New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Postoperative enteral feeding does not prevent intestinal bacterial translocation, but reduces the rate of pulmonary infections in pigs undergoing total orthotopic small bowel transplantation

OBJECTIVE: To assess the effects of a non-elemental liquid diet on nutritional state, composition of bowel flora, intestinal translocation, and pulmonary infections after small bowel transplantation in pigs. DESIGN: Prospective randomised experiment. SETTING: Teaching hospital, Italy. MATERIAL: 32 female Large White pigs. INTERVENTIONS: Group 1 (n = 6) underwent small bowel transplantation, were treated with immunosuppression, and fed on commercial chow. Group 2 (n = 6) were treated similarly except that they were fed with an enteral feed through a tube gastrostomy starting on day 4 postoperatively. Group 3 (n = 6) were treated similarly to group 1 except that they had no immunosuppression, and Group 4 (n = 6) underwent orthotopic small bowel autotransplantation; 8 further pigs underwent a sham operation only to act as controls. MAIN OUTCOME MEASURES: Signs of rejection, graft-versus-host-disease, luminal bacterial overgrowth, bacterial translocation, pneumonia, and the pigs' nutritional state. RESULTS: All animals in group 3 showed signs of acute rejection. There was appreciable overgrowth of aerobic and anaerobic bacteria in all three groups after allotransplantation compared with controls. The counts of anaerobic bacteria were significantly lower in group 2 (enterally fed animals) compared with those given free access to commercial chow [mean (SD) 2.81 (1.39) log CFU/cm2 compared with 4.80 (1.65), p = 0.047]. Bacterial translocation developed to a similar degree after autografts and allografts and pneumonia developed in fewer animals after enteral feeding (1/6) than after conventional feeding (5/6) but the difference was not significant (p = 0.08, odds ratio 25.0, 95% confidence interval of odds ratio 1.20 to 521.13). Enterally fed animals also lost less weight than conventionally fed animals [2.32 (1.23) kg compared with 4.53 (1.74), p = 0.016]. CONCLUSIONS: Enteral feeding for up to a month slightly reduced the rate of pneumonia and resulted in a better nutritional state in pigs after small bowel transplantation. It had no effect on luminal bacterial overgrowth or translocatio

Extended lymph node dissection without routine spleno-pancreatectomy for treatment of gastric cancer : low morbidity and mortality rates in a single center series of 250 patients

Background and Objectives: To verify the hypothesis that avoidance of routine splenectomy and distal pancreatectomy in a modified D-2 resection for gastric cancer can significantly lower the complications rate of this procedure in a population of Western patients. Methods: A series of 250 consecutive Italian patients suffering from localized, histology-proven gastric cancer was submitted to gastrectomy and extended D-2 lymphadenectomy for treatment of their disease during an 8-year period (1994-2002) at the European Institute of Oncology in Milano, Italy. Caudal pancreas and spleen were routinely preserved, unless the tumor was not closely adjacent to or directly invading these organs. Postoperative morbidity, overall mortality, and length of hospital stay were recorded. Results: One hundred forty patients underwent total gastrectomy and 110 a subtotal distal one; splenectomy was performed in 8 cases and spleno-pancreatectomy in 15. The postoperative morbidity rate was 18%, the mortality rate was 1.2% and 9 patients experienced re-operation. The median length of stay was 14.8 days. Conclusions: These results compete favorably with those reported after standard D-1 gastrectomy in Western patients series. D-2 gastrectomy with spleen and pancreas routine preservation can be considered a safe treatment for gastric cancer in Western patients, at least in experienced centers

Dendritic cell sarcoma : an analytic overview of the literature and presentation of original five cases

