Feasibility of detecting atrophy relevant for disability and cognition in multiple sclerosis using 3D-FLAIR.

BACKGROUND AND OBJECTIVES: Disability and cognitive impairment are known to be related to brain atrophy in multiple sclerosis (MS), but 3D-T1 imaging required for brain volumetrics is often unavailable in clinical protocols, unlike 3D-FLAIR. Here our aim was to investigate whether brain volumes derived from 3D-FLAIR images result in similar associations with disability and cognition in MS as do those derived from 3D-T1 images. METHODS: 3T-MRI scans of 329 MS patients and 76 healthy controls were included in this cross-sectional study. Brain volumes were derived using FreeSurfer on 3D-T1 and compared with brain volumes derived with SynthSeg and SAMSEG on 3D-FLAIR. Relative agreement was evaluated by calculating the intraclass correlation coefficient (ICC) of the 3D-T1 and 3D-FLAIR volumes. Consistency of relations with disability and average cognition was assessed using linear regression, while correcting for age and sex. The findings were corroborated in an independent validation cohort of 125 MS patients. RESULTS: The ICC between volume measured with FreeSurfer and those measured on 3D-FLAIR for brain, ventricle, cortex, total deep gray matter and thalamus was above 0.74 for SAMSEG and above 0.91 for SynthSeg. Worse disability and lower average cognition were similarly associated with brain (adj. R2 = 0.24-0.27, p < 0.01; adj. R2 = 0.26-0.29, p < 0.001) ventricle (adj. R2 = 0.27-0.28, p < 0.001; adj. R2 = 0.19-0.20, p < 0.001) and deep gray matter volumes (adj. R2 = 0.24-0.28, p < 0.001; adj. R2 = 0.27-0.28, p < 0.001) determined with all methods, except for cortical volumes derived from 3D-FLAIR. DISCUSSION: In this cross-sectional study, brain volumes derived from 3D-FLAIR and 3D-T1 show similar relationships to disability and cognitive dysfunction in MS, highlighting the potential of these techniques in clinical datasets.

Interpretable deep learning as a means for decrypting disease signature in multiple sclerosis.

Objective.The mechanisms driving multiple sclerosis (MS) are still largely unknown, calling for new methods allowing to detect and characterize tissue degeneration since the early stages of the disease. Our aim is to decrypt the microstructural signatures of the Primary Progressive versus the Relapsing-Remitting state of disease based on diffusion and structural magnetic resonance imaging data.Approach.A selection of microstructural descriptors, based on the 3D-Simple Harmonics Oscillator Based Reconstruction and Estimation and the set of new algebraically independent Rotation Invariant spherical harmonics Features, was considered and used to feed convolutional neural networks (CNNs) models. Classical measures derived from diffusion tensor imaging, that are fractional anisotropy and mean diffusivity, were used as benchmark for diffusion MRI (dMRI). Finally, T1-weighted images were also considered for the sake of comparison with the state-of-the-art. A CNN model was fit to each feature map and layerwise relevance propagation (LRP) heatmaps were generated for each model, target class and subject in the test set. Average heatmaps were calculated across correctly classified patients and size-corrected metrics were derived on a set of regions of interest to assess the LRP contrast between the two classes.Main results.Our results demonstrated that dMRI features extracted in grey matter tissues can help in disambiguating primary progressive multiple sclerosis from relapsing-remitting multiple sclerosis patients and, moreover, that LRP heatmaps highlight areas of high relevance which relate well with what is known from literature for MS disease.Significance.Within a patient stratification task, LRP allows detecting the input voxels that mostly contribute to the classification of the patients in either of the two classes for each feature, potentially bringing to light hidden data properties which might reveal peculiar disease-state factors.

A numerical study of arsenic contamination at the Bagnoli bay seabed by a semi-anthropogenic source. Analysis of current regime.

