Low-dose curcuminoid-loaded in dextran nanobubbles can prevent metastatic spreading in prostate cancer cells.

Preventing recurrences and metastasis of prostate cancer after prostatectomy by administering adjuvant therapies is quite a controversial issue. In addition to effectiveness, absence of side effects and long term toxicity are mandatory. Curcuminoids (Curc) extracted with innovative techniques and effectively loaded by polymeric nanobubbles (Curc-NBs) satisfy such requirements. Curc-NBs showed stable over 30 d, were effectively internalized by tumor cells and were able to slowly release Curc in a sustained way. Significant biological effects were detected in PC-3 and DU-145 cell lines where Curc-NBs were able to inhibit adhesion and migration, to promote cell apoptosis and to affect cell viability and colony-forming capacity in a dose-dependent manner. Since the favourable effects are already detectable at very low doses, which can be reached at a clinical level, the actual drug concentration can be visualized and monitored by US or MRI, Curc-NBs can be proposed as an effective adjuvant theranostic tool.

Long-term response to recombinant human growth hormone treatment: a new predictive mathematical method.

INTRODUCTION: Recombinant GH has been offered to GH-deficient (GHD) subjects for more than 30 years, in order to improve height and growth velocity in children and to enhance metabolic effects in adults. AIM: The aim of our work is to describe the long-term effect of rhGH treatment in GHD pediatric patients, suggesting a growth prediction model. MATERIAL AND METHODS: A homogeneous database is defined for diagnosis and treatment modalities, based on GHD patients afferent to Hospital Regina Margherita in Turin (Italy). In this study, 232 GHD patients are selected (204 idiopathic GHD and 28 organic GHD). Each measure is shown in terms of mean with relative standard deviations (SD) and 95% confidence interval (95% CI). To estimate the final height of each patient on the basis of few measures, a mathematical growth prediction model [based on Gompertzian function and a mixed method based on the radial basis functions (RBFs) and the particle swarm optimization (PSO) models] was performed. RESULTS: The results seem to highlight the benefits of an early start of treatment, further confirming what is suggested by the literature. Generally, the RBF-PSO method shows a good reliability in the prediction of the final height. Indeed, RMSE is always lower than 4, i.e., in average the forecast will differ at most of 4 cm to the real value. CONCLUSIONS: In conclusion, the large and accurate database of Italian GHD patients allowed us to assess the rhGH treatment efficacy and compare the results with those obtained in other Countries. Moreover, we proposed and validated a new mathematical model forecasting the expected final height after therapy which was validated on our cohort.

Is there still a role for computed tomography and bone scintigraphy in prostate cancer staging? An analysis from the EUREKA-1 database.

PURPOSE: According to the current guidelines, computed tomography (CT) and bone scintigraphy (BS) are optional in intermediate-risk and recommended in high-risk prostate cancer (PCa). We wonder whether it is time for these examinations to be dismissed, evaluating their staging accuracy in a large cohort of radical prostatectomy (RP) patients. METHODS: To evaluate the ability of CT to predict lymph node involvement (LNI), we included 1091 patients treated with RP and pelvic lymph node dissection, previously staged with abdomino-pelvic CT. As for bone metastases, we included 1145 PCa patients deemed fit for surgery, previously staged with Tc-99m methylene diphosphonate planar BS. RESULTS: CT scan showed a sensitivity and specificity in predicting LNI of 8.8 and 98 %; subgroup analysis disclosed a significant association only for the high-risk subgroup of 334 patients (P 0.009) with a sensitivity of 11.8 % and positive predictive value (PPV) of 44.4 %. However, logistic multivariate regression analysis including preoperative risk factors excluded any additional predictive ability of CT even in the high-risk group (P 0.40). These data are confirmed by ROC curve analysis, showing a low AUC of 54 % for CT, compared with 69 % for Partin tables and 80 % for Briganti nomogram. BS showed some positivity in 74 cases, only four of whom progressed, while 49 patients with negative BS progressed during their follow-up, six of them immediately after surgery. CONCLUSIONS: According to our opinion, the role of CT and BS should be restricted to selected high-risk patients, while clinical predictive nomograms should be adopted for the surgical planning.

Functional Transcranial Doppler (fTCD) investigation of brain lateralization following visual stimuli.

