Innovative combination strategy to enhance effect and diminish adverse effects of glucocorticoids: another promise?

In a paper by Zimmermann and colleagues in this issue of Arthritis Research & Therapy, results of extended laboratory research with the drug combination of prednisolone and dipyridamole are reported. There seems to be a boost and extension of the glucocorticoid effect by the combination, without a clear increase of adverse effects, potentially allowing the application of lower dosages. However, laboratory models are not patients and the glucocorticoid mechanisms leading to effects and adverse effects are manifold. The next required step will be to demonstrate the improved therapeutic window in patients in adequate comparative clinical trials, assessing predefined beneficial effects and adverse effects in a standardized way.     

Selected immunohistochemical markers in stromal neoplasms of the gastrointestinal tract.

We studied immunohistochemical reactions to vimentin, desmin and protein S-100 in 43 cases of stromal tumors of the gastrointestinal tract. The material studied included: 1 esophageal tumor, 18 gastric tumors, 19 small intestinal tumors and 5 colonic tumors, classified in 13 cases as benign and in 30 cases as malignant neoplasms of various degree of malignancy. Mean age of the patients was 58.9 years. A positive reaction to vimentin was found in 37 cases, a negative reaction concerned an esophageal tumor, two benign tumors (gastric and small intestinal) and three malignant tumors (gastric and two small intestinal). A positive reaction to desmin was detected in an esophageal tumor and in nine gastric tumors. Only one benign small intestinal tumor and three benign colonic tumors showed a positive reaction to desmin. Protein S-100 was found in an esophageal tumor and in 7 out of 18 gastric tumors and in 12 out of 24 intestinal tumors. Coexpression of vimentin and desmin was found in 8 gastric tumors, only in one small intestinal tumor and in three colonic tumors. Three gastric tumors showing both these reactions were all benign. Coexpression of desmin and protein S-100 was found in 7 out of 43 tumors of the alimentary tract. In six cases these tumors were benign. Basing on the results we may say that the presence of these antigens reflects the degree of differentiation of gastrointestinal stromal tumors of the gastrointestinal tract, though it does not allow to choose unequivocally conclusions as to their histogenesis.     

Augmentation of natural killer activity, induction of IFN and development tumor immunity during the successful treatment of established murine renal cancer using flavone acetic acid and IL-2

The investigational drug flavone acetic acid (FAA) has been previously shown to systemically augment NK activity in vivo in normal mice within 24 h of i.p. or i.v. administration. The current study investigates the ability of FAA, and/or rIL-2, to augment NK activity and antitumor responses in mice bearing murine renal cancer (Renca). The results demonstrate that FAA potently augments NK activity in the blood, spleen, and liver of Renca-bearing mice and that the administration of rIL-2 in addition to FAA results in a further augmentation of NK activity over that observed with FAA alone. Renca-bearing mice treated with FAA (200 to 250 mg/kg) plus rIL-2 exhibited a significantly increased incidence of long term survivors (59%) over that observed following treatment with FAA (0%) or rIL-2 (5%) alone. Therapeutic synergy between FAA and rIL-2 was observed against primary tumors, minimal residual disease, and experimental-induced pulmonary metastases. Mice cured of Renca by FAA plus rIL-2 treatment were largely resistant to rechallenge with Renca suggesting a role for T lymphocytes. The augmentation of NK activity and the therapeutic effects of FAA coincided with the rapid induction of high titers of serum IFN of the alpha/beta type within 4 h of FAA administration. Subsequent studies demonstrated that the contribution of FAA could be partially replaced by the administration of several doses of human rIFN-alpha A/D Bg1 before the initiation of rIL-2 administration. The observed synergistic antitumor effects of FAA plus rIL-2 coincided with the augmentation of NK activity, induction of IFN-alpha/beta, and induction of long lasting tumor immunity. Overall, these results suggest that this approach may obviate the need for adoptive immunotherapy in association with rIL-2 administration for at least some tumor types.     

Tritolylporphyrin dimer as a new potent hydrophobic sensitizer for photodynamic therapy of melanoma.

We report the synthesis, photochemical and photophysical properties and preliminary studies on biological effect of a new tritolylporphyrin dimer (T-D). Absorption and emission properties of T-D suggest its possible use in photodynamic therapy. T-D is capable of singlet oxygen production with 0.8 quantum yield. It also has a high photostability. The photodynamic properties of the dimer were examined following the growth of SKMEL 188 (human melanoma) cells irradiated with red light (cut off < 630 nm). The surviving fraction of the cells decreased about 3-fold (vs. non-irradiated cells) for an 81 J/cm dose. Our results suggest that tritolylporphyrine dimer T-D may be an interesting hydrophobic sensitizer for photodynamic therapy.     

