Increased bone marrow microvessel density in newly diagnosed multiple myeloma carries a poor prognosis.

Solid organ tumors associated with neoangiogenesis, as measured by increased microvessel density (MVD), have poorer prognoses. A similar observation of increased MVD has been made in hematologic malignancies; however, its prognostic significance remains unknown. We investigated changes in MVD in 122 newly diagnosed multiple myeloma patients uniformly treated according to the "Total Therapy" protocol (remission induction followed by tandem autotransplants and interferon maintenance) from a set of 231 patients. MVD was measured as mean of 10 fields (MVD) and the single highest field (SHF) on anti-CD34-stained Zenker-fixed paraffin-embedded bone marrow biopsy sections at 400x magnification. MVD was markedly elevated in this population, with a median of 4.4 vessels/field (range, 0.6 to 55.7), and SHF was 13 vessels/field (range, 2 to 80). When compared to 54 patients with less than 4 MVD, 67 patients with mean MVD of greater than 4 had a significantly inferior median duration of event-free survival (EFS) (2.7 v 4.3 years; P =.03), overall survival (OS) (4.3 v 7.9+ years, P =.006), and median complete response (CR) duration (2.2 v 6.8+ years, P=.003). A similarly significant unfavorable relationship to EFS and OS was present for SHF greater than 13. On multivariate analysis of other previously recognized prognostic factors (beta(2)-microglobulin [beta2M], C-reactive protein [CRP], and Bartl grade; and deletion 13), MVD < or = 4 emerged as a major favorable prognostic variable for OS followed by CRP < or = 4, P=.006. Thus, tumor-associated angiogenesis as reflected by MVD is a biologically relevant and important prognostic feature that can be targeted by antiangiogenesis therapy such as thalidomide, which has remarkable antitumor activity in advanced and refractory multiple myeloma.     

Arsenic trioxide: an emerging therapy for multiple myeloma

Arsenic trioxide can inhibit proliferation and induce apoptosis in multiple myeloma (MM) cells in vitro and in vivo. In addition to affecting tumor growth, arsenic trioxide has been shown to inhibit angiogenesis, suggesting that it may have significant potency in the treatment of MM. Based on these observations, the clinical efficacy of arsenic trioxide was evaluated in patients with advanced refractory MM using a fixed-dose intravenous infusion given daily for a maximum of 60 days. Nine patients were evaluable. All nine had extensive prior therapy; seven had two or more high-dose chemotherapy cycles with autologous stem cell support. All nine patients had cytogenetic abnormalities, and six had chromosome 13 deletions. Of the four patients who completed more than 30 days of arsenic trioxide infusion, two had >50% reduction in myeloma paraprotein, one had stable disease, and one progressed. Of the five patients with <30 days infusion, two had stable disease and three progressed. Thus, on an intent-to-treat basis, two of nine (23%) patients responded (>50% paraprotein reduction). The regimen was well tolerated except for development of cytopenia, which responded to G-CSF, and a grade III pulmonary complication in one patient. In summary, arsenic trioxide has activity in end-stage, high-risk myeloma and deserves further evaluation in earlier-stage disease.     

An outbreak of food poisoning in a military establishment

Background: An outbreak of food poisoning in a military establishment mess was investigated and remedial measures suggested.     

Interaction of adeno-associated virus Rep78 with p53: implications in growth inhibition.

Adeno-associated virus (AAV) is a nonpathogenic, single-stranded DNA virus belonging to the parvoviridae family. Onco-suppressive properties of AAV against adenovirus, a DNA tumor virus, have been well documented. Rep78, a major regulatory protein of AAV, is believed to be responsible for its antioncogenic properties. Most DNA tumor viruses disturb the cell cycle pathways by essentially abrogating the functions of p53. Here we present evidence that AAV acts as an antiproliferative agent against adenovirus by protecting the adenoviral-mediated degradation of p53 as confirmed by both Western blot analysis and immunoprecipitation analysis with anti-p53 antibody. Coimmunoprecipitation experiments revealed that the AAV Rep78 is physically bound to p53 in vivo. Furthermore, the binding of purified p53 to the AAV Rep78 affinity column confirms their interaction. These results document for the first time that the antiproliferative effects of AAV against adenovirus are mediated, at least in part, by the interaction of AAV Rep78 with p53.     

TRACHEOSTOMY COMPLICATIONS AND THEIR MANAGEMENT

The word tracheostomy derived from two greek words meaning ‘I cut the trachea’ has been known for about 3500 yrs. The process has evolved over the years and has undergone revolutionary changes in the methodology, instrumentation and indications. Although tracheostomy is now commonly used the complication rate remains high. In our series it was 48% which is comparable with other series. The purpose of this paper is to discuss the complications of tracheostomy with special attention to their management and prevention.KEY WORDS: Complications, Tracheostomy     

Inhibition of platelet function by contrast media: iopamidol and ioxaglate versus iothalamate. Work in progress

The effects of an ionic contrast agent, meglumine iothalamate (Conray-60), and two newer low-osmolality radiographic contrast media, sodium meglumine ioxaglate (Hexabrix) and iopamidol (B-15,000), on platelet aggregation and secretion responses were studied. All three agents inhibited platelet responses during stimulation with adenosine diphosphate (ADP), epinephrine, and collagen. Platelet function was inhibited by iothalamate at concentrations of 11 mg iodine/ml and above, and by the newer agents at concentrations above 30 mg iodine/ml. Addition of exogenous calcium decreased the iothalamate-induced inhibition of aggregation but did not improve dense granule secretion. There was no consistent effect of exogenous calcium on platelet inhibition by iopamidol and ioxaglate. These studies indicate that the newer agents inhibit platelet function less than iothalamate does, and that chelation of Ca2+ may not be the major mechanism of platelet inhibition by contrast agents.     

The pronase resistance of cholesterol-nucleating glycoproteins in human bile

BACKGROUND & AIMS: Many putative pronucleating proteins have been isolated from the biliary concanavalin A (con A)-binding fraction. The pronase resistance of the overall nucleating-promoting activity was almost never taken into consideration. The aim of this study was to identify the major pronase-resistant con A-binding glycoproteins. METHODS: Pronase-treated and -untreated con A-binding glycoproteins were separated on a Superose 12 gel permeation column (Pharmacia, Uppsala, Sweden) and tested in a crystal growth assay. Proteins were identified by amino-terminal sequencing. RESULTS: Con A-binding pronucleating activity eluted in two peaks on the Superose column. This activity was unaltered after pronase treatment. Activity peak I contained too little protein to allow amino-terminal sequencing. In activity peak II, the major pronase-resistant con A-binding glycoproteins were identified as alpha 1-antitrypsin and alpha 1- antichymotrypsin. The 130-kilodalton nucleation promoter was identified as aminopeptidase N, but the full pronase resistance of this protein, reported earlier, was not confirmed. Immunoabsorptive removal of alpha 1-antitrypsin and alpha 1-antichymotrypsin and immunopurification showed that only alpha 1-antichymotrypsin had pronucleating activity. CONCLUSIONS: The pronase resistance of the nucleating-promoting activity of the con A-binding glycoprotein fraction was confirmed. An important part of this activity could be attributed to alpha 1- antichymotrypsin. It is an acute-phase protein, as are many other pronucleating proteins, which might indicate a general mechanism of action in gallstone formation. (Gastroenterology 1996 Jun;110(6):1926-35)