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Background: Common variable immunodeficiency (CVID) encompasses a heterogeneous group of primary antibody deficiency disorders characterized by recurrent infections, autoimmunity and malignancies. Gastrointestinal manifestations are frequently associated with CVID. Objective: In this cross-sectional study, we evaluated gastric and duodenal involvement in a cohort of adult patients with CVID. Methods: Upper gastrointestinal endoscopy was performed in 58 patients (26 males, mean age 47.8±15.6 years), diagnosed with CVID according to 2014 ESID criteria. Random biopsies were collected from gastric antrum and descending duodenum for the all enrolled subjects. Intraepithelial lymphocytosis in descending duodenum was defined as the presence of 25 lymphocytes per 100 enterocytes. Results: The major histopathological findings that we found were: a) chronic active gastritis (44.8%), Helicobacter pylori-associated (8.6%), b) chronic duodenitis (39.6%) with intraepithelial lymphocytosis (31%) and absence of plasma cells (18.9%) and c) autoimmune atrophic gastritis (5.2%). Three patients (5.2%) presented Intestinal Metaplasia (IM) of the gastric antrum. This finding was associated with H. pylori infection and persisted after the eradication in one patient. IM was associated with autoimmune atrophic gastritis in two cases. Giardia lamblia infection was observed in the duodenum samples from three patients (5.2%). A diagnosis of Gastric adenocarcinoma was made in a 58-year-old woman diagnosed with gastric dysplasia one year earlier. Conclusion: In our cohort of CVID patients, gastro-duodenal histopathological findings, including malignancies, are frequent and can affect long-term prognosis. A rigorous endoscopic follow-up is needed in CVID patients irrespective of the gastrointestinal symptoms.

Confirmation of endoscopically suspected esophageal metaplasia (ESEM) requires histology, but confusion in the histological definition of columnar-lined esophagus (CLE) is a longstanding problem. The aim of this study is to evaluate interpathologist variability in the interpretation of CLE. Thirty pathologists were invited to review three ten-case sets of CLE biopsies. In the first set, the cases were provided with descriptive endoscopy only; in the second and the third sets, ESEM extent using Prague criteria was provided. Moreover, participants were required to refer to a diagnostic chart for evaluation of the third set. Agreement was statistically assessed using Randolph's free-marginal multirater kappa. While substantial agreement in recognizing columnar epithelium (K = 0.76) was recorded, the overall concordance in clinico-pathological diagnosis was low (K = 0.38). The overall concordance rate improved from the first (K = 0.27) to the second (K = 0.40) and third step (K = 0.46). Agreement was substantial when diagnosing Barrett's esophagus (BE) with intestinal metaplasia or inlet patch (K = 0.65 and K = 0.89), respectively, in the third step, while major problems in interpretation of CLE were observed when only cardia/cardia-oxyntic atrophic-type epithelium was present (K = 0.05-0.29). In conclusion, precise endoscopic description and the use of a diagnostic chart increased consistency in CLE interpretation of esophageal biopsies. Agreement was substantial for some diagnostic categories (BE with intestinal metaplasia and inlet patch) with a well-defined clinical profile. Interpretation of cases with cardia/cardia-oxyntic atrophic-type epithelium, with or without ESEM, was least consistent, which reflects lack of clarity of definition and results in variable management of this entity.

Introduction: Adiponectin is a protein secreted by the adipose tissue with pleiotropic effects on metabolism. This adipokine play different anti-atherogenic action, such as the improvement of endothelial function and anti-inflammatory status in arterial walls. Two receptors ubiquitously expressed, AdipoR1 and AdipoR2, are involved in its action which. In obesity a mechanism of adiponectin resistance was demonstrated. Aim: To verify if adiponectin-resistance occurs in human atherosclerotic plaques. Methods: RNA from 49 carotid atherosclerotic plaques (advanced lesions), their respective adjacent regions (witha low grade lesions) and 7 healthy arteries (iliac and mesenteric) was extracted, reverse-transcribed and used for real-time PCR by specific TaqMan assays (Applied Biosystems). In vitro experiments for gene regulation studies were performed on primary Human Aortic Endothelial Cells and Smooth Muscle Cells (Lonza) co-cultured with the macrophage cell line THP-1. Results: Expression levels of AdipoR1 were lower in advanced plaques as well as in their respective adjacent regions than in healthy arteries (p = 0.020 and p = 0.001 respectively). AdipoR2 levels gradually decreased from healthy arteries to plaque adjacent regions and to advanced plaques (all comparisons p\0.0001). In both cell types, expression of AdipoR1 was not affected by the co-culture with THP-1. The presence of THP-1 decreased AdipoR2 expression in Smooth Muscle Cells (p = 0.040), whereas a not statistically significant decrease was observed in Endothelial Cells. Conclusions: We demonstrated a decreased expression of adiponectin receptors in initial and advanced plaques, suggesting a mechanism of adiponectin-resistance during atherosclerotic process. A local adiponectin-resistance could be a main cause of the lack of atheroprotective effects mediated by adiponectin. Presence of macrophages could be a contributory cause of AdipoR2 decrease.

Background: Bartonella henselae is a novel bacterial intracellular pathogen causing a self-limited syndrome of fever and regional lymphadenopathy in human immunocompetent hosts. This infection is often under-detected but it is of increased interest for a plethora of subjects including those suffering Cardiovascular Disease (CVD). Moreover, in a particular population, B. henselae can promote a severe disseminated disease with a pathologic vasoproliferation known as bacillary angiomatosis or bacillary peliosis. The role of the host immune response to B. henselae is critical in preventing progression to a major systemic disease causing an extended hepatic and CVD damage. Aim: The spectrum of disease, diagnosis and management of B. henselae infection in solid organ transplant recipients has not been investigated in depth. Until now, only rare cases of bartonellosis in transplant recipients have been reported. The purpose of this study was to evaluate the seroprevalence of B. henselae in patients awaiting heart transplantation in our Regional Reference Transplantation Centre. Methods: The diagnosis of B. henselae is usually based on serological methods (IgM, IgG) since they are practical, simple and rapid. Serum samples from 21 (16M, 5F) patients awaiting heart transplantation, with a median age of 53+/-15SD (range8–68 years), were examined by indirect immunofluorescence assay. Results: In our study, we have found a B. henselae antibody positivity rate of 19.04% (4/21) and, in particular, 1/21 (4.76%) patients presented IgM while 3/21 (14.28%) presented IgG. Our serological data seems to support the concept that B. henselae not only is present in our area and, more interestingly, it can be present in a paricular class of CVD patients represented by those awaiting heart transplantation. Conclusions: Thus, on the basis of our data, we would recommend the relevance of including B. henselae in the multipanel diagnosis in CVD patients awaiting heart transplantation.

Despite the optimization of the local treatment of advanced rectal cancer (LARC), combination of preoperative chemoradiotherapy (CRT) and surgery, approximately one third of patients will develop distant metastases. Since the chemokine receptor CXCR4 has been implicated in metastasis development and prognosis in colorectal cancer, the role of the entire axis CXCR4-CXCL12-CXCR7 was evaluated to identify high relapse risk rectal cancer patients. Tumor specimens of 68 LARC patients undergoing surgery after neoadjuvant-CRT were evaluated for CXCR4, CXCR7, and CXCL12 expression through immunohistochemistry. Multivariable prognostic model was developed using classical prognostic factors along with chemokine receptor expression profiles. High CXCR4 correlated with a shorter relapse-free survival (RFS) (p = 0.0006) and cancer specific survival (CSS) (p = 0.0004). Concomitant high CXCR4-negative/low CXCR7 or high CXCR4-negative/low CXCL12 significantly impaired RFS (p = 0.0003 and p = 0.0043) and CSS (p = 0.0485 and p = 0.0026). High CXCR4/N+ identified the worst prognostic category for RFS (p < 0.0001) and CSS (p = 0.0003). The optimal multivariable predictive model for RFS was a five-variable model consisting of gender, pT stage, N status, CXCR4, and CXCR7 (AUC = 0.92, 95% CI = 0.77-0.98). The model is informative and supportive for adjuvant treatment and identifies CXCR4 as a new therapeutic target in rectal cancer.

Bartonella henselae, the etiologic agent of cat-scratch disease, causes a self-limited syndrome of fever and regional lymphadenopathy in immunocompetent hosts. In immunocompromised hosts, however, B. henselae can cause severe disseminated disease and pathologic vasoproliferation known as bacillary angiomatosis or bacillary peliosis. The role of the host immune response to B. henselae is critical in preventing progression tosystemic disease. The spectrum of disease, diagnosis and management of B. henselae infection in solid organ transplant recipients has not been well characterized. Only rare cases of bartonellosis in transplant recipients have been reported. The purpose of this study has been to determine the seroprevalence of B. henselae in patients awaiting heart transplantation, in our Regional Reference Transplantation Centre. The diagnosis of B. henselae is usually based on serological methods immunoglobulin M (IgM), IgG] because they are practical, simple and rapid. Serum samples from 21 (16 males and 5 females) patients awaiting heart transplantation, with a median age of 53±15 SD (range 8???68 years), were examined by indirect immunofluorescence assay. In our study we have found a B. henselae antibody positivity rate of 19.04% (4/21) and in particular, 1 of 21 (4.76%) patients presented IgM while 3 of 21 (14.28%) presented IgG. Our preliminary serological data seems to indicate that B. henselae is present in our area and more interestingly it can be also present in patients awaiting heart transplantation. Thus, on the basis of our data, we would recommend the importance of including B. henselae diagnosis also in pre-transplant patients.

