An electron microscopic study of the termination of intracortical axons upon Betz cells in area 4 of the monkey.

After small lesions within the cortex of area 4 of the monkey degenerating axon terminals have been seen with the electron microscopy to contact the cell bodies, proximal parts of the apical dendrites and initial segments of Betz cells 0.5 to 2.5 mm from the damage. The degenerating axon terminals make symmetrical synapses which are presumed to be inhibitory in function. The degenerating terminals are probably from the axons of the basket cells described in Golgi-impregnated material, and which correspond to the large stellate cell recognized in electron microscopic studies.     

c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent.

c-erbB-2-positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1alpha (HIF1alpha) production (Laughner et al., Mol Cell Biol 2001;21:3995-4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1alpha expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2-positive and 90 c-erbB-2-negative carcinomas) were stained immunohistochemically for HIF1alpha and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1alpha protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1alpha expression. If activation of c-erbB-2 in humans results in overexpression of HIF1alpha independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2-positive breast tumors.     

Graft-versus-host disease after liver transplantation is associated with bone marrow failure,hemophagocytosis, and DNMT3A mutations

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

     

Anaplastic large-cell lymphomas of B-cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B-cell lymphomas

There is controversy in the literature as to whether anaplastic large-cell lymphoma of B-cell phenotype is related to the t(2;5)-positive T- or 'null' cell lymphoma of the same morphology. We report a study of 24 lymphomas with morphological features of anaplastic large-cell lymphoma which expressed one or more B-cell markers and lacked T-lineage markers. Clinical features were more in keeping with large B-cell lymphoma than with classical t(2;5)-positive anaplastic large-cell lymphoma, and immunostaining for anaplastic lymphoma kinase (ALK) protein provided no evidence for the (2;5) translocation (or one of its variants). The staining patterns for CD20 and CD79 were typical of diffuse large B-cell lymphoma, CD30 expression was variable, and most cases (15/22) lacked epithelial membrane antigen (EMA). These findings support the view that 'B-cell anaplastic large-cell lymphoma' is unrelated to t(2;5)-positive (ALK-positive) lymphoma, and that it represents a morphological pattern occasionally encountered among diffuse large B-cell lymphomas. By the same reasoning, most tumours diagnosed as 'ALK-negative anaplastic large-cell lymphoma of T-cell or null phenotype' probably belong to the spectrum of peripheral T-cell lymphomas.     

T-cell origin of Lennert''s lymphoma

The arrangement of the T-cell receptor and immunoglobulin genes has been analysed in five cases of Lennert's lymphoma. All cases showed rearrangement of the gene coding for the beta chain of the T-cell receptor and a germline configuration of the immunoglobulin genes. This provides strong evidence that Lennert's lymphoma is a T-cell lymphoma.     

Late relapse of myelodysplasia after allogeneic transplantation concomitant with new presentation of invasive liposarcoma as a secondary neoplasm

Second malignancies are uncommon events in the survivors of allogeneic transplant procedures, although they are increased compared to normal control populations. Among these malignancies, sarcomas are exceedingly rare. In addition, relapse of primary myelodysplasia rarely occurs after 5 years from the time of allogeneic transplantation. This report describes an unusual presentation of liposarcoma with concomitant relapse of underlying myelodysplasia developing in a patient 9 years after the first of two allogeneic transplantations.     

BNIP3 expression in follicular lymphoma

AIMS: To investigate the role of BNIP3, a 19-kDa interacting protein of the Bcl-2 family, alongside Bcl-2 in follicular lymphoma in comparison with reactive lymphoid hyperplasia. The results were compared with those from p53 and caspase-3 (apoptotic markers) and Ki67 (proliferation marker). METHODS AND RESULTS: Immunohistochemistry using monoclonal antibodies showed BNIP3 to be strongly expressed in most follicular lymphomas but to be weak to negative in all of the reactive cases. There was also an inverse relationship with Bcl-2 expression. There was no correlation of BNIP3 immunoreactivity with proliferation and caspase and p53 were virtually negative in all follicular lymphomas and reactive lymphoid cases. CONCLUSIONS: BNIP3 is strongly expressed in most follicular lymphomas, especially those that are Bcl-2 negative. BNIP3 may serve as a marker of more aggressive behaviour in follicular lymphoma and be useful diagnostically in the distinction from reactive lymphadenitis.     

Plasmablastic lymphomas may occur as post-transplant lymphoproliferative disorders

AIMS: To describe four cases of plasmablastic lymphoma arising in the unusual setting of a post-transplantation lymphoproliferative disorder (PTLD). METHODS AND RESULTS: Four cases were encountered over 2 years in human immunodeficiency virus (HIV)-negative patients following renal, heart or bone marrow transplantation. The cases were routinely processed and immunohistochemistry was performed. The cases showed blastic non-Hodgkin's lymphoma morphology and plasma cell-like immunophenotypic features: minimal or absent expression of leucocyte common antigen and CD20, variable CD79a and VS38 positivity. Monoclonal light chain restriction was also detected. CONCLUSIONS: The emphasis of this paper is to document further the occurrence of plasmablastic lymphomas in HIV- individuals and to expand the spectrum of PTLD.     

Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme involved in the reversible metabolism of carbon dioxide to carbonic acid and, hence, in physiological pH regulation. It also participates in cellular differentiation and proliferation, its expression being absent in most normal tissues. It has been recently postulated that the hypoxia-inducible factor (HIF-1) pathway up-regulated by hypoxia accounts for CAIX overexpression in most human tumors. In the present study, we examined the expression of this enzyme in diffuse gliomas of astrocytic origin in relation to vascular endothelial growth factor (VEGF) and HIF-1alpha expression, proliferation rate (as assessed with Ki-67 antigen), microvessel morphology, and survival. Of 84 cases analyzed, 61 cases (72.6%) displayed strong membrane and/or cytoplasmic expression of CAIX and were grouped as positive. Immunoreactivity tended to have a perinecrotic distribution and increased in parallel with the extent of necrosis (P < .001) and histologic grade (P < .001). A positive correlation was also noted with HIF-1alpha and VEGF expression (P < .001), proliferation rate (P = .010), microvessel density (P = .004), and microvessel caliber parameters (P = .014-.038). In univariate survival analysis, increased CAIX expression was associated with shortened survival in the entire cohort (P < .0001), along with VEGF (P = .0205) and HIF-1alpha levels (P = .0190). Multivariate analysis selected the interaction model of CAIX, with grade and age as the only parameters independently affecting survival. CAIX expression was also the only significant parameter for the survival of patients with grades II/III. We conclude that CAIX may be used as a prognostic indicator in diffuse astrocytomas to refine the information provided by grade. Given the role of CAIX in the acidification of tumor environment and its up-regulation by hypoxia, it is thought that CAIX expression may be linked to resistance of tumor cells to radiotherapy by allowing them to acclimatize to a hypoxic and acidic microenvironment.     

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium.

Tumour angiogenesis is a complex multistep process regulated by a number of angiogenic factors. One such factor, platelet-derived endothelial cell growth factor has recently been shown to be thymidine phosphorylase (TP). TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. Although known to be generally elevated in tumours, the expression of this enzyme in breast carcinomas is unknown. Therefore, we used ribonuclease protection assays and immunohistochemistry to examine the expression of TP in 240 primary breast carcinomas. Nuclear and/or cytoplasmic TP expression was observed in the neoplastic tumour epithelium in 53% of tumours. Immunoreactivity was also often present in the stromal, inflammatory and endothelial cell elements. Although endothelial cell staining was usually focal, immunoreactivity was observed in 61% of tumours and was prominent at the tumour periphery, an area where tumour angiogenesis is most active. Tumour cell TP expression was significantly inversely correlated with grade (P = 0.05) and size (P = 0.003) but no association was observed with other tumour variables. These findings suggest that TP is important for remodelling the existing vasculature early in tumour development, consistent with its chemotactic non-mitogenic properties, and that additional angiogenic factors are more important for other angiogenic processes like endothelial cell proliferation. Relapse-free survival was higher in node-positive patients with elevated TP (P = 0.05) but not in other patient groups. This might be due to the potentiation of chemotherapeutic agents like methotrexate by TP. Therefore, this enzyme might be a prediction marker for response to chemotherapy.