Radiotherapy in mice with yttrium-90-labeled anti-Ly1 monoclonal antibody: therapy of the T cell lymphoma EL4

Yttrium-90 is a potent beta-emitting radionuclide with potential for therapy of lymphoma. A monoclonal antibody against Ly1, the murine homologue of human CD5, was labeled with 90Y and found to selectively bind to Ly1-positive, radiation-sensitive, EL4 mouse lymphoma cells. When tested in this aggressive model of T cell lymphoma, in vivo studies in C57BL/6 mice showed that a single 140-microCi i.p. dose of 90Y-anti-Ly1, given 1 day after i.v. injection of a lethal dose of EL4 cells, resulted in significant but transient improvement in survival. Protection was selective, since a 90Y-labeled irrelevant control antibody did not prolong survival. Biodistribution studies showed that protection was likely limited by inadequate localization of labeled antibody to tumor. Importantly, labeled anti-Ly1 specifically localized in the immunological tissue (spleen and thymus) and lowered the WBC count, perhaps limiting the tolerated dose. Myelosuppression, which is considered one of the major side effects associated with 90Y usage, was not a lethal complication, since WBC counts recovered in mice given a 140-microCi dose of 90Y-anti-Ly1 without EL4 cells and 100% of these animals survived. The maximum tolerated dose was less than 200 microCi. Despite the high localization of 90Y-anti-Ly1 in spleen, splenectomies of tumor-injected mice did not improve the antitumor efficacy of radiolabeled antibody. Further evidence for inadequate delivery of radionuclide to tumor was shown when external total-body irradiation was given to mice given injections of a lethal dose of EL4 tumor cells. Comparison of internal and external irradiation studies indicated that the partially protective effect of 140 microCi 90Y-Ly1 was equivalent to external radiation of only 100-200 cGy. Because this model reflects the current clinical limitations of radiolabeled antibodies for therapy, including partial antitumor efficacy, delivery of labeled anti-T cell antibodies to the immune system, and low maximum tolerated dose, the model may be useful for examining strategies which could increase the tolerated dose and therapeutic efficacy.     

Interactions of C1(-)-inhibitors from normal persons and patients with type II hereditary angioneurotic edema with purified activated Hageman factor (factor XIIa)

Activated high molecular weight Hageman factor (75 Kd) and Hageman factor carboxy-terminal fragments both formed complexes with purified C1(-)-inhibitor, but the Hageman factor fragments appeared to have a higher affinity for the C1(-)-inhibitor than activated Hageman factor. Therefore, the clot-promoting activity of activated Hageman factor might be relatively unimpaired if Hageman factor fragments are also present. Normal C1(-)-inhibitor was cleaved by Hageman factor fragments. Clot-promoting activity was not generated in Hageman factor by exposure to Hageman factor fragments, nor was Hageman factor cleaved by Hageman factor fragments. When Hageman factor was cleaved by streptokinase-activated plasminogen, a 40 Kd fragment was released. In contrast to their interactions with other proteinases, which are blocked by normal C1(-)-inhibitor, Type II C1(-)-inhibitors from plasmas of affected members of eight different kindred with this form of hereditary angioneurotic edema all inhibited the specific coagulant activity of activated Hageman factor to some degree. They did not all form complexes with activated Hageman factor that were stable during sodium dodecyl sulfate-polyacrylamide gel electrophoresis.     

Hepatic cysts in autosomal dominant polycystic kidney disease

Hepatic cysts are one of several extrarenal manifestations of the ADPKD gene. Several factors, including age, gender, pregnancy, the degree of renal cystic disease, and the extent of renal functional impairment, may modify the expression of hepatic cystic disease. With advances in medical care, such as improvement in the management of end-stage renal disease, hemodialysis, and renal transplantation, patients with ADPKD will experience an increased life expectancy. As a result, complications associated with hepatic cysts may become more common, and physicians may encounter an increasing number of patients with ADPKD who have infected hepatic cysts. Several issues in the management of this complication remain unresolved, but the article by Telenti and associates in this issue of the Proceedings addresses some of the critical issues that physicians who are responsible for the care of these patients will certainly confront in future years.     