Interdigitating and follicular dendritic cell sarcoma (DCS) are very rare diseases, with approximately 184 cases being reported thus far, and their best treatment modality is still on debate. This is a review of all the cases of dendritic cell sarcoma reported from 1981 until April 2006. This review is enriched with the original contribution of five cases occurred at our Institution from 1994 to 2006. The review of the literature pointed out that radical surgery alone was curative in approximately two thirds of these cases, the relapsing rate in patients who received adjuvant treatments being higher than 30%. We pinpoint new five cases of dendritic cell sarcoma (three FDCS and two IDCS). Both the analytic revision of the literature and our data suggest that localized DCS may be effectively treated by radical surgery and do not support the use of adjuvant treatments after radical excisio

Use of totally implantable central venous access ports for high-dose chemotherapy and peripheral blood stem cell transplantation : results of a monocentre series of 376 patients

BACKGROUND: The complication rate of central venous totally implantable access ports (TIAP), used for high-dose chemotherapy with autologous stem cell transplantation support, has not been fully investigated to date, due to the almost exclusive use of externalised, tunnelled devices in this clinical setting. PATIENTS AND METHODS: During a 66-month period (from 1 January 1997 to 30 June 2002), 376 patients suffering from breast cancer, ovarian cancer, lymphoma or multiple myeloma were treated with high-dose chemotherapy and autologous stem cell transplantation at the European Institute of Oncology (Milan, Italy). A single type of port was used, constructed from titanium and silicone rubber, connected to a 7.8 F polyurethane catheter (Port-A-Cath; SIMS Deltec, Inc., St Paul, MN, USA) inserted into the subclavian vein. They were followed prospectively for device-related complications until the device was removed, the patient died or the study was closed (30 June 2002). RESULTS: No TIAP-related deaths were observed in this series. Seven pneumothoraxes (1.8%) occurred as a complication of TIAP placement, one patient only (0.2%) requiring a tube thoracostomy. Port pocket infection occurred twice in this series (0.53%, 0.01 episodes/1000 days of use), whereas three patients suffered from port-related bacteraemia (0.8%, 0.016/1000 days of use). Infections were successfully treated with antibiotics; all three cases had the ports removed at programme completion. Four cases of deep vein thrombosis were detected (1.06%, 0.022/1000 days of use); low molecular weight heparin was given, followed by oral anticoagulants. Finally, one case of extravasation occurred (0.26%, 0.005/1000 days of use), requiring port removal and local medical therapy. CONCLUSIONS: The use of TIAPs has resulted in a safe and effective option for high-dose chemotherapy deliverance and stem cell transplantation, in spite of inducing severe neutropenia and increasing the risk of sepsis in this category of oncology patient

Primary and recurrent retroperitoneal soft tissue sarcoma : prognostic factors affecting survival

To analyze treatment and survival in 34 patients (28 resected) with primary or recurrent retroperitoneal sarcoma (RPS). METHODS: Between July 1994 and January 2001, 34 patients (15M, 19F; mean age: 56 years, range: 25-77) were evaluated. Complete resection was defined as removal of gross tumor with histologically confirmed clear resection margins. RESULTS: Twenty-eight out of 34 patients (82%) (15 were affected by primary RPS, and 13 by recurrent RPS), underwent surgical exploration. Twenty-three patients had a grossly and microscopically complete resection, (3 having a grossly incomplete resection and 2 patients with a grossly complete resection having histologically involved resection margins). Twenty-one out of 28 patients (75%) underwent removal of contiguous intra-abdominal organs. Preoperative mortality was nil, and morbidity occurred in six cases only (21%). High tumor grade results a significant variable for a worse survival in all 28 patients (100% 5 years survival for low grade vs. 0% for high grade; P = 0.0004). Amongst completely resected patients, only histologic grade and peroperative blood transfusions affected disease-free survival (P = 0.04 and P = 0.05, respectively). CONCLUSIONS: An aggressive surgical approach in both primary and recurrent RPS is associated with long-term survival. Copyright 2006 Wiley-Liss, In

