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Macrophages have been implicated in the pathogenesis of classical Hodgkin lymphoma (cHL) and have been suggested to have a negative impact on outcome. Most studies addressing the role of macrophages in cHL have relied on identification of macrophages by generic macrophage antigens, e.g., CD68. We have therefore conducted an in situ analysis of macrophage polarization in a series of 100 pediatric cHL (pcHL) cases using double staining immunohistochemistry, combining CD68 or CD163 with pSTAT1 (M1-like) or CMAF (M2-like). M1- or M2-polarised microenvironment was defined by an excess of one population over the other (>1.5). Expression of STAT1 and LYZ genes was also evaluated by RT-qPCR. Patients <14 years and EBV+ cases displayed higher numbers of CD68+pSTAT1+ cells than older children and EBV- cases, respectively (P=0.01 and P=0.02). A cytotoxic tumor microenvironment, defined by a CD8+/FOXP3+ ratio >1.5 was associated with higher numbers of CD68+pSTAT1+ (P=0.025) and CD163+pSTAT1+ macrophages (P<0.0005). Levels of STAT1 and LYZ expression were associated with the numbers of CD68+pSTAT1+ macrophages. EBV+ cHL cases disclosed a predominant M1 polarized microenvironment similar to Th1 mediated inflammatory disorders, while EBV- cHL showed a predominant M2 polarized microenvironment closer to Th2 mediated inflammatory diseases. Better overall-survival (OS) was observed in cases with higher numbers of CD163+pSTAT1+ macrophages (P=0.02) while larger numbers of CD163+CMAF+ macrophages were associated with worse progression-free survival (PFS) (P=0.02). Predominant M1-like polarization as disclosed by CD163+pSTAT1+/CD163+CMAF+ ratio > 1.5 was associated with better OS (P= 0.037). In conclusion, macrophage polarization in pcHL correlates with prevalent local T cell response and may be influenced by the EBV-status of neoplastic cells. Besides, M1-like and M2-like macrophages displayed differential effects on outcome in pcHL.

Background: Postoperative surgical site infections are one of the most frequent complications after open abdominal surgery, and triclosan-coated sutures were developed to reduce their occurrence. The aim of the PROUD trial was to obtain reliable data for the effectiveness of triclosan-coated PDS Plus sutures for abdominal wall closure, compared with non-coated PDS II sutures, in the prevention of surgical site infections., Methods: This multicentre, randomised controlled group-sequential superiority trial was done in 24 German hospitals. Adult patients (aged ≥18 years) who underwent elective midline abdominal laparotomy for any reason were eligible for inclusion. Exclusion criteria were impaired mental state, language problems, and participation in another intervention trial that interfered with the intervention or outcome of this trial. A central web-based randomisation tool was used to randomly assign eligible participants by permuted block randomisation with a 1:1 allocation ratio and block size 4 before mass closure to either triclosan-coated sutures (PDS Plus) or uncoated sutures (PDS II) for abdominal fascia closure. The primary endpoint was the occurrence of superficial or deep surgical site infection according to the Centers for Disease Control and Prevention criteria within 30 days after the operation. Patients, surgeons, and the outcome assessors were masked to group assignment. Interim and final analyses were by modified intention to treat. This trial is registered with the German Clinical Trials Register, number DRKS00000390., Findings: Between April 7, 2010, and Oct 19, 2012, 1224 patients were randomly assigned to intervention groups (607 to PDS Plus, and 617 to PDS II), of whom 1185 (587 PDS Plus and 598 PDS II) were analysed by intention to treat. The study groups were well balanced in terms of patient and procedure characteristics. The occurrence of surgical site infections did not differ between the PDS Plus group (87 [14·8%] of 587) and the PDS II group (96 [16·1%] of 598; OR 0·91, 95% CI 0·66-1·25; p=0·64). Serious adverse events also did not differ between the groups-146 of 583 (25·0%) patients treated with PDS Plus had at least one serious adverse event, compared with 138 of 602 (22·9%) patients treated with PDS II; p=0·39)., Interpretation: Triclosan-coated PDS Plus did not reduce the occurrence of surgical site infection after elective midline laparotomy. Innovative, multifactorial strategies need to be developed and assessed in future trials to reduce surgical site infections., Funding: Johnson & Johnson Medical Limited., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background & Aims: Detection of hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMC) and/or hepatocytes in absence of HCV RNA in serum, designated as 'occult HCV infection', has been a matter of controversy in recent years. We investigated for the first time the prevalence of occult HCV infection in large cohorts of chronic hemodialysis (CHD) and kidney transplant (KTx) patients., Methods: We enrolled 417 CHD patients, 417 KTx recipients and 2 control groups - 25 anti-HCV (antibody against HCV)-positive and HCV RNA-positive patients with chronic hepatitis C, and 40 anti-HCV-, HCV RNA-, and HBsAg-negative healthy subjects. HCV RNA was tested in serum and PBMC using a sensitive commercial assay., Results: In CHD patients, the prevalence of anti-HCV was 3.6% (15/417) and of positive serum HCV RNA 2.4% (10/417). HCV RNA was detected in PBMC in 1/407 (0.25%) HCV serum RNA-negative patients ("occult HCV infection"). In KTx recipients, prevalence of anti-HCV was 4.8% (20/417) and of positive serum HCV RNA 4.6% (19/417). Occult HCV infection was found in 2/398 (0.5%) serum HCV RNA-negative patients. On a mean longitudinal follow-up of 30months of the 3 patients with occult HCV infection, there was no clinical or virological evidence of HCV infection., Conclusions: The prevalence of occult HCV infection was very low in our CHD and KTx patients, and it did not appear to be clinically relevant. Further studies in geographic populations with high HCV endemicity are required to clarify the significance of occult HCV infection in these patient groups., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use., Patients and Methods: The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed., Results: Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093)., Conclusion: Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Background and Study Aims: Colon capsule endoscopy (CCE) offers an alternative approach for endoscopic visualization of the colon. Some of the current CCE bowel cleansing regimens use sodium phosphate, which has raised safety concerns. Therefore, the aim of the current study was to test the feasibility and efficacy of a new low-volume, sodium phosphate-free polyethylene glycol (PEG) bowel preparation., Methods: The first 26 patients (original cleansing procedure) received a colon cleansing regimen of PEG plus ascorbic acid: patients drank 1 L in the evening and 0.75 L in the morning before capsule ingestion. Patients also drank an additional 0.5 L PEG boost and an optional 0.25 L PEG boost during the capsule procedure. Following an interim analysis, the cleansing procedure of the subsequent 24 patients was modified, with the morning intake before capsule ingestion being increased to 1 L, as well as the second boost (0.25 L) being administered 1 - 2 hours earlier (modified cleansing procedure)., Results: The overall colon cleanliness was considered to be good or excellent in 83 % (original cleansing procedure) and 82 % (modified cleansing procedure) of patients, without any significant difference between regimens (P > 0.05). In 37 /49 (76 %) of the CCE procedures, the hemorrhoidal plexus was identified and thus the examination was considered complete, with no significant differences between the two CCE cleansing procedures. The capsule sensitivity and specificity for detecting colonic polyps ≥ 6 mm were 91 % (95 %CI 70 % - 98 %) and 94 % (95 %CI 87 % - 97 %), respectively, compared with standard optical colonoscopy., Conclusion: A colon cleansing procedure using PEG + ascorbic acid for capsule colonoscopy yielded an adequate cleansing level in > 80 % of patients, a completion rate of 76 %, and good accuracy for detecting polyps. This procedure may be considered as an alternative, particularly for patients in whom sodium phosphate-based preparations are contraindicated., (© Georg Thieme Verlag KG Stuttgart · New York.)

