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Presents a letter to the editor about a lipid fluidity modulating agent.

We collected data to provide evidence that orbital cavernous malformations (CMs) are histopathologically, neuroradiologically, and clinically different from cerebral CMs and may represent a distinct entity.In this study, the main clinical, histopathological and radiological characteristics of 19 patients (11 females and eight males, mean age 49.1 years) with orbital CMs out of a series of 376 orbital tumors are analyzed and compared with 107 cases with cerebral CMs treated in the same period. Decrease of visual acuity and painless progressive proptosis were the main clinical signs observed in 17 patients (89%). Complete microsurgical excision of lesions via individualized approaches was obtained in all cases. Follow-up examinations were obtained after a mean of 3.1 years (11 months to 7 years) and yielded complete recovery in 14 patients, while five remained clinically unchanged. Based on clinicopathological and neuroradiological studies of these 19 patients with orbital and 107 patients with cerebral CMs treated in the same period, we found evidence that orbital CMs have specific features to distinguish them from cerebral CMs. Orbital CMs, in contrast to the cerebral CMs, showed non-degenerated well-developed vessel walls and were covered by a hard and compact capsule. Clinical symptoms are characterized by the growth of orbital CMs due to intraluminal thrombosis and subsequent recanalization of cavernous vessels; there were no signs of hemorrhage. We found evidence to suggest that orbital CMs represent a distinct clinicopathologic and neuroradiologic entity. [ABSTRACT FROM AUTHOR]

Rosai-Dorfman disease (RDD), a rare form of non-Langerhans cell histiocytosis with heterogenous clinical features, arises from precursor cells that give rise to cells of the histiocytic and monocytic lineages. An association with hematological neoplasms has been reported. Testicular RDD is rarely described, with only 9 reported cases in the literature. Genetic data to assess clonal relationships between RDD and other hematological neoplasms remain scarce. We describe an instance of testicular RDD against a background of chronic myelomonocytic leukemia (CMML), with genetic studies in both neoplasms. A 72-year-old patient with a history of CMML sought evaluation of growing bilateral testicular nodules. Solitary testicular lymphoma was suspected; orchidectomy was performed. The diagnosis of testicular RDD was established morphologically and confirmed immunohistochemically. Molecular analysis of testicular lesions and of archived patient bone marrow revealed the KRAS variant c 0.35 G>A / p.G12D in both, suggesting a clonal relationship. These observations support classifying RDD as a neoplasm that can be clonally related to myeloid neoplasms. [ABSTRACT FROM AUTHOR]

Inter-test concordance between the MammaPrint and the EndoPredict tests used to predict the risk of recurrence in breast cancer was evaluated in 94 oestrogen receptor-positive, HER2-negative breast cancers. We correlated histopathological data with clinical risk estimation as defined in the MINDACT trial. 42.6% (40/94) of cases were high-risk by MammaPrint, 44.7% (42/94) by EndoPredict (EPclin), and 45.7% (43/94) by clinical risk definition. Thirty-six percent of genomic risk predictions were discordant with a low inter-test correlation between EndoPredict and MammaPrint (p = 0.012; κ = 0.27, 95% CI [0.069, 0.46]). Clinical risk stratification did not correlate with MammaPrint (p = 0.476) but highly correlated with EndoPredict (p < 0.001). Consequently, clinically high-risk tumours (n = 43) were more frequently high-risk by EndoPredict than by MammaPrint (76.6% vs. 46.5%, p = 0.004), with 44% of cases discordantly classified and no significant association between genomic risk predictions (p = 0.294). Clinicians need to be aware that clinical pre-stratification can profoundly influence multigenomic test performance. [ABSTRACT FROM AUTHOR]

