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Objectives: Radiofrequency ablation (RFA) has been used to treat hepatic, renal and prostate tumors. Preliminary experiences in breast cancer, followed by surgical excision, were encouraging. We performed a pilot trial of ultrasound-guided percutaneous RFA, not followed by surgery, in three elderly inoperable patients with breast carcinoma. The study was undertaken to determine the feasibility of treating small breast malignancies with RFA only and to evaluate the safety and complications related to this treatment., Methods: Three patients with core-needle biopsy-proven invasive carcinoma (<2 cm in greatest dimension) underwent ultrasound-guided RFA under local anesthesia, as outpatient procedure. Treatment was planned to ablate the tumor and a margin of surrounding breast tissue. All the patients were evaluated after a 1, 6, 12 and 18 months of follow-up., Results: All the patients completed the treatment with minimal or no discomfort and returned home after 1 h. The mean age was 81.3 years (range, 76-86 years) and the mean tumor size was 11.6 mm (range, 10-13 mm). The tumors laid more than 10 mm from chest wall and from the skin. The mean time required for ablation was 10.3 min (range, 8-12 min). There were no treatment-related complications. Post-ablation ultrasound scan, mammography, Magnetic Resonance Imaging scan and core biopsy, confirmed the tumor necrosis. After 18 months of follow-up no recurrence occurred., Conclusions: RFA was feasible and safe for minimally invasive treatment of elderly inoperable patients with early-stage, primary breast carcinoma.

Objective: To determine the efficacy of donepezil in the treatment of neuropsychiatric symptoms in patients with Alzheimer disease (AD) in a randomized withdrawal study., Method: Patients with mild to moderate AD with marked neuropsychiatric symptoms at baseline (Neuropsychiatric Inventory [NPI] > 11 points) were treated openly with donepezil 5 mg daily for 6 weeks followed by 10 mg daily for a further 6 weeks. Patients were then randomized (60:40) to either placebo or 10 mg donepezil daily. All patients were assessed at 6 weeks and provided there was no marked cognitive deterioration their blinded treatment was continued for a further 6 weeks. NPI and carer distress were assessed at 6 weekly intervals throughout the study., Results: A total of 134 patients participated. Following randomization patients who continued on donepezil 10 mg for 12 weeks had improvements in NPI compared with the placebo group (mean change -2.9 vs 3.3 points; ITT-LOCF p = 0.02) and in NPI-Distress scores (median change -2.0 vs 1.0 points; ITT-LOCF p = 0.01). During the open-label phase the total NPI and NPI-Distress scores were lower after 12 weeks treatment with open label donepezil compared with baseline (total NPI 22 points vs13 points; ITT-LOCF p < 0.0001; NPI-Distress 13.5 vs 7.9 points; ITT-LOCF p < 0.0001). In the open-label phase all domains of the NPI (with the exception of elation) were improved (all p < 0.05 after Bonferroni correction)., Conclusions: Donepezil has significant efficacy in the treatment of neuropsychiatric symptoms in patients with mild to moderate AD.

The immunoregulatory function of NKT cells is crucial for prevention of autoimmunity. The prototypical NKT cell Ag alpha-galactosylceramide is not present in mammalian cells, and little is known about the mechanism responsible for NKT cell recruitment and activation. Up-regulation of CD1d, the NKT cell restriction molecule, expressed on mononuclear cells infiltrating the target organ, could represent the physiological trigger for NKT cells to self-contain T cell immunity and to prevent autoimmune disease. Recognition of CD1d, either by itself or bound to self-ligands (selfCD1d), could drive NKT cells toward an immunoregulatory phenotype. Hence, ineffective NKT cell-mediated immunoregulation in autoimmune-prone individuals including nonobese diabetic (NOD) mice could be related to defective signals that regulate CD1d expression at time and site of autoimmunity. To test this hypothesis, we transgenically overexpressed CD1d molecules under the control of the insulin promoter within the pancreatic islets of NOD mice (insCD1d). Recognition of overexpressed CD1d molecules rescued NKT cell immunoregulatory function and prevented autoimmune diabetes in insCD1d transgenic NOD mice. Protection from diabetes was associated with a biased IL-4-secreting cytokine phenotype of NKT cells and alteration of the cytokine microenvironment in the pancreatic lymph nodes of transgenic mice. The net effect was a reduced development of the autoimmune T cell repertoire. Our findings suggest that up-regulation of CD1d expression during inflammation is critical to maintain T cell homeostasis and to prevent autoimmunity.

