A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258). EXPERIMENTAL DESIGN: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule. RESULTS: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels. CONCLUSIONS: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.     

Persistent protein losing enteropathy in post measles diarrhoea.

Faecal alpha 1 antitrypsin was measured in two groups of children with diarrhoea aged 6 months to 6 years during the acute and recovery stages of the illness. Group 1 comprised 19 children with a history of measles in the two weeks preceding admission to hospital. In this group there were six cases of Shigella species, six enterotoxigenic Escherichia coli, and five rotavirus, and two did not yield an aetiologic agent. Group 2 comprised 15 children with diarrhoea only. In this group there were five cases of Shigella species, five enterotoxigenic Escherichia coli, and five rotavirus. Children with rotavirus diarrhoea belonging to both groups showed a transient high faecal clearance of alpha 1 antitrypsin during the acute stage. Post measles cases of diarrhoea showed significantly higher faecal clearance of alpha 1 antitrypsin than group 2 subjects in both the acute and recovery stages. The faecal clearance of alpha 1 antitrypsin in both groups was significantly higher during the acute stage compared with the recovery stage. Highest faecal clearances of alpha 1 antitrypsin were observed in children with post measles shigellosis in the acute stage and they also had persistently raised concentrations, thus suggesting prolonged protein losing enteropathy.     

Antioxidant effects of 1,5-anhydro-D-fructose, a new natural sugar, in vitro

The antioxidant effects of 1,5-anhydro-D-fructose (1,5-AF), a unique anhydrohexulose, were studied in 1,1-diphenyl-2-picrylhydrazyl (DPPH) solution, in human cells along with lipid peroxidation of low-density lipoprotein (LDL). We have confirmed that 1,5-AF scavenges DPPH radicals directly in solution and inhibits the formation of hydrogen peroxide and superoxide anion, typical reactive oxygen species (ROS), induced by phorbol myristate acetate (PMA) in a dose-dependent manner in THP-1 cells. We also observed the dose-dependent antioxidant effects of 1,5-AF on copper-mediated LDL oxidation. These findings suggest that 1,5-AF might play a role in reducing the risk of atherosclerosis and may help prevent coronary heart disease.     

Stimulation of the mitogen-activated protein kinase pathway antagonizes TRAIL-induced apoptosis downstream of BID cleavage in human breast cancer MCF-7 cells

We studied the role of the mitogen-activated protein kinase (MAPK) pathway in the regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in breast tumor MCF-7 cells. We found that addition of a protein kinase C (PKC) activator to MCF-7 cultures prevented TRAIL-induced apoptosis, by inhibiting a step downstream of both caspase-8 activation and BID cleavage. TRAIL-induced translocation of Bax from cytosol to mitochondria, release of cytochrome c from mitochondria and activation of caspase-9 were all inhibited by PKC activation. PKC-mediated prevention of mitochondrial apoptotic events and apoptosis was found to be dependent on the MAPK pathway. Since TRAIL is a ligand of potential use in antineoplastic clinical trials, our findings may provide relevant information in cancer therapy.     

Immune response of Bangladeshi children with acute diarrhea who subsequently have persistent diarrhea

BACKGROUND: Because altered immune responses may be a risk factor for persistent diarrhea, various aspects of the immune response were examined to elucidate the underlying immune mechanisms that may be involved in the development of persistent diarrhea. METHODS: Children (7-12 months of age) with watery diarrhea for 6 to 8 days from the Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B), were enrolled. Children were classified as having acute diarrhea (AD) or persistent diarrhea (PD) if diarrhea resolved within 14 days or persisted for more than 14 days, respectively. Uninfected control children (n = 13), from the Nutrition Follow-Up Unit of ICDDR,B were also enrolled. Of the 123 children with diarrhea who were enrolled, 85 had AD and 38 had PD. Comparisons were performed for clinical features, nutritional status (weight for age, plasma transferrin, and serum albumin levels), and immune responses: neutrophil function; peripheral blood mononuclear cell function, delayed-type hypersensitivity (DTH) responses, plasma levels of immunoglobulins, tumor necrosis factor-alpha, and interferon-gamma. Univariate analyses were conducted to assess differences among the three groups of children and between children with AD and PD. Logistic regression was performed to determine risk factors for PD. RESULTS: There were no differences in clinical features and nutritional status among the groups of children studied. More children in whom PD developed had a negative DTH response to tuberculin than those with AD (P = 0.021). Also, a negative DTH response to tuberculin was a significant risk factor for PD (odds ratio [OR] = 3.8, 95% confidence interval [CI] = 1.5-9.9). CONCLUSIONS: Children with acute diarrhea with a negative DTH response to tuberculin are more likely to have development of persistent diarrhea.     

