IFN-alpha1,8 inhibits tumor-induced angiogenesis in murine angiosarcomas.

Interferon-alpha (IFN-alpha) has proved effective in the treatment of hemangiomas, hemangioblastomas, and Kaposi's sarcoma. To investigate the ability of IFNs to inhibit angiosarcoma, we used two transformed murine endothelial cell lines that form angiosarcomas in vivo. SVR and MS1-VEGF cell lines express oncogenic H-ras or vascular endothelial growth factor (VEGF), respectively. IFN-alpha1,8, which is active against murine and human cells, inhibited SVR and MS1-VEGF proliferation in vitro by 40% at 10(3) U/mL (p = 0.028). In vivo, IFN-alpha1,8 inhibited SVR tumor volume by 71% (p = 0.047) and MS1-VEGF volume by 79% (p = 0.003). Tumor-induced angiogenesis was decreased in SVR tumors by 52% (p = 0.005) and in MS1-VEGF tumors by 58% (p = 0.001). Sera from IFN-alpha1,8-treated mice bearing either SVR or MS1-VEGF tumors demonstrated a 5-fold increase in IP-10/CXCL10 (p = 0.001), an IFN-induced antiangiogenic protein. Both recombinant IP-10 and IFN-alpha1,8 inhibited human umbilical vein endothelial cell (HUVEC) vessel formation in the fibrin gel assay, a three-dimensional culture model of angiogenesis, by 56% at 25 ng/mL and 50% at 1.2 ng/mL, respectively (p < 0.001). An IP-10 blocking antibody restored vessel formation to 80% of untreated controls (p = 0.001). Given the magnitude of the in vivo response, these data suggested that the antitumor effects of IFN-alpha1,8 were likely mediated through angiogenesis inhibition rather than solely by direct inhibition of tumor cell proliferation.     

Estrogen and progesterone receptor expression in uterine and extrauterine leiomyosarcomas: an immunohistochemical study.

The authors have noted anecdotal cases of extrauterine leiomyosarcomas (LMS) with estrogen receptor (ER) and progester-one receptor (PR) immunoreactivity. However, there are few studies that have compared ER and PR immunoexpression in LMS of uterine and extrauterine origin. The authors obtained a representative formalin-fixed, paraffin-embedded tissue block from cases of uterine LMS (n = 15) and extrauterine LMS (n = 16) from the archives of the Cleveland Clinic Foundation and performed immunohistochemical staining for ER and PR. Staining was evaluated by 2 observers in a semiquantitative manner using the following scale: 0, no nuclear staining; 1+, 1 to 25% of nuclei stained; 2+, 26 to 50% of nuclei stained; 3+, 51 to 75% of nuclei stained; 4+, 76 to 100% of nuclei stained. The majority of uterine LMS stained for ER (13 of 15, 87%), PR (12 of 15, 80%), or both ER and PR (12 of 15, 80%), with most cases showing 3+ or 4+ positive staining. For the extrauterine LMS cases, staining for ER was seen in 4 of 16 cases (25%), staining for PR was observed in 2 of 16 cases (13%), and staining for both ER and PR was seen in 2 of 16 cases (13%). One extrauterine LMS showed 4+ coexpression of ER and PR, but the remaining extrauterine cases showed only 1+ ER and/or PR immunoreactivity. These data suggest that most uterine LMS coexpress ER and PR, and most extrauterine LMS do not stain for these antigens. However, a subset of extrauterine LMS are ER and/or PR immunoreactive. This raises the possibility that hormonal manipulation may be beneficial in the treatment of these therapeutically recalcitrant tumors.     

Facilitated percutaneous coronary intervention.

The goal of the initial treatment for ST-segment elevation myocardial infarction is rapid and effective reperfusion. Randomized trials have demonstrated that primary angioplasty is preferred over thrombolysis if done in a timely manner and by an experienced team. However, due to many factors, performance of primary angioplasty within the goal of 90 min is often not possible. A combined strategy of immediate thrombolysis in the emergency room or in the ambulance followed by angioplasty theoretically could provide early reperfusion with subsequent angioplasty to insure complete reperfusion. Over 17 clinical trials have been reported. Compared with thrombolysis, facilitated angioplasty in the most recent trials has been shown to have a more favorable long-term outcome. Trials comparing facilitated angioplasty with full- or half-dose thrombolysis versus primary angioplasty have been far less favorable with the largest trial to date, the ASSENT (Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention)-4 trial, demonstrating a worse outcome in the primary end point of death, congestive heart failure, or shock at 90 days. Pending the results of the FINESSE (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events) trial, current data suggest that facilitated angioplasty does not offer any advantage over primary angioplasty and may be harmful.     

Sociometric status and academic, behavioral, and psychological adjustment: a five-year longitudinal study.