The Ligasure vessel sealer in liver resection : a pilot study

Background/Aims: The major complication for liver resection is hemorrhage. Energy sources other than electrosurgery have become popular with the promise of quick and effective vascular control. This study evaluates alternative energy sources in sealing ductal structures for use in liver resection with minimal blood loss. Methodology: Between June 1994 and December 2003, a consecutive 116 patients (59 male; 57 female; mean age: 60 +/- 11 years; range: 27-79 years) underwent surgery for primary (n=30), metastatic liver cancer (n=79), or benign lesions (n=7). The extent of hepatic parenchymal division is marked on the surface with a diathermy-scored line. The arteries, veins, and bile ducts crossing the line of division are grasped, singly or in groups, by the Ligasure (Auto-suture, United States Surgical Corp., Norwalk, CT) electrocautery device. Results: Fifty-eight formal hepatic resections,and 58 non-anatomical wedge resection were performed. The blood loss ranged from 100mL to 3000mL,(median: 430mL). Only 32 patients received preoperative blood transfusions. Perioperative mortality was nil (within 30 days following surgery), and postoperative major complications were seen in 14 patients (12%). Conclusions: The Ligasure device uses bipolar electrothermal energy to coagulate the opposing walls of the target vessels. A feedback-control mechanism ensures that tissues are not charred by overcoagulation. This results in a high-burst strength vessel seal. Sealing is effective in vessels up to 7mm in diameter. Larger vessels require formal suture or stapling. This described technique is simple, rapid, safe for parenchymal division during hepatectomy, resulting in minimal blood loss

Baseline findings of the Italian multicenter randomized controlled trial of once-only sigmoidoscopy-SCORE

BACKGROUND: A single sigmoidoscopy examination at around age 60 years has been proposed as a cost-effective strategy to prevent colorectal cancer. A multicenter randomized controlled trial, the SCORE trial, is in progress in Italy to estimate the impact of this strategy on colorectal cancer incidence and mortality and the duration of the protective effect. We present the baseline screening outcomes. METHODS: A questionnaire was mailed to a random sample of 236 568 people aged 55-64 years to assess their eligibility for and interest in screening. Those reporting a history of colorectal cancer, adenomas, inflammatory bowel disease, recent colorectal endoscopy, or two first-degree relatives with colorectal cancer were excluded. Eligible, interested respondents were assigned randomly to the control group (no further contact) or the intervention group (invitation to undergo sigmoidoscopy). Screenees with colorectal cancer, polyps larger than 5 mm, three or more adenomas, adenomas 5 mm or smaller with a villous component of more than 20%, or severe dysplasia were referred for colonoscopy. RESULTS: Of the 56 532 respondents (23.9% of those invited), 34 292 were enrolled and 17 148 were assigned to the screening group. Of those, 9999 attended and 9911 were actually examined by sigmoidoscopy. Distal adenomas were detected in 1070 subjects (10.8%). Proximal adenomas were detected in 116 of 747 (15.5%) subjects without cancer at sigmoidoscopy who then underwent colonoscopy. A total of 54 subjects was found to have colorectal cancer, a rate of 5.4 per 1000 (54% of which were Dukes' A). The procedures were relatively safe, with two perforations (one in 9911 sigmoidoscopy exams and one in 775 colonoscopies) and one hemorrhage requiring hospitalization after polypectomy during colonoscopy. The pain associated with sigmoidoscopy was described as mild or less than expected by 83.3% of the screenees. CONCLUSION: Sigmoidoscopy screening is generally acceptable to recipients and safe. The high yield of advanced adenomas is consistent with the projected impact of sigmoidoscopy screening on colorectal cancer incidenc

The management of colorectal liver metastases : Expanding the role of hepatic resection in the age of multimodal therapy

Colorectal cancer (CRC) caused nearly 204,000 deaths in Europe in 2004. Despite recent advances in the treatment of advanced disease, which include the incorporation of two new cytotoxic agents irinotecan and oxaliplatin into first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the integrated use of targeted monoclonal antibodies, the 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with colorectal liver metastases, liver resection offers the only potential for cure. This review, based on the outcomes of a meeting of European experts (surgeons and medical oncologists), considers the current treatment strategies available to patients with CRC liver metastases, the criteria for the selection of those patients most likely to benefit and suggests where future progress may occur

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease