Background and Purpose-On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. Methods-We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ≤24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. Results-The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0-2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705-1.488). Conclusions-Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01120301. This series of basic science studies preceded 2 randomized phase IIa and IIb clinical trials, the neurothera effectiveness and safety trials (NEST)-1 and NEST 2, which included 780 patients (120 in NEST 1 and 660 in NEST 2).12,13 These provided reassuring safety data in patients, but the larger trial was neutral on efficacy end points. However, the combined data were interpreted as showing positive trends that justified definitive testing.14 From the second of these trials, a post hoc analysis identified a subgroup that was hypothesized to have higher potential for efficacy and this formed the target population for the present clinical trial. 13 We conducted a randomized trial to test for the benefit of TLT in improving the proportion of patients with good functional outcome (modified Rankin Scale [mRS], 0-2) at 90 days after stroke onset. Methods Study DesignNEST 3 was a double-blind, randomized, sham-controlled, parallel group, multicenter trial intended to enroll ≤1000 patients from ≈150 investigational sites. Patients were eligible for inclusion if they were aged 40 to 80 years, had a clinical diagnosis of acute ischemic stroke, no evidence of hemorrhagic infarct exceeding petechial bleeding along the margins, had a baseline National Instit...
Two distinct monoclonal antibodies (mAbs) were effective in the therapy of breast carcinomas of human origin established and growing in nude mice. Passive administration of either of the antibodies produced very rapid (less than 1 week) and significant reduction of in vivo tumor volume. Each of the mAbs showed in vivo targeting of the tumors. Histological analysis of mAb-treated tumors revealed extensive cellular necrosis. Each of the antibodies in vitro was effective in complement-mediated cytolysis at a concentration <1 ng/ml. The tumoricidal responses show that this is a useful model for passive human immunotherapy using mAbs.The treatment of malignant tumors with heteroantisera has been investigated for many years with interesting but inconclusive results (1). Hybridoma technology has provided monoclonal antibody (mAb) reagents, which may circumvent difficulties associated with the use of heteroantisera (2). Tumor-associated mAbs have been developed in the last few years by many workers, and some have investigated therapeutic efficacy in both animal and human subjects (3-5). Investigators have reported on the ability of mAbs to inhibit tumor growth by the administration of a mAb concurrent with or within several days of the implantation of tumor cells (6,7). However, passive mAb therapy has not been reported to decrease the volume of well established progressively growing solid tumors.Recently, mAbs developed in this laboratory against breast cancer cells have been shown to bind the target cells with high specificity (8). Passive immunotherapy experiments were performed to assess the therapeutic potential of these reagents. MATERIALS AND METHODSAnimals. Four-to six-week-old female Swiss nude (nu/nu) athymic mice were obtained from Sprague-Dawley. The mice were maintained in a laminar-flow apparatus under pathogenlimited conditions. Cells. Human breast carcinomas (BT-20, MCF-7, and MDA-MB-157) were obtained from the Breast Cancer Task Force, National Cancer Institute (9-11). Other human nonmammary tumor cells used were obtained from staff at Roswell Park Memorial Institute. MOLT 4 (T-cell leukemia), (B-cell leukemia), Peer (T-cell leukemia), and U-937 (erythroleukemia) were obtained from J. Minowada; K-562 (monocytoid leukemia), from J. Pauly; Chago (lung carcinoma), from B. Schepart; Daudi (Burkitt's lymphoma) and Palarmo (melanoma), from S. Leong and J. Horoszewicz; and AsPC-1 (pancreas carcinoma), from M. Tan. CCRF/SB (B-cell leukemia) and CCRF/ CEM (T-cell leukemia) were obtained from the American Type Culture Collection.All cell lines were maintained in vitro in RPMI 1640 medium/10% fetal calf serum supplemented with glutamine/pyruvate/nonessential amino acids/insulin. Cultures were maintained at 370C in humidified 5% C02/95% air.Tumors. Cells were scraped, washed, and resuspended in RPMI 1640 medium. Tumor-cell viability was assessed by trypan blue dye exclusion, and only cell suspensions of >95% viability were used. The nude mice were injected with 5-10 x 106 cells subcutaneously on their dor...
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