Bagnoli Coroglio is an urban district of the City of Naples (South Italy), which fronts the Tyrrhenian Sea for nearly 3 km. It is part of the Campi Flegrei caldera, one of the most explosive volcanic areas in Europe. The need for redeveloping the site after the intense industrial activities of the twentieth century has prompted a remarkable research effort to investigate the pollution's degree, nature, and extent at both the land and seafloor. This article focuses on releasing thermal waters from a natural channel as a source of arsenic contamination in the Bagnoli marine sediments; the thermal waters originate from the nearby Agnano hot-springs and have been conveying artificially to the track since the mid-XIX century. As a first part of the outcomes, the work describes the flow regime that characterizes the marine area. The analysis has been conducted via numerical simulations carried out with the software package Delft3D, developed by Deltares, which employs dynamically interfacing modules to account for wave propagation, generation of currents, and presence of coastal structures. Climatic inputs to the software (waves, winds, and tide) have specifically been gathered and analyzed within this research. The numerical study has permitted to furnish, for the first time, a clear and systematic view of the hydrodynamic forcings that characterize the area under investigation. In particular, a leading role in the transport of pollutants could be played by rip current systems, whose characteristics vary with climate intensity (waves and wind) and coastal structures characteristics. Due to its inherently dynamic nature, the proposed approach seems especially desirable in situations where different contamination sources are compared. As such, it could be successfully applied to other sites also.

A multicenter survey on access to care in Multiple Sclerosis-related trigeminal neuralgia.

The prevalence of trigeminal neuralgia (TN) in patients with Multiple Sclerosis (MS) is higher than in the general population and its management can be particularly challenging due to a number of reasons including high recurrence rates, lack of MS-specific treatment guidelines and uncertainties about pain pathophysiology. Aim of this cross-sectional, multicentre survey was to gather information on the current treatment modalities and options of MS-related TN across 23 Italian MS centres. Initial medical management (carbamazepine or oxcarbazepine) of MS-related TN was fairly homogeneous throughout Italian centres. The most commonly available surgical procedure was microvascular decompression, but the frequency and types of surgical procedures available locally differed considerably throughout MS centers, and were unavailable in one quarter of them. This survey reveals some of the issues that could hamper an optimal patient management and underlines the need for a consensus on MS-related TN to support health-care professionals in their approach to this challenging condition and to facilitate the development of local guidelines aimed at ensuring equity in access to care and treatment optimization.

Informing MS patients on treatment options: a consensus on the process of consent taking.

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. AIMS: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. RESULTS: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.

Increase of CSF inflammatory profile in a case of highly active multiple sclerosis.

BACKGROUND: Clinical and imaging follow-up coupled with cerebrospinal fluid (CSF) and possibly serum profiling could provide information on disease activity and disability evolution in multiple sclerosis patients. CASE PRESENTATION: We describe the case of a relapsing-remitting MS patient whose history was characterized by failure of several therapeutic approaches and sustained disease activity. By using a highly sensitive immunoassay methodology, we examined protein expression of 70 inflammatory/cytotoxic molecules in two consecutive paired CSF and serum samples, obtained respectively in 2006 and 2013. At disease diagnosis, elevated CSF protein levels of an inflammatory pattern, including CXCL13, CXCL12, IFNγ, TNF, sTNFR1, IL8, sCD163, APRIL, BAFF, pentraxin III and MMP2 were found compared with a group of controls. At the second lumbar puncture, sustained disease activity was accompanied by considerable (more than 2 fold changes) increase expression of most of these inflammatory molecules while no significant changes in serum inflammatory markers were detected in the two consecutive serum samples. CONCLUSIONS: Elevated CSF protein expression of pro-inflammatory mediators, possibly specifically associated to GM demyelination, could remain stable or increase over time in patients with active multiple sclerosis. We underline the role of fluid analysis in understanding the pathophysiology of the disease and providing information on possible markers of disease activity and evolution.

Intraoperative digital breast tomosynthesis using a dedicated device is more accurate than standard intraoperative mammography for identifying positive margins.

