Personalized treatment planning in eye brachytherapy for ocular melanoma: Dosimetric analysis on ophthalmic structure at risk.

PURPOSE: To evaluate the impact on dose distribution to eye organs-at-risk (eOARs) of a computed tomography (CT)-based treatment planning in eye plaque brachytherapy (EPB) treatment. METHODS: We analyzed 19 ocular melanoma patients treated with ruthenium-106 plaques to a total dose of 100 Gy to tumor apex using conventional central-axis-point dose calculation. Treatments were re-planned using the Plaque Simulator (PS) software implementing two different strategies: a personalized CT-eye-model (CT-PS) and a standard-eye-model (SEM-PS) defined by Collaborative Ocular Melanoma Study. Dice coefficient and Hausdorff distance evaluated the concordance between eye-bulb-models. Mean doses (Dmean) to tumor and eOARs were extracted from Dose-Volume-Histograms and Retinal-Dose-Area-Histogram. Differences between planning approaches were tested by Wilcoxon signed-rank test. RESULTS: In the analyzed cohort, 8 patients (42%) had posterior tumor location, 8 (42%) anterior, and 3 (16%) equatorial. The SEM did not accurately described the real CT eye-bulb geometry (median Hausdorff distance 0.8 mm, range: (0.4-1.3) mm). Significant differences in fovea and macula Dmean values were found (p = 0.04) between CT-PS and SEM-PS schemes. No significant dosimetric differences were found for tumor and other eOARs. The planning scheme particularly affects the OARs closest to the tumor with a general tendency of SEM-PS to overestimate the doses to the OARs closest to the tumor. CONCLUSION: The dosimetric accuracy achievable with CT-PS EPB treatment planning may help to identify ocular melanoma patients who could benefit the most from a personalized eye dosimetry for an optimal outcome in terms of tumor coverage and eOARs sparing. Further research and larger studies are underway.

US and MR imaging findings to detect placental adhesion spectrum (PAS) in patients with placenta previa: a comparative systematic study.

PURPOSE: To compare the performance US and MR in identifying placental adhesion spectrum (PAS) in placenta previa (PP) and to establish a potential method of image interpretation. METHODS: US and MR examinations of 51 patients with PP were selected. The presence of imaging signs commonly used to detect PAS was assessed. Penalized logistic regression was performed considering histology as standard of reference; only signs statistically significant (p < 0.05) were considered for ROC and multivariate analysis. The probability of PAS according to the presence of US and/or MR signs was then assessed. RESULTS: At univariate analysis, loss of retroplacental clear space, myometrial thinning (MT) and placenta lacunar spaces on US, intraplacental dark bands (IDBs), focal interruption of myometrial border (FIMB) and abnormal vascularity (AV) on MR were statistically significant (p < 0.01). Three diagnostic methods for PAS were then developed for both US and MR when at least one (Method 1), two (Method 2) or three (Method 3) imaging signs occurred, respectively. Method 2 for MR showed a significantly (p < 0.05) higher accuracy (91%) compared to the other methods. When MR IDBs and AV as well as IDBs and FIMB were present in combination with US MT the probability of PAS increased from 75 to 90% and from 80 to 91%, respectively. CONCLUSION: MR demonstrated a higher diagnostic accuracy than US to detect PAS. However, since the combination of MR and US signs could improve the probability to detect PAS, a complementary diagnostic role of these techniques could be considered.

Noninvasive Ultrasound Monitoring of Embryonic and Fetal Development in Chinchilla lanigera to Predict Gestational Age: Preliminary Evaluation of This Species as a Novel Animal Model of Human Pregnancy.

