Adjuvant therapy for osteosarcoma in dogs: results of randomized clinical trials using combined liposome-encapsulated muramyl tripeptide and cisplatin

Two randomized, double-blind clinical trials in dogs with spontaneous appendicular osteosarcoma treated with combination chemoimmunotherapy are reported. In both trials, dogs without overt metastasis underwent complete amputation of the affected limb. In trial 1, 40 dogs were treated with cisplatin chemotherapy [(CDDP), 70 mg/m2 i.v. every 28 days x 4]. Following CDDP, dogs without evidence of overt metastasis (n = 25) were randomized to receive liposome-encapsulated muramyl tripeptide phosphatidylethanolamine ](L-MTP-PE), 2 mg/m2 i.v.) or placebo liposomes (lipid equivalent) twice weekly for 8 weeks. Of 14 dogs in the placebo group, 13 (93%) died of metastasis; the median survival time was 9.8 months. Of 11 dogs in the L-MTP-PE group, 8 (73%) developed metastasis; the median survival time was 14.4 months, which was significantly longer than that of the placebo group (P < 0.01). In trial 2, 64 dogs received CDDP (70 mg/m2 i.v. every 21 days x 4) and were randomized to concurrently receive L-MTP-PE (2 mg/m2 i.v.) twice or once weekly, or placebo liposomes once weekly for 8 weeks. Median survival times were 10.3, 10.5, and 7.6 months, respectively. There were no significant differences among the three treatment groups in trial 2. Survival times for dogs receiving L-MTP-PE in trial 1 were significantly longer than those for dogs in trial 2 that received four doses of CDDP concurrently with twice weekly L-MTP-PE (P < 0. 04). The results of the first trial confirm our previous observation that L-MTP-PE has antimetastatic activity in dogs with osteosarcoma when given following amputation. The results of the second trial demonstrate that there is no survival advantage of administering L-MTP-PE concurrently with CDDP.     

Higher levels of interleukin-6 in cystic fluids from patients with malignant versus benign ovarian tumors correlate with decreased hemoglobin levels and increased platelet counts

BACKGROUND: Recently, high pretreatment platelet counts and low pretreatment hemoglobin levels were found to be negative prognostic factors in patients with ovarian cancer. Interleukin-6 (IL-6) is a multifunctional cytokine with a diversity of functions leading to the induction of C-reactive protein (CRP), increased platelet counts, and low hemoglobin levels. Different epithelial ovarian cancer cell lines are found to produce varying amounts of IL-6. In this study, a possible relationship between IL-6 levels in cystic fluids of benign and malignant ovarian tumors and pretreatment serum CRP, platelet counts, and hemoglobin levels was evaluated. METHODS: A bioassay and enzyme-linked immunosorbent assay (ELISA) were performed to determine the IL-6 levels in cystic fluids and serum from 42 patients with benign and malignant ovarian tumors. RESULTS: The median IL-6 level was higher in cystic fluids of malignant tumors (n = 21) when compared with cystic fluids of benign tumors (n = 21) (P < 0.01 for bioassay and ELISA). Serum IL-6 levels in patients with malignant tumors were not significantly higher compared with IL-6 levels in patients with benign tumors, whereas CRP levels were higher in patients with malignant tumors (P < 0.01). Cystic fluid IL-6 levels were related to serum CRP levels (r = 0.60, P < 0.01 [bioassay]; r = 0.41, P < 0.01 [ELISA]), and were related inversely to hemoglobin levels (r = -0.57, P < 0.01 [bioassay]; r = 0.54, P < 0.01 [ELISA]). CONCLUSIONS: IL-6 levels are higher in cystic fluids of malignant ovarian tumors compared with benign tumors. The relationship of cystic fluid IL-6 levels with CRP, platelet counts, and hemoglobin levels suggests a possible causative role of tumor-derived IL-6 in the appearance of general side effects of ovarian cancer, which recently have been recognized as prognostic factors.     

