Emerging role of platelet-derived growth factor receptor-beta inhibition in radioimmunotherapy of experimental pancreatic cancer.

PURPOSE: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. EXPERIMENTAL DESIGN: Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on (131)ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-beta. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of (131)ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. RESULTS: Biodistribution studies revealed a 50% improvement in the tumor uptake of (131)ICC49 in mice treated with imatinib. Tumor development was practically arrested for approximately 3 weeks in response to the treatment composed of (131)ICC49 and imatinib with tumor quadrupling time (T(Q)) of 40.8 days. (131)ICC49 alone and imatinib alone also delayed the tumor growth to T(Q) of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d. for 3 days. Xenografts in control mice receiving injection of PBS had T(Q) of 23 days. CONCLUSIONS: The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodality treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-beta inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.     

Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact

Deletions on chromosome 6q are frequently reported in hematological malignancies. However, their biological or prognostic impact has not yet been clarified. This study analyzed loss of heterozygosity (LOH) at chromosome 6q and compared the LOH findings in pediatric precursor T lymphoblastic lymphoma (T-LBL) with the LOH findings in precursor-T lymphoblastic leukemia (T-ALL). For LOH analyses, a set of 25 microsatellite-markers on 6q14-q24 were examined. All patients were treated uniformly according to ALL-BFM-type treatment-strategy. A total of 1671 markers were successfully analyzed from 108 T-LBL patients. LOH was detected in 21 T-LBL patients. There was clear association between LOH at 6q and an increased risk of relapse. In comparison, 3109 markers were successfully analyzed from 127 T-ALL-patients. LOH was detected in 16 patients, but was not associated with increased relapse-rate. The localization of the common LOH regions identified for T-LBL and T-ALL samples did not overlap. Therefore patterns of LOH at 6q and the prognostic impact of LOH differ between T-ALL and T-LBL. These results hint at biologic differences between the two diseases.     

Difficult airway management in a patient with severe aortic stenosis, coronary artery disease, and heart failure

We report a patient with aortic stenosis, coronary artery disease, and heart failure in whom awake fiberoptic intubation was performed because the patient's mouth opening was insufficient as a result of disc prolapse of the mandibular joint. We planned to perform this procedure during conscious sedation, spontaneous respiration, and with stable hemodynamic parameters (no tachycardia, hypertension, or hypotension). After oral premedication with dikaliumclorazepate, the patient received clonidine. Fiberoptic intubation was performed while the patient breathed spontaneously. Throughout the procedure, no adverse events occurred. Clonidine is a valuable adjunct for conscious sedation and can be used safely for sympathicolysis, even in patients with aortic stenosis.     

Genetic animal models for retinal degeneration

Inherited retinal degenerations are a common cause of blindness in Western countries. A mechanism for most retinal degenerations is still unknown; hence, a suitable treatment for most of these diseases has yet to be found. Before one can rationally design a treatment, it is necessary to understand the pathway from a gene mutation to the phenotype in patients. Animal models are crucial to understand this process and to develop a treatment. Some naturally occurring animal models are known. However, over the past few years, transgenic engineering has allowed the generation of a rapidly growing number of animal models. In this review, we give an overview of the broad variety of genetic animal models for retinal degeneration.     

The effect of cryoprotectants on the physical properties of large liposomes containing sodium diclofenac

Large liposomes (1-10 microm) containing sodium diclofenac were prepared and lyophilized using lactose or mannitol (7.5% in respect to the lipid content) as cryoprotectants. The physical studies of liposomes were performed during 30 days of storage in a dry or resuspended form. Lyophilization of large liposomes and storage in the dry form at 5 degrees C increases their physical stability. Lactose is a cryoprotectant which does not influence changes of properties of liposomes regarding their size, encapsulation efficacy and release rate. Large liposomes lyophilized in the presence of mannitol tend to increase in size and encapsulation efficacy, but the lipid bilayers are stabilized and less permeable to the drug.     

Synthesis and effects on chloroquine susceptibility in Plasmodium falciparum of a series of new dihydroanthracene derivatives

To suggest a mechanism of action for drugs capable to reverse the chloroquine resistance, a new set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was synthesized and compounds were tested with the aim to assess their effect on chloroquine susceptibility in Plasmodium falciparum resistant strains. With respect to this, reversal of resistance and change in drug accumulation were compared. Structure-activity relationship and molecular modeling studies made it possible to define a pharmacophoric moiety for reversal agents and to propose a putative model of interaction with some selected amino acids.     

Risk factors for ischemic heart disease and glycosaminoglycans (GAG's) in plasma in atherosclerosis obliterans

GAGs (glycosoaminoglycans) derive from damaged artery endothelium cells. Theoretically their concentration could be used to measure the level of atherosclerosis process. The aim of the study was to estimate the concentration of glucosamine and galactosamine in plasma in patients with AO in comparison to the main risk factors of CHD: smoking, hyperlipidemia, hypertension. Investigated group: the subject of the study were 35 men and 26 women suffering from AO. The control group comprised 20 men and 28 women. People from both groups were 36-65 years old. The concentration of glucosamine and galactosamine were determined by automatic amino acid analyzer LC 6001 Biotronic. The lipids in plasma were determined by conventional methods. Results 100% of men and 81% of women with AO were smokers to compare 70% and 17% in the control group. Systolic blood pressure in men with AO was 134 +/- 13 mm Hg and in women 136 +/- 16 mm Hg. In the control groups they were respectively 122 +/- 10 mm Hg and 124 +/- 10 mm Hg. The difference between the groups is statistically significant. Diastolic and systolic pressures in women with AO were higher then in the control group. In men with AO systolic pressure, but not diastolic pressure, was higher than in the control group. It was observed that in women with AO the concentration of total cholesterol, LDL-chol, apo B in serum, apo B in LDL, TG, TC-HDL-chol/HDL-chol, LDL/HDL were higher, HDL-chol was lower in comparison with the control group. In men with AO total cholesterol, LDL-chol/HDL-chol and TC-HDL-chol/HDL-chol were higher then in the control group, HDL-chol was lower. 80% of women and 74% of men with AO suffered from hyperlipidemia compared with 36% and 60% in the control group respectively. Mixed hyperlipidemia was the most important factor differentiating patients with AO and the control group, when compared to other types of hyperlipidemia. The coexistence of risk factors was more frequently observed in patient with AO then in the control group. Differences in concentrations of glucosamine and galactosamine between the patients with AO and the control group were not statistically significant in women and only slightly statistically significant in men. CONCLUSIONS: Classical risk factors of CHD differentiate patients with AO from the healthy people. The concentrations of glucosamine and galactosamine in plasma cannot be used to determine the atherosclerosis process.     

Role of osteopontin in the formation of microcalcifications in breast cancer

INTRODUCTION: Osteopontin, a non-collagen, Ca-binding phosphoprotein, plays roles in both physiological and pathological mineralisation processes. Its expression may be severely altered in malignant tumours. AIM: To investigate the presence of this protein in breast tumours showing mammographic microcalcifications. MATERIAL: In this study the authors investigated immunohistochemically the osteopontin expression in 26 breast tumours. The elemental composition of the microcalcifications of the same tumours was also examined with energy dispersive spectrometer linked to a scanning electron microscope. RESULTS: Osteopontin expression was found within the tumours in the tumour cells, in vascular smooth muscle cells, in the myoepithelial cells of the normal ducts, and in macrophages. Extracellular osteopontin positivity was seen around calcified foci. There was no correlation between osteopontin positivity and the examined prognostic factors: grade, type and size of the tumour, axillary lymph nodes status, or age. Two types of microcalcifications were seen: 1. Ca-phosphate only, 2. Those composed of various other elements. CONCLUSION: The presence of osteopontin in the vicinity of calcified foci and in the vessel walls seems to support the hypothesis that osteopontin takes part in calcification process.