AIM: To compare a standard intra-operative mammography (IM) device with digital breast tomosynthesis using a dedicated device (Mozart system) in the evaluation of surgical margins at first excision. MATERIALS AND METHODS: The study received institutional review board approval and written informed consent was obtained from participants. From January 2018 to December 2018, a prospective analysis of the images of IM device and intra-operative digital breast tomosynthesis with a dedicated device (Mozart system) in n=89 breast cancer patients (average patients age: 58 years, age range: 35-76 years) was undertaken. Images were evaluated by two expert breast radiologists independently of each other and blinded to each other's interpretation, who indicated the positive cases requiring surgical re-excision intra-operatively. RESULTS: Mean cancer size was 12.5±4.5 mm. Radiological signs of the lesions were microcalcifications (n=71), nodules (n=10), and architectural distortions (n=8). A total of 20/89 (17%) patients underwent intra-operative re-excision for positive margins. Intra-operative digital breast tomosynthesis with a dedicated device and IM showed discrepancies in 15/89 cases (17%). Mozart system results informed the necessity to perform a re-excision (n=15). Overall, receiver operating characteristic (ROC) curve analysis showed and area under the ROC curve (AUC) of 0.82 for the Mozart system versus 0.65 for IM. ROC analysis of radiological findings with microcalcifications showed an AUC of 0.92 for the Mozart system versus 0.74 for IM, whereas AUC in cases with no microcalcifications were 0.87 and 0.75, respectively. CONCLUSION: Intra-operative digital breast tomosynthesis with a dedicated device provides more information (better accuracy) than IM and facilitated a reduction in re-excision rates.

Effect of glatiramer acetate on cerebral grey matter pathology in patients with relapsing-remitting multiple sclerosis.

INTRODUCTION: In this two year longitudinal study we compare the progression of grey matter (GM) damage in MS patients treated with glatiramer acetate (GA) for relapsing-remitting multiple sclerosis (RRMS) respect to untreated patients. METHODS: We studied thirty-five treated with GA and thirty-five untreated RRMS subjects matched for age, gender, disease duration and EDSS. Each patient underwent neurological examination every 6 months and 3-Tesla MRI at study entry (T0), after 1 year (T1) and 2 years (T2). At T0, T1 and T2, the number of new cortical lesions (CLs) was assessed on double inversion recovery images. By using the longitudinal stream of FreeSurfer, the cortical thickness and volume changes of several cerebral structures were evaluated after 2 years. RESULTS: The mean number of new CLs was significantly lower in GA group compared to untreated patients both at T1 (0.9 ±â€¯1.0 vs 1.7 ±â€¯1.0, p < 0.05) and at T2 (1.4 ±â€¯1.3 vs 2.9 ±â€¯1.8, p < 0.001). Volume loss of thalamus (-0.5% ±â€¯0.2% vs. -1.1% ±â€¯0.4%; p < 0.001), globus pallidus (-4.4% ±â€¯3.1% vs. -8.2% ±â€¯4.5%; p < 0.001), hippocampus (-0.7% ±â€¯0.3% vs. -1.5% ±â€¯0.5%; p < 0.001) and cerebellum (-0.5% ±â€¯0.3% vs. -0.9% ±â€¯0.4%; p < 0.001) was also lower in the GA group. A more pronounced cortical thinning was observed in cingulate (p = 0.04), cuneus and frontomarginal gyrus (p = 0.01 for both comparisons) of the untreated patients. CONCLUSION: Our findings suggest that GA exerts its immunomodulatory action at the level of GM either reducing the accumulation of CLs and slowing down the GM atrophy progression. Despite a confirmation in a larger sample size is required, our results suggest a possible effect of GA on GM damage.

Endotelina-1, proteína C reactiva ultrasensible y actividad antioxidante en pacientes con hipotiroidismo subclínico y en eutiroideos con autoinmunidad tiroidea. Efectos del tratamiento con levotiroxina / Endothelin-1, high sensitivity C reactive protein and antioxidant activity in subclinical hypothyroid patients. Effects of levothyroxine treatment

RESUMEN La Endotelina-1 (ET1) y Proteína C Reactiva ultrasensible (PCRus) como marcadores de disfunción endotelial (DE) e inflamación vascular en hipotiroidismo subclínico (HS) han mostrado resultados controvertidos. El rol del estrés oxidativo y defensa antioxidante (TRAP) es motivo de discusión. Objetivos Establecer si el HS y la autoinmunidad tiroidea (AIT), excluyendo otros factores de riesgo cardiovascular, pueden causar DE e inflamación vascular, evaluadas a través de ET1 y PCRus, respectivamente. Establecer si TRAP juega algún rol. Evaluar cambios en ET1 y PCRus luego del tratamiento con levotiroxina (LT4). Material y métodos Se evaluaron prospectivamente 70 pacientes divididos en 3 grupos: HS: 41 pacientes (T4 normal,TSH >4,2 y <10 mUI/L), AIT: 10 pacientes eutiroideos (TSH <4,2 mUI/L) con aTPO y/o aTg (+) y Control: 19 pacientes eutiroideos sin AIT. Se excluyeron otros factores de riesgo cardiovascular. Se midió basalmente ET1, PCRus y TRAP plasmáticos, y en HS bajo LT4 (n = 24): ET1 y PCRus. Resultados No hubo diferencias significativas en edad, IMC, perfil lipídico y TRAP. ET1 y PCRus fueron significativamente mayores en pacientes con HS (media ± DS 1,77 ± 0,85 pg/ml y 1,5 ± 0,6 mg/l vs. controles (0,8 ± 0,3 pg/ml y 0,5 ± 0,2 mg/l) p <0,0001 y <0,008 respectivamente. Del mismo modo en AIT (1,4 ± 0.4 pg/ml y 2,3 ± 1,3 mg/l) vs controles p <0,0001 y <0,034, respectivamente. La TSH fue mayor en el grupo AIT vs. Control 2,57 ± 0,88 vs. 1,64 ± 0,5 mUI/L; p = 0,002. En HS bajo LT4 (8,7 ± 3,8 meses) se observó descenso de ET1 (p <0,001). ET1 correlacionó con TSH (r = 0,5 p <0,0001). El punto de corte de ET1 mediante curva ROC fue 1,32 pg/ml (Sensibilidad 81,6%-Especificidad 75%). Conclusiones ET1 y PCRus resultaron marcadores útiles para evaluar DE e inflamación vascular asociadas a HS. La defensa antioxidante no ejercería un rol en estos mecanismos. El tratamiento con LT4 produjo una significativa caída de ET1, pudiendo necesitarse un período más largo de eutiroidismo para normalizarla. En AIT, niveles de TSH >2,5 mUI/L podrían sugerir un mínimo grado de hipotiroidismo justificando la elevación en ET1 y PCR, sin descartar el rol de la AIT "per se".

ABSTRACT The measurement of endothelin-1 (ET1) and high sensitivity C-reactive protein (hsCRP) as markers of endothelial dysfunction (ED) and vascular inflammation in subclinical hypothyroidism (SH) has shown controversial results. The role of oxidative stress and antioxidant defense (TRAP) is a matter of discussion. Objectives To establish if SH and thyroid autoimmunity (TAI), excluding other cardiovascular risk factors, may cause ED and vascular inflammation, evaluated through the measurement of ET1 and hsCRP respectively. To determine if TRAP could have some role. Additionally, changes in these parameters after treatment with levothyroxine (LT4) will be evaluated. Material and methods: 70 patients were prospectively evaluated. They were classified into: SH Group: 41 patients (normal T4, TSH> 4.2 and <10 mIU/L), TAI Group: 10 euthyroid patients (TSH <4.2 mUI/L) with positive aTPO and/or aTg and Control Group: 19 euthyroid patients without TAI. Other cardiovascular risk factors were excluded in patients and controls. Plasma ET1, hsCRP and TRAP were measured basally, and ET1 and hsCRP under LT4 therapy in the HS Group. Results There were no significant differences between the 3 groups in age, BMI, lipids and TRAP. ET1 and hsCRP were significantly higher in patients with SH (mean ± SD 1.77 ± 0.85 pg/ml and 1.5 ± 0.6 mg/l) vs. controls (0.8 ± 0.3 pg/ml y 0.5 ± 0.2 mg/l) p <0.0001 y <0.008 respectively. Similarly, in TAI patients (1.4 ± 0.4 pg/ml y 2.3 ± 1.3 mg/l) vs controls, p <0.0001 and <0.034, respectively. TSH was higher in the TAI patients versus control group (2.5 ± 0.88 versus 1.64 ± 0.5 mIU/L, p = 0.002). Twenty-four patients with SH showed a significant decrease in ET1 (p <0.001) under treatment with LT4 (8.7 ± 3.8 months). ET1 had a highly significant correlation (p <0.0001) with TSH (r = 0.5). The cut-off level of ET1 established by ROC curve was 1.32 pg/ml (Sensitivity 81.6%-Specificity 75%). Conclusions ET1 and hsCRP were useful markers to evaluate ED and vascular inflammation associated with SH. There were no differences in TRAP levels between patients and controls, so it does not appear that oxidative stress would have played any role. Treatment with LT4 produced a significant drop in ET1. Probably, a longer period of euthyroidism might be necessary to normalize ET1 levels. In TAI Group, TSH levels >2.5 mUI/L could suggest a "minimal degree" of hypothyroidism justifying the elevation in ET1 and hs CRP. The role of the TAI "per se" couldn't be completely ruled out.