This preliminary investigation of the local cerebral perfusion evaluated by Transcranial Doppler (TCD) monitoring of the Posterior Cerebral Arteries shows that selective stimulation of visual hemifields evokes significantly different vascular responses. TCD can therefore allow for functional evaluation of lateralized enhancements in cerebral metabolism.Clinical Relevance-The cerebral lateralization evaluated with the functional TCD can be a useful and low-cost approach to evaluate the effectiveness of the rehabilitation therapy in post stroke subjects experiencing hemianopia or to assess cerebral reorganization after cerebrovascular accidents.

A Compartmental Model for the Iron Trafficking Across the Blood-Brain Barriers in Neurodegenerative Diseases.

Iron accumulation in the brain is supposed to play a central role in the induction of oxidative stress and consequently in neurodegeneration. The sensitive balance of iron in the brain is maintained by the brain barriers system, i.e., the blood-brain barrier between the blood and brain interstitial fluid and the blood-cerebrospinal fluid barrier between the blood and cerebrospinal fluid (CSF). In this work, we proposed a three-compartmental mathematical model simulating iron trafficking between blood, CSF, and cerebral space, describing the direction of fluxes based on the structural and functional characteristics of the brain barriers system. Different techniques of sensitivity analysis were used to evaluate the most important parameters, providing an indication for the most relevant biological functions that potentially affect the physiological transport of iron across brain barriers.

A mathematical model for the evaluation of iron transport across the blood-cerebrospinal fluid barrier in neurodegenerative diseases.

Iron plays important roles in healthy brain but altered homeostasis and concentration have been correlated to aging and neurodegenerative diseases. Iron enters the central nervous system by crossing the brain barrier systems: the Blood- Brain Barrier separating blood and brain and the Blood-Cerebrospinal Fluid Barrier (BCSFB) between blood and CSF, which is in contact with the brain by far less selective barriers. Herein, we develop a two-compartmental model for the BCSFB, based on first-order ordinary differential equations, performing numerical simulations and sensitivity analysis. Furthermore, as input parameters of the model, experimental data from patients affected by Alzheimer's disease, frontotemporal dementia, mild cognitive impairment and matched neurological controls were used, with the aim of investigating the differences between physiological and pathological conditions in the regulation of iron passage between blood and CSF which can be possibly targeted by therapy.

Cancer metabolism and the dynamics of metastasis.

Cancer growth dynamics, commonly simulated with a Gompertzian model, is analyzed in the framework of a more recent and realistic model. In particular, we consider the setting of a tumor embedded in a host organ and investigate their interaction. We assume that, at least in some cases, tumor metastasis may be triggered by an 'energetic crisis', when the tumor exceeds the 'carrying capacity' of the host organ. As a consequence, dissemination of clusters of cancer cells is set in motion, with a statistical probability given by a Poisson distribution. The model, although still at a preclinical level, is fully quantitative and is applied, as an example, to the case of prostate cancer. The results confirm that, at least for the more aggressive cancers, metastasis starts very early during tumorigenesis and a quantitative link is found between the tumor's doubling time, its 'aggressiveness' and the metastatic potential.

Radio hyperthermia for re-treatment of superficial tumours.

PURPOSE: Relapse remains an unsolved problem for previously radio-treated patients. Our purpose is to evaluate the role of radio-hyperthermia (RT-HT) in the retreatment of superficial recurrences. MATERIALS AND METHODS: From 1998 to 2007, 51 patients affected by four histological types (breast recurrences (group A), melanoma recurrences (group B), head and neck recurrences (group C), and others (group D)) of 76 superficial lesions, were enrolled at Mauriziano Hospital at the Research Institute of Cancer Care Candiolo (IRCC) in Turin. All patients had previously undergone RT except 6 patients of group B. The total mean retreatment dose was 31.8 Gy (20-60 Gy), while the mean of HT sessions was 5 (1 to 8), temperature ranged from 38.5 degrees C (T min) to 44 degrees C (T max). RESULTS: Acute cutaneous toxicity was 77.6% G1, 22.4% G2, none for G3. Forty-five days later we observed: for group A 65.9% complete response (CR), 29.5% partial response (PR), 4.5% non-response (NR); for group B 33.3% CR, 25% PR and 41.7% NR; for group C 40% CR, 13.3% PR, 46.7% NR, for group D 60% CR and 40% NR. 18 months later group A presented 72.7% local control (LC), 20.5% stable disease (SD) and 6.8% non-control (NC), group B 50% LC, 16,7% SD and 33.3% NC, group C 33.3% LC, 40% SD and 26.7% NC, group D 40% LC and 60% NC. Early response, size of lesions < or =3 cm, T max > or =42 degrees C and RT doses > or =40 Gy were predictive outcome factors. CONCLUSIONS: We confirmed that radio-hyperthermia is useful in re-irradiation with a very high patient compliance.

