Molecular Expression of bone marrow angiogenic factors, cell-cell adhesion molecules and matrix-metallo-proteinase plasma cellular disorders: a molecular panel to investigate disease progression

Increasing levels of angiogenesis play an important role in the pathogenesis and progression of multiple myeloma (MM). Malignant plasma cells promote a gradual increase in the degree of angiogenesis, modulation of specific cell-cell adhesion molecules and secretion of matrix-metallo-proteinases (MMPs), changing the BM composition from benign conditions, such as MGUS, to smouldering multiple myeloma (SM) and to active MM. We aimed to identify a gene expression profile, helpful to discriminate the “angiogenic potential” in BM and PB plasma cells from MGUS, SMM and active MM patients analyzed at diagnosis. We analyzed the expression of cell-cell adhesion molecules such as VE-Cadherin, E-Cadherin MCAM/MUC18/CD146 and of the MMP-2 and MMP-9. MCAM/MUC18 expression resulted mostly associated with that of the pivotal angiogenic factors VEGF and Ang2, and in MGUS the pattern was different in steady state, compared to progression towards SM. Furthermore, E-Cadherin, the main epithelial cell-cell-adhesion molecule, unexpectedly resulted overexpressed in MM

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

Acute promyelocytic leukemia (APL) accounts for 10-15% of newly diagnosed acute myeloid leukemias (AML) and is typically caused by the fusion of promyelocytic leukemia with retinoic acid receptor alpha (RARA) gene. The prognosis is excellent, thanks to the all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy. A small percentage of APLs (around 2%) is caused by atypical transcripts, most of which involve RARA or other members of retinoic acid receptors (RARB or RARG). The diagnosis of these forms is difficult, and clinical management is still a challenge for the physician due to variable response rates to ATRA and ATO. Herein we review variant APL cases reported in literature, including genetic landscape, incidence of coagulopathy and differentiation syndrome, frequent causes of morbidity and mortality in these patients, sensitivity to ATRA, ATO, and chemotherapy, and outcome. We also focus on non-RAR rearrangements, complex rearrangements (involving more than two chromosomes), and NPM1-mutated AML, an entity that can, in some cases, morphologically mimic APL

Increased Occurrence of Cutaneous Leiomyomas and Dermatofibromas in Patients with Uterine Leiomyomas without Fumarate Hydratase Gene Mutations

Leiomyomas are smooth muscle-derived benign neoplasms that can affect all organs, most frequently in the uterus. Fumarate hydratase gene (FH) mutation is characterised by an autosomal dominant disease with increased occurrence of renal tumours, but also by cutaneous (CLs) and uterine leiomyomas (ULs). So far, an increased occurrence of skin tumours in non-mutated patients with ULs has not been verified. To this aim, a case-group of women who were FH non-mutated patients surgically treated for ULs (n = 34) was compared with a control-group (n = 37) of consecutive age-matched healthy women. The occurrence of skin neoplasms, including CLs and dermatofibromas (DFs), was evaluated. Moreover, the microscopic features of FH non-mutated skin tumours were compared with those of an age-matched population group (n = 70) who presented, in their clinical history, only one type of skin tumour and no ULs. Immunohistochemical and in vitro studies analysed TGFβ and vitamin D receptor expression. FH non-mutated patients with ULs displayed a higher occurrence of CLs and DFs (p p p < 0.01), but a similar distribution of TGFβ-receptors and SMAD3. In vitro studies documented that TGFβ-1 treatment and vitamin D3 have opposite effects on α-SMA, TGFβR2 and VDR expression on dermal fibroblast and leiomyoma cell cultures. This unreported increased occurrence of CLs and DFs in FH non-mutated patients with symptomatic ULs with vitamin D deficiency suggests a potential pathogenetic role of vitamin D bioavailability also for CLs and DFs

Chronic Lymphocytic Leukemia

this report, 7 patients have died at a median time of 16 months (range: 12-23 months) after the start of FAND, 5 because of a new disease progression and 2 because of infection. Myelosuppression was the main toxicity observed during treatment. Severe granulocytopenia (WHO grade 3) occurred after 86 of the 124 administered courses (69%). However, only 10 of the 86 courses of therapy (12%) followed by granulocytopenia were characterized by the occurrence of major infections (pneumonia diagnosed on clinical basis: 7 patients; Gram-positive septicemias: 2 patients; peri-anal abscess: 1 patient) requiring parental antibiotics. During the first part of the study (10 patients), no G-CSF support was given in the presence of severe neutropenia that occurred after 16 courses and 3 cases of pneumonia were observed (3/16: 19%). During the second part of the study (21 patients), GCSF support was given after 70 courses characterized by severe neutropenia and 7 cases of pneumonia were observed (7/70: 10%). Herpetic infections (dermatomal herpes-varicella zoster: 1 patient; herpes simplex: 4 patients) were observed in the first 5 patients enrolled in the study. No further cases of herpetic infection were recorded after the introduction of acyclovir prophylaxis. One patient devel- F.R. Mauro et a

The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenibresistant human melanoma xenografts. Here, we report that subtoxic concentrations of this compound significantly reduced invasiveness of BRAF-V600D mutated WM115 and WM266.4 melanoma cell lines derived from the primary lesion and related skin metastasis of the same patient, respectively. The strong antimetastatic activity of MC3181 was observed in both 2D monolayer cultures and 3D multicellular tumor spheroids, and confirmed in vivo by the significant decrease in the number of B16-F10 melanoma lung metastases in drug-treated mice. Our data also show that MC3181 affects the lactate production in the high glycolytic WM266.4 cell line. To unveil the MC3181 mechanism of action, we analyzed the ability of MC3181 to affect the degree of activation of different MAPK pathways, as well as the expression/activity levels of several proteins involved in angiogenesis, invasion, and survival (i.e. AP2, MCAM/MUC18, N-cadherin, VEGF and MMP-2). Our data disclosed both a decrease of the phospho-active form of JNK and an increased expression of the transcription factor AP2, events that occur in the very early phase of drug treatment and may be responsible of the antimetastatic effects of MC318