Risks and Benefits of Transplantation in the Cure of Type 1 Diabetes: Whole Pancreas Versus Islet Transplantation. A Single Center Study

BACKGROUND: Pancreas and islet transplantation are the only available options to replace beta-cell function in patients with type 1 diabetes. Great variability in terms of rate of success for both approaches is reported in the literature and it is difficult to compare the respective risks and benefits. OBJECTIVES: The aim of this study was to analyze risks and benefits of pancreas transplantation alone (PTA) and islet transplantation alone (ITA) by making use of the long-term experience of a single center where both transplantations are performed. We focused on the risks and benefits of both procedures, with the objective of better defining indications and providing evidence to support the decision-making process. The outcomes of 33 PTA and 33 ITA were analyzed, and pancreas and islet function (i.e., insulin independence), perioperative events, and long-term adverse events were recorded. RESULTS: We observed a higher rate of insulin independence in PTA (75%) versus ITA (59%), with the longer insulin independence among PTA patients receiving tacrolimus. The occurrence of adverse events was higher for PTA patients in terms of hospitalization length and frequency, re-intervention for surgical and immunological acute complications, CMV reactivation, and other infections. CONCLUSIONS: In conclusion, these results support the practice of listing patients for PTA when the metabolic control and the progression of chronic complications require a rapid normalization of glucose levels, with the exception of patients with cardiovascular disease, because of the high surgical risks. ITA is indicated when replacement of beta-cell mass is needed in patients with a high surgical risk

Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses

Italian multicenter, prospective study to evaluate the negative predictive value of 16- and 64-slice MDCT imaging in patients scheduled for coronary angiography (NIMISCAD-Non Invasive Multicenter Italian Study for Coronary Artery Disease)

Abstract This was a prospective, multicenter study designed to evaluate the utility of MDCT in the diagnosis of coronary artery disease (CAD) in patients scheduled for elective coro- nary angiography (CA) using different MDCT systems from different manu- facturers. Twenty national sites pro- spectively enrolled 367 patients between July 2004 and June 2006. Computed tomography (CT) was performed using a standardized/ optimized scan protocol for each type Coronary angiography (CA) represents the standard of reference to assess epicardial vessels and establish the presence of significant coronary artery disease (CAD). CA is a bi-dimensional diagnostic technique that allows evalua- tion of the vessel lumen [1] at high spatial (50 lps/cm) and temporal (<20 ms) resolution. However, CA has its limitations: it is an invasive technique, involves high costs, requires hospitalization, and has low patient compliance. The risks associated with CA are related to its invasiveness and result in a morbidity rate of 1.5% and a mortality rate of 0.15% [2]. In addition, a considerable proportion of patients undergoing CA are subsequently found not to have clinically significant disease [3, 4]. These limitations may justify the increasing clinical use of alternative non-invasive imaging techniques for the evaluation and exclusion of clinically significant CAD. Many centers have reported their experiences in using different multidetector computed tomography (MDCT) technologies, all of which have been characterized by high diagnostic accuracy in the assessment of patients scheduled for CA. Whether the reported diagnostic accuracy can be replicated in clinical practice needs to be established at different centers with varying expertise, in non-selected patient populations and with different MDCT systems before extensive clinical application of MDCT for CAD assessment. The primary aim of this study was to assess the negative predective value (NPV) of MDCT in a multicenter study using different MDCT machines/manufacturers to deter- mine if the technique could replace an invasive procedure to exclude the presence of significant CAD. Secondary objectives were to investigate whether MDCT performance is affected by patient characteristics such as pre-test CAD risk, body mass index (BMI), and coronary artery calcium score (CACS). Safety was also investigated. Materials and methods This was a national, multicenter, prospective trial sponsored by the Italian Society of Medical Radiology (SIRM). Adult patients previously scheduled for an elective CA evaluation for a diagnostic workup at each of the participating centers were consecutively evaluated for inclusion in the study. Exclusion criteria included preg- nancy or lactation, contraindication to intravenous admin- istration of iodinated contrast media, heart rate >70 beats per minute (bpm) despite beta-blocker treatment, absence of sinus rhythm, New York Heart Association (NYHA) class III–IV, previous coronary artery bypass graft surgery (CABG) or stenting, and creatinine value >2 mg/dl. The Institutional Review Boards of all centers approved the study protocol, and written informed consent was obtained from all patients before study inclusion in accordance with the national legislation and the Declaration of Helsinki. Patient preparation Patients with heart rates >70 bpm were given an oral dose of metoprolol tartrate 45–60 min before MDCT imaging or an intravenous beta-receptor blocker just before the scan. Heart rate, electrocardiogram (ECG), and blood pressure were monitored. MDCT protocol and image reconstructions Patients underwent 16- or 64-slice MDCT with a standardized and optimized protocol for each type of CT machine. Unenhanced prospective ECG-gated MDCT was performed for the assessment of calcium deposits by Agatston Score (AS). A bolus of 100– 120 ml of non-ionic iodinated contrast medium Ultra- vist® (Iopromide 370; Bayer Schering Pharma, Berlin, Germany) was intravenously injected, preferably through the right antecubital vein, at a flow rate of 3– 4 ml/s for the 16-slice MDCT system and 4–6 ml/s for the 64-slice MDCT system, and followed by a 40–50-ml saline chaser at the same flow rate. The main scan parameters have been given for each scanner type in Table 1, including the number of patients scanned on each CT system. ficity, and DA were 0.73 (95% CI 1115 of MDCT system (≥16 slices) and compared with quantitative CA per- formed within 2 weeks of MDCT. A total of 284 patients (81%) were studied by 16-slice MDCT systems, while 66 patients (19%) by 64-slice MDCT scanners. The primary analysis was on-site/off-site evaluation of the negative predictive value (NPV) on a per-patient basis. Secondary analyses included on-site evaluation on a per- artery and per-segment basis. On-site Introduction evaluation included 327 patients (CAD prevalence 58%). NPV, positive predictive value (PPV), sensitivity, specificity, and diagnostic accuracy (DA) were 0.91 (95% CI 0.85–0.95), 0.91 (95% CI 0.86–0.95), 0.94 (95% CI 0.89–0.97), 0.88 (95% CI 0.81– 0.93), and 0.91 (95% CI 0.88–0.94), respectively. Off-site analysis in- cluded 295 patients (CAD prevalence 56%). NPV, PPV, sensitivity, speci- 0.65–0.79), 0.93 (95% CI 0.87–0.97), 0.73 (95% CI 0.65–0.79), 0.93 (95% CI 0.87–0.97), and 0.82 (95% CI 0.77–0.86), respectively. The results of this study demonstrate the utility of MDCT in excluding significant CAD even when conducted by centers with varying degrees of expertise and using different MDCT machines

Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT Study): Interim results

PURPOSE: To prospectively compare clinical breast examination (CBE), mammography, ultrasonography (US), and contrast material-enhanced magnetic resonance (MR) imaging for screening women at genetic-familial high risk for breast cancer and report interim results, with pathologic findings as standard. MATERIALS AND METHODS: Institutional review board of each center approved the research; informed written consent was obtained. CBE, mammography, US, and MR imaging were performed for yearly screening of BRCA1 or BRCA2 mutation carriers, first-degree relatives of BRCA1 or BRCA2 mutation carriers, or women enrolled because of a strong family history of breast or ovarian cancer (three or more events in first- or second-degree relatives in either maternal or paternal line; these included breast cancer in women younger than 60 years, ovarian cancer at any age, and male breast cancer at any age). RESULTS: Two hundred seventy-eight women (mean age, 46 years +/- 12 [standard deviation]) were enrolled. Breast cancer was found in 11 of 278 women at first round and seven of 99 at second round (14 invasive, four intraductal; eight were <or=10 mm in diameter). Detection rate per year was 4.8% (18 of 377) overall; 4.3% (11 of 258) in BRCA1 or BRCA2 mutation carriers and first-degree relatives of BRCA1 or BRCA2 mutation carriers versus 5.9% (seven of 119) in women enrolled because of strong family history; and 5.3% (nine of 169) in women with previous personal breast and/or ovarian cancer versus 4.3% (nine of 208) in those without. In six (33%) of 18 patients, cancer was detected only with MR imaging. Sensitivity was as follows: CBE, 50% (95% confidence interval [CI]: 29%, 71%); mammography, 59% (95% CI: 36%, 78%); US, 65% (95% CI: 41%, 83%); and MR imaging, 94% (95% CI: 82%, 99%). Positive predictive value was as follows: CBE, 82% (95% CI: 52%, 95%); mammography, 77% (95% CI: 50%, 92%); US, 65% (95% CI: 41%, 83%); and MR imaging, 63% (95% CI: 43%, 79%). CONCLUSION: Addition of MR imaging to the screening regimen for high-risk women may enable detection of otherwise unsuspected breast cancers

Human vitreous in proliferative diabetic retinopathy: Characterization and translational implications

Diabetic retinopathy (DR) is one of the leading causes of visual impairment in the working-age population. DR is a progressive eye disease caused by long-term accumulation of hyperglycaemia-mediated pathological alterations in the retina of diabetic patients. DR begins with asymptomatic retinal abnormalities and may progress to advanced-stage proliferative diabetic retinopathy (PDR), characterized by neovascularization or preretinal/vitreous haemorrhages. The vitreous, a transparent gel that fills the posterior cavity of the eye, plays a vital role in maintaining ocular function. Structural and molecular alterations of the vitreous, observed during DR progression, are consequences of metabolic and functional modifications of the retinal tissue. Thus, vitreal alterations reflect the pathological events occurring at the vitreoretinal interface. These events are caused by hypoxic, oxidative, inflammatory, neurodegenerative, and leukostatic conditions that occur during diabetes. Conversely, PDR vitreous can exert pathological effects on the diabetic retina, resulting in activation of a vicious cycle that contributes to disease progression. In this review, we recapitulate the major pathological features of DR/PDR, and focus on the structural and molecular changes that characterize the vitreal structure and composition during DR and progression to PDR. In PDR, vitreous represents a reservoir of pathological signalling molecules. Therefore, in this review we discuss how studying the biological activity of the vitreous in different in-vitro, ex-vivo, and in-vivo experimental models can provide insights into the pathogenesis of PDR. In addition, the vitreous from PDR patients can represent a novel tool to obtain preclinical experimental evidences for the development and characterization of new therapeutic drug candidates for PDR therapy