Histopathological changes in leiomyomata treated with leuprolide acetate

Several studies have shown a decrease in uterine and/or leiomyoma volume when treated with leuprolide acetate (LA), a widely used gonadotropin-releasing hormone agonist. The mechanism by which these changes occur is unknown. In this study, the histopathological slides of 31 women of reproductive age who underwent hysterectomy or myomectomy were blindly reviewed by a pathologist. Seventeen women underwent myomectomy. Among those, 10 were treated with LA. The tumors in all of these patients were reduced in size after therapy. Histopathologically, the LA treatment correlated with a significant reduction in cellularity. No significant change in fibrosis, edema, or mitotic activity was seen.     

Estrogen receptors in skin appendage tumors and extramammary Paget's disease.

Determination of estrogen receptors (ER) in breast carcinoma is valuable in the management of patients. However, little is known about the presence of these receptors in other tumors. Normal skin appendages and their neoplasms, including extramammary Paget's disease (EPD), might be expected to express ER since the breast is histogenetically related to sweat glands. In this study, 41 cases of skin appendage tumors (SAT) and 11 cases of EPD were stained using the ER-ICA monoclonal kit (Abbott, Chicago, IL) with a modified technique for paraffin-embedded sections. Controls included 10 biopsies of primary breast carcinoma and 4 cases of metastatic breast carcinoma to skin, all positive for ER. None of the samples of SAT or EPD showed staining for ER. Normal skin appendages were also negative. Normal vaginal epithelium in one case of EPD showed positive nuclear staining for ER. ER determination using immunohistochemical technique in paraffin-embedded sections may be useful in the differential diagnosis between malignant SAT and metastatic breast carcinoma in the skin. The absence of ER in normal skin appendages suggests that its apparition is a feature of specialized differentiation of breast epithelium.     

The coagulant-active phospholipid content is a major determinant of in vivo thrombogenicity of prothrombin complex (Factor IX) concentrates in rabbits

In vitro evaluation of prothrombin complex concentrates in a thrombin generation assay, using DAPA and purified components of the prothrombinase complex, demonstrated significant levels of coagulant- active "phospholipid replacing" activity. Quantification of this activity showed a significant correlation (r = 0.8747, p less than 0.01) with thrombogenicity measured in vivo in a stasis model in rabbits. Extracted lipid material retained full phospholipid replacing activity in the vitro assay. Thin-layer chromatographic characterization confirmed the presence of phospholipids with known coagulant activity in vitro. In vivo, the extracted material was nonthrombogenic but augmented the thrombogenicity of purified factor Xa. Substitution of a synthetic coagulant-active phospholipid (phosphatidylcholine-phosphatidylserine lipid vesicles) for the extracted phospholipid produced a similar augmentation of a factor-Xa- induced thrombogenicity in vivo. It is concluded that the coagulant- active phospholipid content of prothrombin complex concentrates is a major determinant of thrombogenicity but requires the presence of activated clotting factors for its expression in vivo.     

Hypocalcaemia in severe meningococcal infections

AIM: To determine the incidence of hypocalcaemia in critically ill children with meningococcal disease. METHODS: In a prospective cohort study, 70 of 80 patients admitted consecutively with a clinical diagnosis of meningococcal disease to intensive care had measurements of total and ionised calcium on admission. Parathormone and calcitonin were measured in a proportion of the children. RESULTS: Total and ionised calcium concentrations were low in 70% of the children. There was a weak relation of calcium concentration to the volume of blood derived colloid which had been given, but a good relation to disease severity, where sicker children had lower calcium concentrations. Although the parathormone concentration was higher in children with lower calcium concentrations, some children had low ionised calcium concentrations, without an increase of parathormone concentration. Serum calcitonin concentration was not related to calcium concentrations. CONCLUSION: Hypocalcaemia is common in meningococcal disease.     