Epstein-Barr virus (EBV) replicates in superficial differentiated cells of oral hairy leukoplakia (OHL). Differentiation of squamous epithelial cells depends on B-lymphocyte-induced maturation protein 1 (Blimp1). Here we show that expression of the EBV immediate-early protein BZLF1 is restricted to Blimp1-positive epithelial cells in OHL. Luciferase assays revealed Blimp1-dependent induction of the BZLF1 promoter Zp in epithelial cell lines. Expression of ZEB1, a negative regulator of Zp, and of Xbp-1, which mediates the Blimp1 effect on Zp in B-cells, was not affected by enforced Blimp1 expression. Moreover, Xbp-1 protein expression was not detected in differentiated epithelial cells of OHL. Thus, Blimp1 induces BZLF1 expression in epithelial cells independently of ZEB1 and Xbp-1. In contrast to epithelial cells of OHL, BZLF1 expression was also observed in Blimp1-negative lymphoid cells in infectious mononucleosis tonsils, suggesting that EBV replication in B-cells may be induced independently of terminal differentiation.

Background: Numerous technical and surgical innovations took place in laparoscopic surgery in the recent past. It is debatable whether single-access surgery or natural orifice surgery (NOS) will establish for several standard procedures. Most of the NOS-procedures are controversial and single-access surgery still has to prove its equality in controlled trials. In the intention to reduce the ingress incisons and to facilitate instrumentation, we decided to test the barrier-free AirSeal(®)-trocar in clinical practice., Materials and Methods: Laparoscopically we performed a cholecystectomy, gastric wedge-resection and a fundoplication using the barrier-free AirSeal(®) 12-mm-trocar. This trocar works without any mechanical barrier so that via this trocar the use of two instruments is possible., Results: All three operations were successful., Conclusion: Laparoscopic standard procedures are feasible using this barrier-free trocar without a higher degree of difficulty. Because of the facilitated instrumentation, it is possible to work more efficiently and to maintain the focus on the surgical field.

A role for Epstein-Barr virus (EBV) in myasthenia gravis pathogenesis has been suggested recently. Using in situ hybridization for the detection of the EBV-encoded RNAs and EBNA1-specific immunohistochemistry, we found no latently infected cells in a series of thymus specimens from patients with myasthenia gravis showing lymphofollicular thymitis. In addition, using immunohistochemistry and an antibody specific for the viral immediate early protein BZLF1, no evidence of lytic EBV infection was seen in these cases. Our results therefore do not support a direct role of thymic EBV infection in the pathogenesis of myasthenia gravis., (Copyright © 2011 American Neurological Association.)