Aims: Spindle cell differentiation is not an uncommon finding in common acquired naevi, and may represent a form of neurotisation with Schwannian differentiation of melanocytes. Perineurial differentiation in this context appears to be very rare, and is only poorly documented in the literature. We therefore aimed to study this rare form of neurotisation in melanocytic naevi more comprehensively. Methods and results: We have identified six melanocytic tumours showing spindle cell morphology and perineurial differentiation from routine and referral material. Clinical data and follow‐up were obtained, and the histological and immunohistochemical features were analysed. The tumours affected middle‐aged adults (median, 48 years; range, 26–74 years), with a wide anatomical distribution and benign follow‐up (median, 13 months; range, 6–48 months). All tumours were nodular and circumscribed but asymmetrical, with extension into the deep dermis and superficial subcutis. A characteristic finding was a biphasic growth pattern with a lentiginous compound naevus in the superficial aspect and abrupt transition to a prominent nodular spindle cell proliferation in the deeper reaches. Spindle cells were bland and uniform, and arranged singly and in short fascicles in a loose fibromyxoid stroma. In areas, a whorled arrangement of slender spindle cells with wavy nuclei was seen. Distinctive intratumoral hypocellular nodules and peripheral lymphoid aggregates were additional features. By immunohistochemistry, the spindle cells were mainly S100‐positive melanocytes. In areas, S100‐negative/epithelial membrane antigen‐positive spindle cells showing coexpression of Glut‐1 and claudin‐1 were closely admixed. Conclusion: This perineurial differentiation probably represents a rare and unusual form of neurotisation. The tumours are benign but may be mistaken for desmoplastic melanoma. Awareness of and careful attention to the clinicopathological and immunohistochemical features allow reliable separation. [ABSTRACT FROM AUTHOR]

Introduction: Correct risk assessment of disease recurrence in patients with early breast cancer is critically important to detect patients who may be spared adjuvant chemotherapy. In clinical practice this is increasingly done based on the results of gene expression assays. In the present study we compared the concordance of the 70-gene signature MammaPrint (MP) with the 12 gene assay EndoPredict (EP). Methods: Representative tissue of 48 primary tumours was analysed with the MP during routine diagnostic purposes. Corresponding formalin-fixed, paraffin-embedded tissue was thereafter analysed by the EP test. Risk categories of both tests were compared. Results: 41 of 48 tumours could be directly compared by both tests. Of the 17 MP low risk cases, only 9 were considered low risk by EP (53% agreement) and of the 24 MP high risk cases, 18 were high risk by EP (75% agreement). Discrepancies occurred in 14 of 41 cases (34.1%). There was only a weak and non-significant correlation between the MP and EP test with an overall concordance of only 66%. The original therapeutic recommendation was based on the MP and would have been changed in 38% of the patients following EP test results. 4 patients developed distant metastases. The respective tumours of these patients were all classified as high risk by the EP, but only 3 were classified as high risk by the MP. Conclusion: Both tests resulted in different treatment recommendations for a significant proportion of patients and cannot be used interchangeably. The results underscore the urgent need for further comparative analyses of multi-genomic tests to avoid misclassification of disease recurrence risk in breast cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Endoscopic techniques have successfully reduced the invasiveness of hysterectomy, when compared to open procedures. Power morcellation, as a part of the minimal invasive concept, carries the risk of disseminating cells from the tissue specimen. The present observational study reports on first experiences using a new system (More-Cell-Safe, A.M.I., Austria) for contained in-bag morcellation during laparoscopic hysterectomy.Materials and Methods: The dual opening system allows two-port access without bag puncture. The optic is protected against spread cell contamination with a disposable sleeve. Application data were prospectively recorded on the first n = 7 consecutive patients and compared to n = 7 preceding patients undergoing uncontained morcellation.Results: Bag system use was surgically successful in 6 of 7 cases (85.7 %). Morcellated specimen weight ranged from 205 to 638 g (mean 413.33 ± 176.85; median 413). In one patient, the uterine specimen (1050 g) proved too large to be placed into the bag. Average time associated to the bag use was 16.2 ± 7.65 min, ranging from 8.5 to 26.5 min (median 14 min). Removed bags contained bloody fluid with residual tissue fragments weighing overall between 21 and 85 g. Spread spindle cells were detected in two cases after uncontained morcellation, but not after in-bag morcellation.Conclusion: The experiences from our small pilot series prove technical feasibility in the clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: Minimal invasive approaches have proven beneficial for patients undergoing myomectomy and hysterectomy, but necessary tissue morcellation carries the risk of cell dissemination in rare cases of inadvertent malignancy. Performing the morcellation process within a contained bag system may prevent spilling and therefore enhance safety of the laparoscopic procedures.Material and Methods: The present study describes the development and experimental evaluation of a new bag system in vitro and in vivo in a pig model of laparoscopic supracervical hysterectomies.Results: The main results on n = 8 procedures with in-bag morcellation compared to n = 8 controls without bag indicate reproducible feasibility and protective effect of the new bag, which is the first published to our knowledge that does not require puncturing in a standard multiport laparoscopy setting. Overall surgery time was significantly prolonged in the bag group by 12.86 min (P = 0.0052; 95 % confidence interval 4.64-21.07), but peritoneal washings were negative for muscle cells in all cases with bag use, compared to positive cytology in 5/8 cases without bag (P = 0.0256).Conclusion: Clinical trials will now be necessary to investigate the reproducibility of these encouraging data in human application. [ABSTRACT FROM AUTHOR]