Six hundred fourth-graders rated how much they liked to play with each of their classmates and then nominated their three best friends; 296 of the 600 children were assigned sociometric classifications of popular, neglected, average, controversial, or rejected status (the remaining 304 children failed to meet inclusion criteria). Five years later, 267 of the 296 classified children (90.2%) were evaluated on measures of academic performance, social behavior, and psychological adjustment. The number and type of contacts with the juvenile justice system were also determined. In general, children classified as rejected or controversial tended to fare more poorly on indices of long-term adjustment than did children classified as popular, neglected, or average. Results are discussed in terms of the predictive validity of sociometric rating and nomination procedures and their utility in identifying children at risk for later maladjustment.     

A formalism for independent checking of Gamma Knife dose calculations

For stereotactic radiosurgery using the Leksell Gamma Knife system, it is important to perform a pre-treatment verification of the maximum dose calculated with the Leksell GammaPlan (DLGP) stereotactic radiosurgery system. This verification can be incorporated as part of a routine quality assurance (QA) procedure to minimize the chance of a hazardous overdose. To implement this procedure, a formalism has been developed to calculate the dose DCAL(X,Y,Z,dav,t) using the following parameters: average target depth (dav), coordinates (X,Y,Z) of the maximum dose location or any other dose point(s) to be verified, 3-dimensional (3-dim) beam profiles or off-centerratios (OCR) of the four helmets, helmet size i, output factor Oi, plug factor Pi, each shot j coordinates (x,y,z)i,j, and shot treatment time (ti,j). The average depth of the target dav was obtained either from MRI/CT images or ruler measurements of the Gamma Knife Bubble Head Frame. DCAL and DLGP were then compared to evaluate the accuracy of this independent calculation. The proposed calculation for an independent check of DLGP has been demonstrated to be accurate and reliable, and thus serves as a QA tool for Gamma Knife stereotactic radiosurgery.     

Effect of influenza A virus on leukocyte histamine release

Viral respiratory infections provoke asthma in many patients. In the following study we examined the effect of an in vitro incubation of influenza A on leukocyte histamine release. After incubation with a live influenza A (H3N2) virus, calcium ionophore A23187 (0.5, 1.0, and 1.5 microgram/ml)-induced leukocyte histamine release (HR) was enhanced (p less than 0.05). This effect was also found with heat- or ether-inactivated virus. Similarly, influenza A-exposed leukocytes had augmented leukocyte HR during subsequent incubation with ragweed AgE. Incubation of the leukocyte suspension with interferon (800 IU/ml) for 24 hr was also associated with enhanced HR to ragweed AgE. In contrast, interferon did not alter the calcium ionophore A23187 HR. Therefore, although interferon may mediate the enhanced leukocyte HR when ragweed AgE is the inciting stimulus, it does not change HR to the calcium ionophore.     

Augmentation in the infectivity of SV40 virus DNA by amphotericin B methyl ester

Summary The methyl ester of amphotericin B (100 µg/ml) enhanced the infectivity of SV40 virus DNA for CV-1 cells up to 300-fold. Amphotericin B methyl ester may prove useful for augmenting cellular penetration of macromolecules and for probing biological mechanisms.With 2 Figures     

Assessment of the antigenic response in humans to a recombinant mutant interferon beta

Cancer patients were given a recombinant mutant interferon by alternating IM and IV injections with weekly escalation of doses from 0.1 to 400 million U. Antibodies specific to the interferon of the IgG class were detected in 24 of 30 patients using an indirect enzyme-linked immunosorbent assay. Serum from only 1 of the 30 patients had detectable ability to neutralize interferon biological activity. Thein vivo interferon serum level, assayed as antiviral activity immediately after IV injection, was not lower than levels seen in the absence of antibodies. Antibodies did not alter the kinetics of clearance of interferon from the serum after IV administration. Antibody levels progressively decreased when interferon administration was discontinued. In most patients antibody levels decreased during a maintenance period when interferon was being administered only by the IV route. In a subsequent trial interferon was given IV, and antibody developed in only 2 of 36 patients. In contrast, in a trial in which interferon was given IM, 20 of 25 patients developed antibody. No antibody-related clinical sequelae could be detected in any of these patients.     

Effect of interferon alpha,interferon beta,and interferon gamma on the in vitro growth of human renal adenocarcinoma cells

Interferon-, interferon-, and interferon- differ in their antiproliferative effects for several cell lines. Interferons were thus assessed for their activity in inhibiting proliferation of three renal cell carcinoma cell lines. The malignant epithelial phenotype of each of these cell lines was confirmed by electron microscopy, histology, karyotype and tumorigenicity. When compared on an anti-viral unit basis, naturally produced interferon- was more effective than natural interferon- for all cell lines and clones. Proliferation of each of the cell lines was inhibited by interferon-. In all cases, removal of interferons from culture media resulted in resumption of the rate of cell growth after a variable delay of 6–10 days. If the antiproliferative effects of interferons predominate in mediating tumor regression, clinical response may depend upon the type of interferon to which the tumor is exposed.