Aim: Bartonella henselae, the etiologic agent of cat-scratch disease, causes a self-limited syndrome of fever and regional lymphadenopathy in immunocompetent hosts. In immunocompromised hosts, however, B. henselae can cause severe disseminated disease and pathologic vasoproliferation known as bacillary angiomatosis or bacillary peliosis. The spectrum of disease, diagnosis and management of B. henselae infection in solid organ transplant recipients has not been well characterized. The purpose of this study has been to determine the seroprevalence of B. henselae in patients awaiting heart transplantation, in our Regional Reference Transplantation Centre. Methods: The diagnosis of B. henselae is usually based on serological methods (IgM, IgG). Immunofluorescent assays (IFA) are used for the detection of IgG or IgM antibodies against specific antigens. Bartonella IgM and IgG test kits are designed to detect the antigen-antibody complexes when diluted sera are presented with Bartonella antigens on commercially produced slides. A fluorescein-labeled anti-IgG or IgM conjugate is responsible for visualization of reactions. Results: Serum samples from 21 (16M, 5F) patients awaiting heart transplantation, with a median age of 53 ± 15SD (range 8-68 years) and 20 healthy donors (10M and 10F), with a median age of 37 ± 5.9SD (range 28-49 years) were examined by indirect immunofluorescence assay. In our study we have found, in patients awaiting heart transplantation, a B. henselae antibody positivity rate of 19.04% (4/21) and in particular, 1/21 (4.76%) patients presented IgM while 3/21 (14.28%) presented IgG. All healthy donors were found negative. Conclusions: Our preliminary serological data seems to indicate that B. henselae is present in our area and more interestingly it can be also present in patients awaiting heart transplantation. Thus, on the basis of our data, we would recommend the importance of including B. henselae diagnosis also in pre-transplant patients.

The authors describe an unusual case (a 79-year-old woman) of secondary extramedullary plasmacytoma (EMP) involving the duodenum. While all the previously reported cases of duodenal involvement by EMP (namely 20 cases) were characterized by the presence of ulcerative masses or ischemic necrotic lesions, in our case EMP led to the unusual finding of several non-polypoid lesions with a depressed central area. The final diagnosis was multiple myeloma IgA lambda, stage II A, with secondary duodenal EMP. To our knowledge this is the first report showing duodenal involvement by EMP with the aspect of multiple non-polypoid lesions.

Background: Liposarcoma is the most common type of soft tissue sarcoma (STS). It is divided into five groups according to histological pattern: well-differentiated, myxoid, round cell, pleomorphic, and dedifferentiated. Dedifferentiated liposarcoma most commonly occurs in the retroperitoneum, while an intraperitoneal location is extremely rare. Only seven cases have been reported in literature. Many pathologists recognize that a large number of intra-abdominal poorly differentiated sarcomas are dedifferentiated liposarcomas. We report a case initially diagnosed as undifferentiated sarcoma that was reclassified as intraperitoneal dedifferentiated liposarcoma showing an amplification of the MDM2 gene. Case presentation: A 59-year-old woman with abdominal pain and constipation was referred to the Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy, in November 2012. On physical examination, a very large firm mass was palpable in the meso-hypogastrium. Computed tomography (CT) scan showed a heterogeneous density mass (measuring 10 x 19 cm) that was contiguous with the mesentery and compressed the third part of the duodenum and jejunum. At laparotomy, a large mass occupying the entire abdomen was found, adhering to the first jejunal loop and involving the mesentery. Surgical removal of the tumor along with a jejunal resection was performed because the first jejunal loop was firmly attached to the tumor. Macroscopic examination showed a solid, whitish, cerebroid, and myxoid mass, with variable hemorrhage and cystic degeneration, measuring 26 x 19 x 5 cm. Microscopic examination revealed two main different morphologic patterns: areas with spindle cells in a myxoid matrix and areas with pleomorphic cells. The case was initially diagnosed as undifferentiated pleomorphic sarcoma. Histological review showed areas of well-differentiated liposarcoma. Fluorescence in situ hybridization (FISH) analysis was performed and demonstrated an amplification of the MDM2 gene. Definitive diagnosis was intraperitoneal dedifferentiated liposarcoma. No adjuvant therapy was given, but 5 months after laparotomy, the patient presented with a locoregional recurrence and chemotherapy with high-dose ifosfamide was started. Conclusions: No guidelines are available for the management of intraperitoneal dedifferentiated liposarcoma. We report this case to permit the collection of a larger number of cases to improve understanding and management of this tumor. Moreover, this study strongly suggests that poorly differentiated sarcomas should prompt extensive sampling to demonstrate a well-differentiated liposarcoma component and, if possible, FISH analysis.