Objective Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response. Paneth cells secrete antimicrobial peptides and inflammatory mediators, protect from pathogens and shape the commensal microbiota. Prompted by the genetic association of the locus harbouring the type I interferon (IFN) receptor (IFNAR1) with Crohn's disease, and a transcriptional signature for type I IFN signalling in Paneth cells, we studied the function of IFNAR1 in IECs. Design Type I IFN signalling was studied in mice with conditional deletion of Ifnarl in IECs. Phenotype was characterised at baseline, and gut microbiota composition was assessed by 16S rDNA ribotyping. The role of IFNAR1 was also investigated in experimental colitis induced by dextran sodium sulfate (DSS) and colitis-associated cancer induced by DSS in conjunction with azoxymethane (AOM). Results Ifnar1-/-(IEC) mice displayed expansion of Paneth cell numbers and epithelial hyperproliferation compared with Ifnarl-sufficient littermates. While Ifnarl-/-(IEC) mice did not exhibit spontaneous inflammation or increased severity in DSS colitis compared with Ifnar1-/-(IEC) mice, they exhibited an increased tumour burden in the AOM/DSS model. Both hyperproliferation and tumour promotion were dependent on the microbial flora, as the differences between genotypes were marked upon separately housing mice, but disappeared when Ifnarl-/-(IEC) and Ifnar1-/-(IEC) mice were co-housed. Accordingly, ribotyping revealed marked differences between Ifnar1-/-(IEC) and Ifnar1-/-(IEC) mice that where diminished upon co-housing. Conclusions IFNAR1 in IECs, and Paneth cells in particular, contributes to the regulation of the hostmicrobiota relationship, with consequences for intestinal regeneration and colitis-associated tumour formation. [ABSTRACT FROM AUTHOR]

Background Studies of Merkel cell polyomavirus ( MCPyV) in nonmelanoma skin cancers ( NMSC) other than Merkel cell carcinoma ( MCC) produced controversial results. Therefore, we studied the prevalence of MCPyV in basal cell carcinoma ( BCC) and in squamous cell carcinoma ( SCC). Methods Tissue specimens were analyzed for the presence of MCPyV DNA by conventional polymerase chain reaction ( PCR). Expression of MCPyV large T protein was determined by immunohistochemistry. Results MCPyV DNA was frequently detected in skin cancers by PCR, in 36 of 88 BCCs, in 21 of 75 SCCs and in 10 of 47 normal skin samples. In BCC, a significant difference in the detection rate compared to normal skin was observed. In contrast, weak reactivity for MCPyV large T antigen was detected only sporadically in immunosuppressed patients (2 of 88 BCCs, 1 of 75 SCCs). Mutations of the large T antigen of MCPyV were more frequently observed in MCC than in BCC/ SCC. Conclusions Our results suggest that the frequent detection of the MCPyV genome in NMSC by PCR reflects ubiquitous spread of the virus. However, the low immunohistochemical detection rate of MCPyV and the lack of MCC-specific MCPyV mutations argue against an essential role of MCPyV in the development of skin cancers other than MCC. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the case of a 60-year old male patient with metastatic colorectal cancer (CRC) that shows two different Kirsten ras (KRAS) gene mutations (G12D and G12V).

