Citations

Background: p45 S phase kinase-associated protein-2 (p45skp2), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCFskp2). The latter has been implicated in the ubiquitination and degradation of p27kip1 (p27) and G1-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated. Methods: Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. Results: The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression (≥ 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P = .002) and Ki-67 proliferative index (r = 0.44; P < .0001), but not with p27 expression (r = −0.02; P = .80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival. Conclusion: These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.

Purpose: To study the efficacy and safety of percutaneous cisplatin-epinephrine (CDDP-EPI) injectable gel in patients with localized unresectable hepatocellular carcinoma (HCC). Patients and Methods: Eligible patients had histologically proven HCC, no prior treatment except for surgery, and no more than three tumors (each measured ≤ 7 cm, total tumor volume ≤ 200 cm3). They were treated percutaneously under ultrasound or computed tomography (CT) guidance, with up to 10 mL of CDDP-EPI gel (1 mL contains 4 mg of CDDP and 0.1 mg of EPI) per treatment and four treatments in 6 weeks to a maximum of eight treatments. The primary end points were tumor response, defined by change of percentage of tumor necrosis according to CT criteria, and safety. Survival parameters were secondary end points. Results: From June 1997 to April 2000, 58 patients (median age, 65 years) entered the study. All patients were assessable for safety, and 51 were assessable for efficacy. The median number of treatments was four (range, one to eight treatments). Objective response rate was 53% (27 of 51 patients), including 16 complete and 11 partial responses. Of the 27 responders, 14 (52%) subsequently developed progressive disease, but in most of them (93%), a new tumor arose at untreated liver sites. Median survival was 27 months (range, 18.4 to 35.7 months). The 1-, 2-, and 3-year survival rates were 79%, 56%, and 14% respectively. The procedure was well tolerated with only minor side effects. Conclusion: Percutaneous local ablation with CDDP-EPI injectable gel can induce significant tumor necrosis and local control for localized unresectable HCC, and the treatment is well tolerated.

Background— BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). Methods and Results— CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 μg · kg −1 · min −1 ; n=8) or NTG (1 and 5 μg · kg −1 · min −1 ; n=6). Administration of 10 μg · kg −1 · min −1 BAY 41-2272 reduced mean arterial pressure (113±8 to 94±6 mm Hg; P <0.05), pulmonary artery pressure (29±2 to 25±2 mm Hg; P <0.05), and pulmonary capillary wedge pressure (25±2 to 20±2 mm Hg; P <0.05). Cardiac output (2.1±0.2 to 2.3±0.2 L/min; P <0.05) and renal blood flow (131±17 to 162±18 mL/min; P <0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance. Conclusion— The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.

Background— The prevalence and characteristics of sleep-disordered breathing in patients with asymptomatic left ventricular (LV) dysfunction are unknown. Therefore, we evaluated the prevalence of sleep-disordered breathing in patients with LV dysfunction without overt heart failure and tested the hypothesis that sleep-disordered breathing is linked to greater hemodynamic and autonomic impairment. Methods and Results— We studied 47 patients with LV ejection fractions ≤40% without any history of heart failure. Central sleep apnea (CSA), as defined by an apnea-hypopnea index ≥15/h, was present in 26 patients (55%), 17 (36%) of whom had severe CSA (apnea-hypopnea index ≥30/h). Obstructive sleep apnea was evident in 5 patients (11%). The prevalence and severity of CSA were higher in patients with ischemic cardiomyopathy than in patients with nonischemic cardiomyopathy ( P <0.05). Exercise tolerance and echocardiographic indices of systolic and diastolic function were similar in patients without CSA, with mild CSA, and with severe CSA. Heart rate variability was markedly depressed in patients with CSA ( P <0.05). Patients with severe CSA also had a higher incidence of nonsustained ventricular tachycardia ( P =0.05). Conclusions— CSA is highly prevalent in patients with asymptomatic LV dysfunction. The severity of CSA may not be related to the severity of hemodynamic impairment. Severe CSA is associated with impaired cardiac autonomic control and with increased cardiac arrhythmias.

A combination of magnetic cell sorting (MACS) and fluorescent in situ hybridization (FISH) techniques was used to detect clonal cytogenetic markers in different myeloid and lymphoid cell types of the peripheral blood from 4 patients with myelofibrosis with myeloid metaplasia (MMM) that was associated with either a 13q− or a 20q− karyotypic abnormality. Interphase cytogenetics studies demonstrated abnormal clonal FISH signal patterns in neutrophil, myeloid, erythroid, megakaryocyte, and B- and T-cell preparations in 3 of the 4 patients. In one patient, FISH results were within normal limits in T cells and slightly abnormal in B cells. In general, the percentage of abnormal nuclei was variable in both lymphocyte populations but always higher in B lymphocytes compared with T lymphocytes. The current study provides direct evidence for the clonal involvement of both B and T lymphocytes in MMM. A larger study is needed to clarify the relevance of the observed interpatient heterogeneity in clonal constitution.

The allergic reaction begins with the antigen-induced aggregation of occupied high-affinity IgE receptors expressed on mast cell surface, their activation, and the release of proinflammatory mediators that cause the “early phase” of this process. In addition, mast cell activation induces the onset of a “late phase” reaction characterized by the tissue infiltration of inflammatory cells, mainly eosinophils. We have hypothesized that during the late phase mast cells interact with and are activated by eosinophils. Here we report that highly purified human lung mast cells became responsive to eosinophil major basic protein (MBP) when in coculture with human lung fibroblasts. In addition, cord blood–derived mast cells maintained in coculture with 3T3 fibroblasts released more histamine and prostaglandin D2 (PGD2) compared with cells maintained in suspension. The fibroblast-derived membrane form of stem cell factor (SCF) was found to be involved in the mast cell increased responsiveness to MBP. In fact, cord blood–derived mast cells cocultured with 3T3 in the presence of antisense for SCF or cocultured with fibroblasts that do not express the membrane form of SCF were inhibited in their histamine-releasing activity toward MBP. In addition, this form of SCF induced the expression of a pertussis toxin–sensitive Gi protein, Gi3 that interacts with MBP to trigger mast cell non-IgE–dependent activation in a manner similar to other cationic compounds such as compound 48/80. Mast cell responsiveness to eosinophil mediators is a potentially novel evidence for an alternative pathway of allergen-independent activation able to contribute to the perpetuation of allergy.

Angiogenesis plays an important role in the biology of multiple myeloma (MM) and has prognostic importance in this disease. Solitary plasmacytoma is a localized plasma cell malignancy that progresses to MM in a significant number of patients. We examined if angiogenesis is increased in solitary plasmacytoma and if it can help identify patients likely to progress to myeloma. We studied angiogenesis in plasmacytoma biopsy samples and bone marrow biopsies from 25 patients. High-grade angiogenesis was present in 64% of plasmacytomas. In contrast, bone marrow angiogenesis was low in all patients. Patients with high-grade angiogenesis in the plasmacytoma sample were more likely to progress to myeloma and had a shorter progression-free survival compared with patients with low-grade angiogenesis (P = .02). Angiogenesis is increased in solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma.