[The emotions of oncologists]. / Az onkológusok érzelmei.

Emotions are parts of organizational reality to an ever increasing extent. Importantly, they are not just tools in the hand of healthcare workers to achieve better physician / healthcare professional-to-patient interactions but intrinsic processes and characteristics with psychic, cognitive and somatic actions. For a thorough investigation of the issue, a PANAS-X questionnaire was used to examine the emotions of 187 physicians and other healthcare professionals, all engaged in oncology, in 2009. The research succeeded in exploring the overall emotional state oncology professionals had assumed in relation with their job as well as enabled the authors of this study to draw the respondents' emotional map and assess their fundamental emotional attitudes. Furthermore, the authors managed to identify groups of respondents that had felt more intense positive, and/or less intense negative emotions that are socially accepted than others. They included those of senior experienced oncologists, males, individuals with families, childless individuals, ward workers, and skilled professionals. According to the findings, the range of emotions an oncologist experiences / feels intently during his everyday work is dependent upon a great number of factors.

Spontaneous insertion of a b2 element in the ptpn6 gene drives a systemic autoinflammatory disease in mice resembling neutrophilic dermatosis in humans.

We found a spontaneous autosomal mutation in a mouse leading to neutrophil infiltration with ulceration in the upper dermis of homozygous offspring. These animals had increased neutrophil numbers, associated with normal lymphocyte count, in peripheral blood and bone marrow, suggesting a myeloproliferative disorder; however, granulocyte precursor proliferation in bone marrow was actually reduced (because circulating neutrophils were less susceptible to apoptosis). Neutrophil infiltration of the skin and other organs and high serum levels of immunoglobulins and autoantibodies, cytokines, and acute-phase proteins were additional abnormalities, all of which could be reduced by high-dose corticosteroid treatment or neutrophil depletion by antibodies. Use of genome-wide screening localized the mutation within an 0.4-Mbp region on mouse chromosome 6. We identified insertion of a B2 element in exon 6 of the Ptpn6 gene (protein tyrosine phosphatase, non-receptor type 6; also known as Shp-1). This insertion involves amino acid substitutions that significantly reduced the enzyme activity in mice homozygous for the mutation. Disease onset was delayed, and the clinical phenotype was milder than the phenotypes of other Ptpn6-mutants described in motheaten (me, mev) mice; we designated this new genotype as Ptpn6(meB2/meB2) and the phenotype as meB2. This new phenotype encompasses an autoinflammatory disease showing similarities to many aspects of the so-called neutrophilic dermatoses, a heterogeneous group of skin diseases with unknown etiology in humans.

Successful immunomodulatory therapy in castleman disease with paraneoplastic pemphigus vulgaris.

Castleman disease is a rare lymphoproliferative disorder. The clinical signs and symptoms of the disease are primarily mediated by cytokines, especially interleukin-6. We presented the case of a young female. In May 2004, a 30-year-old otherwise healthy looking woman presented with oral ulcerations resistant to topical and systemic antibiotic and antimycotic treatment. Bullous mucosal lichen or pemphigus vulgaris were suspected. Histological examination and direct and indirect immunofluorescence confirmed the diagnosis of pemphigus. Search for neoplasm revealed a retroperitoneal Castleman tumour sized 15 x 6 x 5 cm in the abdominal MRI. The tumour was a bleeder, so the removal was partial. Histological examination showed hyalin hypervascular Castleman disease. Considering her young, fertile age and the multicentric Castleman disease, non-cytostatic immunomodulatory therapy was started including steroid, cyclosporine-A and thalidomide treatment. The control abdominal CT showed a small residual tumour on the bladder. The residual tumour was removed in repeated surgery. At this time the histological examination showed transient type tumour between plasma cell and vascular variant. Currently, i.e. 4 years after the onset of the disease. (18)FDG PET/CT examination showed low metabolic active mass in the right iliacal region, but our patient had no symptoms or complaints. She is on 200 mg thalidomide a day and no tumour progression can be seen. Castleman disease can be successfully treated with non-cytostatic immunomodulatory therapy.