The effect of surgical procedures on monocyte function in patients with carcinoma of the colon and rectum

The whole blood monocyte count (WBMC), migratory response (MMR), phagocytic index (MPI), chemiluminescence (MCL) and serum opsonic activity (SOA) were measured in a group of 31 patients before and after undergoing elective operation for carcinoma of the colon and rectum (group 1). In the early postoperative period, there was a reduction of the WBMC (preoperatively: 54.1 +/- 41.8, 24 hours; 38.4 +/- 24.8, 48 hours, and 39.1 +/- 24.2 X 10(4) per milliliter, both p less than 0.05), impairment of MMR (preoperatively, 72.2 +/- 34.4; 24 hours, 56.7 +/- 28.6, and 48 hours, 54.7 +/- 30.8 cells per high power field [HPF], both p less than 0.01), enhancement of the MPI (preoperatively, 208.1 +/- 44.1, 24 hours, 225.9 +/- 45.6, p less than 0.05, and 48 hours, 242.0 +/- 48.0, p less than 0.01) and an increase of the MCL (preoperatively, 26,091 +/- 14,419; 24 hours, 30,896 +/- 13,741, and counts per minute [CPM], not significant and 48 hours: 33,576 +/- 18,167 CPM, p less than 0.02). There was also a small reduction in monocyte SOA during this period (preoperatively, 89.4 +/- 13.9; 24 hours, 83.0 +/- 20.1, and 48 hours, 78.3 +/- 29.3 per cent control, both p less than 0.05). At one week after operation, monocyte function tended to return to the normal range in patients who had undergone uncomplicated curative resection. These functions tended to be increased in those patients with complications. The administration of the immunostimulant levamisole (5 milligrams per kilogram) preoperatively to a group of 20 patients with carcinoma of the colon and rectum (group 2) did not result in any significant differences of the postoperative monocyte functions when compared with the patients in group 1.     

Ineffectiveness of tamoxifen in advanced endometrial carcinoma after failure of progestin treatment

Between May 1980 and November 1983, 46 eligible patients with advanced, objectively evaluable endometrial carcinoma were treated with tamoxifen, 10 mg twice daily. Twenty-two of the patients had previously received progestational agents. None of the progestin-refractory patients experienced tumor regression on tamoxifen treatment, while five of the 24 previously untreated with progestins did experience tamoxifen-induced tumor regression. Of the five patients previously treated with cytotoxic drugs, only one experienced objective tumor regression on tamoxifen. Although 28 of these 46 patients were completely ambulatory at the beginning of tamoxifen treatment, only 26% were alive 1 year later; median survival for the entire group was only 120 days. Tamoxifen in this dose cannot be recommended routinely as effective secondary treatment for patients with progestin-refractory advanced endometrial carcinoma.     

Digital imaging of the chest

During the past several years, image acquisition in nuclear medicine, computed tomography, ultrasonography, subtraction angiography, and magnetic resonance has been by digitization. Despite these advances, research in the development of digital imaging in conventional radiography has lagged behind. Although studies with a variety of digital techniques have been carried out on several fronts, we still do not possess a method that has captured the imagination of the majority of radiologists and other physicians to a point where it could replace conventional screen-film imaging. This article reviews the current status and general principles of the technology, focusing on the four digital radiographic techniques that have shown the greatest promise - film digitization, an image intensifier - based system, photostimulable phosphor plates, and a scanned projection system. The physical aspects of each of the four systems and the clinical results that have been reported to date, as well as the advantages and disadvantages of each system, are presented.     

