Two- to three-year follow-up of patients with single-vessel coronary artery disease randomized to PTCA or medical therapy (results of a VA cooperative study). Veterans Affairs Cooperative Studies Program ACME Investigators. Angioplasty Compared to Medicine

Despite increasing use of percutaneous transluminal coronary angioplasty (PTCA) to treat stenotic coronary artery disease, there are relatively few prospective studies evaluating its long-term effectiveness. We prospectively randomized 212 stable patients with provocable myocardial ischemia and single-vessel subocclusive coronary disease to receive primary therapy with either PTCA or medical therapy. This report presents the clinical follow-up of these patients at a mean, after randomization, of 2.4 years for interview and 3.0 years for exercise testing. Of the 212 patients originally randomized, 175 received an extended follow-up interview, and 132 underwent exercise testing; 62% of patients in the PTCA group were angina free compared with 47% of patients in the medical group (p <0.05). Furthermore, exercise duration as measured by treadmill testing was prolonged by 1.33 minutes over baseline in the PTCA group, whereas it decreased by 0.28 minutes in the medical group (p <0.04). Although the angina-free time on the treadmill was not different (p=0.50), fewer patients in the medical group developed angina on the treadmill at 3 years than those in the PTCA group (p=0.04). By 36 months, excluding the initial randomized PTCA, use of PTCA and use of coronary artery bypass surgery were not different in the 2 treatment groups. These data indicate that some of the early benefits derived from PTCA in patients with single-vessel coronary artery disease are sustained, making it an attractive therapeutic option for these patients.     

Linear accelerator output variations and their consequences for megavoltage imaging

An experimental study of radiation output intensity fluctuations of a Philips SL25 linear accelerator is presented. Measurements are obtained using an electronic portal imaging device, and the consequences of the measured fluctuations for various different applications of megavoltage imaging including portal imaging, transit dosimetry and megavoltage computed tomography (MVCT) are discussed with examples. Fluctuations in output of +/- 0.7% (1 SD) are seen on every radiation pulse after photon noise and uncertainties caused by the detection system have been accounted for. Large fluctuations are also seen during the initial beam stabilization period (15%), during normal accelerator operation after the beam has been on for more than 1 min (4.5%) and during are therapy as a repeatable function of gantry angle (9%). Such output intensity fluctuations are shown to produce image artifacts in portal imaging devices with scanned detector readout and can also produce systematic errors in detector calibration that would lead to uncertainty in transit dose calculations. The propagation of these intensity fluctuations through MVCT image reconstruction is shown to produce ring artifacts in the reconstructed image. Sample portal and MVCT images are presented. All observed fluctuations in accelerator output are well within the manufacturer's specifications and do not affect the total dose delivered during normal treatment. Finally, megavoltage imaging is shown to be a powerful tool for accelerator quality assurance and treatment verification.     

Anti-CD45 and anti-CD52 (Campath) monoclonal antibodies effectively eliminate systematically disseminated human non-Hodgkin's lymphoma B cells in Scid mice

