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The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.

The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.

The introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for non-small cell lung cancer (NSCLC) with activating mutations of the EGFR has opened a new area of lung cancer treatment strategies and led to an enthusiastic search for additional mutations. Since then, numerous driver mutations such as EML4-ALK and ROS1 have been detected and specific treatment options have already been developed. However, molecular tests have to follow specific rules if applied in daily practice. The Austrian Working Group on Pulmonary Pathology and Oncology (AWGPPO) is presenting an updated version of their previous recommendation published in 2011. Several practical questions raised during the last 2 years will be addressed, such as reflex testing, selection of tissues, order of molecular tests, and the issue of resistance mechanisms.

Summary Animal-type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey-white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle-shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).

This article focuses on the role that devolution planning should occupy in an agency’s continuity planning effort. A devolution plan is an integral part of a Continuity of Operations (COOP) plan; however, many agencies do not expend the necessary time and effort to develop these essential plans. There are several reasons for this, including the difficult nature of the concepts at issue, as well as the practical challenges inherent with implementation of a devolution plan. This article gives a brief overview of COOP planning, with particular attention given to the reconstitution period. It then gives the definition of devolution and attempts to explain different ways that planners approach this issue, considering both internal and external devolution. Finally, the article reviews some of the core elements that should be included in every devolution plan.

The Notch signaling pathway is a cell program that is active during early development of multicellular organisms and is required for the formation of basic structures in the growing embryo. Scientific evidence which has accumulated during the last years clearly indicates that aberrant pathway activation may also be critical for the pathogenesis of malignant disease. Despite some limited information the exact role of the Notch signaling pathway in acute myeloid leukemia (AML) remains poorly defined. Immunohistochemical staining of paraffin-embedded bone marrow biopsies from 97 patients with AML, treated between February 1994 and May 2011, for NOTCH-1 was performed according to standardized procedures. Immunological, cytological, pathological, molecular and clinical data were obtained from the hospitals database and patient records. Hyperexpression of NOTCH-1 was seen in 7/97 AML specimens, the other patients showed some expression of NOTCH-1. There was a significant correlation between hyperexpression of NOTCH-1 and the morphological subgroup M0/1 - AML without morphologic maturation (p

The topography of the nerve of Henle was reviewed. Fifty-two human cadaveric upper extremities were studied. In 30 (58%) the nerve was well defined; in 22 (42%) its origin from the ulnar nerve was unidentifiable. The palmar cutaneous branch of the ulnar nerve separated from the ulnar nerve 5 to 11 cm distal to the medial epicondyle of the humerus to divide into its terminal branches in the distal forearm. Four patterns were detected: ulnar, radioulnar, vessel-related, and radial. These shared a consistent vascular branch, which sent 2 branches to the ulnar artery just proximal to the distal ulnar tunnel. Using a tyrosine hydroxylase antibody-based immunohistochemistry technique the nerve was shown to carry sympathetic fibers. Motor fibers were ruled out with Karnovsky's stain, which was used in combination with the tyrosine hydroxylase method in 10 specimens.

Mucosa-associated lymphoid tissue (MALT) lymphomas most frequently involve the gastrointestinal tract and are the most common subset of extranodal non-Hodgkin lymphoma (NHL). Here we describe overexpression of BCL10, a novel apoptotic signalling gene that encodes an amino-terminal caspase recruitment domain (CARD), in MALT lymphomas due to the recurrent t(1;14)(p22;q32). BCL10 cDNAs from t(1;14)-positive MALT tumours contained a variety of mutations, most resulting in truncations either in or carboxy terminal to the CARD. Wild-type BCL10 activated NF-kappaB but induced apoptosis of MCF7 and 293 cells. CARD-truncation mutants were unable to induce cell death or activate NF-kappaB, whereas mutants with C-terminal truncations retained NF-kappaB activation but did not induce apoptosis. Mutant BCL10 overexpression might have a twofold lymphomagenic effect: loss of BCL10 pro-apoptosis may confer a survival advantage to MALT B-cells, and constitutive NF-kappaB activation may provide both anti-apoptotic and proliferative signals mediated via its transcriptional targets.

The tissue concentrations of urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were investigated by an ELISA technique in normal and malignant samples of the prostate from 24 patients undergoing radical prostatectomy for organ-confined prostate cancer. The median concentration of u-PA was significantly higher in cancerous than in normal prostate tissue (p = 0.006). No significant increase of u-PAR, PAI-1 and t-PA was found in cancer tissue in comparison with the benign samples (p > 0.05). Assessment of the relationship between fibrinolytic proteins and DNA ploidy revealed an increased u-PA, u-PAR and PAI-1 in diploid prostate cancer as compared with the normal controls. However, in aneuploid cancer u-PA remained high but u-PAR and PAI-1 were decreased. This led to a higher local concentration of u-PA in aneuploid samples than in normal prostate and in diploid prostate cancer. No alteration of median t-PA was found in benign prostate or in diploid or aneuploid prostate cancer. The altered expression of u-PA, u-PAR and PAI-1 in diploid and aneuploid prostate cancer suggests a possible role of fibrinolytic proteins in the different biologic behavior of tumors, and may be one explanation for the higher metastatic potential of aneuploid tumors.