Ultrasound is a noninvasive routine method that allows real-time monitoring of fetal development in utero to determine gestational age and to detect congenital anomalies and multiple pregnancies. To date, the developmental biology of Chinchilla lanigera has not yet been characterized. This species has been found to undergo placentation, long gestation, and fetal dimensions similar to those in humans. The aim of this study was to assess the use of high-frequency ultrasound (HFUS) and clinical ultrasound (US) to predict gestational age in chinchillas and evaluate the possibility of this species as a new animal model for the study of human pregnancy. In this study, 35 pregnant females and a total of 74 embryos and fetuses were monitored. Ultrasound examination was feasible in almost all chinchilla subjects. It was possible to monitor the chinchilla embryo with HFUS from embryonic day (E) 15 to 60 and with US from E15 to E115 due to fetus dimensions. The placenta could be visualized and measured with HFUS from E15, but not with US until E30. From E30, the heartbeat became detectable and it was possible to measure fetal biometrics. In the late stages of pregnancy, stomach, eyes, and lenses became visible. Our study demonstrated the importance of employing both techniques while monitoring embryonic and fetal development to obtain an overall and detailed view of all structures and to recognize any malformation at an early stage. Pregnancy in chinchillas can be confirmed as early as the 15th day postmating, and sonographic changes and gestational age are well correlated. The quantitative measurements of fetal and placental growth performed in this study could be useful in setting up a database for comparison with human fetal ultrasounds. We speculate that, in the future, the chinchilla could be used as an animal model for the study of US in human pregnancy.

Diagnostic accuracy of magnetic resonance imaging in assessing placental adhesion disorder in patients with placenta previa: Correlation with histological findings.

OBJECTIVE: To evaluate MRI accuracy in assessing placental adhesion disorders (PAD) in patients with placenta previa correlating imaging results with histological findings. MATERIALS AND METHODS: Sixty-one patients who underwent abdomino-pelvic magnetic resonance imaging (MRI) for ultrasound suspicion of PAD were prospectively evaluated. T1- and T2-weighted images, with and without fat suppression, were obtained in the three conventional planes using a 1.5 T MRI scanner. MRI accuracy to evaluate the presence of PAD was assessed on the basis of the occurrence of the following abnormal MRI signs: 1) intraplacental dark bands; 2) focal interruption of myometrial border; 3) intraplacental abnormal vascularity; 4) uterine bulging; 5) tenting of the bladder and/or 6) direct visualization of adjacent tissues invasion only in case of percretism. Imaging results were classified as suggestive or not of PAD using histological data as standard of reference; two methods of imaging analysis were used represented by the presence of at least one (Method A) or two (Method B) abnormal MRI signs; the correlation between the presence of each abnormal MRI sign of PAD and the corresponding histological finding was also assessed. RESULTS: The accuracy, as the area under the receiver operating characteristic curve, was significantly (p = 0.001) higher for Method B (0.92, C.I. 95%: 0.82-0.97) compared to Method A (0.764, C.I. 95%: 0.64-0.86). Among the abnormal MRI signs, intraplacental dark bands and focal interruption of myometrial border were those highly correlated with histological proof of PAD (ρ > 0.71, p < 0.001, for both); as result, a modified version of Method B (Method C) was identified considering as criterion for PAD the combined presence of the two abnormal MRI signs highly correlated with histologically proven PAD; however, the accuracy of Method C was significantly (p = 0.005) lower (0.80, C.I. 95%: 0.67-0.89) than Method B and comparable to Method A. CONCLUSIONS: MRI is a useful imaging technique to assess PAD in patients with placenta previa; in particular, the presence of at least two among all the abnormal MRI signs represents the most accurate criterion (Method B) to identify PAD. Although intraplacental dark bands and focal interruption of myometrial border showed the highest correlation with histological proof of PAD as well as this association was the most frequent in PAD, the combination of these latter MRI signs along with other abnormal signs should be considered diagnostic for PAD.

Predictors of Asymptomatic Radiation-induced Abdominal Atherosclerosis.