Errors in surgery

Making errors is part of normal human behaviour. However when errors have significant consequences or occur in high risk industries they become of paramount importance. There has been little research in why and how errors occur in the healthcare industry. Errors occur throughout healthcare, but in particular, surgery as a high risk speciality. Surgery is a dynamic speciality with a milieu of possible mishaps waiting to happen. So to understand and prevent errors in surgery we must explore this intricate multi-cogwheel process. This article will summarise the epidemiology of surgical errors, factors which influence them in the patient pathway, explain concepts and models of why errors occur, technical skill error assessment and possible strategies to prevent or reduce surgical errors. Practicing surgery in the new millennium will embrace new innovations, medications, technologies, equipment, operations, all which aim to improve the treatment and care of patients. However we must remember with this constant evolution in healthcare the error goalposts are forever moving, so we must be vigilant not to take our eye off the error ball.     

Technical skills errors in laparoscopic cholecystectomy by expert surgeons

Background: Performing laparoscopic surgery involves a complex cascade of cognitive skills, which may inherently have a constant technical error rate. We assess generic and specific minor and major error rates in laparoscopic cholecystectomies (LCs) performed by consultant surgeons.Methods: Checklists of generic (11) and specific technical minor (six) and major events (eight) were devised for LCs. Two experienced surgeons assessed each full-length operation blindly and independently.Results: A total of 37 LCs were performed by eight consultants. There were no major intraoperative or postoperative complications. Mean inter-rater reliability was κ = 0.91 (range 0.80–0.98) for each of the error categories. Error rates were generic (27/407) 6.6%, minor (59/222) 26.6%, and major (8/296) 2.7%, respectively. There was a significant statistical difference between the minor error group and the other groups, p ≤ 0.05.Conclusions: Performing laparoscopic surgery may always have a background technical error rate. Our present study demonstrates a migration of surgical technical errors in expert laparoscopic surgeons. The surgeons migrate technically when they execute a high rate of procedure-specific minor errors. However, when it comes to the major fundamental aspects of the operation, they dynamically adapt and migrate away from performing major technical errors. We aim to continue the study to increase cases, assess trainees as well, and also explore other factors that may affect the surgeon when executing surgical technical tasks.Presented at the 12^th annual meeting of the European Association for Endoscopic Surgery, Barcelona, Spain, June 2004     

Early and late complications following laparoscopic adjustable gastric banding

There is limited U.S. data on short- and long-term complications of laparoscopic adjustable gastric banding (LAGB) as a treatment option for morbid obesity. Hereafter, we present our experience with the first 154 consecutive LAGBs performed at Loyola University Medical Center. Inpatient and outpatient charts were reviewed retrospectively for all patients undergoing LAGB between November 2001 and February 2003 for perioperative morbidity and mortality and repeat operations. Thirty-seven men (24%) and 117 women (76%) underwent LAGB in a 16-month period. There was one (0.6%) death from postoperative myocardial infarction (MI) and one (0.6%) pulmonary embolism. Six (3.9%) patients required readmission to the hospital for dehydration. During a mean follow-up of 33 weeks (range, 4-69 weeks), 14 (9%) patients required repeat operations. There were five (3.2%) band slippages and one (0.6%) gastric erosion. Three bands were removed laparoscopically. Three slippages were revised laparoscopically. One patient underwent laparoscopic cholecystectomy. Seven patients (4.5%) required port revisions for catheter disconnection (4), leak at port site (2), or flipped port (1). LAGB is a safe operative approach for the management of morbid obesity. The incidence of postoperative complications can be minimal with application of a standardized technique. LAGB should be strongly considered for morbidly obese patients who have failed nonoperative management.     

Systems approaches to surgical quality and safety: from concept to measurement

OBJECTIVE: This approach provides the basis of our research program, which aims to expand operative assessment beyond patient factors and the technical skills of the surgeon; to extend assessment of surgical skills beyond bench models to the operating theater; to provide a basis for assessing interventions; and to provide a deeper understanding of surgical outcomes. SUMMARY BACKGROUND DATA: Research into surgical outcomes has primarily focused on the role of patient pathophysiological risk factors and on the skills of the individual surgeon. However, this approach neglects a wide range of factors that have been found to be of important in achieving safe, high-quality performance in other high-risk environments. The outcome of surgery is also dependent on the quality of care received throughout the patient's stay in hospital and the performance of a considerable number of health professionals, all of whom are influenced by the environment in which they work. METHODS: Drawing on the wider literature on safety and quality in healthcare, and recent papers on surgery, this article argues for a much wider assessment of factors that may be relevant to surgical outcome. In particular, we suggest the development of an "operation profile" to capture all the salient features of a surgical operation, including such factors as equipment design and use, communication, team coordination, factors affecting individual performance, and the working environment. Methods of assessing such factors are outlined, and ethical issues and other potential concerns are discussed.