Purpose: Forty-one months after we performed bilateral implantation of in vitro endothelialized femoropopliteal bypass grafts in a 69-year-old patient, we obtained a central graft segment for histologic and ultrastructural investigation. Methods: Before implantation the grafts were confluently lined with autologous first passage mass cultures of pure cephalic vein endothelial cells. The precoating of the expanded polytetrafluoroethylene prosthesis was done with fibrinolytically inhibited fibrin glue. Reoperation became necessary because of symptomatic unilateral atherosclerotic lesions located in the center of one of the two in vitro lined grafts. A 21 cm long graft segment was removed and replaced by a new in vitro endothelialized expanded polytetrafluoroethylene graft. Results: On scanning electron microscopy a confluently covering mature endothelium was found throughout the whole length of the removed prosthesis. The endothelial identity was confirmed by a positive immunohistochemical CD 34, von Willebrand factorstaining, and the ultrastructural demonstration of Weibel Pallade bodies. The endothelium rested on a collagen IV positive basement membrane. Histologic cross sections revealed uniformly developed subintimal tissue of 1.21 ± 0.19 mm thickness, which was separated from the intima by a distinct internal elastic membrane. The cells of this cell-rich matrix stained strongly positive for actin. Ultrastructurally, this matrix was dominated by highly contractile myofibroblasts loaded with peripherally located well-developed actin fillaments. A number of these cells also showed signs of secretory cells with a distinct endoplasmic reticulum and a Golgi complex. In areas of atherosclerotic lesions the subendothelial matrix was partially exposed, and the internal elastic membrane had to a certain extent disintegrated. Only in these areas KP-1 and MG-Ml positive foamy macrophages and CD 34 positive capillaries were found. The myofibroblasts of this diseased part of the subintimal tissue contained large lipid vacuoles. Conclusions: We conclude that the confluent in vitro lining of synthetic vascular grafts with pure autologous endothelial cells facilitates graft healing, which may result in a hybrid structure with features of a native vessel.

The existence of a confluently covering endothelium that is free of any thrombotic appositions can be proved 30 days after clinical implantation of an in vitro endothelialized expanded polytetrafluoroethylene graft. The recipient of the mesosystemic H-graft was a 69-year-old man who had a thrombosed portal vein following pancreatitis. Autologous endothelial cells were obtained from the external jugular vein under local anesthesia, applying the in situ cannulation technique. After low-density plating, first-passage mass cultures of 1.22 × 10 6 endothelial cells were obtained 14 days after vein excision. After precoating was accomplished with fibrinolytically inhibited fibrin glue, a 10 mm expanded polytetrafluoroethylene graft was confluently lined with the autologous endothelial cells at a seeding density of 1.2 × 10 5 cells/cm 2 . After a maturation period of an additional 9 days and the microbiologic exclusion of a possible infection, an 11 cm graft segment was implanted between the superior mesenteric vein and the inferior vena cava. In spite of a patent shunt the patient had a repeat bleeding episode, needed parenteral nutrition, and died of sepsis on day 30. Immediately after the graft had been taken out, specimens were processed by scanning electron microscopy and light microscopy for the immunohistochemical proof of the endothelial nature of the surface-covering cell layer. The entire graft surface displayed a confluent cell lining that was free of any thrombotic appositions. A strongly positive stain result for both factor VIII – related antigen and the fixation-resistant CD34 molecule identified these cells as endothelial. No α-actin – positive cells could be detected. The underlying protein matrix was well preserved and unaltered in thickness and appearance, compared with preimplantation samples. None of the specimens showed any evidence of infection. This human demonstration of an intact endothelium on a patent venous prosthesis further establishes in vitro lining as a method that actually creates a persistent and functioning endothelium on a synthetic graft surface. (J VASC SURG 1994;19:549-54.)

Animal-type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey-white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle-shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).

We report the clinicopathologic findings of 41 patients with Ki-1 (CD30)-positive large cell lymphoma. The median age was 50 years; 13 patients were under 40 years of age. Ten patients presented with extranodal disease. Fifty-five percent of the patients presented with stage I or II disease, and bone marrow involvement was histologically documented in 30% and occurred exclusively in patients over 40 years of age. Two cytomorphologically distinct groups of Ki-1--positive large cell lymphomas could be separated. Group A lymphomas consisted of pleomorphic large cells, sometimes with wreathlike and embryo-like nuclei, whereas group B lymphomas displayed a rather monomorphic appearance. Clinically the two groups of lymphomas differed with respect to stage of disease, frequency of bone marrow involvement, and median survival. On paraffin sections, the Ki-1--related antibody Ber-H2 provided excellent staining results in all cases. Immunologic phenotyping disclosed a T cell type in the majority of cases, revealed marked loss of differentiation antigens, and frequent expression of HLA-DR and IL-2 receptor. The overall median survival was 13 months. Age below 40 years, limited stage of disease (I and II), and, although not statistically significant, lymphoma morphology were associated with longer survival. We conclude, that Ki-1--positive large cell lymphomas represent a morphologically and immunologically heterogeneous category of hematolymphoid neoplasms derived from dedifferentiated and activated lymphoid cells with marked age-dependent prognosis.