AIMS: To identify predictors of asymptomatic radiation-induced abdominal atherosclerosis in patients treated with radiotherapy and evaluated by abdominal vascular ultrasonography. MATERIALS AND METHODS: Forty-two testicular classic seminoma patients (median age 34 years, range 16-56) undergoing radical inguinal orchiectomy were analysed. Twenty-six patients underwent post-surgery radiotherapy (median total dose 25 Gy, range 25-43), two of them also received chemotherapy (CHT) and 16 patients were treated with surgery alone or by surgery followed by CHT (control group). The presence of stenosis in an abdominal vessel and renal resistive index (RRI), evaluated by echo-colour Doppler (ECD), were considered as indicators of late vascular damage. Chi-square and Mann-Whitney tests were used to compare groups. For the radiotherapy group, near maximum (D2%) and mean dose (Dmean) metrics of critical structures (abdominal arteries and renal hila) were extracted from retrievable dose maps (18 of 26 radiotherapy patients). To evaluate clinical and dosimetric factors associated with vascular damage, univariate and multivariate analyses were carried out. The impact of dose to arteries, evaluated as separate subvolumes, was analysed comparing the stenotic arteries with normal ones by logistic regression. The area under the receiver operator characteristic curve (AUC) was used to evaluate the test accuracy. RESULTS: In the radiotherapy group there was a significantly different incidence of stenosis (31% versus 0%, P = 0.016) and a higher median average RRI (0.63 versus 0.60, P = 0.032) compared with the control group. The median time intervals between treatment and ECD were 64 months (range 12-120) and 48 months (range 12-168) in the radiotherapy and control groups (P = 0.399), respectively. A younger age at radiotherapy was the only clinical risk factor for stenosis (P = 0.006). Artery Dmean was significantly associated with stenosis (P = 0.008), with an odds ratio of 1.13 (95% confidence interval 1.01-1.26) and an AUC of 0.85 (95% confidence interval 0.77-0.91). Renal hilum D2% was correlated with RRI (Rs = 0.406, P = 0.02). CONCLUSIONS: Late vascular damage represents a potential effect of abdominal radiotherapy, even at a moderate dose. Younger age at irradiation, artery and renal hila dose metrics are associated with increased risk. Ultrasound-based follow-up may allow for non-invasive early detection of asymptomatic radiation-induced damage, helping to prevent severe vascular events.

Quality of life and cognitive functions in early onset multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease of the CNS occurring in young adults and even in children in 5% of cases. Lower quality of life (QoL) and cognitive impairment (CI) (40-54%) have been reported in early-onset MS (EO-MS) patients. OBJECTIVE: To assess QoL and cognitive function in EO-MS and their relationship, also considering demographic and clinical variables. METHODS: Paediatric Quality of life inventory Version 4.0 for patients aged 13-18 and 19-25 years, Beck Depression Inventory II (BDI II) and the Rao Brief Repeatable Battery were performed in EO-MS patients (onset age ≤25years). EDSS and MSSS were performed at same time. After testing for normal distribution, group comparisons were performed through the two-tailed Student's t test, one-way analysis of variance (ANOVA) and linear or logistic regression when appropriate. The Bonferroni correction for multiple testing was used when appropriate. RESULTS: 59 patients were included (mean age: 20 ± 3.6; Female sex 52.54%). 34 patients had a paediatric onset (<18 years) while 20 patients had a juvenile onset (18 < age < 25 years) of disease. 5 patients were excluded for missing data. HR-QoL was higher in paediatric than juvenile MS patients (p = 0.02), and it was inversely related to EDSS (p = 0.0005) and Multiple Sclerosis Severity score (MSSS) (p = 0.0001). Sixtyone % of patients showed a CI at BRB. No association was found between CI and any socio-demographic and clinical data. HR-QoL total score was not related to CI status nor to any domain-specific cognitive function score, even considering BDI as possible bias. CI was related to social, physical functioning score and EDSS (p = 0.01) at a logistic regression backward stepwise estimation. CONCLUSION: HR-QoL resulted to be better in paediatric than juvenile MS onset patients and was inversely related to rapidity of disability accumulation, while cognitive impairment was influenced by physical disability and poor social involvement (school, education …). Social participation, affective relations and psychological flexibility could have a protective function on CI.

Contrast-enhanced ultrasound evaluation of peripheral microcirculation in diabetic patients: effects of cigarette smoking.

