First bacteraemic human infection with Escherichia albertii.

The facultative anaerobic Gram-negative species Escherichia albertii has been isolated from human faeces in gastrointestinal infection and from a range of wild bird species. Here we report the first case of a febrile infection associated with E. albertii bacteraemia in a 76-year-old woman with gastric dysplasia.

Neodymium yttrium-aluminium-garnet laser resection significantly improves quality of life in patients with malignant central airway obstruction due to lung cancer.

Neodymium yttrium-aluminium-garnet (Nd : YAG) laser resection is one of the mostly used interventional pulmonology techniques for urgent desobstruction of malignant central airway obstruction (CAO). The major aim of this trial was to evaluate potential influence of Nd : YAG laser resection on overall quality of life (QoL) in patients with central lung cancer. Patients with malignant CAO scheduled for Nd : YAG laser resection were prospectively recruited in the trial. All patients were given European Organization for Research and Treatment, Quality of Life questionnaire (EORTC QLQ-30 v.3) before the procedure and approximately 2 weeks after the treatment. There were 37 male and 10 female patients, average age 54 ± 10 years. Most common tumour type was adenocarcinoma diagnosed in 51% of patients. Majority of patients were diagnosed in stage IIIB (53.2%) and stage IV (25.5%). Most common Eastern Cooperative Oncology Group performance status was 1 (72.3%). Nd : YAG laser resection significantly improved (P<0.0001) QoL and overall health according to EORTC QLQ-30. However, in some of the questions dealing with nausea, vomiting, diarrhoea, constipation, family life, social activities and financial situation, we did not observe statistically significant improvement. Nd : YAG laser resection of malignant CAO significantly improves QoL and overall health in patients with lung cancer.

HLA-G expression in basal cell carcinomas of the skin recurring after radiotherapy.

Basal cell carcinoma (BCC) of the skin represents the most common malignancy in the fair-skinned population worldwide. HLA-G is one of the molecules implicated in immunotolerance. To investigate the role of HLA-G in recurring BCCs, we constructed a tissue microarray containing 38 primary BCCs that underwent radiotherapy and 14 secondary BCCs recurring on the primary site after radiotherapy, and evaluated the HLA-G protein expression by immunohistochemistry. The HLA-G protein was most frequently expressed in aggressive sclerosing BCCs. Nodular BCC demonstrated the strongest HLA-G expression. Interestingly, tumor infiltrating mononuclear cells (TIMC) expressed the HLA-G molecule in BCCs that showed no recurrence. After comparing primary BCCs and BCCs relapsed after radiotherapy, we observed decreased HLA-G expression on tumor cells and the loss of HLA-G expression on TIMC in relapsed BCCs. After radiotherapy, immunobiology of BCC may change resulting in the down-regulation of HLA-G expression on tumor and on tumor-infiltrating cells.

Imiquimod in basal cell carcinoma: how does it work?

Imiquimod is a topical immune response modifier that binds to Toll-like receptor-7 and -8, inducing interferon-alpha. We treated superficial basal cell carcinomas (BCC) with imiquimod 5% cream daily for 5-8 days. The BCC lesions were biopsied before treatment and following imiquimod treatment, when the lesion showed the signs of erosion. We applied histology, immunohistochemistry and gene array technology (Affymetrix) to gain further insight into the mode of action of imiquimod. Our findings demonstrate that imiquimod-induced BCC regression is associated with a strong activity of the innate immune response, mediated by cells of macrophage-monocyte origin and is associated with the induction of apoptosis.

Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production.

Immune evasion in lung cancer results from both structural and functional alterations of human leukocyte antigen (HLA) class I molecules and the local release of immunosuppressive cytokines. Recent data suggest that HLA-G, a nonclassical class Ib molecule, is involved in immune evasion by tumor cells. We sought to determine whether HLA-G could contribute to immunescape in lung cancer. All of 19 tumor specimens examined demonstrated detectable membrane-bound (HLA-G1), as well as soluble (HLA-G5) isoform transcription. Nine of 34 (26%) tumors were positive by immunohistochemistry using monoclonal antibody (mAb) 4H84, recognizing all denatured HLA-G isoforms, of which six were positive using mAb 16G1, recognizing soluble HLA-G. HLA-G immunoreactivity correlated with high-grade histology, with HLA-G being preferentially expressed on large-cell carcinomas. In these patients, loss of classical HLA class I molecules was observed to associate with HLA-G protein up-regulation. Moreover, we found interleukin-10 expressed in 15 of 34 (44%) tumors, and in most of the HLA-G-positive cases (7 of 9), suggesting up-modulation of HLA-G by interleukin-10. It is conceivable that HLA-G expression in lung cancer might be one of the ways how the tumor down-regulates host immune response, in addition to interleukin-10 production and HLA class I loss.

The interferon inhibiting cytokine IK is overexpressed in cutaneous T cell lymphoma derived tumor cells that fail to upregulate major histocompatibility complex class II upon interferon-gamma stimulation.

Cutaneous T cell lymphomas are characterized by an accumulation of malignant clonal lymphocytes in the skin and occasionally in the blood. We compared gene transcription profiles from cultured clonal lymphocytes with autologous healthy blood lymphocytes by microarray hybridization. Cutaneous T cell lymphoma derived cells transcribed high amounts of an interferon inhibiting cytokine factor. The presence of an interferon inhibiting cytokine factor was confirmed in 12 skin biopsies of mycosis fungoides and Sézary syndrome derived blood lymphocytes by reverse transcriptase-polymerase chain reaction. The presence of interferon inhibiting cytokine factor mRNA in Sézary syndrome derived lymphocytes was associated with a lack of HLA class II upregulation after stimulation with interferon-alpha and interferon-gamma. This was not due to a loss of the interferon signaling cascade as the presence of interferon-signaling components was confirmed by reverse transcriptase--polymerase chain reaction on the transcriptional level. The elevated constitutive interferon inhibiting cytokine factor expression observed in cutaneous T cell lymphoma derived cells was insensitive to interferon-gamma stimulation, but was enhanced in normal peripheral blood mononuclear cells. We suggest that interferon inhibiting cytokine factor contributes to the lack of HLA class II upregulation in lymphoma cells. Interferon inhibiting cytokine factor may participate in providing a microenvironment at the tumor site insensitive to interferon-gamma stimulation and thus prevents an efficient local immune response.

Decreased intraindividual HLA class I expression is due to reduced transcription in advanced melanoma and does not correlate with HLA-G expression.

The presentation of endogenously synthesized peptides in association with HLA class I molecules allows the activation of CD8(+) lymphocytes. Tumor cells often fail to present antigenic peptides resulting in the immune escape of metastasizing cells. The aim of this study was to elucidate possible molecular mechanisms leading to reduced antigen presentation in melanoma. Melanoma cell short-time cultures were genotypically and phenotypically HLA-typed by sequence-specific primer polymerase chain reaction and complement-mediated microlymphocytotoxicity assays, respectively. Flow cytometric analysis of HLA-A2 and HLA-A3 allospecificities were performed to confirm typing results. Transcriptional levels of classical HLA-A, HLA-B genes and nonclassical HLA-G genes were detected using quantitative real-time reverse transcriptase polymerase chain reaction (LightCycler). We found loss or downregulation of HLA proteins in 18% (for HLA-A) and 53% (for HLA-B) of all tested metastases. Genomic analysis, however, revealed the presence of the corresponding HLA class I gene in six out of seven cases. On the level of gene transcription we observed a differential regulation of HLA-A, HLA-B, and HLA-G mRNA expression. There was no correlation between classical and nonclassical HLA gene transcription, but the transcriptional levels of classical HLA corresponded to the protein expression levels. Furthermore, an overall reduced amount of HLA class I gene transcription was observed in melanoma metastases during disease progression in three individuals. We postulate that there is a transcriptional regulation of HLA class I gene expression in melanoma cells. These data suggest that treatment approaches aimed at activating specific cytotoxic T lymphocytes are most successful in early disease.

Pathogenesis of cutaneous lymphomas.

Cutaneous lymphomas are a heterogeneous group of lymphoproliferative disorders derived from T cells, B cells and, in rare cases, natural killer cells. The precise mechanisms of the lymphomagenesis are still obscure. However, there are various factors involved. These factors include environmental, especially infectious factors, translocations, mutations and genetic instability. The special microenvironment in the skin is responsible for the peculiar behavior of these neoplasms by providing various key factors, such as adhesion molecules and cytokines. Newly identified molecular disturbances in cutaneous lymphomas might be targeted by specific molecular or immunologic interventions in the future.