Objective: To determine the interest of Chromogranin A (CgA) determination for diagnosis and follow-up in patients with gastroenteropancreatic endocrine tumours (GEP-ET) and multiple endocrine neoplasia type 1 (MEN-1)., Patients and Methods: CgA levels were measured with an immunoradiometric assay in 124 sporadic GEP-ET, 34 MEN-1 and 127 controls. Serial determinations were performed in 56 patients (212 visits). Changes in CgA levels over 25% were considered as significant., Results: Using a cut-off value of 130 micro g/l, established from a receiver-operating characteristic curve, the specificity of CgA was 98.4%, with a sensitivity of 62.9%, higher in secreting than in nonsecreting tumours (73%vs. 45%; P < 0.003) and related to the extent of metastatic spreading (P < 0.001). In nonsecreting tumours, the positive predictive value (PPV) of CgA for the presence of metastases was 100% but the negative predictive value (NPV) was only 50%. In MEN-1, high CgA levels indicated a pancreatic tumour with a 100% specificity but the sensitivity was 59%. During the follow-up, the concordance between CgA and tumour evolution was 80%, whatever the secretory status. In patients with carcinoid tumours, the concordance was higher for CgA than for serotonin (81%vs. 54%; P < 0.001)., Conclusion: Due to its high specificity, CgA determination may help to discriminate the endocrine character of a GEP tumour and to indicate a pancreatic tumour in MEN-1. However, its low NPV in nonsecreting tumours limits its interest for diagnosis and staging. By contrast, serial evaluation of CgA seems of particular interest for the follow-up of GEP-ET tumours.

Recent experimental evidence shows that vaccination with amyloid-beta peptide (Abeta) of transgenic mouse models of Alzheimer's disease protects from the pathological accumulation of amyloid within the CNS. Phase I/II clinical trials of Abeta vaccination in mild to moderate Alzheimer's disease have been undertaken. Un expectedly, one of these trials has been suspended because 15 patients showed clinical signs consistent with CNS inflammation. Here, we show that C57BL/6 mice immunized with Abeta1-42 peptide develop an inflammatory disease of the CNS characterized by the presence both in the brain and spinal cord of perivenular inflammatory foci containing macrophages, T and B cells, and immunoglobulins. The experimental disease was observed only when pertussis toxin, an agent known to favour autoimmune processes, was co-administered. The immune-mediated CNS reaction was associated to Abeta-induced CD4(+) cells showing a Th1-type cytokine expression profile and to elevated levels of circulating anti-Abeta immunoglobulins. Our results indicate that vaccination with Abeta could determine, under certain circumstances, an aberrant autoimmune-type reaction to Abeta resulting in a perivenular inflammatory encephalomyelitis.

PRUNE, the human homologue of the Drosophila gene, is located in 1q21.3, a region highly amplified in human sarcomas, malignant tumours of mesenchymal origin. Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired affinity towards the nm23-H1 S120G mutant associated with advanced neuroblastoma. Based on these observations, we previously suggested that prune may act as a negative regulator of nm23-H1 activity. We found amplification of PRUNE in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant fibrous histiocytomas (MFH) as well as in the less malignant liposarcomas. PRUNE amplification was generally accompanied by high mRNA and moderate to high protein levels. The sarcoma samples expressed nm23-H1 mostly at low or moderate levels, whereas mRNA and protein levels were moderate to high in breast carcinomas. For the more aggressive sarcoma subtypes, 9/13 patients with PRUNE amplification developed metastases. A similar situation was observed in all breast carcinomas with amplification of PRUNE. Infection of NIH3T3 cells with a PRUNE recombinant retrovirus increased cell proliferation. Possibly, amplification and overexpression of PRUNE has the same effect in the tumours. We suggest that amplification and overexpression of PRUNE could be a mechanism for inhibition of nm23-H1 activity that affect the development or progression of these tumours.

Purpose: To evaluate and compare the intraaneurysmal pressure (IAP) after exclusion using two different endovascular grafts., Methods: Eight mongrel dogs had a 3 x 3 cm polytetrafluoroethylene (PTFE) aneurysm sewn as an interposition graft of the infrarenal aorta. A pressure transducer implanted into the aneurysm wall permitted continuous electronic IAP monitoring. Four aneurysms were excluded with a transluminally placed endovascular graft made of a PTFE graft and two Palmaz stents (PTFE-EG), three were excluded with a tantalum-Dacron endovascular graft (TD-EG), and one was surgically treated with a standard PTFE graft (PTFE-Surg). The dogs were observed for 18 to 50 days (mean, 37.5 days) and were evaluated after surgery with duplex and spiral computed tomographic scans., Results: All grafts successfully excluded the aneurysms without perigraft channels or leaks as documented by arteriogram and duplex and computed tomographic scans. The mean IAPs after repair with all PTFE-EGs were significantly lower (p < 0.001) than the mean systemic pressures. In addition, the mean IAP reduction was significantly greater (p < 0.005) in the PTFE-EG group than in the TD-EG group., Conclusions: Aneurysm exclusion with PTFE-EG significantly lowered IAP, did so significantly better than the TD-EG, and approached the IAP reduction obtained by standard repair. Such pressure reduction is necessary for effective protection against aneurysm rupture.

Thirty-one patients dependent on benzodiazepines were randomly assigned to either slow withdrawal (SW) or abrupt withdrawal under propranolol cover (PW). Of 16 patients in the SW group, 11 successfully withdrew from their drugs, while only 4 out of 15 in the PW group did so. Patients in the SW group had only mild withdrawal symptoms, while those in the PW group suffered more severe symptoms, which lasted around four weeks. In all, 81% of the whole group suffered withdrawal symptoms of some kind. Patients in both groups were significantly less anxious at the end of the study than at baseline. Younger subjects and those who were more severely anxious at the start of the trial had more difficulty in withdrawing than older and less anxious patients.