients; HLLV ≥ 370 cm3 was a predictor of OSAHS with a sensitivity of 66%, a specificity of 70%, a positive and negative predictive values of 85 and 44%, respectively (AUC = 0.67, p < 0.005). A multivariate logistic model was used including age, BMI, NC, and HLLV (the only independent predictors of AHI in a multiple linear regression analyses), and a cut off value for the predicted probability of OSAHS equal to 0.7 provided the best diagnostic results (AUC = 0.79, p < 0.005) in terms of sensitivity (76%), specificity (89%), negative and positive predictive values (59 and 95%, respectively). All patients with severe OSAHS were identified by this prediction model. In conclusion, HLLV, an established index of visceral adiposity, represents an anthropometric parameter closely associated with OSAHS in severely obese women

UNet and MobileNet CNN-based model observers for CT protocol optimization: comparative performance evaluation by means of phantom CT images

Purpose: The aim of this work is the development and characterization of a model observer (MO) based on convolutional neural networks (CNNs), trained to mimic human observers in image evaluation in terms of detection and localization of low-contrast objects in CT scans acquired on a reference phantom. The final goal is automatic image quality evaluation and CT protocol optimization to fulfill the ALARA principle. Approach: Preliminary work was carried out to collect localization confidence ratings of human observers for signal presence/absence from a dataset of 30,000 CT images acquired on a PolyMethyl MethAcrylate phantom containing inserts filled with iodinated contrast media at different concentrations. The collected data were used to generate the labels for the training of the artificial neural networks. We developed and compared two CNN architectures based respectively on Unet and MobileNetV2, specifically adapted to achieve the double tasks of classification and localization. The CNN evaluation was performed by computing the area under localization-ROC curve (LAUC) and accuracy metrics on the test dataset. Results: The mean of absolute percentage error between the LAUC of the human observer and MO was found to be below 5% for the most significative test data subsets. An elevated inter-rater agreement was achieved in terms of S-statistics and other common statistical indices. Conclusions: Very good agreement was measured between the human observer and MO, as well as between the performance of the two algorithms. Therefore, this work is highly supportive of the feasibility of employing CNN-MO combined with a specifically designed phantom for CT protocol optimization programs

Long-Term Outcome After Adoptive Immunotherapy With Natural Killer Cells: Alloreactive NK Cell Dose Still Matters

Recently, many reports were published supporting the clinical use of adoptivelytransferred natural killer (NK) cells as a therapeutic tool against cancer, including acutemyeloid leukemia (AML). Our group demonstrated promising clinical response usingadoptive immunotherapy with donor-derived alloreactive KIR-ligand-mismatched NK cellsin AML patients. Moreover, the antileukemic effect was correlated with the dose of infusedalloreactive NK cells (“functional NK cell dose”). Herein, we update the results of ourprevious study on a cohort of adult AML patients (median age at enrollment 64) infirstmorphological complete remission (CR), not eligible for allogeneic stem celltransplantation. After an extended median follow-up of 55.5 months, 8/16 evaluablepatients (50%) are still off-therapy and alive disease-free. Overall survival (OS) and disease-free survival (DFS) are related with the dose of infused alloreactive NK cells (≥2×105/kg

The baseline comorbidity burden affects survival in elderly patients with acute myeloid leukemia receiving hypomethylating agents: Results from a multicentric clinical study

Background: In older patients with acute myeloid leukemia (AML), the definition of fitness, prognosis, and risk of death represents an open question. Methods: In the present study, we tested the impact on survival of disease- and patient-related parameters in a large cohort of elderly AML patients homogeneously assigned to treatment with hypomethylating agents (HMAs). Results: In 131 patients with a median age of 76 years, we confirmed that early response (&lt;0.001) and biology-based risk classification (p&nbsp;=&nbsp;0.003) can select patients with better-predicted survival. However, a full disease-oriented model had limitations in stratifying our patients, prompting us to investigate the impact of baseline comorbidities on overall survival basing on a comorbidity score. The albumin level (p&nbsp;=&nbsp;0.001) and the presence of lung disease (p&nbsp;=&nbsp;0.013) had a single-variable impact on prognosis. The baseline comorbidity burden was a powerful predictor of patients' frailty, correlating with increased incidence of adverse events, especially infections, and predicted overall survival (p &lt; 0.001). Conclusion: The comorbidity burden may contribute to impact prognosis in addition to disease biology. While the therapeutic armamentarium of elderly AML is improving, a comprehensive approach that combines AML biology with tailored interventions to patients' frailty is likely to fully exploit the anti-leukemia potential of novel drugs

Cancer associated venous thromboembolism

Cancer represents a well recognized risk factor for venous thromboembolism. Patients with cancer have a 4–7 fold higher risk for venous thromboembolism than patients without the disease. Some sites of cancer (e.g. pancreas, stomach) are associated with a higher risk than others (e.g. breast, prostate); advanced stage is also associated with a higher risk. Finally, numerous chemotherapeutic agents contribute to the development of venous thromboembolism. Despite the high incidence of thromboembolism, routine primary prophylaxis is not recommended in most cancer patients. Scores that evaluate site, stage and concomitant risk factors are being evaluated but have not gained widespread acceptance to date. Screening patients with venous thromboembolism for occult cancers has shown little impact on survival and in general is not recommended. The pathogenesis of thrombosis in cancer patients, although extremely complex, involves the synthesis of proinflammatory mediators by the host that contributes to the activation of the coagulation cascade, as well as the synthesis of the procoagulant and proangiogenic factor, tissue factor, by the tumor. Patients with venous thromboembolism and active cancer are usually treated with low molecular weight heparin for 6 months; after that, there are no clear guidelines to suggest the best therapeutic approach. The new direct oral anticoagulants are currently not indicated in these patients; however, clinical studies are in progress to evaluate their promising role in this setting