Diagnostic procedure in cholecystolithiasis. Diagnostic approach, repeat examinations and (incidental) findings

If non-surgical methods are to be taken into account in the therapeutic decision-making process in cholecystolithiasis, an expanded diagnostic work-up including not only stone parameters but also gallbladder function, is needed. In 2270 patients (1649 women, 621 men; age: 47.2 +/- 14 years) with (suspected) "cholecystolithiasis" attending the special gallstone outpatient clinic at a university medical department within a period of 5 years the diagnostic procedures most commonly used in both the doctor's office and hospital were abdominal ultrasonography (52%/78%), laboratory investigations (28%/39%) and plain films of the biliary tract (27%/39%). In the doctor's office gallbladder function testing took the form of an cholecystogram (17% of the patients); in the hospital ultrasonography to determine gallbladder contractility (38%). With decreasing frequency, the following additional procedures were carried out (office/hospital): CT 3%/19%, esophagogastroduodenoscopy 7%/3%, intravenous cholegram 6%/0.6%, abdominal X-ray 1%/0.4%, ERCP 1%/0.4%, chest X-ray 0.8%/1.6%. Duplicated examinations showed a relevant frequency only for ultrasonography (39% of the cases), laboratory investigations (18%) and plain films of the gallbladder (4%). Pathologic secondary findings were established in 22% of the cases.     

Laser lithotripsy of difficult bile duct stones: results in 60 patients using a rhodamine 6G dye laser with optical stone tissue detection system

INTRODUCTION: Laser lithotripsy of bile duct stones has become a widely accepted endoscopic treatment modality for giant, impacted, or very hard stones. The procedure is usually carried out under direct endoscopic control in view of the potential risk of bile duct injuries in "blind" laser application. AIMS: To investigate the use of a rhodamine 6G laser lithotriptor with an integrated optical stone tissue detection system (oSTDS). METHODS: From 1 September 1991 to 7 March 1997, 60 patients with giant or impacted common bile duct stones refractory to endoscopic papillotomy stone extraction, and mechanical lithotripsy were treated via the endoscopic retrograde route using a rhodamine 6G dye laser (595 nm, 2.5 micros, 80-150 mJ pp, Lithognost Telemit/Baasel Corp., Germany) with integrated oSTDS. In case of tissue contact oSTDS cuts off the laser pulse after 190 ns (transmission of 5-8% of the total pulse energy). 47 patients (78.3%) were subjected to x ray targeting (oSTDS) alone, five (8.3%) to choledochoscope targeting alone, and eight (13.3%) to both techniques. RESULTS: At the end of treatment 52 (87%) patients were completely stone-free. The only major complications included transient haemobilia, cholangitis, and pancreatitis in five patients. All five were successfully treated by conservative methods. CONCLUSIONS: Laser lithotripsy using the described rhodamine 6G dye laser with oSTDS seems to be safe and effective and allows "blind" fragmentation of difficult common bile duct stones under radiological control only.     

Should third-generation cephalosporins be the empirical treatment of choice for severe community-acquired pneumonia in adults?

The choice of empirical treatment for community-acquired pneumonia (CAP) is highly controversial. Our survey of 42 Australian emergency department doctors showed that monotherapy with a third-generation cephalosporin was the preferred regimen for severe CAP (14/42; 33%). We argue that cheaper regimens with a narrower spectrum are likely to be just as effective as third-generation cephalosporins and will have fewer adverse effects on the microbial ecology of hospitals. We suggest penicillin or ampicillin (to cover pneumococci--even if penicillin "resistant"--and Haemophilus influenzae), plus a macrolide (e.g., azithromycin or erythromycin; to cover Legionella and other "atypical" pathogens), plus a single large dose of an aminoglycoside (e.g., gentamicin; to cover gram-negative bacilli such as Klebsiella pneumoniae) as empirical therapy for severe CAP.     

Graft permeabilization facilitates gene therapy of transplant arteriosclerosis in a rabbit model