MRI of cortical lesions and its use in studying their role in MS pathogenesis and disease course.

Cortical grey matter (GM) demyelination is present from the earliest stages of multiple sclerosis (MS) and is associated with physical deficits and cognitive impairment. In particular, the rate of disability progression in MS, both in the relapsing and progressive phases, appears to be strictly associated with degenerative GM demyelination and diffuse cortical atrophy. In the last decade, several histopathological studies and advanced radiological methodologies have contributed to better identify the exact involvement/load of cortical pathology in MS, even if the specific inflammatory features and the precise cell and molecular mechanisms of GM demyelination and neurodegeneration in MS remain still not fully understood. It has been proposed that a combined neuropathology, imaging and molecular approach may help to define a more detailed characterization and precise assessment of the heterogeneous features of GM injury and inflammation in MS. This, in turn, will possibly identify specific imaging and biohumoral (cerebrospinal fluid/serum) correlates of cortical pathology that may have an important role in predicting and monitor the disease evolution.

A case of acute fulminant multiple sclerosis treated with alemtuzumab.

We describe the case of a woman who came to our attention for acute onset and very rapidly worsening left hemiplegia, vision loss and cognitive impairment. MRI, laboratory and clinical investigations were highly suggestive of an active inflammatory demyelinating disease. Following exclusion of other possible etiologies, a diagnosis of Marburg's variant multiple sclerosis was made. After repeated high-dose steroids and plasma-exchange, the patient was treated with a first course of alemtuzumab followed by improvement of the clinical and MRI picture. This is the first reported case of Marburg type multiple sclerosis treated with alemtuzumab.

Heterogeneity of Cortical Lesion Susceptibility Mapping in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been used to characterize iron and myelin content in the deep gray matter of patients with multiple sclerosis. Our aim was to characterize the susceptibility mapping of cortical lesions in patients with MS and compare it with neuropathologic observations. MATERIALS AND METHODS: The pattern of microglial activation was studied in postmortem brain tissues from 16 patients with secondary-progressive MS and 5 age-matched controls. Thirty-six patients with MS underwent 3T MR imaging, including 3D double inversion recovery and 3D-echo-planar SWI. RESULTS: Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. Quantitative susceptibility mapping hyperintensity edge found in the proximity of the pial surface or at the white matter/gray matter interface in some of the quantitative susceptibility mapping-hyperintense cortical lesions accurately mirrors the microglia activation observed in the neuropathology analysis. CONCLUSIONS: Cortical lesion susceptibility maps are highly heterogeneous, even at individual levels. Quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation.

Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy.

Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

QTc interval in patients with multiple sclerosis: an inference from the insula of Reil?

BACKGROUND AND PURPOSE: The aim of this study was to investigate the correlation between the duration of the QTc interval and the brain lesion load at the level of the structures involved in superior autonomic control (insula, cingulate cortex and amygdala-hippocampus) in multiple sclerosis (MS) patients. METHODS: Thirty-one consecutive patients with relapsing-remitting MS were recruited. The QT interval was measured manually in all 12 leads by a single blinded observer, with the longest QT value adjusted for heart rate by using the Bazett's formula. All patients performed a brain magnetic resonance imaging (MRI) scan including three-dimensional double inversion recovery and three volumetric fast-field echo sequences. The following MRI measures were obtained: (i) global and regional cortical thickness (CTh); (ii) white matter lesion load volume; (iii) cortical damage blindly assessed by a trained observer who assigned, on the basis of the number of cortical lesions, a score from 0 to 5 for each of the brain areas analysed. RESULTS: In all, 16% of the patients had an increased QTc interval. The QTc interval was correlated with disease duration, cortical insular lesion volume and grey matter lesion volume in the three examined areas and inversely correlated with global and insular CTh. CONCLUSIONS: An increased QTc interval in patients with MS may have a cerebral origin possibly driven by involvement of the insular cortex. With the recent introduction in clinical practice of treatments with potential cardiac effects such as fingolimod, the recognition of a long QTc interval could be clinically crucial and should encourage appropriate electrocardiographic monitoring in order to prevent the risk of malignant ventricular pro-arrhythmia and iatrogenic sudden death.

