The aim of this study was to evaluate the expression of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) in prostate cancer in the main tumor mass and tumor cells at the positive margin as well as the influence of these biomarkers on the biochemical recurrence of the disease in prostatectomy patients. Tissue microarrays of 120 archival prostate carcinoma samples were immunohistochemically evaluated for MMP-2 and MMP-9 expression and compared with clinicopathological parameters. Tumors with positive surgical margins showed significantly higher overall expression of MMP-9 versus tumors with negative resection margins (P = 0.0121). MMP-9 expression was significantly elevated in tumors from patients who had biochemical recurrence (P = 0.0207). In the group of patients with negative margins, MMP-9 expression above the cut-off value was significantly associated with recurrence (P = 0.0065). Multivariate analysis indicated that MMP-9 is a good predictor of biochemical recurrence (odds ratio = 10.29; P = 0.0052). Expression of MMP-2 in tumor cells was significantly higher at the positive margins than in the main tumor mass (P = 0.0301). The present results highlight the potential value of MMP-2 and MMP-9 expression for predicting the behavior of prostate tumors after prostatectomy with both positive and negative surgical margins.

BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.

c A female patient age 69 years with .10-year history of type 2 diabetes (T2D), on a therapy of premixed aspart insulin, presented with poor glycemic control (HbA 1c 8.7%). c Change of therapy to three injections of short-acting aspart and once-daily glargine improved glycemic control but resulted in severe lipoatrophy at all sites of injection, a rare complication of insulin therapy almost exclusively associated with type 1 diabetes (T1D). c The patient had C-peptide levels within normal range and lacked autoantibodies against GAD, islet antigen 2 (IA-2), and tissue transglutaminase (tTg), excluding T1D. c Glargine injection was replaced by degludec, but this did not prevent formation of new indentures. c Histological analysis of tissue biopsies revealed strong tissue remodeling at affected sites including fibrosis, reduction of adipocyte size, and increased vascularization. c Immunohistochemical staining showed a strong influx of CD4 T cells in affected sites but no apparent signs of T cell-mediated cell death. c Flow cytometry of peripheral blood leukocytes did not show an overt effector cell profile of CD4 T cells, indicating that the response was mediated locally. c Our findings indicate that insulin-induced lipoatrophy in the context of T2D is distinct from that seen in T1D and appears to depend on CD4 T cell-mediated tissue remodeling.

Simultaneous occurrence of T-cell and B-cell neoplasms is rare, and etiologic relationships between these 2 malignancies are poorly understood. We describe the case of a 66-year-old woman who was admitted to the hospital because of fever, hemoptysis, lymphadenopathy, and skin rash. Enlarged lymph nodes in axillary, pectoral, paratracheal, and periportal regions as well as slight hepatomegaly and splenomegaly were confirmed. A peripheral blood smear revealed rouleaux formation and numerous circulating plasma cells, with plasmacytoid lymphocytes. Immunofixation-electrophoresis detected a monoclonal band defined as immunoglobulin (IgG)-lambda light chains with broad-band polyclonal IgA. The patient died from abrupt splenic rupture before diagnostic work-up was finished. Postmortem examination revealed infiltration of atypical lymphoid cells exhibiting high proliferative activity admixed with typical and atypical plasma cells in several organs. Thus, plasma cell leukemia (IgG-lambda) as a rare and aggressive variant of plasma cell myeloma in the present case was associated with aggressive peripheral T-cell lymphoma and polyclonal (IgA) plasmacytosis.

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