Prognostic and predictive significance of p53, EGFr,Ki-67 in larynx preservation treatment

Background

The optimal management of advanced laryngeal and hypopharyngeal cancers (L&HC) must involve consideration of both survival and functional effect of the given treatment approach. Despite over two decades of investigations of several treatment options, including surgery, radiotherapy, chemotherapy or some combinations thereof, little consensus exists as to which treatment offers the best survival, together with functional speech and swallowing.

Aim

To determine predictive and prognostic value of p53, EGFr, Ki-67 in patients with advanced laryngeal and hypopharyngeal cancer, treated with larynx preservation intent.

Materials and methods

Thirty-three patients received 2–3 cycles of induction chemotherapy (ICHT) consisting of cisplatin and fluoruracil and underwent subsequent radical radiotherapy. Immunohistochemical analyzes of p53, EGFr and Ki-67 were performed.

Results

Response to ICHT was obtained in 24 patients (75%). Better response to ICHT was correlated only with EGFr expression (p = 0.04, RR = 1.91). The 5-year loco-regional control (LRC) and disease-specific survival (DSS) rates were 48% and 57%, respectively. The 5-year larynx preservation rate was 68% in responders to ICHT compared to 21% in non-responders (p = 0.02). It was also higher in patients without EGFr expression (but not significantly, p = 0.43).

Conclusion

Lack of EGFr expression is a favorable predictive factor for response to ICHT. Neither p53 nor Ki-67 have predictive and prognostic value in larynx preservation treatment.     

Bleeding complications after pacemaker or cardioverter-defibrillator implantation in patients receiving dual antiplatelet therapy

Introduction. The aim of the study was to define the prevalence of bleeding events in patients treated with dual antiplatelet therapy (DAT) in comparison with patients receiving only acetylsalicylic acid (ASA). Methods. Prospective two-centre registry of all first implantations of pacemakers, cardioverter-defibrillators and cardiac resynchronisation therapy units in patients receiving ASA (n=194) or DAT (n=53). Results. Bleeding complications were detected in 27 (16.2%) patients in the ASA group and in 13 (24.5%) in the DAT group. There was no significant difference in the overall number of complications between the patients receiving ASA or DAT, although there was a trend towards a higher incidence of overall complication rates in the DAT group (p=0.0637). The incidence of major complications (requiring blood transfusion or surgical intervention or prolonging hospital stay) was low (3.6%), and similar in both groups (3.6 and 3.8% respectively, ns). The rate of minor complications (subcutaneous haematomas) was greater in the DAT group (p=0.015). Conclusions. Treatment with DAT does not increase the risk of major bleeding complications as a result of device implantation; however, minor complications are significantly more frequent. Our results suggest that DAT could be continued in patients undergoing device implantation with a moderate risk of bleeding complications. (Neth Heart J 2010;18:230-5.)     

Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics

The healthy synovial lining layer consists of a single cell layer that regulates the transport between the joint cavity and the surrounding tissue. It has been suggested that abnormalities such as somatic mutations in the p53 tumor-suppressor gene contribute to synovial hyperplasia and invasion in rheumatoid arthritis (RA). In this study, expression of epithelial markers on healthy and diseased synovial lining tissue was examined. In addition, we investigated whether a regulated process, resembling epithelial to mesenchymal transition (EMT)/fibrosis, could be responsible for the altered phenotype of the synovial lining layer in RA. Synovial tissue from healthy subjects and RA patients was obtained during arthroscopy. To detect signs of EMT, expression of E-cadherin (epithelial marker), collagen type IV (indicator of the presence of a basement membrane) and alpha-smooth muscle actin (alpha-sma; a myofibroblast marker) was investigated on frozen tissue sections using immunohistochemistry. Fibroblast-like synoviocytes (FLSs) from healthy subjects were isolated and subjected to stimulation with synovial fluid (SF) from two RA patients and to transforming growth factor (TGF)-beta. To detect whether EMT/fibrotic markers were increased, expression of collagen type I, alpha-sma and telopeptide lysylhydroxylase (TLH) was measured by real time PCR. Expression of E-cadherin and collagen type IV was found in healthy and arthritic synovial tissue. Expression of alpha-sma was only found in the synovial lining layer of RA patients. Stimulation of healthy FLSs with SF resulted in an upregulation of alpha-sma and TLH mRNA. Collagen type I and TLH mRNA were upregulated after stimulation with TGF-beta. Addition of bone morphogenetic protein (BMP)-7 to healthy FLS stimulated with SF inhibited the expression of alpha-sma mRNA. The finding that E-cadherin and collagen type IV are expressed in the lining layer of healthy and arthritic synovium indicates that these lining cells display an epithelial-like phenotype. In addition, the presence of alpha-sma in the synovial lining layer of RA patients and induction of fibrotic markers in healthy FLSs by SF from RA patients indicate that a regulated process comparable to EMT might cause the alteration in phenotype of RA FLSs. Therefore, BMP-7 may represent a promising agent to counteract the transition imposed on synoviocytes in the RA joint.