Automatic detection of transient EEG events during sleep can be improved using a multi-channel approach.

OBJECTIVE: Automatic methods developed to detect transient EEG events during sleep may present a degree of arbitrariness in the choice of appropriate channels or amplitude thresholds for the analysis. To overcome these limitations, we propose a multi-channel and temporal coincidences approach. METHODS: A two-step automatic detection (AD) of peculiar transient synchronized EEG events (TE) was performed in stage 2 and stage 3 sleep periods obtained from 10 normal sleep recordings and included: (a) detection of candidate TE from all the EEG traces and averaged signals, based on amplitude thresholds selections in both the time and frequency domains; (b) cross-checking of TE by evaluation of the coincidences in different EEG traces. TE found by AD but not confirmed by visual analysis (false positives, FP) and TE evidenced by visual analysis and missed by AD (false negatives, FN) were then counted. RESULTS: AD performed in averaged signals significantly reduced the number of FP but slightly increased FN, compared to single-channel analysis. However, when TE were confirmed by inter-channel temporal coincidences, a significant reduction of total errors (FN+FP) was achieved. The minimum error was obtained after C3-A2 and C4-A1 averaging and signal cross-checking with at least three channels (C3-A2 or C4-A1, plus both O1-A2 and O2-A1). CONCLUSIONS: This study describes a novel method for automatic detection of transient EEG events occurring during sleep that takes into account all the available channels. SIGNIFICANCE: This approach reduces the need of human supervision and may overcome most of the difficulties encountered by automatic methods based on single-channel analysis.

Growth laws in cancer: implications for radiotherapy.

Comparing the conventional Gompertz tumor growth law (GL) with the "Universal" law (UL), which has recently been proposed and applied to cancer, we have investigated the implications of the growth laws for various radiotherapy regimens. According to the GL, the surviving tumor cell fraction could be reduced ad libitum, independent of the initial tumor mass, simply by increasing the number of treatments. In contrast, if tumor growth dynamics follows the Universal scaling law, there is a lower limit of the surviving fraction that cannot be reduced further regardless of the total number of treatments. This finding can explain the so-called tumor size effect and re-emphasizes the importance of early diagnosis because it implies that radiotherapy may be successful provided that the tumor mass at treatment onset is rather small. Taken together with our previous work, the implications of these findings include revisiting standard radiotherapy regimens and treatment protocols overall.

Curvature affects Doppler investigation of vessels: implications for clinical practice.

In clinical practice, blood velocity estimations from Doppler examination of curved vascular segments are normally different from those of nearby straight segments. The observed "accelerations," sometimes considered as a sort of stochastic disturbances, can actually be related to very specific physical effects due to vessel curvature (i.e., the development of nonaxial velocity [NAV] components) and the spreading of the axial velocity direction in the Doppler sample volume with respect to the insonation axis. The relevant phenomena and their dependence on the radius of curvature of the vessels and on the insonation angle are investigated with a beam-vessel geometry as close as possible to clinical setting, with the simplifying assumptions of steady flow, mild vessel curvature, uniform ultrasonic beam and complete vessel insonation. The insonation angles that minimize the errors are provided on the basis of the study results.

Umbilical Doppler waveforms and placental villous angiogenesis in pregnancies complicated by fetal growth restriction.

