Comparison between numerical and mri data of ascending aorta hemodynamics in a circulatory mock loop

The possibility to obtain in-vitro evaluation of hemodynamic flows and pressures is of capital importance in understanding cardiovascular pathologies and validating new devices. The in-vitro approach brings different advantage including the possibility to evaluate fluid dynamic parameters non invasively and to support in-silico simulations. In this study, a patient specific mock circulatory loop is developed to reproduce the fluid dynamic physiological conditions. A full sequence of 4D flow MRI is used as a benchmark for extraction of anatomical and functional patient specific data. The anatomical MRI data were used to realize a 3D printed rigid phantom of the complete aortic branch. The phantom is realized with a single inlet at aortic root level and 4 outlets corresponding to the supra-aortic arteries and the descending aorta. The model is then inserted inside a custom mock-circulatory loop, composed by an active component and a series of passive components to model the systemic resistances and compliances at each branch. The active component is responsible for the imposition of the flow rate waveform at the inlet section and it is constituted by a custom speed-controlled piston pump. The inlet flow rate is set by automatically interpolating the patient specific aortic flow from MRI data. The functional MRI data were used to validate the flow condition at each outlet branch. In the present work the preliminary results of the circulatory mock loop are compared with MRI data and with the results of numerical simulations carried out for the considered aorta geometry and inlet flow rate by using Simvascular. The in-vitro flow profiles are compared with the in-vivo and the numerical ones in the descending aorta and at each outlet branch. The reproduction of the flow rate is successful, with errors at systolic peaks of 5 cc/s and 1.66 cc/s for the supra-aortic and the descending aorta level respectively. Also the physiological pressure range is rather well reproduced in the in-vitro experiments

Radiomics and machine learning applications in rectal cancer: Current update and future perspectives

The high incidence of rectal cancer in both sexes makes it one of the most common tumors, with significant morbidity and mortality rates. To define the best treatment option and optimize patient outcome, several rectal cancer biological variables must be evaluated. Currently, medical imaging plays a crucial role in the characterization of this disease, and it often requires a multimodal approach. Magnetic resonance imaging is the first-choice imaging modality for local staging and restaging and can be used to detect high-risk prognostic factors. Computed tomography is widely adopted for the detection of distant metastases. However, conventional imaging has recognized limitations, and many rectal cancer characteristics remain assessable only after surgery and histopathology evaluation. There is a growing interest in artificial intelligence applications in medicine, and imaging is by no means an exception. The introduction of radiomics, which allows the extraction of quantitative features that reflect tumor heterogeneity, allows the mining of data in medical images and paved the way for the identification of potential new imaging biomarkers. To manage such a huge amount of data, the use of machine learning algorithms has been proposed. Indeed, without prior explicit programming, they can be employed to build prediction models to support clinical decision making. In this review, current applications and future perspectives of artificial intelligence in medical imaging of rectal cancer are presented, with an imaging modality-based approach and a keen eye on unsolved issues. The results are promising, but the road ahead for translation in clinical practice is rather long

Effects of the Distribution in Space of the Velocity-Inlet Condition in Hemodynamic Simulations of the Thoracic Aorta

In the present paper the effects of the spatial distribution of the inlet velocity in numerical simulations of the thoracic aorta have been investigated. First, the results obtained by considering in-vivo measured inlet velocity distribution are compared with the ones obtained for a simulation having the same flow rate waveform and plug flow condition at the inlet section. The results of the two simulations are consistent in terms of flow rate waveform, but differences are present in the pressure range and in the wall shear stresses, especially in the foremost part of the ascending aorta. This motivates a stochastic sensitivity analysis on the effect of the distribution in space of the inlet velocity. This distribution is modeled through a truncated-cone shape and the ratio between the upper and the lower base is selected as the uncertain parameter. The uncertainty is propagated through the numerical model and a continuous response surface of the output quantities of interest in the parameter space can be recovered through a “surrogate” model. A stochastic method based on the generalized Polynomial Chaos (gPC) approach is used herein. The selected parameter appears to have a significant influence on the velocity distribution in the ascending aorta, whereas it has a negligible effect in the descending part. This, in turn, produces significant effects on the wall shear stresses in the ascending aorta, confirming the need of using patient-specific inlet conditions if interested in the hemodynamics and stresses of this region

