Studio di marcatori biologici prognostici nel linfoma di Hodgkin

Recent reports showed that early-interim PET-scan is the only tool predicting treatment outcome in advanced-stage classical Hodgkin lymphoma (asCHL). We evaluated the prognostic impact of a series of immunohistochemical markers, mentioned in literature as prognostic factors, on tissue microarrays assembled from biopsies of 220 patients: STAT1, SAP, TOP2A, PCNA and CD20, both in neoplastic (HRSC) and microenvironment cells (MC); RRM2, MAD2, CDC2, BCL2, P53, BCL11A and EBER in HRSC; ALDH1A1, TIA-1, granzyme B, perforin, FOXP3, and PD-1 in MC. All patients had been treated with standard ABVD ± Rx therapy. Interim-PET after 2 ABVD courses was evaluated according to the criteria indicated by Gallamini in his study (Journal of Clinical Oncology, 2007). The survival analysis has been performed in a subset of 138 patients whose complete clinical information were available: the mean age was 33.3 years (14-79), the stage III-IVB in 98 and IIB in 40, and the mean follow-up 38.1 months (7.6-71.9). Histopathology review showed: NS-I 75, NS-II 22, MC 20, DL 3, and CHL/nos 18 cases. Interim-PET was positive in 30 patients, while treatment failure was recorded in 32. In univariate analysis the factors related to treatment outcome were BCL2 on HRSC (cut-off value 50%), STAT1/SAP on MC, and PET (Log-rank 6.9, 7.9 and 93.9 respectively). The combined expression of STAT1 and SAP was scored in three levels depending on the architectural pattern: score 0 for expression of both with a diffuse/rosetting pattern; score 1 for discordant combination of diffuse/rosetting and scattered patterns; score 2 for both markers with a scattered pattern; the 3y-PFS were 87.4%, 69.9% and 61.9% respectively. In multivariate analysis PET, BCL2 and STAT1/SAP remained significant (HR: 24.8, 4.6, 7.5 and 5.6, respectively; p<.01). The proposed model is able to predict treatment response in AsCHL, even if with a lower efficacy than PET. However, unlike PET, it can be applied upfront therapy.

The cardio-renal axis. Non ST-segment elevation myocardial infarction risk stratification according to renal dysfunction

Background: Chronic kidney disease (CKD) is one of the strongest risk factor for myocardial infarction (MI) and mortality. The aim of this study was to assess the association between renal dysfunction severity, short-term outcomes and the use of in-hospital evidence-based therapies among patients with non–ST-segment elevation myocardial infarction (NSTEMI). Methods: We examined data on 320 patients presenting with NSTEMI to Maggiore’s Emergency Department from 1st Jan 2010 to 31st December 2011. The study patients were classified into two groups according to their baseline glomerular filtration rate (GFR): renal dysfunction (RD) (GFR<60) and non-RD (GFR≥60 ml/min). Patients were then classified into four groups according to their CKD stage (GFR≥60, GFR 59-30, GFR 29-15, GFR <15). Results: Of the 320 patients, 155 (48,4%) had a GFR<60 ml/min at baseline. Compared with patients with a GFR≥60 ml/min, this group was, more likely to be female, to have hypertension, a previous myocardial infarction, stroke or TIA, had higher levels of uric acid and C-reactive protein. They were less likely to receive immediate (first 24 hours) evidence-based therapies. The GFR of RD patients treated appropriately increases on average by 5.5 ml/min/1.73 m2. The length of stay (mean, SD) increased with increasing CKD stage, respectively 5,3 (4,1), 7.0 (6.1), 7.8 (7.0), 9.2 (5.8) (global p <.0001). Females had on average a longer hospitalization than males, regardless of RD. In hospital mortality was higher in RD group (3,25%). Conclusions: The in-hospital mortality not was statically difference among the patients with a GFR value ≥60 ml/min, and patients with a GFR value <60 ml/min. The length of stay increased with increasing CKD stages. Despite patients with RD have more comorbidities then without RD less frequently receive guideline –recommended therapy. The GFR of RD patients treated appropriately improves during hospitalization, but not a level as we expected.

The vulnerable carotid plaque. Identification of endothelial markers predictive of plaque weakness, rupture predisposition and neoangiogenesis