Severe combined immunodeficient (Scid) mice inoculated with the human (t(14;18)-positive B cell lines DoHH2 and BEVA develop lethal systemically disseminated lymphoma (de Kroon et al., Leukemia 8:1385, and Blood 80 [suppl 1]:436). These models were used to study the therapeutic effect of rat-anti-human CD52 (Campath-1G) or CD45 monoclonal antibodies (mAbs) on systemically disseminated tumor cells and on tumor cells present in solid tumor masses. Both mAbs were effective in inhibiting growth of systemically disseminated malignant cells. When treatment with anti-CD52 or anti-CD45 mAbs at a dose of 30 micrograms/mouse/d for 4 days was started 24 hours after intravenous inoculation of human DoHH2 or BEVA cells, a 3-log kill of tumor cells was observed as measured by prolonged survival. After treatment, surviving animals injected with high numbers of BEVA cells showed tumor masses in liver, kidney, and mesenteric lymph nodes. In contrast to nontreated animals, however, only low numbers of malignant cells were found in peripheral blood, and bone marrow was free of tumor cells. Similarly, after mAb treatment of mice inoculated subcutaneously (sc) with DoHH2 cells, no tumor cells could be found in the bone marrow, and few DoHH2 cells could be detected in the peripheral blood, spleen, liver, kidney, or lung. In contrast, tumor cells present in subcutaneous tumors and axillary lymph nodes were relatively unaffected by mAb therapy. The presence of rat immunoglobulin (Ig) could be demonstrated on surviving tumor cells. The presence of murine macrophages in areas in these tumors that were depleted of DoHH2 cells suggested that the mAb-mediated antitumor effect observed in the Scid mouse model is mediated by cellular mechanisms. Apparently these mechanisms were not sufficient to eliminate the fast-growing tumor cells present in the protected sites. Our results indicate that treatment with anti-CD52 or anti-CD45 mAbs potentially may be useful as adjuvant immunotherapy for systemically disseminated B cell lymphoma.     

Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches

Patients with monoclonal gammopathies of uncertain significance (MGUS) may develop an acquired bleeding disorder similar to congenital von Willebrand disease, called acquired von Willebrand syndrome (AvWS). In these patients, measures to improve hemostasis are required to prevent or treat bleeding episodes. We diagnosed 10 patients with MGUS and AvWS: 8 had IgGkappa (3) or lambda (5) MGUS and 2 IgM-kappa MGUS. Three therapeutic approaches were compared in them: (1) desmopressin (DDAVP), (2) factor VIII/von Willebrand factor (FVIII/vWF) concentrate, and (3) high-dose (1 g/kg/d for 2 days) intravenous Ig (IVIg). In patients with IgG-MGUS, DDAVP and FVIII/vWF concentrate increased factor VIII and von Willebrand factor in plasma, but only transiently. IVIg determined a more sustained improvement of the laboratory abnormalities and prevented bleeding during surgery (short-term therapy). In addition to the standard 2-day infusion protocol, a long-term IVIg therapy was performed in 2 patients with IgG-MGUS: repeated (every 21 days) single infusions of IVIg did improve laboratory abnormalities and stopped chronic gastrointestinal bleeding. On the other hand, IVIg failed to correct laboratories abnormalities in patients with IgM-MGUS. These comparative data obtained in a relative large and homogeneous group of patients with AvWS and MGUS confirm that DDAVP and FVIII/vWF concentrates improve the bleeding time (BT) and FVIII/vWF measurements only transiently, whereas IVIg provides a sustained treatment of AvWS associated with IgG-MGUS, but not with IgM-MGUS.     

Timecourse of development of the wallaby trigeminal pathway. I. Periphery to brainstem