Misoprostol Modulation of Dendritic Cell Function in Immune Responses

Dendritic cells (DC) from blood and other tissues are potent accessory cells for primary immune responses. Because prostaglandins from monocytes and macrophages can suppress DC and T-cell function, we sought to investigate the binding properties of misoprostol (MPL), a prostaglandin E(1) analog, and its regulation of DC function. Results of mouse and human experiments have suggested 1) that MPL could significantly inhibit DC-induced T-cell proliferation in oxidative mitogenesis and allogeneic mixed leukocyte reactions by decreasing interleukin-2 production in DC-T cell cocultures, and 2) that MPL could bind to human peripheral blood mononuclear cells via specific high-affinity MPL binding sites as well as through nonspecific MPL uptake. Taken together, these data suggest that MPL can bind high-affinity and/or nonspecific cell surface receptors and subsequently regulate T-cell growth and cytokine production such as that induced by DC and associated with primary immune responses.     

Respiratory insufficiency in neuronopathic and neuropathic disorders

Twenty-nine patients with a neuronopathic or neuropathic disorder were referred for assessment of respiratory insufficiency between 1978 and 1994. Diagnoses included spinal muscular atrophy (6), chronic idiopathic demyelinating neuropathy (4), Vialetto-van Laere syndrome (3), hereditary motor and sensory neuropathy (3) and a miscellaneous group (5). We also describe seven patients with Guillain-Barre syndrome (GBS) who required long-term ventilatory support for over 6 months to 7 years after the initial illness. Respiratory insufficiency occurred as a consequence of respiratory muscle weakness, impaired bulbar function and restrictive lung defects. In some groups presentation was with progressive nocturnal hypoventilation culminating in acute respiratory failure. Five patients with GBS or chronic idiopathic demyelinating neuropathy were weaned from ventilatory support up to 18 months after the initial illness. The remaining 24 patients required continuous or nocturnal ventilatory support using intermittent positive-pressure ventilation (13), negative pressure ventilation (4), nasal-mask-delivered intermittent positive-pressure ventilation (4), nasal-mask-delivered continuous positive-pressure ventilation (3), mouthpiece-assisted ventilation by day (2) and rocking bed (1). None have been weaned from support after a period of ventilation ranging from one month to 10 years. Eight patients have subsequently died.      

An innovative interdisciplinary approach to self-directed learning with a focus on the continuum of patient care.

Current regulatory review standards emphasize the hospital's role in providing continuum of care. Today, patient care staff must know more about the "continuum of care" concept so they can help patients more fully understand their treatment and take an active role in their own care. One of the challenges is finding creative and effective ways to get the message across to everyone on the staff. This article describes one approach to self-directed learning that takes into consideration individual learning styles and level of proficiency with a focus on the continuum of patient care.     

Effect of mate tea (Ilex paraguariensis) on the expression of the leukocyte NADPH oxidase subunit p47phox and on circulating inflammatory cytokines in healthy men: a pilot study

Increased superoxide production by phagocytic NADPH oxidase has been associated with inflammatory conditions. Growing evidences suggest that dietary polyphenols may modulate the expression of NADPH oxidase subunits. Herein, we examined whether soluble mate tea (SMT) consumption – a polyphenol-rich beverage – affects the expression of the leukocyte NADPH oxidase protein p47^phox and/or circulating biomarkers of inflammation and antioxidant biomarkers in humans. In a two-phase study, nine men were requested to drink water (control) for 8 d and then follow a second 8-d period drinking SMT. Blood samples were analysed for p47^phox protein in CD16⁺/CD14^? cells, interleukin (IL)-1β (IL-1β), tumour necrosis factor-alpha (TNF-α), IL-6, total phenols, and reduced and oxidised glutathione (GSH and GSSG, respectively) after each study phase. After SMT intake, CD16⁺/CD14^? cells' p47^phox protein and serum TNF-α and IL-6 levels were significantly attenuated (P?<?.05) while plasma phenolic compounds and blood GSH:GSSG ratio were significantly enhanced (P?<?.05). Consumption of SMT favourably affected leukocytes' p47^phox expression and inflammatory cytokine and antioxidants levels in peripheral blood, which may help decrease oxidative stress and low-grade inflammation.