Background. Neoangiogenesis is crucial in plaque progression and instability. Previous data from our group demonstrated that intra-plaque neovessels show both a Nestin+/WT+ and a Nestin+/WT1- phenotype, the latter being correlated with complications and plaque instability. Aims. The aims of the present thesis are: (i) to confirm our previous results on Nestin/WT1 phenotype in a larger series of carotid atheromatous plaques, (ii) to evaluate the relationship between the Nestin+/WT1- neoangiogenesis phenotype and plaque morphology, (iii) to evaluate the relationship between the immunohistochemical and histopathological characteristics and the clinical instability of the plaques. Materials and Methods. Seventy-three patients (53 males, 20 females, mean age 71 years) were consecutively enrolled. Symptoms, brain CT scan, 14 histological variables, including intraplaque hemorrhage and diffuse calcifications, were collected. Immunohistochemistry for CD34, Nestin and WT1 was performed. RT-PCR was performed to evaluate Nestin and WT1 mRNA (including 5 healthy arteries as controls). Results. Diffusely calcified plaques (13 out of 73) were found predominantly in females (P=0.017), with a significantly lower incidence of symptoms (TIA/stroke) and brain focal lesions (P=0.019 and P=0.013 respectively) than not-calcified plaques, but with the same incidence of intraplaque complications (P=0.156). Accordingly, both calcified and not calcified plaques showed similar mean densities of positivity for CD34, Nestin and WT1. The density of Nestin and WT1 correlated with the occurrence of intra-plaque hemorrhage in all cases, while the density of CD34 correlated only in not-calcified plaques. Conclusions. We confirmed that the Nestin+/WT1- phenotype characterizes the neovessels of instable plaques, regardless the real amount of CD34-positive neoangiogenesis. The calcified plaques show the same incidence of histological complications, albeit they do not influence symptomatology and plaque vulnerability. Female patients show a much higher incidence of not-complicated or calcified plaques, receiving de facto a sort of protection compared to male patients.

Design and characterization of wideband Hall current sensors in BCD technology for smart power and metering applications

Power electronic circuits are moving towards higher switching frequencies, exploiting the capabilities of novel devices to shrink the dimension of passive components. This trend demands sensors capable enough to operate at such high frequencies. This thesis aims to demonstrate through experimental characterization, the broadband capability of a fully integrated CMOS X-Hall current sensor in current mode interfaced with a transimpedance amplifier (TIA), chip CH09, realized in CMOS technology for power electronics applications such as power converters. The system exploits a common-mode control system to operate the dual supply system, 5-V for the X-Hall probe and 1.2-V for the readout. The developed prototype achieves a maximum acquisition bandwidth of 12 MHz, a power consumption of 11.46 mW, resolution of 39 mArms, a sensitivity of 8 % /T, and a FoM of 569-MHz/A2mW, significantly higher than current state-of-the-art. Further enhancements were proposed to CH09 as a new chip CH100, aiming for accuracy levels prerequisite for a real-time power electronic application. The TIA was optimized for a wider bandwidth of 26.7 MHz with nearly 30% reduction of the integrated input referred noise of 26.69 nArms at the probe-AFE interface in the frequency band of DC-30 MHz, and a 10% improvement in the dynamic range. The expected input range is 5-A. The chip incorporates a dual sensing chain for differential sensing to overcome common mode interferences. A novel offset cancellation technique is proposed that would require switching of polarity of bias currents. Thermal gain drift was improved by a factor of 8 and will be digitally calibrated utilizing a new built-in temperature sensor with a post calibration measurement accuracy greater than 1%. The estimated power consumption of the entire system is 55.6 mW. Both prototypes have been implemented through a 90-nm microelectronic process from STMicroelectronics and occupy a silicon area of 2.4 mm2.

Vascular access in patients with peripheral arterial disease undergoing TAVI: the hostile registry

BACKGROUND The optimal access route in patients with severe peripheral artery disease (PAD) undergoing TAVI remains undetermined. OBJECTIVE To compare clinical outcomes with transfemoral access (TFA), transthoracic access (TTA), and non-thoracic alternative access (TAA) in TAVI patients with severe PAD. METHODS Patients with PAD and hostile femoral access (TFA impossible, or possible only after percutaneous treatment) undergoing TAVI at 28 international centers were included in this registry. The primary endpoint was the propensity-adjusted risk of 30-day major adverse events (MAE) defined as the composite of all-cause mortality, stroke/transitory ischemic attack (TIA) or main access site-related VARC 3 major vascular complications. Outcomes were also stratified according to the severity of PAD using a novel risk score (Hostile score). RESULTS Among the 1,707 patients included in the registry, 518 (30.3%) underwent TAVI with TFA after percutaneous treatment, 642 (37.6%) with TTA, and 547 (32.0%) with TAA (mostly transaxillary). Compared with TTA, both TFA (adjusted HR=0.58, 95%CI 0.45-0.75) and TAA (adjusted HR=0.60, 95%CI 0.47-0.78) were associated with lower 30-day rates of MAE, driven by fewer access site-related complications. Composite risks at 1 year were also lower with TFA and TAA compared with TTA. TFA compared with TAA was associated with lower 1-year risks of stroke/TIA (adjusted HR=0.49, 95%CI 0.24-0.98), a finding confined to patients with low Hostile scores (Pinteraction=0.049). CONCLUSIONS Among patients with PAD undergoing TAVI, both TFA and TAA were associated with lower 30-day and 1-year rates of MAE compared with TTA, but 1-year stroke/TIA rates were higher with TAA compared with TFA.