Bartonella henselae è un batterio gram-negativo intracellulare facoltativo responsabile della malattia da graffito del gatto (cat-scratch disease), un infezione caratterizzata da linfoadenopatia o da un decorso asintomatico in pazienti immunocompetenti. Tuttavia, l'angiomatosi bacillare e la peliosi epatica, nonché l'endocardite in pazienti con malattie valvolari, la batteriemia con febbre, e malattie epatiche o spleniche, sono tra le manifestazioni più comuni dell'infezione in pazienti immuno-compromessi. Bacteroides fragilis è un batterio anaerobio gram-negativo appartenente alla microflora intestinale, di recente è stato dimostrato che protegge da colite sperimentale indotta da Helicobacter hepaticus attraverso il polisaccaride A (PSA). Lo scopo del presente studio è stato stabilire se la colonizzazione di B. fragilis può proteggere dall'infezione da B. henselae in un modello animale di coinfezione. Analisi morfologiche e ultrastrutturali mediante colorazione ematossilina-eosina e microscopia elettronica sui tessuti murini hanno rivelato che i danni da B. henselae possono essere ridotti nella coinfezione con B. fragilis, ma che tale effetto non si verifica con il ceppo mutante difettivo nella capacità di produrre PSA (B. fragili delta PSA). Analisi immunoistochimiche con anticorpi anti-Bartonella hanno, inoltre, mostrato che il numero di cellule positive per campo è ridotto di almeno il 50% nel fegato (20±4 vs 50±8), aorta (5±1 vs 10±2) e milza (25±3 vs 40±6) dei topi coinfettati rispetto agli animali infettati solo con B. henselae. Questa diminuzione è meno evidente nella coinfezione con il ceppo DeltaPSA (35±6 nel fegato, 5±1 nell'aorta e 30±5 nella milza). Tali dati suggeriscono che la colonizzazione di B. fragilis possa essere in grado di prevenire i danni indotti da B. henselae tramite il PSA.

Incidental diagnosis of stromal tumor of the stomach by percutaneous

Aims: Atherosclerosis is an inflammator y disease which molecular mechanisms are not been completely investigated. Our aim is to perform a wide expression study of inflammation related genes in human atherosclerotic plaques. Methods: The Human Inflammation Array (Applied Biosystems) was used to perform the mRNA quantification of 92 inflammation-related genes in 12 atherosclerotic plaques, their respective adjacent regions (with a lower grade lesion) and 7 healthy ar teries. The principle of the array is the real-time PCR amplification with a TaqMan probe specific for each gene. Data analysis was performed with SDS 2.3 software with the comparative Ct method using the gene beta-2-microglobulin as housekeeping and one of analysed samples as calibrator. Results: The mRNA levels of 42 genes result to be differently expressed:13 genes were up-regulated in atherosclerotic plaques respect to control ar teries whereas 29 were down-regulated. Their expression levels show an increasing or a decreasing trend from healthy ar teries to plaque adjacent regions and to advanced plaques. These genes belong to many different functional classes. In particular, we observed the dys-regulation of genes encoding for enzymes involved in the arachidonic acid metabolism that lead to generation of prostaglandins and leukotrienes. Conclusions: This is the first study in which the expression of a wide panel of inflammation-related genes was investigated. Results clarify the mechanisms of inflammation involvement during atherosclerotic process and highlight newpossible target for anti-inflammator y therapy in cardiovascular disease.