PURPOSE: Cigarette smoking and diabetes mellitus predisposes to vascular disease. Our study aimed to evaluate the chronic effects of cigarette smoking on peripheral microcirculation assessed with contrast-enhanced ultrasound (CEUS) in diabetic patients. MATERIALS AND METHODS: The study population comprised ten smoker (7/3 M/W, age 42-76 years) and 16 nonsmoker (8/8 men/women, age 47-80 years) diabetic patients. The ankle-brachial index (ABI) was determined, and colour Doppler ultrasound (CDUS) of the lower legs was performed to determine the presence of peripheral arteriopathy disease (PAD). Microvascular blood flow in the gastrocnemius muscle was evaluated with CEUS. RESULTS: No differences were observed in ABI and CDUS examination between smokers and nonsmokers. Smoking had a significant effect on microcirculatory function. Timeto-peak (TTP), arrival time in tissue (ATt) and artery/ tissue transit time (A/Ttt) were significantly prolonged in smokers (TTP 43.76 ± 9.38 s vs. 34.12 ± 6.8 s, p=0.011, ATt 28.9 ± 7.5s vs. 22.4 ± 6.4 s, p=0.017 and A/Ttt 6.81 ± 4.52 s vs. 3.25 ± 3.27 s, p=0.02), with no significant differences between patients with and without PAD. CONCLUSIONS: The long-term exposure to cigarette smoke affects microcirculatory function. Contrast imaging is a noninvasive technique that can document these effects.

Predictive factors of neutralizing antibodies development in relapsing-remitting multiple sclerosis patients on interferon Beta-1b therapy.

The identification of predictive factors of NAbs development might have a relevant impact on clinical practice. Our objective is to look after predictive factors of NAbs development in MS IFN Beta-1b-treated patients. Database was screened for patients on IFN Beta-1b treatment with an Expanded Disability Status Scale (EDSS) at a baseline between 1 and 3.5, disease duration shorter than 15 years, and NAbs analysis performed every 6 months. The NAbs positive status was analysed in relation to baseline clinical, neuropsychological and brain imaging measures. Forty-nine patients were included. Sixteen patients had become NAbs positive at some point on IFN therapy (35%). NAbs producers differed from not producers for higher incidence of cognitive deficit and higher lesion load (OR = 5.0 and 5.6, respectively). Our study suggests that NAbs development might be a marker of a more aggressive disease and that worse outcome in NAbs producers might be biased by baseline condition.

The Italian affair: the employment of parallel-plate ionization chambers for dose measurements in high dose-per-pulse IORT electron beams.

PURPOSE: At the high dose-per-pulse rates used by some intraoperative radiotherapy (IORT) units, the employment of ionization chambers for dose measurements needs an appropriate correction (k(sat)) for ion recombination. Through a revision of the existing literature, the authors compared different methods for the determination of the recombination correction factor and their impact on clinical dosimetry. METHODS: A dosimetric characterization of IORT electron beams from a Linac Hitesys Novac7 (Aprilia-Latina, Italy) was performed. Dose-to-water (D(w)) values were measured with dose-per-pulse independent chemical dosimeters (operated by the Italian Primary Standard Dosimetry Laboratory, ENEA) and compared to doses obtained by two different parallel-plate ionization chamber models (Markus and Advanced Markus, PTW, Freiburg, Germany). For dose measurements using ionization chambers, the authors applied two different methods for the determination of the ion recombination correction factor (k(sat)), as suggested in previous articles. The first method is based on the experimental estimation of the free-electron fraction values p; the second one is based on the "nonstandard" two-voltage analysis including the free-electron component. RESULTS: For a Markus type chamber, there is a good agreement between the results on k(sat) and those reported in the literature for both methods, while for the Advanced Markus chamber, no data are available for comparison. CONCLUSIONS: Comparing values of D(w) obtained by dose-per-pulse independent dosimeters and by ionization chambers measurements corrected using the two different approaches, the authors can conclude that the k(sat) factor determination is very critical and that only an experimental protocol using ionization chamber intercalibration can be considered reliable.

Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance imaging study.