In the present phase II study, we tested the efficacy of a single course of rituximab (375 mg/m2 on days 1, 8, 15 and 22) as treatment for relapsed myeloma. The rationale for this study was the identification of a population of clonotypic CD20+ B cells that are believed to be precursors of malignant plasma cells. In addition, CD20 was expressed on 10% and 50% of bone marrow plasma cells in two of the ten patients enrolled. Following rituximab treatment, none of the patients achieved an objective response. Two patients had stable disease at month 6, the predefined end of the study, while, at that time, two patients were classified as having progressive disease. One patient opted to withdraw from the study at month 3, at which time he had stable disease. The other five patients had to be withdrawn early from the post-treatment observation because of need of salvage therapy for progressive disease. WHO grade

We report a case of idiopathic myelofibrosis with trisomy 13 as the sole clonal aberration, as demonstrated by metaphase cytogenetics. The clinical course was especially poor in this case, with death in blast crisis occurring within two weeks from diagnosis. The dismal outcome bears striking similarity to two previous cases of idiopathic myelofibrosis and trisomy 13 reported in the literature. Therefore trisomy 13 may be a predictor of a rapidly fatal outcome in this otherwise indolent disease. Fluorescence in situ hybridisation (FISH) with a chromosome 13 specific probe may enhance the detection of this aberration, since only 50% of cases of idiopathic myelofibrosis are karyotyped successfully using conventional techniques.

MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) has been shown to be expressed by neoplastic B-cells and to be closely linked to poor survival in large B-cell lymphomas. Information on a possible expression of MUM1 in myeloma cells and on a possible role as prognostic marker has not been presented up to now. Hence, we aimed to analyse these issues in a cohort of well characterized patients with multiple myeloma. Fifty-three patients with multiple myeloma, median age 70 years, were enrolled. Nine presented with Durie Salmon stage I, 6 had stage II, and 38 stage III. Forty-five were newly diagnosed and 8 pretreated (median number of treatment lines: 2). MUM1 mRNA expression was analysed by real time PCR in freshly isolated unsorted as well as CD 138 enriched myeloma cells and controls. Survival was calculated using the Kaplan-Meier product limit method. For multivariate analyses the Cox proportional hazards method was used. MUM1 mRNA levels were detected in all 53 unsorted myeloma samples with a distribution range covering 3 orders of magnitude (0.35 to 261.38-fold, median: 10.5 relative to normal blood=1). MUM1 RNA expression was validated in CD138 enriched myeloma cells (N=10). A strong but heterogeneous expression was found in the CD 138 positive cell fraction while low expression was found in the remaining CD138 negative cell fraction. When patients were divided regarding the magnitude of MUM1 expression by using a cut off level of 13 (relative to the level detected in normal blood) 32 were found with low and 21 with high MUM1 expression. Median survival was significantly shorter in patients with high MUM1 expression compared to low expressers (45 months, vs. 58 months, p =8x10−5, Hazard Ratio 9.65). Among the following parameters: ß2-microglobulin (>5mg/ml), CRP, albumin, creatinine, M-component, and bone marrow plasma cell infiltration tested, only increased MUM1 expression (p = 0.00088), high ß2-microglobulin (>5mg/ml, p = 9x10−4), creatinine (p 5mg/ml and MUM1 expression >13) had very short survival (median: 3 months). In contrast median survival was 58 months in the 41 patients with none or only one adverse prognostic factor (p = 6.71 x 10−11). In conclusion, high MUM1 RNA expression in myeloma cells was found in 40% of patients. High MUM1 RNA expression strongly correlated with poor survival both in univariate and in multivariate analysis. The latter analysis revealed MUM1 RNA expression together with high ß2-microglobulin levels as only parameters independently predicting for poor outcome.

A program of computer-assisted texture analysis was applied to evaluate its usefulness for objective description of changes in tumor architecture due to primary medical treatment in patients with locally advanced breast cancer. Changes in values of parameters of the statistical pattern recognition technique were compared to ultrasonographically depictable, subjectively recorded changes in echogenicity and echotexture (brightness, homogeneity) and reviewed with regard to histopathologic evaluation of tumor regression. Characteristic trends of defined quantitative texture parameters (mean gradient, mean gray value, contrast from the co-occurrence matrix) corresponded to visually depictable changes of the B-mode image and underlying histopathologic changes. The results indicate that quantitative texture analysis may aid in noninvasive monitoring of tumor response to neoadjuvant chemotherapy.