Serum albumin (SA) accumulation by bronchogenic tumours: a tracer technique may help with patient selection for SA-delivered chemotherapy

Systemic toxicity and inadequate tumour uptake of chemotherapeutic agents limit effective therapy of disseminated malignant disease. We seek to use macromolecules for improved delivery of therapeutic agents to tumours, and hope to use radiotracer procedures to identify those malignancies able to accumulate the transport molecule. A literature search identified in vitro and animal experimental data which indicated that serum albumin is taken up in malignancies. Selected cytostatic drugs can be bound to albumin, which suggests the suitability of the molecule as a potential transport vehicle. We therefore evaluated indium-111 labelled human serum albumin (HSA) to determine the frequency of its accumulation in bronchogenic tumours. Single-photon emission tomographic (SPET) images were obtained in 23 patients 48 h after intravenous injection of 1.5 mCi¹¹¹In diethylenetriamine penta-acetic acid (DTPA)-HSA. SPET imaging with technetium-99m labelled erythrocytes was included in the protocol to assess the influence which vascularity has on the HSA-based images. All patients went on to surgery. We documented the histological diagnosis, T-stage and differentiation grade. The scintigraphic examination demonstrated HSA uptake in three squamous cell carcinomas and four adenocarcinomas. Of these, six malignancies accumulating HSA had 2.2–5.4 times the tracer concentrations observed in comparable background regions. Small cell carcinoma failed to accumulate the labelled HSA during the 2-day scintigraphic evaluation. The HSA images did not appear to represent tumour vascularity. T-stage and differentiation grade failed to predict which tumours would demonstrate HSA uptake. Initial results suggest that HSA merits evaluation as a potential transport molecule for inmour-directed therapeutic agents, since approximately 35% of the examined malignancies showed HSA uptake. At the same time the relatively infrequent tumour HSA incorporation may mandate using scintigraphy and labelled HSA for selecting those individuals who may profit from HSA-delivered drug therapy. The described selection and therapy approach was tried in two patients who had an¹¹¹In-DTPA-HSA tumour to background ratio of 1.45:1 and 5.3:1 respectively. Both received experimental chemotherapy with methotrexate (MTX)-HSA.     

Rhenium-186 hydroxyethylidenediphosphonate (186Re HEDP) for the treatment of hemophilic arthropathy: first results

OBJECTIVES: The aim of this study was to evaluate the efficacy of a systemic application of rhenium-186 hydroxyethylidenediphosphonate (Re HEDP) for pain treatment in patients with hemophilic arthropathies. METHODS: Twelve patients with hemophilic arthropathy with at least 3 involved joints with persistent pain were included in this prospective study. A single dose of 15 mCi (555 MBq) Re HEDP was administered intravenously. Before and 12 weeks after treatment, pain assessment was performed using the visual analog scale (VAS). The pain status assessment included the general status, pain of all joints affected, and pain of the 3 mostly involved joints. Furthermore, quality of life was assessed. RESULTS: With regard to the 3 most involved joints, an improvement of the pain symptoms in 25 of 36 (69.4%) joints was observed. With regard to all involved joints a median of 3 joints per patient improved after Re HEDP therapy. General pain status after treatment was 2.0 VAS points lower as compared with pretreatment. The total number of involved joints remained unchanged in 7 patients, increased in 1 patient, and decreased in the remaining 4 patients. CONCLUSIONS: The results of this study show an improvement of the pain symptoms of the involved joints 12 weeks after therapy with Re HEDP in patients with hemophilic arthropathy. The only moderate success regarding a reduction of the total number of involved joints is by the fact that despite this improvement most affected joints remained still painful on a lower level after the therapy or due to newly affected joints not painful before initiation of the radionuclide therapy.     

Kr-81m for determination of right ventricular ejection fraction (RVEF)

A 10–12 mCi ⁸¹Rb^81mKr generator was connected to a specially designed short-period infusion set, to produce an equilibrium activity distribution in the right heart. This procedure was tested in 25 individuals to calculate the right ventricular ejection fraction (RVEF). On average 30 heart cycles were analyzed per study. No background activity from the left heart was visualized because of the radionuclide exhalation. The background from the lungs could be neglected, which is partially due to the ultrashort half-life of the nuclide (t _1/2=13s). Thus, an easy automatic procedure can be applied to delineate the ventricle and to calculate the RVEF. The data showed excellent reproducibility, when investigations were repeated. The method would benefit from use of higher activity generators.     