[Anti-VEGF therapy with bevacizumab in breast cancer]. / Az angiogén utak gátlása bevacizumabbal az emlorák kezelésében.

The growth of new blood vessels, angiogenesis is important for tumour progression and metastasis. Vascular endothelial growth factor (VEGF) plays multiple roles in cancer development. Due to it the VEGF seems to be an optimal therapeutic target in breast cancer therapy. The plasma level of this growth factor is highest early in disease suggests that anti-VEGF agents may provide their greatest benefit in firts-line chemotherapy with metastatic breast cancer (MBC). A phase III trial, E2100 evaluated weekly paclitaxel with or without bevacizumab (Avastin), the specific humanised anti-VEGF monoclonal antibody in patients with previously untreated locally recurrent or MBC, doubling of progression-free survival for all patient subgroups. Bevacizumab is generally well tolerated. The most common adverse events observed in trials hypertension, proteinuria, and wound-healing complications, most of which are grade 1-2 in severity. The registration of bevacizumab for MBC therapy brings new hope for patients. Novel approach of bevacizumab for MBC would be combination chemotherapy and different targeted therapies. Phase III clinical trials of bevacizumab are ongoing in different stages in different settings.

CD44, but not l-selectin, is critically involved in leucocyte migration into the skin in a murine model of allergic dermatitis.

CD44 and l-selectin (CD62L) are major adhesion receptors that mediate leucocyte recruitment at inflammatory sites and lymph nodes, by supporting cell rolling under blood flow. Both CD44 and CD62L have been implicated in inflammatory skin disorders, but their specific involvement in an immediate-type allergic reaction remains uncertain. We used mice deficient in CD44 or CED62L or both in order to determine whether one or both of these molecules were required for leucocyte extravasation in an atopic dermatitis-like allergic response. Wild-type (WT) mice and mice deficient in CD44, CD62L or both were immunized with ovalbumin (OVA). Inflammatory reaction in the ear was elicited once by means of intradermal injection of OVA. Effective sensitization of CD62L knockout (KO) mice required intraperitoneal antigen injection; however, OVA-specific T helper 2 (Th2)-type immune responses and IgE production in mice lacking CD44, CD62L or both were comparable to those in WT mice following intraperitoneal immunization. We employed intravital videomicroscopy to monitor the recruitment of fluorescence-labelled leucocytes to the ear tissue following challenge with OVA. The number of adherent leucocytes was significantly reduced in CD44 KO and CD44/CD62L double KO mice, indicating that CD44 was involved in firm adhesion, the committed step of leucocyte extravasation. Histology of the OVA-challenged ears showed a diminished leucocyte infiltration in the ears of CD44 KO and double KO mice. The results of our study demonstrate that CD44, but not CD62L, is required for leucocyte extravasation during a Th2-type inflammatory response.

Expression of L-selectin, but not CD44, is required for early neutrophil extravasation in antigen-induced arthritis.

L (leukocyte)-selectin (CD62L) and CD44 are major adhesion receptors that support the rolling of leukocytes on endothelium, the first step of leukocyte entry into inflamed tissue. The specific contribution of L-selectin or CD44 to the regulation of cell traffic to joints in arthritis has not been investigated. We used CD44-deficient, L-selectin-deficient, and CD44/L-selectin double knockout mice to determine the requirement for these receptors for inflammatory cell recruitment during Ag-induced arthritis. Intraperitoneal immunization resulted in similar activation status and Ag-specific responses in wild-type and gene-targeted mice. However, extravasation of neutrophil granulocytes, but not the emigration of T cells, into the knee joints after intra-articular Ag injection was significantly delayed in L-selectin-deficient and double knockout mice. Intravital videomicroscopy on the synovial microcirculation revealed enhanced leukocyte rolling and diminished adherence in mice lacking either CD44 or L-selectin, but CD44 deficiency had no significant effect on the recruitment of L-selectin-null cells. Compared with wild-type leukocytes, expression of L-selectin was down-regulated in CD44-deficient cells in the spleen, peripheral blood, and inflamed joints, suggesting that reduced expression of L-selectin, rather than the lack of CD44, could be responsible for the delayed influx of granulocytes into the joints of CD44-deficient mice. In conclusion, there is a greater requirement for L-selectin than for CD44 for neutrophil extravasation during the early phase of Ag-induced arthritis.

