Pre-fibrotic/early primary myelofibrosis vs. WHO-defined essential thrombocythemia: The impact of minor clinical diagnostic criteria on the outcome of the disease.

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.

Hyperexpression of NOTCH-1 is found in immature acute myeloid leukemia.

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<0.001). Significant correlation between NOTCH-1 hyperexpression and coexpression of CD7, a phenotypic marker of immaturity (p<0.001) was also seen. Patients with hyperexpression of NOTCH-1 were found to have an inferior overall survival in this retrospective study. Our results indicate that a specific subgroup of AMLs may be associated with hyperexpression of components of the Notch signaling pathway. Better knowledge in pathway signaling in AML could help to identify patient subsets that may benefit from administration of pathway inhibitors and could also contribute to tailored treatment.

Animal-type melanoma - tumor cell invasion of dermal lymphatics and molecular identification of lymph node metastasis.

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).

Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma.

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