Contact-dependent transfer of TiO2 nanoparticles between mammalian cells

Cellular organelles have been shown to shuttle between cells in co-culture. We hereby show that titanium dioxide (TiO₂) nanoparticles (NPs) can be transferred in such a manner, between cells in direct contact, along with endosomes and lysosomes. A co-culture system was employed for this purpose and the NP transfer was observed in mammalian cells including normal rat kidney (NRK) and HeLa cells. We found that the small GTPase Arf6 facilitates the intercellular transfer of smaller NPs and agglomerates. Spherical, anatase nano-TiO₂ with sizes of 5 (Ti5) and 40?nm (Ti40) were used in this study. Humans are increasingly exposed to TiO₂ NPs from external sources such as constituents of foods, cosmetics, and pharmaceuticals, or from internal sources represented by Ti-based implants, which release NPs upon abrasion. Exposure to 5?mg/l of Ti5 and Ti40 for 24?h did not affect cellular viability but modified their ability to communicate with surrounding cells. Altogether, our results have important implications for the design of nanomedicines, drug delivery and toxicity.     

Influence of physiologic cardiac hypertrophy on the prevalence of heart valve regurgitation.

OBJECTIVE: Chronic dynamic exercise leads to regulative and structural adaptations of the heart (athlete's heart). To what extent the enlargement and physiologic hypertrophy of the heart lead to changes in the function of the valves, particularly regurgitation, is not yet clear. The aim of this study was to examine the regurgitation levels of different states of "athlete's heart." METHODS: Our study population consisted of 5124 healthy subjects (4046 male and 1078 female, 18-60 years), regularly exercising 1 to 20 h/wk. Subjects were divided into 3 groups depending on their relative heart volumes (RHVs): (1) very enlarged heart group (VEHG; male, n = 1251; female, n = 201), with RHVs of greater than 14 (male) and 13 (female) mL/kg; (2) mildly enlarged heart group (MEHG; male, n = 702; female, n = 224), with RHVs of 12 to 14 (male) and 11 to 13 (female) mL/kg; and (3) control subjects (CS; male, n = 2093; female, n = 653), with RHVs of less than 12 (male) and 11 (female) mL/kg. RESULTS: According to US Food and Drug Administration criteria for valve regurgitation, it could be shown by Doppler sonography that as physiologic enlargement and hypertrophy increased significantly, the frequency and severity of aortic valve regurgitation (mean +/- SD: VEHG, 0.04 +/- 0.09; MEHG, 0.09 +/- 0.10; CS, 0.10 +/- 0.11; P < .05) and high mitral regurgitation (VEHG, 0.10 +/- 0.17; MEHG, 0.20 +/- 0.29; CS, 0.26 +/- 0.32; P < .01) decreased. On the contrary, pulmonary regurgitation (VEHG, 0.79 +/- 0.45; MEHG, 0.47 +/- 0.33; CS, 0.35 +/- 0.38; P < .01) and tricuspid valve regurgitation (VEHG, 0.42 +/- 0.29; MEHG, 0.47 +/- 0.33; CS, 0.35 +/- 0.38; P < .01) increased highly significantly with heart size. CONCLUSIONS: These findings strongly support the view of athlete's heart as a physiologic adaptation of the heart, at least on the left side, not causing increased valvular regurgitation.     

Clinical outcomes of HIV-HCV co-infection in a large cohort of hemophiliac patients

OBJECTIVE: To determine the disease progression of HIV-HCV co-infected hemophiliacs in a large cohort of patients (n = 288) cared for at a single medical institution. PATIENTS AND METHODS: Annual mortality rates for AIDS- and liver-related death were calculated and Kaplan-Meier survival plots were drawn to determine the progression to AIDS and death. RESULTS: Between January 1985 and December 2002, 179 (62.2%) and 195 (67.7%) of these patients had developed AIDS or died, respectively. Overall, AIDS accounted for 128 deaths, which almost entirely (93.7%) occurred prior to the introduction of highly active antiretroviral therapy (HAART) at the end of 1995. A total of 29 patients died of liver failure, most of them (69%) during the years 1991-1996. Since 1997, only five cases of fatal liver failure were reported. Non-HIV-HCV related reasons were responsible for 38 deaths and occurred predominantly (47%) in the years 1997-2002. Starting November 1995, 72 patients were treated with HAART. However, by December 2002, only 52.5% and 83% of all HAART-treated patients had a stable viremia (<400 copies/ml) and a sufficient CD4(+) T-cell count (>200/microl), respectively. CONCLUSION: These data indicate that liver-related mortality peaked in the years 1991-1996, but subsequently tended to decline. Moreover, despite widespread treatment of patients with HAART, a significant proportion of individuals had an unsatisfactory immunological and virological status at the end of 2002.