Elevated rate of Thelper1 (T(H)1) lymphocytes and serum IFN-gamma levels in psoriatic patients.

Several disorders are known to be associated with altered Thelper1/Thelper2 (T(H)1/T(H)2) cytokine balance. Psoriasis is characterized by increased systemic and local production of T(H)1 and pro-inflammatory cytokines. Furthermore recent data indicate the dominant presence of T(H)1 lymphocytes in the circulation and T(H)1 and Tcytotoxic1 (T(C)1) cells in lesional skin of psoriatic patients. In order to assess the systemic T(H)1/T(H)2 imbalance in psoriasis most of the studies so far tested isolated peripheral mononuclear cells. As a new approach we applied a whole blood flow cytometric assay to determine the rate of circulating T(H)1/T(H)2 and T(C)1/Tcytotoxic2 (T(C)2) lymphocytes based on their intracellular IFN-gamma, IL-4 and IL-10 expression. Besides, serum levels of these cytokines were determined in healthy controls and psoriatic patients by commercial ELISAs. In psoriatic patients we found significantly (P<0.02) increased rates of CD4(+)/IFN-gamma(+) lymphocytes (30.3+/-8.8%) while the percent of CD4(+)/IL-4(+) cells (0.37+/-0.31%) were significantly (P<0.03) lower compared to healthy controls (CD4(+)/IFN-gamma(+): 20.1+/-7.3% and CD4(+)/IL-4(+): 0.78+/-0.44%). The IL-10-positive CD4(+) and CD8(+) cells also had higher rate in psoriasis, but the difference between patients and controls was not significant, similarly to the rate of CD8(+)/IFN-gamma(+) and CD8(+)/IL-4(+) lymphocytes. Beside cellular expression, serum IFN-gamma levels were also significantly higher (control: 4.9+/-6.4 pg/ml; psoriatic patients: 35.9+/-47.0 pg/ml; P<0.05). Our results provide further evidence for an altered T(H)1/T(H)2 balance in psoriasis measured in non-separated whole blood T cells.

Role of the extracellular and cytoplasmic domains of CD44 in the rolling interaction of lymphoid cells with hyaluronan under physiologic flow.

CD44 can function as an adhesion receptor that mediates leukocyte rolling on hyaluronan (HA). To study the contributions of different domains of the standard isoform of CD44 to cell rolling, a CD44-negative mouse T lymphoma AKR1 was transfected with wild type (WT) or mutated cDNA constructs. A parallel flow chamber was used to study the rolling behavior of CD44 transfectants on immobilized HA. For CD44WT transfectants, the fraction of cells that rolled and the rolling velocity was inversely proportional to the amount of cell surface CD44. When the cytoplasmic domain distal to Gly(305) or sequences that serve as binding sites for cytoskeletal linker proteins, were deleted or replaced with foreign sequences, no significant changes in the rolling behavior of mutant cells, compared with the transfectant expressing CD44WT, were observed. Transfectants lacking 64 amino acids of the cytoplasmic tail distal to Cys(295) adhered to HA but showed enhanced rolling at low shear forces. When 83 amino acids from the "non-conserved" membrane-proximal region of the CD44 extracellular domain were deleted, cells adhered firmly to the HA substrate and did not roll at any fluid shear force tested. Unlike wild type cells that exhibited a nearly homogeneous distribution of CD44 on a smooth cell surface, cells expressing the non-conserved region deletion mutant accumulated CD44 in membrane protrusions. Disruption of the actin cytoskeleton with cytochalasin B precluded the formation of membrane protrusions, however, treated cells still adhered firmly to HA and did not roll. We conclude that interaction between the cytoplasmic domain of CD44 and the cytoskeleton is not required for cell rolling on immobilized ligand. The strong effect of deletion of the non-conserved region of the extracellular domain argues for a critical role of this region in CD44-dependent rolling and adhesion interactions with HA under flow.