OBJECTIVE: To test the hypothesis that the characteristics of umbilical artery Doppler flow velocity waveforms in growth-restricted fetuses indicate angiogenesis within placental stem and gas-exchanging villi. METHODS: We examined 18 placentas from singleton fetuses that were normal structurally and chromosomally but were growth-restricted, preterm, and complicated by preeclampsia. Ten cases with positive end-diastolic flow and eight with absent or reverse end-diastolic flow were compared with six gestational age-matched controls. Sections of villous placenta were examined to determine structural composition (percentage of fibrinoid, intervillous space, and villous tissue), relative proportion of villous types (stem, immature intermediate, and gas-exchanging villi), and the frequency distribution of stem arterial vessel calibers and their branching pattern. RESULTS: Placentas with positive end-diastolic flow had a significantly (P < .05) higher percentage of gas-exchanging villi (median 69.6%, range 62.5-80.8%) than those with absent or reverse end-diastolic flow (58.3%, 29.9-71.9%) or controls (60.8%, 43.1-65.6%). The gas-exchanging villi from placentas with absent or reverse end-diastolic flow were slender, elongated, poorly branched, and poorly capillarized. There was a progressive trend toward reduced branching of the stem arteries from the controls (median 22%, range 2-38%), through the positive end-diastolic group (17%, 11-20%), to the absent or reverse end-diastolic group (13%, 4-23%). CONCLUSION: Compared with absent or reverse end-diastolic flow, the placentas from growth-restricted fetuses with positive end-diastolic flow showed a normal pattern of stem artery development, accompanied by increased capillary angiogenesis and terminal villous development. These features suggest an adaptive pathway for the placenta in the face of uteroplacental ischemia.

Perfusion and thermal field during hyperthermia. Experimental measurements and modelling in recurrent breast cancer.

Recurrences of malignant tumours in the chest wall are proposed as a valuable model of tissue mainly perfused by small size vessels (the so-called 'phase III' vessels). Invasive thermal measurements have been performed on two patients affected by cutaneous metastasis of malignant tumours during hyperthermic sessions. Thermal probes were inserted into catheters implanted into the tissue at different depths. In one of the catheters a probe connected with laser-Doppler equipment was inserted to assess blood perfusion in the tumour periphery. The perfusion was monitored throughout the sessions, and a noticeable temporal variability was observed. The effect of the perfusion on the thermal map in the tissue was evaluated locally and the 'effective conductivity' of the perfused tissue was estimated by means of the numerical integration of the 'bio-heat' equation. The tumour temperature, at the site where the perfusion probe is located, can be predicted by the numerical model provided two free parameters, alpha and beta, are evaluated with a fitting procedure. Alpha is related to the effective conductivity and beta to the SAR term of the bio-heat equation. The model aimed at estimating the 'effective conductivity' K(eff) of the perfused tissue, and average values of K(eff) of 0.27 +/- 0.03 W m(-1) degrees C(-1) in Patient 1 and of 0.665 +/- 0.005 W m(-1) degrees C(-1) in Patient 2 were obtained throughout the treatment. However, when the average temperature in a larger tumour volume is to be predicted but only a single, 'local' measurement of the perfusion is available and is assumed to be representative for the whole region, the model results are far less satisfactory. This is probably due to the fact that changes of blood perfusion throughout hyperthermic sessions occur to different extents within the tumour volume, and the differences in perfusion cannot be ignored. The above result suggests that, in addition to the 'temperature map', also a 'perfusion map' within the heated volume should be monitored routinely throughout hyperthermic sessions.

Modelling the feto-placental circulation: 1. A distributed network predicting umbilical haemodynamics throughout pregnancy.

The modifications of the Doppler flow velocity parameters occurring in the feto-placental circulation throughout pregnancy have been reproduced on the basis of a mathematical model. Some simple assumptions were made, such as the progressive development of a dichotomous villous vessel network and the increase of the perfusion pressure and of the umbilical arteries dimensions throughout pregnancy. Moreover, both the viscous and capacitive characteristics of the vascular bed were taken into consideration in order to predict the mean values of blood volume, flow and velocity and the pulsatility index. Their value is shown to depend on few parameters, and mainly on the cross-sectional area ratio between the vessels belonging to two succeeding generations.

Modelling the feto-placental circulation: 2. A continuous approach to explain normal and abnormal flow velocity waveforms in the umbilical arteries.

A mathematical model of the feto-placental circulation which describes the development of the placental vasculature throughout pregnancy on the basis of simple assumptions is used to simulate some abnormalities of the villous vascular tree which may affect the values of Doppler indices. In normal cases, the model shows a decreasing trend of the pulsatility index (PI) throughout pregnancy which is comparable to that observed in vivo. When a pathological interruption of the villous growth is simulated, the PI does not decrease any further, unless the input pressure keeps increasing. When various degrees of obliteration of the villous tree are simulated, either through an occlusive process or a reduction of the lumen of the vessels, the PI values increase and the volume flow decreases to a greater extent. The data predicted by the model are compared to those obtained in clinical studies and in experimental animal models.