Uncertainty quantification applied to hemodynamic simulations of thoracic aorta aneurysms: Sensitivity to inlet conditions

In this work, the numerical simulation of the blood flow inside a patient specific aorta in presence of an aneurysm is considered. A systematic sensitivity analysis of numerical predictions to the shape of the inlet flow rate waveform is carried out. In particular, two parameters are selected to describe the inlet waveform: the stroke volume and the period of the cardiac cycle. In order to limit the number of hemodynamic simulations required, we used a stochastic method based on the generalized polynomial chaos (gPC) approach, in which the selected parameters are considered as random variables with a given probability distribution. The uncertainty is propagated through the numerical model and a continuous response surface of the output quantities of interest in the parameter space can be recovered through a “surrogate” model. For both selected uncertain parameters, we first assumed uniform Probability Density Functions (PDFs) on a given variation range, and then we used clinical data to construct more accurate beta PDFs. In all cases, the two input parameters appeared to have a significant influence on wall shear stresses, confirming the need of using patient-specific inlet conditions

Gastrinomas and non-functioning pancreatic endocrine tumors in multiple endocrine neoplasia syndrome type-1 (MEN-1)

Multiple endocrine neoplasia type-1 (MEN-1) is a rare hereditary autosomal dominant syndrome due to frameshift and non-sense mutations in the MEN-1 tumor suppressor gene localized on the long arm of chromosome 11 [1]. Also known as Wermer syndrome, it has a prevalence of 2–20/100,000 individuals who may develop multiple neoplastic lesions arising in the parathyroid (90–95%) as well as the pituitary glands (40–50%), the pancreatic islet cells (50–60%) and the duodenal wall (35–40%) [2]. While the most common clinical onset of patients affected by MEN-1 is due to primary hyperparathyroidism [3], pancreatic endocrine tumors (PNETs) represent the main cause of cancer-related death, which is most commonly due to non-functioning (NF) subtypes [4]. Indeed, these tend to have a more aggressive behavior compared to their sporadic counterparts with a malignant potential reported to be size-related with a cut-off value set at 2 cm [5,6,7]. Hence, active surveillance with endoscopic ultrasonography (EUS) combined with either contrast-enhanced multi-detector-CT (MDCT) [8] or magnetic resonance imaging [9] is strongly recommended in patients with MEN-1 syndrome. As far as contrast-enhanced MDCT is concerned, recent advances suggest that contrast-enhancement patterns of PNETs may be indeed predictive of tumor grading defined as the rate of expression of the proliferation index Ki-67 [10]. As most G1 (Ki-67 <3%) tumors usually appear as hypervascular lesions, G2 (Ki-67 3–20%) or G3 (Ki-67 >20%) tumors typically manifest as hypovascular lesions [11,12,13]. However, as PNETs in MEN-1 syndrome are usually multifocal [14], the co-existence of lesions with different contrast-enhancement patterns and different biological behavior may indeed occur in clinical practice. Herein, we describe a case of 48-year-old male with a genetic diagnosis of MEN-1 syndrome who had a Zollinger–Ellison syndrome due to duodenal gastrinomas shown by an EUS and confirmed by contrast-enhanced MDCT, which also depicted loco-regional adenopathies and three other NF-PNETs with different contrast-enhancement patterns and biological behavior

MOLECULAR AND SEROLOGICAL DIVERSITY OF NEISSERIA MENINGITIDIS CARRIER STRAINS ISOLATED FROM ITALIAN STUDENTS AGED 14-22 YEARS.