Purpose: The purpose of this study was to assess the apparent diffusion coefficient (ADC) of neuroblastic tumours and to evaluate if the ADC can enable differentiation of neuroblastoma and ganglioneuroma/ganglioneuroblastoma., Patients and Methods: 16 histologically classified tumours (10 neuroblastomas and 6 ganglioneuroma/ganglioneuroblastoma) were investigated in 15 children. Diffusion-weighted echo-planar imaging was performed with a b-value of 800s/mm². The contrast of tumour tissue depicted with T2-weighted images and diffusion-weighted images was evaluated by means of region-of-interest (ROI) measurements and a calculation of the ADC by a software tool. The ADC of the psoas-muscle was measured to establish an internal standard, too., Results: The mean ADC of the 10 neuroblastomas was 0.81×10⁻³mm²/s (SD 0.29×10⁻³mm²/s, range 0.39-1.47×10⁻³)mm²/s). The mean ADC of the four ganglioneuroma and two ganglioneuroblastoma was 1.6×10⁻³mm²/s (SD 0.340×10⁻³mm²/s, range 1.13-1.99)×10⁻³mm²/s. The difference was significant in the t-test (p=0.01). We found no ganglioneuroma or ganglioneuroblastoma with an ADC below 1.1×10⁻³mm²/s., Discussion: There is a significant difference of the ADC of neuroblastoma compared to the ADC of ganglioneuroma/ganglioneuroblastoma. These first results suggest that the diffusion-weighted imaging could differentiate neuroblastoma and ganglioneuroma/ganglioneuroblastoma by calculating the ADC., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Transesophageal migration of a foreign body into the mediastinum in human adults is rare. This event can result in life-threatening situations and is associated with a high mortality rate. Only a few case reports of thoracoscopic removal of a foreign body in adults have been published so far. The authors describe the case of a successfully performed thoracoscopic approach to remove an ingested needle from the mediastinum posterior of a 69-year-old patient. The authors are discussing why, in similar cases, removal of the foreign body should be performed and they describe the preliminary conditions for this method. A video file is attached.

Metastatic adenocarcinoma of unknown primary site, eg, to lymph nodes, liver, or lung, may originate from many organs. Microscopic differentiation of adenocarcinomas from the pancreaticobiliary and upper gastrointestinal tracts may be difficult because of shared histologic and immunohistologic features. A high prevalence of cytokeratin (CK)17 expression in pancreaticobiliary adenocarcinoma was reported, and preliminary data indicate infrequent or missing expression in gastric adenocarcinoma. The prevalence of CK17 expression in gastric cardiac and esophageal adenocarcinomas has not been studied. We studied CK17 expression in tissue microarrays of 67 distal gastric, 71 gastric cardiac, and 46 esophageal adenocarcinomas and compared it with expression in 55 pancreatic, 23 extrahepatic bile duct, and 49 colorectal adenocarcinomas. CK17 expression was as follows: pancreatic, 88%; bile duct, 59%; esophageal, 30%; distal gastric, 28%; gastric cardiac, 27%; and colorectal adenocarcinoma, 6%. These differences were statistically significant for all tumor types except in comparisons of esophageal, cardiac, and distal gastric adenocarcinoma. The prevalence of CK17 expression in pancreatic and extrahepatic bile duct adenocarcinomas is substantially higher than in upper gastrointestinal tract and colorectal adenocarcinomas. However, in individual cases of adenocarcinoma of unknown primary site, CK17 results alone are insufficient to differentiate the analyzed tumor entities.

The current study was performed to determine whether the histopathological appearance of oesophageal adenocarcinoma (AC) differs significantly from that of cardiac or gastric AC. Therefore, HE-stained slides of 215 primarily resected oesophageal AC, 108 cardiac and 184 gastric AC were classified according to a variety of clinico-pathologic parameters. According to Lauren's classification, oesophageal AC (1.4%) less frequently belonged to the diffuse type than cardiac (2.8%) and gastric AC (23.9%; p<0.0001). Tubular and papillary AC, as defined by the WHO classification, were more frequent among oesophageal (94.4%) than among cardiac (87.0%) and gastric AC (59.2%; p<0.0001). Solid carcinomas, according to Carneiro's classification, were less frequent among oesophageal (2.8%) than among cardiac (10.2%) and gastric AC (9.2%; p<0.0001). Oesophageal AC were graded more frequently G1/G2 (53.9%) than cardiac (30.6%) and gastric AC (27.7%; p<0.0001). Among oesophageal AC, Lauren's classification (p=0.0067), Carneiro's classification (p=0.0170), tumour grade (p=0.0005), lymphatic vessel invasion (p<0.0001) but not WHO classification were histological predictors of postoperative survival. In conclusion, oesophageal AC displays the same histological spectrum as cardiac and gastric AC. However, the relative proportion of differentiated, gland-forming carcinomas is significantly more frequent in the oesophagus than in the cardia and in the stomach.