Assessment of the effect of vessel curvature on Doppler measurements in steady flow.

Blood vessel curvature is responsible for the appearance of nonaxial velocity components and for minor changes in the pattern of the axial flow. All the velocity components are expected to contribute to the Doppler signal produced by the ultrasound (US) backscattered by the insonated blood cells, the axial velocity, contributing to the actual volumetric blood flow, and the transverse velocity, causing the recirculating vortices. A detailed, separate analysis of the velocity components is, therefore, mandatory to quantify how vessel curvature can affect results and clinical diagnosis. Both experimental in vitro measures and numerical simulations were performed on a curved tube and the Doppler power spectra so obtained were compared. The satisfactorily agreement of the above spectra shows that the nonaxial velocity components are easily detectable with clinical equipment and that their amplitude, as expected, is not negligible and can bias Doppler measurements and resulting clinical diagnosis.

Quantitative Doppler measures in coiled vessels: investigation on excised umbilical veins.

Quantitative assessment of umbilical venous blood velocity with Doppler ultrasound (US) must cope with the coiled structure of the vein inside the cord. Both an experimental and a theoretical approach showed remarkable variations in the insonation angle when the probe was moved along the vein, provided the inclination between the Doppler probe and the cord was kept constant. Inaccurate signal processing, stochastic variability and flow disturbances could, however, mask the influence of the geometry. The above hypotheses were assessed by investigating five cords in vitro a few hours after delivery from normal pregnancies at term. The Doppler signal was sampled at different sites along each cord and the mean Doppler shift estimated by FFT spectral analysis, both directly and through the noise rejection D'Alessio's algorithm, which proved effective in improving the Doppler shift estimate in condition of low signal-to-noise ratio (SNR).

PC-aided assessment of the thermal performances of a MW applicator for oncological hyperthermia.

The thermal performances of an MW oncological hyperthermic (OH) system have been assessed with a PC-aided procedure. Measurements were performed on a muscle-equivalent phantom. Between the applicator and the phantom a water bolus was interposed which, to simulate real OH treatments, could be connected to a forced cooling water circulation system. Direct thermal measurements of temperatures and SAR (using the 'short pulse technique') and simulation by numerical modelling were performed, both aiming at describing the 3-D thermal field inside the phantom. Accuracy and manageability of the automated procedure proved suitable for characterization and quality assurance of MW applicators in clinical hyperthermia and encourage further efforts towards the development of computerized treatment simulations in OH.

Model-based assessment of pressure and flow-dependent coronary responses following abrupt pressure drops.

The response of the coronary vasculature to an experimental manoeuvre of step-like decrease of the perfusion pressure has been investigated with a model. The coronary vasculature was simulated using a 'windkessel' scheme. Proximal resistance and compliance were assumed to be pressure-independent. The distal resistance, on the contrary, was controlled by a feed-back loop which accounts for the smooth muscle activation induced by the pressure variation. Three more parameters were introduced, and namely the smooth muscle activation time constant and the pressure-induced and flow-induced gains. The parameter values were assessed by comparing the model predicted coronary flow with the one actually measured in animals.

Temperature monitoring using ultrasound contrast agents: in vitro investigation on thermal stability.

Invasiveness of temperature monitoring devices is presently one of the most serious limitations to the application of oncological hyperthermia (HT). A promising approach aims at detecting temperature variations by monitoring the mean grey level (MGL) of the ultrasonographic image of the tissue. Gaseous ultrasound contrast agents (UCA), enhancing Ultrasonic (US) imaging, are expected to be sensitive to temperature, and are therefore a good candidate as temperature monitoring medium. The present study evaluates the 'in vitro' temporal and thermal stability and the correlation between temperature and MGL using a gaseous UCA (SonoVue) as phantom. No statistical differences were detected between the MGL value of the phantom kept at 43.5 degrees C before (215.2+/-3.5) and after 1 h (214.8+/-2.5), showing good stability at HT temperatures. Data of MGL image vs. temperature were obtained during both heating and cooling experiments in the HT range (30-43 degrees C). A good linearity of MGL vs. temperature (R2=0.976) was found with a good accuracy (2.5%) and a sensitivity of about 6.6 MGL/degrees C.