Intestinal transplantation has evolved into an established treatment for patients with intestinal failure. Although acute rejection episodes are reversible, late onset and chronic rejections remain major prognostic factors. We describe here our experience with endoscopic and histologic long-term monitoring through a cutaneous enterostomy. Between 1989 and 2003, 24 intestinal transplants were performed. After revascularization and reconstruction of proximal intestinal continuity, a side-to-end ileo-enterostomy was performed 20 cm from the stoma and the terminal allograft ileostomy left in the abdominal wall. Approximately after 2 months, in eight patients (nine transplants), the stoma was excluded from the gastrointestinal continuity, allowing ongoing endoscopy and histologic examination. Of 280 forceps biopsies, 64 (23%) were performed through the ‘blind ostomy’. Eleven acute allograft rejections were diagnosed between days 3 and 51, with two episodes in three cases. Through the ‘blind ostomy’, a late mild acute rejection was diagnosed in five instances, three to 37 months after transplantation. In all these patients, basal immunosuppression was intensified. Chronic rejection was seen in three cases 4–26 months after transplantation. In one of the three patients, chronic rejection was diagnosed from the excluded blind enterostomy. A long-term cutaneous enterostomy, even if disconnected from the intestinal continuity, enables simple long-term monitoring of small bowel allografts. [ABSTRACT FROM AUTHOR]

Peritoneal injury is often associated with alterations of the mesothelium, resulting in peritoneal healing and adhesion formation. We analyzed the effects of pro-inflammatory cytokines on cell morphology and proliferation of human peritoneal mesothelial cells (HPMC). After 48 hours, HPMC formed a confluent layer with cell volumes of 2,662±111 fL. Treatment of HPMC with interleukin-1β and tumor necrosis factor-α (TNF-α) induced mesothelial disintegration and alterations in mesothelial cell morphology, which were associated with an interleukin-1β–triggered increase in cell volume (3,028±118 fL; p<0.05) and exfoliation of cells into the supernatants of cell cultures ( p<0.05). Whereas TNF-α arrested HPMC in the G0/G1 phase ( p<0.05), interleukin-1β caused an increase of cells into the S phase of the cell cycle. In addition, interleukin-1β and interferon-γ exerted a proliferative effect on HPMC. These changes were independent from mesothelial Na+/H+ antiporter-1 expression. Our data indicate that the response of HPMC to inflammatory injury is regulated by interleukin-1β and TNF-α reflecting their putative role in peritoneal wound healing and adhesion formation. [ABSTRACT FROM AUTHOR]

The fulminant form of post-transplant lymphoproliferative disorder (PTLD) is very uncommon and occurs in approximately 1% of PTLD patients. Approximately 85% of these lesions are of B-cell origin, and most of them are associated with Epstein–Barr virus infection. Fulminant PTLD is frequently associated with a systemic inflammatory response syndrome, and may be difficult to differentiate from septicemia. We describe the case of a 59-yr-old man who suffered from prolonged septicemia in the immediate post-transplant period, and presented again four months after cardiac transplantation with fever, painful liver edge and gastrointestinal bleeding. The diagnosis of fulminant PTLD with advanced multiorgan infiltration by a diffuse large-cell lymphoma of B-cell phenotype was made. During treatment with rituximab, the patient died from Enterococcus faecium septicemia. The sequence of septicemia, PTLD and, finally again, septicemia is an unusual challenge and urges for an aggressive diagnostic approach, where markers like procalcitonin may aid in the discrimination of fulminant PTLD from septicemia. [ABSTRACT FROM AUTHOR]

Unlabelled: Invasive meningococcal disease (IMD) is an important cause of morbidity and mortality in children and adults. This study was conducted to determine a possible increase in IMD in recent years with special interest focused on serogroup C disease. From January 1st 1993 to December 31st 2002, IMD was studied in one million residents of Austria. We used active, population-based surveillance data from the Office of Public Health. A total of 126 patients with positive blood and/or cerebrospinal fluid culture or positive swabs for Neisseria meningitidis were studied. The median age of all patients was 9.5 years (range 1 month to 63 years). The average incidence of all IMD subgroups was 1.05 cases per 100,000 person years and was highest in children 0-4 years old (7.08 cases per 100,000 person years) followed by young adults aged 15 to 19 years (4.35 cases per 100,000 person years). Serogroup C IMD occurred in 1.30 cases/100,000 person years in patients aged 0 to 4 years and in 1.92 cases/100,000 person years in patients aged 15 to 19 years. Overall mortality was 11.1%. There was a significant increase (P =0.001) in IMD due to serogroup B disease within the last 10 years. In contrast, serogroup C disease did not increase during the last decade.Conclusion: Currently, we do not recommend mass vaccination against serogroup C disease in Austria, but young adults aged 15 to 19 years display a high incidence of meningococcal C disease. In this age group, vaccination against serogroup C disease should be considered. [ABSTRACT FROM AUTHOR]