BACKGROUND: Anderson-Fabry disease is a multisystem X linked disorder of lipid metabolism frequently associated with cardiac symptoms, including left ventricular (LV) hypertrophy gradually impairing cardiac function. Evidence showing that enzyme-replacement therapy (ERT) can be effective in reducing LV hypertrophy and improving myocardial function in the long term is limited. OBJECTIVE: This study aimed to assess the long-term effects of ERT with recombinant alpha-galactosidase A (agalsidase beta, Fabrazyme) on LV function and myocardial signal intensity in 11 patients with Anderson-Fabry disease. PATIENTS: Eleven patients (eight males, three females) with varying stages of genetically confirmed Anderson-Fabry disease were examined by means of physical examination and magnetic resonance imaging before ERT with agalsidase beta at 1 mg/kg every other week (study 1) and after a mean treatment duration of 45 months (study 2). RESULTS: At 45 months of treatment, LV mass and LV wall thickness had significantly reduced: 188 (SD 60) g versus 153 (47) g, and 16 (4) mm versus 14 (4) mm, respectively. Furthermore, a significant reduction in myocardial T2 relaxation times was noted in all myocardial regions, that is, interventricular septum 80 (5) ms versus 66 (8) ms, apex 79 (10) ms versus 64 (10) ms, and lateral wall 80 (8) ms versus 65 (16) ms. Changes in LV ejection fraction were not significant. Amelioration of clinical symptoms was observed in all patients. CONCLUSIONS: Long-term therapy with agalsidase beta at 1 mg/kg every 2 weeks was effective in significantly reducing LV hypertrophy, improving overall cardiac performance and ameliorating clinical symptoms in patients with Anderson-Fabry disease.

Measurement of the intrarenal arterial resistance index for the identification and prediction of diabetic nephropathy.

BACKGROUND AND AIMS: High intrarenal resistance index (RI) predicts renal function in several conditions; its use in the prediction of diabetic nephropathy (DN) is little explored. We aimed (1) to compare RI in diabetic and non diabetic hypertensive patients, and (2) to evaluate whether high RI is associated with clinical signs of DN and its progression over time. DESIGN: observational, prospective. PARTICIPANTS: 92 type 2 diabetic patients and 37 non-diabetic controls aged 40-70, with hypertension and normal renal function. We measured ultrasound RI and, among others, creatinine, estimated glomerular filtration rate and urinary albumin excretion rate (AER) at baseline and after 4.5 years follow-up. Progression of albuminuric state (i.e., transition from baseline normo-microalbuminuria to follow-up micro-macroalbuminuria) was evaluated. RI was significantly higher in diabetic than non-diabetic participants (0.69+/-0.05 vs 0.59+/-0.05, p<0.001). Diabetic patients with RI>or=0.73, i.e., above the 80th percentile of the RI distribution, had significantly higher baseline AER and a more frequent progression of the albuminuric state compared to patients with RI<0.73 (27.7microg/mg [12.1-235.4] vs 15.1microg/mg [8.6-33.4]; 52.9% vs 9.5%, respectively). AER increased significantly from baseline to follow-up in patients with RI>or=0.73 (from 27.7microg/mg [12.1-235.4] to 265.0microg/mg [23.8-1018.1], p<0.01), but not in those with RI<0.73 (from 15.1microg/mg [8.6-33.4] to 16.1microg/mg [10.7-67.2], ns). OR for progression of albuminuric state, adjusted for established predictors of DN, including baseline AER, was 5.01 (1.4-17.7, 95% CI) for patients with RI>or=0.73 vs <0.73. Findings were confirmed in patients with normoalbuminuria at baseline. CONCLUSIONS: In diabetic patients, high RI (>or=0.73) is associated with features of DN and its progression over time, independent of albuminuria.

Multislice CT with single-phase technique in patients with suspected pancreatic cancer.

PURPOSE: The purpose of this study was to evaluate the role of multislice computed tomography (MSCT) with a single-phase technique in patients with suspected pancreatic cancer (PC). MATERIALS AND METHODS: Seventy-eight patients underwent MSCT with the following technical parameters: collimation: 4x1 mm; pitch 1; 120 kVp; 260 mAs. The pre-contrast scan was followed by a single acquisition phase in the caudocranial direction from the inferior hepatic margin to the diaphragm with a 60-s delay after IV administration of 150 ml of iodinated contrast material at a rate of 3 ml/s. Two radiologists assessed the single images independently. Receiver operating characteristics (ROC) curves were obtained for each of the two observers. RESULTS: The final diagnosis was pancreatic cancer in 46 cases and chronic pancreatitis in 32 cases. Areas under the curve (AZ) for diagnosis and evaluation of disease resectability were 0.97 and 0.93 for the first observer (p=ns), and 0.97 and 0.90 for the second observer (p=ns). The mean difference in tissue attenuation values between the cancer and normal pancreas was 72 +/- 3 Hounsfield units (HU). No statistically significant differences were observed in the degree of opacification between the peripancreatic arteries and veins. CONCLUSIONS: MSCT with a single-phase technique is an accurate and reproducible method for diagnosis and evaluation of disease resectability in patients with suspected PC, ensuring optimal tumour-to-pancreas contrast and maximal opacification of the main peripancreatic arterial and venous structures.

