Combined vascular endothelial growth factor receptor/epidermal growth factor receptor blockade with chemotherapy for treatment of local, uterine, and metastatic soft tissue sarcoma

PURPOSE: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. EXPERIMENTAL DESIGN: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). RESULTS: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. CONCLUSIONS: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.     

Trends in adult cigarette smoking in California compared with the rest of the United States, 1978-1994

OBJECTIVES: This study compared trends in adult cigarette smoking prevalence in California and the remainder of the United States between 1978 and 1994. METHODS: We used data from National Health Interview Surveys and Behavioral Risk Factor Surveillance System surveys to compare trends in smoking prevalence among persons 18 years and older. RESULTS: In both California and the remainder of the United States, the estimated annual rate of decline in adult smoking prevalence accelerated significantly from 1985 to 1990: to -1.22 percentage points per year (95% confidence interval [CI] = -1.51, -0.93) in California and to -0.93 percentage points per year (95% CI = -1.13, -0.73) in the remainder of the nation. The rate of decline slowed significantly from 1990 to 1994: to -0.39 percentage points per year (95% CI = -0.76, -0.03) in California and to -0.05 percentage points per year (95% CI = -0.34, 0.24) in the remainder of the United States. CONCLUSIONS: The presence of an aggressive tobacco control intervention has supported a significant decline in adult smoking prevalence in California from 1985 to 1990 and a slower but still significant decline from 1990 to 1994, a period in which there was no significant decline in the remainder of the nation. To restore nationwide progress in reducing smoking prevalence, other states should consider similar interventions.     

Effect of surfactant substitution on lung effluent phospholipids in respiratory distress syndrome: evaluation of surfactant phospholipid turnover, pool size, and the relationship to severity of respiratory failure

The turnover and pool size of surfactant has been studied in animals, but there is little similar information in humans. In the present investigation lung effluent phospholipids were studied in 29 small preterm infants with severe RDS. Thirteen were treated with mechanical ventilation, and 16 additionally received natural human surfactant. The first dose (60 mg surfactant/kg body wt) was given between 2 and 10 h of age, and the surfactant was given again if there was an insufficient response. Together 260 aspirates, recovered during routine suctioning of the airways, were analyzed for phospholipids. Phosphatidylglycerol, present only in exogenous surfactant, was used as a specific marker to estimate the apparent pool size and the half-life of surfactant phospholipid. In addition, the saturated phosphatidylcholine/sphingomyelin ratios were correlated with the ventilatory index (mean airway pressure X fractional inspiratory oxygen/arterial oxygen tension). There was a linear correlation between the ventilatory index and the saturated phosphatidylcholine/sphingomyelin (r approximately -0.70) but no consistent correlation between the ventilatory index and the amount of phospholipids in the aspirate. The saturated phosphatidylcholine/sphingomyelin ratio increased during the surfactant-induced remission of respiratory failure, decreased during the recovery. The control infants tended to have lower saturated phosphatidylcholine/sphingomyelin ratios during the first week than the surfactant-treated infants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combating infectious diseases through multivalent design

Many biological interactions are multivalent, linking two particles via many copies of the same ligand-receptor binding pair. Examples of multivalent binding range from cell-cell adhesion to the assembly of large protein complexes from constituent multimers to the binding of AB5 bacterial toxins at the cell surface. Multivalent interactions can be effectively mimicked, inhibited, or disrupted through the design of suitable multivalent ligands. We review here recent work on multivalent ligand design based on a number of different chemical scaffolds, with a specific emphasis on the use of structure-based ligand design to target multimeric bacterial toxins.     

Advantages of real-time spatial compound sonography of the musculoskeletal system versus conventional sonography

