Rituximab Plus Chemotherapy Provides No Clinical Benefit in a Peripheral T-Cell Lymphoma Not Otherwise Specified with Aberrant Expression of CD20 and CD79a: A Case Report and Review of the Literature

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is the most common entity of mature T-cell neoplasms. PTCL-NOS generally has an aggressive behavior and is often refractory to standard therapy. Only a few cases of PTCL with aberrant expression of B-cell antigens have been reported so far. This phenotypic aberrancy may lead to misdiagnosis as B-cell non-Hodgkin lymphomas and eventual inappropriate patient management, whereas in an accurately diagnosed PTCL, the presence of CD20 may appear as an appealing therapeutic target. In this setting, response to anti-CD20 monoclonal antibody in combination with chemotherapy has been poorly explored. We describe the case of a 59-year-old male diagnosed by a pathological and molecular approach as PTCL-NOS with aberrant co-expression of the B-cell antigens CD20 and CD79a, which proved non-responsive to the addition of rituximab to standard polychemotherapy. This case highlights that the presence of CD20 in PTCL may be misleading in the diagnosis and also act as a lure for the clinician to adopt a rituximab-based treatment, the effectiveness of which is undefined as the molecular mechanisms underlying B-cell marker expression in PTCL

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16C NK cells, and a higher frequency of GrzBC cells in CD56dim, CD56bright, and CD16C NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon g (IFNg) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16- dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNg production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies

Severe and prolonged myelosuppression during concomitant temozolomide and radiotherapy treatment in a patient with glioblastoma multiforme

Aims: We describe the case of a patient with glioblastoma (GBM) who developed severe and prolonged myelosuppression during concomitant daily temozolomide (TMZ) and radiotherapy (RT) treatment. Analysis of polymorphisms in genes correlated with TMZ-induced myelotoxicity was also performed. Presentation of the Case: A 67–year-old man with diagnosis of GBM undergoing concomitant RT-TMZ treatment developed severe and prolonged pancytopenia that led to discontinuation of TMZ and required frequent platelet and red cells transfusions. Analysis of single nucleotide polymorphisms (SNPs) in the genes NAD(P)H dehydrogenase, quinone 1 (NQO1) and glutathione S-transferase pi 1 (GSTP1) was carried out. Both SNPs were found to be wild-type. Discussion: TMZ is an oral alkylating agent used for the treatment of glioblastoma. TMZ is usually considered well tolerated and safe, with nausea and mild myelosuppression being the most common side effects. However, severe haematologic adverse events have been also reported. Recently, there has been growing interest in gene polymorphisms that might be associated with an increased risk of hematologic toxicity. Conclusion: Myelosuppression is a side effect that can occur relatively early during concomitant TMZ treatment and can negatively impact on patient’s quality of life. Further studies are warranted to find out a correlation between genetic factors and the occurrence of severe hematologic toxicity

Junctional Adhesion Molecule, a Novel Member of the Immunoglobulin Superfamily That Distributes at Intercellular Junctions and Modulates Monocyte Transmigration

Tight junctions are the most apical components of endothelial and epithelial intercellular cleft. In the endothelium these structures play an important role in the control of paracellular permeability to circulating cells and solutes. The only known integral membrane protein localized at sites of membrane–membrane interaction of tight junctions is occludin, which is linked inside the cells to a complex network of cytoskeletal and signaling proteins. We report here the identification of a novel protein (junctional adhesion molecule [JAM]) that is selectively concentrated at intercellular junctions of endothelial and epithelial cells of different origins. Confocal and immunoelectron microscopy shows that JAM codistributes with tight junction components at the apical region of the intercellular cleft. A cDNA clone encoding JAM defines a novel immunoglobulin gene superfamily member that consists of two V-type Ig domains. An mAb directed to JAM (BV11) was found to inhibit spontaneous and chemokine-induced monocyte transmigration through an endothelial cell monolayer in vitro. Systemic treatment of mice with BV11 mAb blocked monocyte infiltration upon chemokine administration in subcutaneous air pouches. Thus, JAM is a new component of endothelial and epithelial junctions that play a role in regulating monocyte transmigration

