A strategy to prevent substance abuse in an academic anesthesiology department

Substance abuse is the most serious occupational safety issue associated with the practice of anesthesiology, with an incidence as high as 1% per year of training. The Cleveland Clinic's Anesthesiology Institute approached the process from the perspective of active prevention, including specific mandatory education programs for all department personnel on a recurring basis, strengthened procedures for the detection and prevention of diversion of controlled substances, enhanced skill building for detection of impairment, and implemented a multi-faceted drug testing program, including random and “for cause” urine screens, for prevention and early detection of abused anesthetic drugs and other substances of abuse. After 18 months of preparation, a Substance Abuse Prevention Protocol was created, which has been fully implemented as of September 1, 2007.     

Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma

PURPOSE: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.     

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.     

The genetics of cutaneous melanoma

Although germline mutations in CDKN2A are present in approximately 25% of large multicase melanoma families, germline mutations are much rarer in the smaller melanoma families that make up most individuals reporting a family history of this disease. In addition, only three families worldwide have been reported with germline mutations in a gene other than CDKN2A (i.e., CDK4). Accordingly, current genomewide scans underway at the National Human Genome Research Institute hope to reveal linkage to one or more chromosomal regions, and ultimately lead to the identification of novel genes involved in melanoma predisposition. Both CDKN2A and PTEN have been identified as genes involved in sporadic melanoma development; however, mutations are more common in cell lines than uncultured tumors. A combination of cytogenetic, molecular, and functional studies suggests that additional genes involved in melanoma development are located to chromosomal regions 1p, 6q, 7p, 11q, and possibly also 9p and 10q. With the near completion of the human genome sequencing effort, combined with the advent of high throughput mutation analyses and new techniques including cDNA and tissue microarrays, the identification and characterization of additional genes involved in melanoma pathogenesis seem likely in the near future.     

The impact on colorectal cancer survival of cases registered by 'death certificate only': implications for national survival rates.

This paper describes the effect of including death certificate only (DCO) registrations on 5 year relative survival rates for colorectal cancer in four district health authorities (DHAs) in south-east England. A retrospective case note study was set up to examine all cases of colorectal cancer listed in the Thames Cancer Registry (TCR) as having been diagnosed in 1983 and 1988 and resident in one of four districts, A, B, C and D. A total of 673 sets of cases notes were requested from all hospitals within the four districts, including 150 sets on DCO cases. Of 465 (69%) sets of case notes retrieved, 378 (72.3%) were non-DCO cases. Of these, 14 were excluded from survival analysis because of missing dates of diagnosis or death in the notes. Eighty-seven (58.0%) sets of case notes were retrieved on DCO registrations, of which seven were excluded because no date of diagnosis was available in the notes. Retrieval rates on case note registrations varied by DHA of residence: 73.3% in DHA A, 96.6% in DHA B, 34.5% in DHA C and 79.2% in DHA D. The corresponding figures for DCO registrations were 63.5%, 69.0%, 7.4% and 76.2%. Cumulative relative 5 year survival rates by DHA of residence were calculated first for cases registered from case notes and then for all cases including those registered solely from a death certificate. The total number of cases used in the survival analysis was 444 (18% DCOs). In all four DHAs, 5 year survival decreased with the inclusion of DCO registrations: by 9.1% in district A (from 52.8 to 43.7), by 4.5% in district B (from 59.6 to 55.1), by 4.8% in district C (from 80.0 to 75.2) and by 7.6% in district D (from 31.4 to 23.8). The overall reduction in survival was 8.6%. The exclusion of death certificate only registrations from survival data is an important source of bias. Using TCR data, we compared DCO proportions for colorectal cancer with other sites. DCO proportions were shown to vary by tumour site and survival time. The DCO registration is an important quality measure of ascertainment and follow-up. OPCS should publish DCO proportions by registry area and cancer site. Registries should implement DCO monitoring as part of quality improvement programmes.     

Severe anti-C hemolytic disease of the newborn.

OBJECTIVE: Because of referral of a C-alloimmunized pregnant woman with a previous hydropic death whose fetus survived after four intraperitoneal transfusions, prevalence and severity of anti-C hemolytic disease of the newborn were investigated. STUDY DESIGN: The numbers of C- or Ce-alloimmunized pregnancies in Manitoban women and their outcome for the 28-year period ending Oct. 31, 1990, were reviewed. The literature relating to C or Ce alloimmunization from 1944 to 1990 was surveyed. RESULTS: In Manitoba for the period reviewed there were 120 pregnancies in 80 C- or Ce-alloimmunized women. Twenty-two ended in abortion and two in fetal death unrelated to anti-C or anti-Ce. Of the remaining 96, 33 fetuses of 32 pregnancies were affected but only eight (6.7%) required treatment after birth. None were severely affected. In the literature there are only three other reported deaths from C or Ce hemolytic disease; two of the three may have been the same patient. The prevalence of C or Ce alloimmunization reported in various series, including our own, ranged from 8.7 to 185 per 100,000 pregnancies. CONCLUSIONS: Because on rare occasions, C or Ce alloimmunization can cause severe hemolytic disease, criteria for investigative measures such as amniocentesis or cordocentesis do not differ from the criteria for instituting these measures in Rho (D)-alloimmunized pregnancies.     

Effect of artificial food colours on childhood behaviour.

We performed an objective evaluation of 39 children whose behaviour was observed by their parents to improve on an artificial food additive free diet and to deteriorate with dietary lapses. Only 19 children completed a double blind placebo controlled challenge study with artificial food colours. In these children food colours were shown to have an adverse effect on a daily Conners'' rating of behaviour, but most parents could not detect these changes. A pharmacological mechanism of food additive intolerance is proposed to explain these effects.     

Human peri-tumoral and lung fibroblasts produce paracrine motility factors for recently established human sarcoma cell strains

Paracrine motogenic cytokines secreted by normal cells can stimulate metastatic cell invasion. For example, human fibroblasts secrete hepatocyte growth factor/scatter factor (HGF/ SF), which stimulates paracrine migration of epithelial and certain carcinoma cells, and migration-stimulating factor (MSF), which stimulates autocrine migration of fibroblasts from certain breast carcinomas. We found that human peri-tumoral and lung fibroblasts secrete motility-stimulating activity for several recently established human sarcoma cell strains. Motility of lung metastasis-derived SYN-I sarcoma cells was preferentially stimulated by human lung and peri-tumoral fibroblast motility-stimulating factors (FMSFs). FMSFs were non-dialyzable, susceptible to trypsin and sensitive to dIthiothreitol. Cycloheximide inhibited accumulation of FMSF activity in conditioned medium; however, addition of cycloheximide to the migration assay did not significantly affect motility-stimulating activity. Purified HGF/SF, rabbit anti-hHGF and RT-PCR analysis of peri-tumoral and lung fibroblast HGF/SF mRNA expression indicated that FMSF activity was unrelated to HGF/SF. Partial purification of FMSF by gel exclusion chromatography revealed several peaks of activity, suggesting multiple FMSF molecules or complexes. Since human soft tissue sarcomas have a distinctive hematogenous metastatic pattern (predominantly lung), FMSF may play a role in this process independent of HGF/SF. © 1995 Wiley-Liss, Inc.