Abstract: Objective : Inflammatory or malignant peritoneal diseases are associated with high levels of ascitic vascular endothelial growth factor (VEGF). We compared the VEGF secretion by human peritoneal mesothelial cells (HPMC) and ovarian carcinoma (OVCA) cells and its regulation by pro-inflammatory cytokines. Materials and methods : VEGF secretion in cultured HPMC, established human OVCA cell lines, and inflammatory or OVCA-associated ascites was determined by enzyme linked immunosorbent assay. Results : HPMC constitutively produced VEGF at median levels of 43 ± 7 pg/105 cells. Treatment of HPMC with 1 ng/ml IL-1β (567 ± 213 pg/105 cells) or TNF-α (89 ± 1 pg/105 cells) resulted in a 13-fold (P &#60; 0.01) or 2-fold (P &#60; 0.05) elevation of the VEGF secretion. In OVCA, the constitutive VEGF expression was 8-fold higher than VEGF levels in HPMC (364 ± 185 pg/105 cells; P &#60; 0.001). VEGF secretion in OVCA cells was also increased by IL-1β (514 ± 105 pg/105 cells; P &#60; 0.01) or TNF-α (458 ± 168 pg/105 cells; P &#60; 0.01) reaching similar levels as in IL-1β-activated HPMC. Median VEGF levels in malignant ascites (2761 ± 1549 pg/ml) were 11-fold higher compared with levels in inflammatory fluids (244 ± 170 pg/ml; P &#60; 0.01). VEGF levels in both inflammatory- and OVCA-associated fluids correlated with ascitic IL-1β levels (P &#60; 0.05). Conclusion : We identified ovarian cancer cells and/or IL-1β-activated peritoneal mesothelial cells as important sources of ascitic VEGF. The present data indicate that IL-1β-triggered VEGF production by neoplastic and normal cells is a common pathomechanism for ascites formation in both inflammatory and malignant conditions. [Copyright &y& Elsevier]

Background/Aims: Severe alcoholic hepatitis (AH) is associated with high mortality. Tumor necrosis factor-alpha (TNFα) has been demonstrated to play an important role in its pathophysiology.Methods: Twelve patients with biopsy-confirmed AH and a Maddrey discriminant factor >32 were treated with a single infusion of the anti-TNF monoclonal antibody Infliximab at a dose of 5 mg/kg body weight. Serial measurements were made for various cytokines using specific enzyme-linked immunoassays (ELISA). In four patients, liver biopsy samples were available pretreatment and on day+28 of therapy.Results: Ten of the 12 patients are alive at a median of 15 (12–20) months. Two patients died within 30 days from septicemia. Serum bilirubin levels, Maddrey score, neutrophil count and C-reactive protein fell significantly within the first month. There was an early, though not significant, decrease in plasma levels of proinflammatory cytokines (interleukins (IL)-1β, IL-6, IL-8, interferon-gamma), whereas plasma levels of TNFα remained near the sensitivity limit of the assay throughout the treatment course. While TNFα mRNA expression in the liver did not change, expression of IL-8, a cytokine regulated mainly by TNFα, was almost absent on day+28.Conclusions: Our data suggest that randomized controlled trials of anti-TNF antibody in severe AH are warranted. [Copyright &y& Elsevier]

Examines the associations between cellular immune effector function, iron metabolism, and disease activity in patients with chronic hepatitis C virus infection. Iron and immune status in cirrhotic and noncirrhotic patients; Correlation between liver iron concentration and serum ferritin levels.

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). [ABSTRACT FROM AUTHOR]