Spheres Derived from Lung Adenocarcinoma Pleural Effusions: Molecular Characterization and Tumor Engraftment

Malignant pleural effusions (MPEs) could represent an excellent source to culture a wide variety of cancer cells from different donors. In this study, we set up culture conditions for cancer cells deriving from MPEs of several patients affected by the most frequent form of lung cancer, namely the subset of non small cell lung cancers (NSCLC) classified as Lung Adenocarcinomas (AdenoCa) which account for approximately 40% of lung cancer cases. AdenoCa malignant pleural effusions gave rise to in vitro cultures both in adherent and/or in spheroid conditions in almost all cases analyzed. We characterized in greater detail two samples which showed the most efficient propagation in vitro. In these samples we also compared gene profiles of spheroid vs adherent cultures and identified a set of differentially expressed genes. Finally we achieved efficient tumor engraftment in recipient NOD/SCID mice, also upon inoculation of small number of cells, thus suggesting indirectly the presence of tumor initiating cells

The Pathogenetic Role of the HGF/c-Met System in Papillary Carcinoma of the Thyroid

The MET oncogene encodes for Met protein, a trans-membrane tyrosine kinase identified as the high affinity receptor for hepatocyte growth factor (HGF). Immunohistochemical studies have demonstrated that Met protein is intensely expressed in tumor cells of >95% cases of thyroid papillary carcinoma. High density of Met protein in tumor cells is the result of increased transcription of a normal MET gene, probably due to a combination of intracellular and extracellular signals. Over-expression of Met protein is more pronounced at the invading front of the tumor and can profoundly affect the tumorigenesis of papillary carcinoma of the thyroid. In fact, Met protein-positive papillary carcinoma cells are highly responsive to hepatocyte growth factor (HGF), which is effective in stimulating tumor cell adhesion, migration and invasiveness. In addition, HGF stimulation of papillary carcinoma of the thyroid (PTC) cells causes up-regulation of COX-2 and down-regulation of CD82/KAI-1; both these molecules have a major role in controlling tumor cell invasiveness. Finally, HGF stimulation of tumor cells may significantly affect the tumor microenvironment. In fact, HGF induces tumor cells to release chemokines active in the recruitment of dendritic cells, and is involved in regulating the production of proangiogenic factors

Macrophage activation for tumor cytotoxicity: increased lymphokine responsiveness of peritoneal macrophages during acute inflammation

Peritoneal inflammation induced by sterile irritants led to accumulation of macrophages that were more responsive to lymphokines than macrophages from resident cell populations of untreated mice. Lymphokine responsiveness was quantitated by measurement of macrophage-mediated tumor cytotoxicity induced by supernatants from antigen-stimulated immune spleen cell cultures. Tumor cytotoxicity by lymphokine-activated inflammatory macrophages was about 10-fold greater than that by equal numbers of lymphokine-treated resident cells. Analysis of the time course of activation and of lymphokine dose-response demonstrated that the increased responsiveness of inflammatory cells was a consequence of quantitative changes. Lymphokine-responsive cells in both resident and inflammatory populations were identical; the numbers of response cells increased with inflammation. Changes in numbers of lymphokine-responsive cells during acute inflammation were coincident with similar changes in numbers of peroxidase-positive macrophages. This finding suggested that the increased lymphokine responsiveness of inflammatory cells was dependent upon influx of young peroxidase-positive mononuclear phagocytes rather than stimulation of resident macrophages. This concept was further strengthened by the finding that whole body x-irradiation diminished the numbers of both peroxidase-positive and of lymphokine-responsive macrophages in inflammatory and resident cell populations. These data suggest that the lymphokine-responsive precursor or the activated tumoricidal macrophage during both steady-state and acute inflammatory conditions was the newly formed blood-derived mononuclear phagocyte. The 10-fold increase in numbers of lymphokine responsive macrophages in peritoneal exudate over resident cell populations reflected a similar increase in macrophage turnover induced by inflammation