Faculty Bibliography

ABSTRACT: Classical Hodgkin lymphoma (CHL) is a B-cell lymphoproliferative disorder with a relatively good prognosis. A small but significant percentage of patients, however, will respond poorly to therapy. A recent gene expression profiling study has identified a macrophage signature which has been correlated with primary treatment failure, and immunohistochemical tissue microarray for CD68 was shown to reflect the gene signature as a potentially clinically useful marker to predict adverse prognosis.We examined 44 cases of CHL, mostly nodular sclerosis subtype, in which the immunohistochemical stains for the histiocytic markers CD68 and CD163 were performed. The staining intensity was graded for each stain (< 5, 5-25, and > 25 percent of cells positive in the Hodgkin cell (HC) rich nodules) and background staining characteristics were recorded.CD163 staining was lower than CD68 in HC rich nodules, with lower background staining (p 0.03). There was no significant difference between either CD68 or CD163 and disease recurrence in a subset (N = 41) of cases.In conclusion, we demonstrate that CD163 staining is lower than CD68, with less non-specific staining of background inflammatory cells and Hodgkin cells, therefore is a better marker for tumor associated macrophages. However, we did not identify a correlation between staining for CD68 or CD163 and recurrence of disease. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1460518258831620.

Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit gamma-secretase (gammaSE) complex. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue

The effect of thrombin on tumor cell cycle activation and spontaneous growth was examined in synchronized serum-starved tumor cell lines and a model of spontaneous prostate cancer development in TRAMP mice. BrdUrd incorporation and propidium iodide staining of prostate LNCaP cells arrested in G(0) and treated with thrombin or serum revealed a 48- and 29-fold increase in S phase cells, respectively, at 8 hours. Similar results were obtained with TRAMP cells and a glioblastoma cell line, T98G. Cell cycle kinases and inhibitors in synchronized tumor cells revealed high levels of p27(Kip1) and low levels of Skp2 and cyclins D1 and A. Addition of thrombin, TFLLRN, or serum down-regulated p27(Kip1) with concomitant induction of Skp2, Cyclin D1, and Cyclin A with similar kinetics. LNCaP p27(Kip1)-transfected cells or Skp2 knockdown cells were refractory to thrombin-induced cell cycle activation. MicroRNA 222, an inhibitor of p27(Kip1), was robustly up-regulated by thrombin. The in vitro observations were tested in vivo with transgenic TRAMP mice. Repetitive thrombin injection enhanced prostate tumor volume 6- to 8-fold (P < 0.04). Repetitive hirudin, a specific potent antithrombin, decreased tumor volume 13- to 24-fold (P < 0.04). Thus, thrombin stimulates tumor cell growth in vivo by down-regulation of p27(Kip1)

BACKGROUND: "Maximal medical therapy" is the standard of care for chronic rhinosinusitis (CRS) treatment before the recommendation for surgery. However, this therapy is not consistent. Therefore, as a first step in determining the role of the disparate "maximal medical" treatments for CRS, American Rhinologic Society (ARS) members were surveyed. METHODS: A survey was mailed to all nonresident members of the ARS (n=723). Focusing on the time period before surgical intervention is first considered for CRS patients, the survey assessed types of therapies, frequency of use, details on antibiotic and steroid usage, use of computed tomography (CT), and demographic data of respondents. All responses were anonymous. RESULTS: Three hundred eight surveys were returned (43%). A majority of respondents used oral antibiotics and nasal steroids "almost always (>90%)". Oral antibiotics, oral steroids, nasal steroids, saline irrigation, and allergy testing were most commonly used at least "usually (50-90%)". The median antibiotic length was 3.1-4 weeks. The mean peak prednisone dose was 51.7 mg when oral steroids were used. Therapies that were rarely or never used by the majority included oral antifungals, antifungal spray, antibiotic spray, antibiotic nebulizer, steroid nebulizer, and i.v. antibiotics. CONCLUSION: Oral antibiotics (median, 3.1-4 weeks) and nasal steroids are used >90% of the time by a majority of ARS members for maximal medical treatment of CRS.