Objective: To assess the etiology, management and outcome of iliac pseudoaneurysms following renal transplantation. Methods: Eleven patients who underwent repair between 1982 and 2007 were identified. Five (Group 1) presented pseudoaneurysm at the anastomosis of the donor renal and native iliac arteries, and six (Group 2) presented iliac pseudoaneurysm following transplant nephrectomy. Intraoperative cultures and immunohistochemical examinations were obtained from all surgical cases to determine the existence of a relationship between infection or transplant rejection and pseudoaneurysm formation. Results: Endovascular repair (EVR) was used to treat three patients, while eight patients underwent open repair (OR). Transplant nephrectomy was needed in all cases but one after anastomotic pseudoaneurysm repair. After pseudoaneurysm excision, arterial reconstruction was performed in all cases, with a limb salvage rate of 100%. At 30 days, no patients died in the EVR subgroup. In the OR subgroup, one patient died of sepsis (12.5%). Cultures taken from the pseudoaneurysm wall and content grew Candida albicans and E. coli in two febrile patients. Pathologic evaluation of donor renal arteries revealed evidence of chronic rejection in three patients (60%) in Group 1, and in two (33.3%) in Group 2. No patients in either Group presented late infection, failure of vascular reconstruction nor pseudoaneurysm recurrence. The follow-up ranges from 20 to 89 months. Conclusions: The etiology of pseudoaneurysms in this location is multifactorial, however, an association with chronic rejection must be considered. Though rare, the development of pseudoaneurysms at the donor renal-external iliac artery anastomosis results in high rates of transplant nephrectomy. Less invasive endovascular techniques offer a new therapeutic option in this challenging scenario notwithstanding the fact that they require further validation. © 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.

Background. Pre-operative chemoradiation is now standard treatment for stage II-III rectal cancer. Capecitabine (CAP) and oxaliplatin (OX) are synergistic with radiotherapy (RT) and active in colorectal neoplasms. Patients and Methods. Two cycles of CAP 825 mg/m2 bid (days 1-14) and OX 50 mg/m2 (days 1 & 8) every 3 weeks were given concomitantly with pelvic conformal RT (45 Gy). Patients with a ≥ T3 and/or node-positive rectal tumour were eligible. The pathologic tumour response was defined according to the Tumour Regression Grade (TRG) scale. Results. Forty-six patients were enrolled. Gastrointestinal adverse events were mostly G1-G2; only 2 patients experienced G3 vomiting and diarrhoea; 6 patients had G1 peripheral neuropathy. Haematological toxicity was rare. G2 proctitis and anal pain occurred in 2 patients. Pathological complete response (TRG1) was observed in 9 patients (20.9%; 95% CI 8.7-33.1%); TRG2 in 19 patients (44.2%); TRG3 in 12 patients (27.9%); TRG4 in 3 patients (7%). Overall, 9 patients recurred: 5 with distant metastases, 1 with local recurrence, and 3 with both local recurrence and distant metastases. Conclusions. CAP-OX-RT as pre-operative treatment for rectal cancer induces a remarkable rate of complete or near-complete pathological responses, and is well tolerated.

Immunostimulating Toll-like receptor 9 (TLR9) agonists cause antitumor activity interfering also with cancer proliferation and angiogenesis by mechanisms still incompletely understood. We hypothesized that modified TLR9 agonists could impair epidermal growth factor receptor (EGFR) signaling and, by this means, greatly enhance EGFR inhibitors effect, acting on both the receptor targeting and the immunologic arm. EXPERIMENTAL DESIGN: We used a novel second-generation, modified, immunomodulatory TLR9 agonist (IMO), alone and in combination with the anti-EGFR monoclonal antibody cetuximab or tyrosine kinase inhibitor gefitinib, on the growth of GEO and cetuximab-resistant derivatives GEO-CR colon cancer xenografts. We have also evaluated the expression of several proteins critical for cell proliferation, apoptosis, and angiogenesis, including EGFR, mitogen-activated protein kinase, Akt, bcl-2, cyclooxygenase-2, vascular endothelial growth factor, and nuclear factor-kappaB. RESULTS: IMO inhibited GEO growth and signaling by EGFR and the other proteins critical for cell proliferation and angiogenesis. IMO plus the anti-EGFR antibody cetuximab synergistically inhibited tumor growth, signaling proteins, and microvessel formation. EGFR signaling inhibition by IMO is relevant because IMO cooperated also with EGFR tyrosine kinase inhibitor gefitinib in GEO tumors, while it was inactive against GEO-CR xenografts. On the other hand, IMO boosted the non-EGFR-dependent cetuximab activity, causing a cooperative antitumor effect in GEO-CR cells. Finally, combination of IMO, cetuximab and chemotherapeutic irinotecan eradicated the tumors in 90% of mice. CONCLUSION: IMO interferes with EGFR-related signaling and angiogenesis and has a synergistic antitumor effect with EGFR inhibitors, especially with cetuximab, boosting both the EGFR dependent and independent activity of this agent. Moreover, this therapeutic strategy could be translated in patients affected by colorectal cancer.