Epilepsy in multiple sclerosis: The role of temporal lobe damage.

BACKGROUND: Although temporal lobe pathology may explain some of the symptoms of multiple sclerosis (MS), its role in the pathogenesis of seizures has not been clarified yet. OBJECTIVES: To investigate the role of temporal lobe damage in MS patients suffering from epilepsy, by the application of advanced multimodal 3T magnetic resonance imaging (MRI) analysis. METHODS: A total of 23 relapsing remitting MS patients who had epileptic seizures (RRMS/E) and 23 disease duration matched RRMS patients without any history of seizures were enrolled. Each patient underwent advanced 3T MRI protocol specifically conceived to evaluate grey matter (GM) damage. This includes grey matter lesions (GMLs) identification, evaluation of regional cortical thickness and indices derived from the Neurite Orientation Dispersion and Density Imaging model. RESULTS: Regional analysis revealed that in RRMS/E, the regions most affected by GMLs were the hippocampus (14.2%), the lateral temporal lobe (13.5%), the cingulate (10.0%) and the insula (8.4%). Cortical thinning and alteration of diffusion metrics were observed in several regions of temporal lobe, in insular cortex and in cingulate gyrus of RRMS/E compared to RRMS ( p< 0.05 for all comparisons). CONCLUSIONS: Compared to RRMS, RRMS/E showed more severe damage of temporal lobe, which exceeds what would be expected on the basis of the global GM damage observed.

PO-03 - Khorana score and histotype predict the incidence of early venous thromboembolism (VTE) in Non Hodgkin Lymphoma (NHL). A pooled data analysis of twelve clinical trials of Fondazione Italiana Linfomi (FIL).

BACKGROUND: Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors. AIMS: To better clarify the epidemiology of early (within six months from treatment start) VTE in NHL we conducted a pooled data analysis of 12 clinical trials from FIL. Our analysis included basic demographic features, lymphoma-related characteristics as well the Khorana score (based on histology, BMI, platelets WBC and HB counts) which is extensively used in solid tumors to predict VTE risk. PATIENTS AND METHODS: From Jan. 2010 to Dec. 2014, all pts with B-cell NHL enrolled in prospective clinical trials from FIL for frontline treatment were included. For 9 studies study period included the entire trial population was included. The analyses were conducted based on CRFs as well as pharmacovigilance reports. VTE definition and grading was stated according to standard criteria of toxicity (CTCAE V4.0). Cumulative incidence of VTE from the study enrollment was estimated using the method described by Gooley et al. accounting for death from any causes as a competing risk. The Fine & Gray survival model was used to identify predictors of VTE among NHL pts. Factors predicting the grade of VTE were investigated using an ordinal logistic regression model. This pooled data analysis was approved by local IRB. RESULTS: Overall, 1,717 patients belonging to 12 studies were evaluated. Eight were phase I/II or II (25% of pts) and 4 phase III (75% of pts). M/F ratio was 1.41, Median age was 57, (IQ range (IQR) 49-66). Histologies were: DLCL-B 34%, FL 41%, MCL 18%, other 6%. Median BMI was 25 (IQR 22-28). Median Hb, WBC and platelets counts were 13g/dl) (IQR 11.5-14.2), 7.1*10^(9)/l (IQR 5.6-10.3), 224*10^(9)/l (IQR 169-298), respectively. 1189 pts were evaluable Khorana score: 58% low risk, 30% intermediate risk, 12% were high risk. Human erythropoetin support was given to 9% of patients. All pts received Rituximab. Planned therapeutic programs included ASCT in 27% of pts, conventional chemotherapy in 67% a conventional chemotherapy plus lenalidomide in 6%. Overall 59 any grade VTE episodes occurred in 51 pts (2.9%), including 21 grade III-IV VTE (18 pts). None was fatal. Median time from study enrolment to VTE was 63 days (IQR: 35-110). Considering death as a competitive event the 6 months cumulative incidence of VTE was 2,2% in low risk Khorana score, 4.5% (95%IC: 2.3-6.7) in intermediate and 6.6% (95%IC: 2.4-10.8) in high risk (p=0.012) (figure 1). Khorana score was predictive also for grade III-IV events as they were 0,7% (95% CI:0.1-1.4) in low risk and 2.0% (95% CI:0.8-3.3) in intermediate-high risk (p=0.048). The results were similar also after excluding lenalidomide containing studies. The Fine and Gray multivariate analyses, adjusted for age and stage, showed that Khorana score (intermediate risk adjHR=1.96; 95%IC: 0.84-4.56 and high risk adjHR=3.81; 95%IC: 1.51-9.58) and DLCL-B histotype (adjHR=2.58; 95% CI: 1.01-6.55) were independently associated to an increased risk of VTE. Moreover an ordinal logistical regression model indicated that the increase of one point in the Khorana score resulted in an increased risk of VTE (OR=1.85; 95% CI: 1.23-2.79). CONCLUSIONS: Our results suggest that DLCL-B histotype and Khorana score are predictors of VTE in NHL. The latter might become a simple and effective tool to assess the risk of VTE in NHL. Prospective validation including also patients not eligible for clinical trials is needed.