Neisseria meningitidis is an obligate human commensal that commonly colonizes the oropharyngeal mucosa. Carriage is age dependent and very common in young adults. The relationships between carriage and invasive disease are not completely understood. In this work, we performed a longitudinal carrier study in adolescents and young adults (173 subjects). Overall, 32 subjects (18.5%) had results that were positive for meningococcal carriage in at least one visit (average monthly carriage rate, 12.1%). Only five subjects tested positive at all four visits. All meningococcal isolates were characterized by molecular and serological techniques. Multilocus sequence typing, PorA typing, and sequencing of the 4CMenB vaccine antigens were used to assess strain diversity. The majority of positive subjects were colonized by capsule null (34.4%) and capsular group B strains (28.1%), accounting for 23.5% and 29.4% of the total number of isolates, respectively. The fHbp and nhba genes were present in all isolates, while the nadA gene was present in 5% of the isolates. The genetic variability of the 4CMenB vaccine antigens in this collection was relatively high compared with that of other disease-causing strain panels. Indications about the persistence of the carriage state were limited to the time span of the study. All strains isolated from the same subject were identical or cumulated minor changes over time. The expression levels and antigenicities of the 4CMenB vaccine antigens in each strain were analyzed by the meningococcal antigen typing system (MATS), which revealed that expression can change over time in the same individual. Future analysis of antigen variability and expression in carrier strains after the introduction of the MenB vaccine will allow for a definition of its impact on nasopharyngeal/oropharyngeal carriage

Predicted Strain Coverage of a New Meningococcal Multicomponent Vaccine (4CMenB) in Spain: Analysis of the Differences with Other European Countries

BACKGROUND: A novel meningococcal multicomponent vaccine, 4CMenB (Bexsero®), has been approved in Europe, Canada, Australia and US. The potential impact of 4CMenB on strain coverage is being estimated by using Meningococcal Antigen Typing System (MATS), an ELISA assay which measures vaccine antigen expression and diversity in each strain. Here we show the genetic characterization and the 4CMenB potential coverage of Spanish invasive strains (collected during one epidemiological year) compared to other European countries and discuss the potential reasons for the lower estimate of coverage in Spain. MATERIAL AND METHODS: A panel of 300 strains, a representative sample of all serogroup B Neisseria meningitidis notified cases in Spain from 2009 to 2010, was characterized by multilocus sequence typing (MLST) and FetA variable region determination. 4CMenB vaccine antigens, PorA, factor H binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA) were molecularly typed by sequencing. PorA coverage was assigned to strain with VR2 = 4. The levels of expression and cross-reactivity of fHbp, NHBA and NadA were analyzed using MATS ELISA. FINDINGS: Global estimated strain coverage by MATS was 68.67% (95% CI: 47.77-84.59%), with 51.33%, 15.33% and 2% of strains covered by one, two and three vaccine antigens, respectively. The predicted strain coverage by individual antigens was: 42% NHBA, 36.33% fHbp, 8.33% PorA and 1.33% NadA. Coverage within the most prevalent clonal complexes (cc) was 70.37% for cc 269, 30.19% for cc 213 and 95.83% for cc 32. CONCLUSIONS: Clonal complexes (cc) distribution accounts for variations in strain coverage, so that country-by-country investigations of strain coverage and cc prevalence are important. Because the cc distribution could also vary over time, which in turn could lead to changes in strain coverage, continuous detailed surveillance and monitoring of vaccine antigens expression is needed in those countries where the multicomponent vaccine is introduced. This is really important in countries like Spain where most of the strains are predicted to be covered by only one vaccine antigen and the chance for escape mutants to emerge with vaccine use is higher. Based on the observed data, cc213 should receive special attention as it is associated with low predicted strain coverage, and has recently emerged in Spain.This work was partially supported by Novartis Vaccines & Diagnostics.S

Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma

Purpose: Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent-based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. Methods: We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent-based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. Results: In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P < .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P < .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003). Conclusion: In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials. Copyright © 2015 American Society of Clinical Oncology. All rights reserved

Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.

This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) aged 6565 years or who were ineligible for autologous stem cell transplantation. Patients (N=58) received CCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year PFS and OS rates were 76% and 87%, respectively. The most frequent grade 3-5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grade 1-2 (9%). Fourteen percent of patients discontinued treatment owing to adverse events, and 21% of patients required carfilzomib dose reductions. This is the first study of carfilzomib in combination with an alkylating agent in elderly patients with NDMM; results showed high complete response rates and a good safety profile. This study was registered at clinicaltrials.gov, identifier: NCT01346787