OBJECTIVE: Spatial compound sonography is a method that obtains sonographic information from several different angles of insonation and combines them to produce a single image. By reducing speckle and improving definition of tissue planes, this method can potentially improve image quality in musculoskeletal sonography. The purpose of our study was to compare real-time spatial compound sonography with conventional high-resolution musculoskeletal sonography. MATERIALS AND METHODS: Thirty-four patients underwent sonography of the musculoskeletal system for a variety of indications. All patients were evaluated using conventional high-resolution sonography and real-time spatial compound sonography performed with a 12-5-MHz multifrequency linear array transducer. Conventional images and compound images depicting the same musculoskeletal structure were obtained in pairs. A total of 118 images (59 image pairs) were randomly assorted and reviewed on a computer monitor by three experienced sonologists working independently. The reviewers were unaware of the type of images they were evaluating. Image quality was rated using a 5-point scale. The image parameters evaluated were definition of tissue planes, speckle, other noise, and image detail. RESULTS: Analysis of variance revealed that real-time spatial compound sonography significantly improved definition of soft-tissue planes, reduced speckle and other noise, and improved image detail when compared with conventional high-resolution sonography (p < 0.0001 for all evaluated parameters). CONCLUSION: Real-time spatial compound sonography significantly improved sonographic image quality in the musculoskeletal system when compared with conventional high-resolution sonography. Because musculoskeletal sonography is highly dependent on image quality and tissue-plane definition, spatial compound sonography represents an important development.     

Inactive free : total prostate specific antigen ratios in ejaculate from men with suspected and known prostate cancer, compared with young control men

OBJECTIVE: To measure free : total prostate specific antigen (PSA) ratios in ejaculate from men with suspected and known prostate cancer, and in young control men, to determine if this ratio might be useful in discriminating benign from malignant prostatic conditions. Patients, subjects and methods Forty-seven men with prostate cancer (positive biopsies), 52 men with suspected prostate cancer but who had negative biopsies and 28 young men (< 30 years old) and with no family history of cancer, provided either a single ejaculate specimen (total 59) or multiple specimens (total 193) on subsequent occasions. Free and total PSA were measured using appropriate assays. All specimens were diluted in a PSA-negative female serum pool. RESULTS: The median free : total PSA ratios were 0.76-0.81 among the patient groups and control men, and there was no statistical difference between the groups. These data presumably only reflect the inactive component of free PSA, given that any alpha2-macroglobulin or alpha1-antichymotrypsin in the assay serum diluent was likely to have bound the active free PSA component in these samples. Similar results were obtained from those providing single and multiple samples, suggesting that a single specimen is sufficient to reflect the seminal plasma free : total PSA ratio over that period. There was no relationship between seminal plasma free : total PSA ratio and age for the controls or the positive biopsy group, although there was a negative relationship (i.e. a decline with age) that almost reached significance in those with negative biopsies (P = 0.058, R2 = 0.07). CONCLUSIONS: This is the first report of free : total PSA ratios in the ejaculate of men with suspected and known prostate cancer compared with young control men. Although no significant changes were detected in the free : total PSA ratios in ejaculate, these results may be confounded by differences in ratios with age, as is the case for serum PSA or different molecular forms of PSA. Indeed, these data suggest that a large proportion of free PSA in seminal plasma may be inactive. Further studies are needed to determine the potential utility of measuring free : total PSA, or other candidate markers, in ejaculate to better discriminate benign from malignant prostate disease.     

Myelin thickenings in val 102/fs null mutation of MPZ gene

Painful sensory neuropathies consist of a wide range of neuropathies that can involve large as well as small nerve fibres. Even if most cases remain of unknown cause, some of them may be associated with an underlying disorder such as diabetes, HIV, infections, amyloidosis, and Sjogren's syndrome. Since in some cases an autoimmune mechanism has been postulated, we investigated a panel of circulating autoantibodies including anti‐gliadin (AGA), anti‐endomysium (EmA), anti‐transglutaminase (tTGA) and anti‐nuclear (ANA) antibodies in the sera of patients with unexplained painful sensory neuropathies in order to identify other potentially treatable disorders. We tested the sera of 10 patients (4M; 6F) previously investigated for other causes of neuropathies, including anti‐nerve, onconeural, anti‐extractable nuclear, anti‐neutrophil cytoplasmic, anti‐thyroglobulin (TgA) and anti‐peroxidase (TPOA) antibodies. We found the presence of AGA positivity in 4 patients (40%), ANA in 7 (70%) and AGA + ANA in 4 (40%), two of whom were negative for celiac disease by gastrointestinal biopsy. None of the patients had EmA positivity. Three (30%) had TgA and TPOA and none had anti‐nerve or onconeural antibodies. Whether the presence of circulating autoantibodies in patients with unexplained painful neuropathy reflects an autoimmune involvement which may be amenable to immune therapy and not only to symptomatic treatment remains to be established.