Estimation of percentage breast tissue density: comparison between digital mammography (2D full field digital mammography) and digital breast tomosynthesis according to different BI-RADS categories.

OBJECTIVE: To compare breast density estimated from two-dimensional full-field digital mammography (2D FFDM) and from digital breast tomosynthesis (DBT) according to different Breast Imaging-Reporting and Data System (BI-RADS) categories, using automated software. METHODS: Institutional review board approval and written informed patient consent were obtained. DBT and 2D FFDM were performed in the same patients to allow within-patient comparison. A total of 160 consecutive patients (mean age: 50±14 years; mean body mass index: 22±3) were included to create paired data sets of 40 patients for each BI-RADS category. Automatic software (MedDensity(©), developed by Giulio Tagliafico) was used to compare the percentage breast density between DBT and 2D FFDM. The estimated breast percentage density obtained using DBT and 2D FFDM was examined for correlation with the radiologists' visual BI-RADS density classification. RESULTS: The 2D FFDM differed from DBT by 16.0% in BI-RADS Category 1, by 11.9% in Category 2, by 3.5% in Category 3 and by 18.1% in Category 4. These differences were highly significant (p<0.0001). There was a good correlation between the BI-RADS categories and the density evaluated using 2D FFDM and DBT (r=0.56, p<0.01 and r=0.48, p<0.01, respectively). CONCLUSION: Using DBT, breast density values were lower than those obtained using 2D FFDM, with a non-linear relationship across the BI-RADS categories. These data are relevant for clinical practice and research studies using density in determining the risk. ADVANCES IN KNOWLEDGE: On DBT, breast density values were lower than with 2D FFDM, with a non-linear relationship across the classical BI-RADS categories.

Increased incidence of multiple sclerosis in the Veneto region, Italy.

BACKGROUND: To what extent the progressive increase in the incidence of multiple sclerosis (MS) observed in the province of Padova over the period 1970-1999 was an expression of a real increased risk of developing MS remained unclear. OBJECTIVE: The objective of this paper is to update the epidemiological figures of MS and probe whether the risk of having MS has increased in the province of Padova during the decade 2000-2009. METHODS: All patients born in Italy and having a diagnosis of MS or possible MS identified through analysis of all available sources of information were included in the study. The incidence and prevalence rates between 2000 and 2009 were obtained and compared with our previously published data. RESULTS: On 31 December 2009, the overall prevalence was 139.5/100,000, 192.0 ± 9.5 for females and 83.9 ± 6.3 for males. During the decade 2000-2009, the overall incidence rate of MS was 5.5 ± 0.5, 7.4 ± 0.8 for females and 3.5 ± 0.6 for males. The onset-diagnosis delay, the female/male ratio and the mean age at onset did not significantly change compared to the prior period of observation. CONCLUSION: Our findings support the hypothesis of a real increased risk of developing MS in the province of Padova. Moreover, the actual prevalence of 1.4/1000 makes our region a high-risk geographical area for MS. The role played by exogenous factors in determining susceptibility to MS needs to be thoroughly investigated.