Multisection-multiecho MR imaging: effect on image quality

An analysis of the effects of multisection-multiecho imaging on signal intensity is presented using a gaussian excitation pulse. The number of sections acquired, size of the intersection gap, and the number of echoes were all varied independently to evaluate their effect on image intensity. The results indicate that one should take a conservative approach in multisection-multiecho imaging, leaving at least a 2-mm-intersection gap and approximately a 20-msec delay between section excitations to avoid image signal loss owing to partial saturation effects.     

In vivo and in vitro enhanced antitumor effects by pentoxifylline in human cancer cells treated with thiotepa

Methylxanthines enhance lethality of alkylating agents in human cancer cells, a phenomenon attributed to the prevention of DNA repair. Pentoxifylline is a nontoxic methylxanthine, used clinically for claudication. Using human cancer cells in culture or in a mouse xenograft model, we studied combination treatments with alkylating agents and pentoxifylline or other methylxanthines. With human bladder cancer cells in culture, cytotoxicity of thiotepa was increased up to 10-fold (P less than 0.01) by posttreatment with pentoxifylline, with a major clinical metabolite of pentoxifylline, or with caffeine; the pentoxifylline concentrations required (0.4-1.0 mM) are clinically achievable in the bladder after nontoxic p.o. doses. With human bladder or breast cancer xenografts in a modified subrenal capsule assay, enhancement of thiotepa was also observed by in vivo posttreatment with pentoxifylline. In contrast, these combinations produced no increased toxicity to normal tissues in these animals, measured by weight, lethality, or histological changes of the normal bladder urothelium. These results provide evidence for a novel approach to improve the therapeutic index of thiotepa and other alkylators, used for topical therapy of bladder cancer and, possibly, systemic therapy of other malignancies.     

Factor V Quebec revisited

Factor V Quebec has been described as a bleeding disorder that exhibits an autosomal dominant inheritance pattern and presents severe bleeding after trauma. Two members of a fourth-generation (IV.13 and IV.15) Canadian family have been studied in detail and are the subject of this report. Their clinical presentations and histories have been described previously (Tracy et al: J Clin Invest 74:1221, 1984). Persistent abnormalities include mild thrombocytopenia and defective platelet factor V. Plasma factor V is present at near normal concentration and is fully functional. Thus, the bleeding diathesis appears to reflect the absence of platelet factor V activity. The recent report (Hayward et al: Blood 84:110a, 1994 [suppl, abstr]) of multimerin deficiency in these individuals led us to reevaluate these patients. Western blot analyses of platelet lysates developed with a variety of monoclonal antibodies show that the alpha-granule proteins, fibrinogen, von Willebrand factor, factor V and osteonectin are decreased in concentration and significantly degraded in the platelets of these patients. Thrombospondin, while not degraded, is substantially decreased. In contrast, platelet factor 4 and beta-thromboglobulin do not appear to be affected. These observations suggest that the alpha- granules are correctly assembled but the contents are subsequently subjected to proteolytic degradation. The results indicate that factor V Quebec disorder is probably associated with a generalized defect that leads to degradation of most proteins of the alpha-granules.     

Immune hemolytic anemia associated with tolmetin and suprofen

This article reports the first case of immune hemolytic anemia possibly associated with the ingestion of suprofen. The patient suffered from massive hemoglobinuria and acute renal failure. Serologic studies of the patient's serum revealed suprofen-dependent red cell antibodies. However, tolmetin-dependent antibodies were also found in the serum, showing the same properties as the suprofen antibodies and an even higher titer. The patient not only had drug-dependent antibodies in the serum, but also had developed autoantibodies, a phenomenon that has been described for several other drugs. The working mechanism by which suprofen and tolmetin caused immune hemolysis had properties of both the immune complex model and the induction of autoimmunity. Although it was unclear whether the immune hemolytic anemia was the result of suprofen, tolmetin, or cross-reacting antibodies, we feel that suprofen should be added to the list of nonsteroidal anti-inflammatory drugs associated with a positive direct antiglobulin test.     

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.