Hypericin photosensitization of tumor and metastatic cell lines of human prostate.

We have investigated the photoactivating effect of hypericin on two cancer cell lines: PC-3, a prostatic adenocarcinoma non-responsive to androgen therapy and LNCaP, a lymphonodal metastasis of prostate carcinoma responsive to androgen therapy. The two cell lines are incubated for 24 h with hypericin at concentrations ranging from 0.001 to 0.3 microg/ml in cell culture medium. The cells are irradiated at 599 nm (fluence = 11 J/cm2) using a dye laser pumped by an argon laser. Hypericin exerts phototoxic effects on both cell lines, while it does not produce toxic effects in the absence of irradiation. These results suggest that photodynamic therapy (PDT) with hypericin could be an alternative approach to the treatment of prostatic tumors, and could be beneficial in tumors that are non-responsive to androgen therapy.

MS-2 fibrosarcoma characterization by laser induced autofluorescence.

BACKGROUND AND OBJECTIVE: MS-2 fibrosarcoma implanted in BALB-CDF1 mice was investigated by frequency and time domain measurements of the autofluorescence (AF) radiation emitted upon excitation by a N(2) laser beam (337.1 nm). STUDY DESIGN/MATERIALS AND METHODS: AF spectra were obtained by using a spectrograph, a multichannel plate and an optical multichannel analyzer for the steady state detection. Time-resolved spectra were performed by means of a monochromator, a photomultiplier, and a digital signal analyzer. RESULTS: Spectral measurements show that the autofluorescence intensity of pathologic tissue is lower than that of healthy one in the 400- to 500- spectral region. In the same spectral range, we found the fluorescence decay to be the sum of a fast and a slow component. The lifetime of the fast component of tumoral tissue is significantly lower than that of healthy samples. CONCLUSION: Frequency and time domain measurements used in combination show that MS2-fibrosarcoma is characterized by the probable presence of the free form of NADH.

In vitro photo-activation of newly synthesized chlorin derivatives with red-light-emitting diodes.

We investigated the in vitro photo-activation properties of two chlorin derivatives, i.e. 8-cis-heptylchlorin dicarboxylic acid and 3-trans-heptylchlorin bisamidoglucose derivative, which exhibit lipophilic properties similar to those of the active fractions of Photofrin II, on a normal epithelial cell line (FRTL-5). We used as an irradiation source an array of diodes emitting red light (lambda = 675 nm), which produced a fluence of 7mW cm-2 on the cells. We found that photo-activation with chlorin derivatives in the concentration range 1-100 ng ml-1 greatly enhanced the mortality of the irradiated cells (energy density, 0.25 J cm-2) with respect to the control cells kept in the dark. This response is immediate and appears to be an "all or none' effect. Taking into account that compounds exhibit a strong absorbance peak in the long wavelength region of visible light where tissues are relatively transparent, our results suggest that chlorins can be considered to be good candidates for application in photodynamic therapy.

Detection of x rays with a fiber-optic interferometric sensor.

A fiber-optic Mach-Zehnder interferometer was used for x-ray detection. A single-mode, polarization-preserving silica fiber is exposed to a high-flux x-ray beam (x-ray tube for diagnostic radiology, 30 kV, 16.8-keV average energy, 17-40-mA anodic current), modulated at f = 9 Hz by a chopper with steel blades. The energy absorbed produces a modulated temperature rise that induces a phase shift in the propagation of a He-Ne laser beam with respect to the unirradiated arm of the interferometer. We measured the linearity of the temperature rise with the energy released to the fiber and the linearity of the peak amplitude at frequency f in the power spectrum of the interferometric signal with the anodic current of the x-ray tube. A possible application of this technique to synchrotron radiation monitoring is discussed.