BACKGROUND:Smooth muscle cell (SMC) replication plays a central role in the pathogenesis of transplant arteriosclerosis. One strategy to eliminate dividing cells is to express a herpesvirus thymidine kinase (tk) gene that phosphorylates the nucleoside analogue ganciclovir into a toxic form leading to cell killing. However, medial SMCs are resistant to gene transfer unless the artery undergoes deendothelialization. We hypothesized that manipulations that increase the "porosity" of the artery can make SMCs prone to gene transfer without denudation. METHODS AND RESULTS:In organ culture of rabbit aorta, longitudinal stretch and supraphysiological pressure applied for 3 hours during incubation with adenoviral vector facilitated gene transfer into medial SMCs without denudation. Of the SMCs, 10.2+/-3.8% expressed a reporter gene of human placental alkaline phosphatase (hpAP), whereas SMCs in control arteries did not express hpAP. To evaluate the feasibility of transgene expression in arterial grafts, we performed such permeabilization-assisted reporter gene transfer into aortas of donor Dutch Belted rabbits and transplanted them into carotid arteries of recipient New Zealand White rabbits. Unstretched transfected grafts were used as a control. SMCs expressed hpAP (7. 3+/-2.4% of cells in 2 days and 4.2+/-1.9% in 2 weeks) in stretched grafts only. In the next series of experiments, we transfected stretched grafts with ADV-tk and combined transplantation with systemic administration of ganciclovir. Stretched ADV-hpAP grafts were used as a control. In 2 weeks, the formation of intimal thickening in tk-expressing grafts was significantly reduced (P<0. 01) because of a decrease in proliferating SMCs. CONCLUSIONS:Manipulations within target tissues can enhance the efficiency of gene transfer into SMCs. Although mechanical permeabilization is clinically problematic, in principle, targeting SMC replication may provide a genetic approach to the treatment of transplant arteriosclerosis.     

Drug therapy before coronary artery surgery: nitrates are independent predictors of mortality and beta-adrenergic blockers predict survival

We conducted this study to evaluate whether there is an association between preoperative drug therapy and in-hospital mortality in patients undergoing coronary artery graft surgery. We collected data on 1593 consecutive patients undergoing coronary artery surgery. The relative risk of in-hospital mortality was determined by logistic regression with in-hospital mortality as the dependent variable, and independent variables that included known risk factors and preoperative cardioactive or antithrombotic drug treatment, i.e., age; left ventricular function; left main coronary artery disease; urgent priority; gender; previous cardiac surgery; concurrent cardiovascular surgery; chronic lung disease; creatinine concentration; hemoglobin concentration; diabetes; hypertension; cerebrovascular disease; recent myocardial infarction; prior vascular surgery; number of arteries bypassed; and regular daily treatment with beta-blockers, aspirin within 5 days, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, digoxin, or warfarin. In-hospital mortality was 3.3%. The relative risk of in-hospital mortality (with 95% confidence intervals of the relative risk) associated with the following drug treatments was: nitrates 3.8 (1.5-9.6), beta-blockers 0.4 (0.2-0.8), aspirin within 5 days 1.0 (0.5-1.9), calcium antagonists 1.1 (0.6-2.1), ACE inhibitors 0.8 (0.4-1.5), digoxin 0.7 (0.2-1.8), and warfarin 0.3 (0.1-1.6). We conclude that in-hospital mortality is positively associated with preoperative nitrate therapy and negatively associated with beta-adrenergic blocker therapy. A significant association between in-hospital mortality and the preoperative use of calcium antagonists, ACE inhibitors, aspirin, digoxin, and warfarin was not confirmed. Implications: We examined the association between common drug treatments for ischemic heart disease and short-term survival after cardiac surgery using a statistical method to adjust for patients' preoperative medical condition. Death after surgery was more likely after nitrate therapy and less likely after beta-blocker therapy.     

Sialidase gene transfection enhances epidermal growth factor receptor activity in an epidermoid carcinoma cell line, A431

Glycosphingolipids expressed in cancer cells have been implicated in the modulation of tumor cell growth through their interaction with transmembrane signaling molecules such as growth factor receptors. For glycosphingolipids to interact with growth factor receptors, the presence of sialic acid seems to be essential. Stable transfection of a gene encoding a soluble Mr 42,000 sialidase into a human epidermoid carcinoma cell line (A431) provided an approach by which the level of terminal lipid-bound sialic acid on the cell surface could be altered. In the sialidase-positive clones, the level of ganglioside GM3 was diminished, and little change was observed in protein sialylation. Sialidase-transfected cells grew faster than control cells. Sialidase expression did not modify the binding of epidermal growth factor (EGF) to its receptor but enhanced EGF receptor (EGFR) tyrosine autophosphorylation as compared to that of parental cells or cells transfected with the vector (pcDNA3) alone. Moreover, the phosphorylation of the EGFR, as well as other protein substrates, was observed at low EGF concentrations, suggesting an increase in the receptor kinase sensitivity. These data provided evidence that changes in ganglioside expression in cancer cells by appropriate gene transfection can dramatically affect EGFR kinase activity. Hence, the modulation of ganglioside expression may represent an approach to alter tumor cell growth.