Imiquimod treatment induces expression of opioid growth factor receptor: a novel tumor antigen induced by interferon-alpha?

PURPOSE: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-alpha. EXPERIMENTAL DESIGN: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays. RESULTS: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-alpha or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-alpha-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041). CONCLUSIONS: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.     

Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart-lung transplantation. The Munich Lung Transplant Group

Bronchiolitis obliterans syndrome (BOS) is the most serious long-term sequel of lung or heart-lung transplantation (H/LTX). Neutrophilia in the lower respiratory tract is a prominent feature of BOS. Because polymorphonuclear leukocytes (PMN) are capable of releasing large quantities of reactive oxygen species, we measured indicators of oxidative stress and glutathione levels representing antioxidant defense in H/LTX patients (HLTX, n=6; double-LTX, n=7; single-LTX, n=9). We analyzed 19 bronchoalveolar lavage (BAL) samples from 13 non-BOS patients (nine female, four male: age 39+/-4 years) and 17 BAL samples from nine BOS patients (five female, four male: age 33+/-2 years). PMN were the predominant BAL cell population in BOS (61.7+/-7.8% vs. 12.3+/-3.4%, P<0.001). Myeloperoxidase activity in the epithelial lining fluid and oxidized methionine residues in BAL-derived proteins were elevated in BOS (8.6+/-1.6 U/ml vs. 2.2+/-0.6 U/ml, P<0.01; and 12.6+/-1.1% vs. 7.7+/-0.8%, P<0.001, respectively). In addition, the concentration of reduced glutathione in epithelial lining fluid was decreased in BOS (162.6+/-20.1 microM vs. 345.8+/-57.1 microM, P<0.01), whereas the proportion of oxidized glutathione was increased (13.9+/-2.0O% vs. 6.7+/-1.2%, P<0.001). PMN, myeloperoxidase, and oxidized methionine residues were inversely correlated, whereas reduced glutathione was positively correlated with forced expiratory volume in 1 sec (P<0.05 to P<0.001). We conclude that excessive oxidative stress and a lack of glutathione are associated with BOS after H/LTX and may play relevant roles in the development of this disorder.     

Berufskrebs Stellenwert von Biomarkern in der Risikofaktorenanalyse von Karzinomen der Kopf-Hals-Region

Am 17.10.1997 fand der zweite Workshop der Arbeitsgruppe Berufskrebs innerhalb der Arbeitsgemeinschaft Onkologie der Deutschen Gesellschaft für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, in Heidelberg statt. Die abgehandelten Schwerpunktthemen werden nachfolgend kurz dargestellt.     

Staging of rectal cancer by double-contrast MR imaging using the rectally administered superparamagnetic iron oxide contrast agent ferristene and IV gadodiamide injection: results of a multicenter phase II trial

The aim of this study was to assess the accuracy of double-contrast magnetic resonance imaging (MRI) with rectal application of the superparamagnetic iron oxide contrast agent (SPIO) ferristene and IV gadodiamide for preoperative staging of rectal cancer. In a randomized phase II dose-ranging trial, 113 patients were studied preoperatively with one of four different formulations of ferristene (Abdoscan) as an enema before MRI. T1-weighted spin-echo (T1w SE) and T2w turbo spin-echo (TSE) single-contrast images were obtained as well as T1w SE and gradient-echo (GRE) double-contrast images after IV gadodiamide injection (Omniscan). Images were assessed qualitatively, and TNM tumor stage was compared with histopathology. High-viscosity ferristene formulations were superior to low-viscosity formulations in tumor staging (accuracy 90% vs 74%, P < 0.01). There was no significant difference between high and low iron content ferristene. MRI had a sensitivity of 97%, specificity of 50%, and accuracy of 82% for staging of rectal carcinoma higher than T2 stage. At receiver operator characteristic (ROC) analysis, MR differentiation between T1/T2 and T3/T4 tumor stages yielded a ROC index of 0.848. Double-contrast MRI is an accurate method for preoperative staging of rectal cancer.     

The epidemiology of fractures of the distal femur

Between 1980 and 1989, reports on 2,165 fractures of the distal part of the femur (1,051 women and 1,114 men) were collected by AO Documentation and are analyzed in the present paper. The number of fractures showed a bimodal pattern with a marked variation in the number of fractures in relation to gender and age. A larger prevalence of fractures was observed either in young men (about 20 years old, traffic or sport) and in old women (about 70, fall at home, osteoporosis).     

Cognitive improvement in schizophrenic patients does not require a serotonergic mechanism: randomized controlled trial of olanzapine vs amisulpride.

Combined serotonin-2A (5-HT(2A)) and dopamine-2 (D2) receptor blockade has been proposed as a candidate mechanism by which second-generation antipsychotics (SGAs) improve both cognition and negative symptoms in schizophrenic patients, in contrast to antipsychotics of the first generation. The SGA amisulpride, however, only binds to D2/D3 receptors, which makes it an interesting tool to test this assumption. In a randomized controlled trial, 52 schizophrenic patients were allocated to treatment with either olanzapine (10-20 mg/day) or amisulpride (400-800 mg/day). A comprehensive neuropsychological test battery and clinical ratings were used to assess participants at inclusion and after 4 and 8 weeks. Cognitive improvements of moderate size were observed, with effect sizes similar to those obtained in previous studies on the cognitive effects of SGAs. Importantly, amisulpride was not inferior to olanzapine for any cognitive domain. Combined 5-HT(2A)/D2 receptor blockade is probably not necessary for cognitive improvement by SGAs.     

Chinikomycins A and B: isolation, structure elucidation, and biological activity of novel antibiotics from a marine Streptomyces sp. isolate M045

In our screening of marine Streptomycetes for bioactive principles, two novel antitumor antibiotics designated as chinikomycins A (2a) and B (2b) were isolated together with manumycin A (1), and their structures were elucidated by a detailed interpretation of their spectra. Chinikomycins A (2a) and B (2b) are chlorine-containing aromatized manumycin derivatives of the type 64-pABA-2 with an unusual para orientation of the side chains. They exhibited antitumor activity against different human cancer cell lines, but were inactive in antiviral, antimicrobial, and phytotoxicity tests.     

Acquired immunodeficiency syndrome manifested by chronic primary genital herpes

Herpes genitalis is commonly seen by the obstetrician-gynecologist. Prolonged persistence of herpes is unusual and may herald an underlying disorder. A case of chronic primary herpes is presented, in which the diagnosis of acquired immunodeficiency syndrome was delayed because of a low degree of suspicion.