The development of the vibrissae and their innervation and the maturation of the brainstem trigeminal sensory nuclei have been studied in the wallaby, Macropus eugenii, from birth to adulthood. At birth, developing vibrissal follicles consist of solid epidermal pegs surrounded by dermal condensations. The developing follicles and adjacent skin are innervated by trigeminal afferents. Ten days after birth the follicle contains a dermal papilla and the deep vibrissal nerve can be recognised. A hair cone is present at postnatal day (P) 30 and hairs are apparent on the skin surface by P35. By P63 the deep vibrissal nerve can be seen innervating Merkel cells in the outer root sheath; in addition, the first signs of the blood sinus can be recognised. Innervation of the inner conical body and lanceolate and lamellated receptors supplying the mesenchymal sheath and waist region are not seen until P119, when the follicle resembles that seen in the adult. At birth, central processes of the trigeminal ganglion cells have entered the trigeminal tract and extend from the rostral pons to the upper cervical cord. Labelling with a carbocyanine dye at P0 shows afferents extending medially from the tract into the trigeminal subnuclei at all levels. At this stage the trigeminal nuclei appear as areas of increased cell density in the lateral brainstem. By P30-40 the four subnuclei can be distinguished on the basis of shape, cytoarchitecture, and succinic dehydrogenase reactivity. Adult morphology is not fully established until P210. In mature animals, nucleus principalis contains closely packed, polymorphic cells, frequently aligned parallel to thick fibre bundles that traverse the nucleus obliquely. Subnuclei oralis and interpolaris contain sparsely distributed, medium to large cells, randomly oriented, as well as prominent rostrocaudally directed fibre bundles. Subnucleus caudalis consists of the marginal layer, substantia gelatinosa, and magnocellular layers as described in other species. Patches of increased succinic dehydrogenase or cytochrome oxidase reactivity, presumably corresponding to the vibrissae, are present in subnuclei principalis, interpolaris, and caudalis in developing and adult animals, although the pattern is less clear than in rats. The brainstem patches are first seen at P40, approximately 6 weeks before the corresponding vibrissal-related pattern develops in the cortex. This suggests that the onset of patch formation may be regulated independently at different levels of the pathway.     

5-[125I]iodo-2'-deoxyuridine in the radiotherapy of brain tumors in rats

Glial neoplasms of the human central nervous system have defied treatment, in part because of the limited selectivity of available cytotoxic agents. The thymidine analog 5-iodo-2'-deoxyuridine radiolabeled with the Auger electron emitter 125I (125IUdR) is highly toxic to dividing cells when it is deoxyribonucleic acid incorporated, but it is relatively innocuous when located outside the nucleus. Previous studies have shown that 125IUdR has significant antineoplastic potential against mammalian cells in vitro and direct administration of 125IUdR is effective therapy for ovarian ascites tumors in mice and neoplastic meningitis in rats. Studies using external gamma imaging and autoradiography have also shown that direct intratumoral administration of 123IUdR/125IUdR into intracerebral 9L gliosarcomas in rats results in selective uptake of the radionuclide into tumor cells. Based on these encouraging results, we have evaluated the therapeutic potential of 125IUdR in rats bearing intracerebral 9L gliosarcomas. METHODS: Iodine-125-IUdR was infused intracerebrally over a 2-day period into rats bearing 1-day-old 9L tumors and over a 6-day period into animals with 9-day-old 9L tumors; equimolar concentrations of 127IUdR were infused into control animals. Tumor growth was monitored by contrast-enhanced 1H MRI and animal survival was followed over time. RESULTS: Intracerebral tumors (3-7 mm) were readily detected by MRI. Tumor-bearing rats treated with 127IUdR succumbed within 17-24 days, whereas tumor-bearing animals treated with 125IUdR survived significantly longer, and 10%-20% of the animals were cured of tumors. CONCLUSION: These data substantiate the antineoplastic potential of 5-[125I]iodo-2'-deoxyuridine and indicate that it may be a useful agent for the therapy of solid tumors that are accessible to direct radiopharmaceutical administration.     

Supplementary anti-hepatitis C virus (HCV) testing with 2nd and 3rd generation recombinant immunoblot assay and matrix applied to enzyme immunoassay positive sera and comparison with HCV-RNA detection

Following the same general principles of its two predecessors in 1973 and 1986, the 1996 National Roadside Survey of weekend, nighttime drivers in the 48 contiguous states interviewed and breath tested over 6000 noncommercial four-wheel vehicle operators between September 6 and November 9, 1996. Results indicated that the total number of drinking drivers fell by about one-third between 1986 and 1996; however, there was no significant change in the number of drivers at blood alcohol concentrations (BACs) at or above 0.05. Compared to 1973, the proportion of women drivers on the roads during weekend nights has increased significantly. Moreover, relative to males, the proportion of female drivers who have been drinking has increased over the last decade. The number of drivers under the age of 21 with a BAC at or above 0.10 decreased significantly from 1986 to 1996.