Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study.

Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m(-2) at first infusion followed by weekly 250 mg m(-2) combined with gemcitabine 1000 mg m(-2) as a 100 min infusion on day 1 and oxaliplatin 100 mg m(-2) as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31-78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in 24 of the evaluable 61 patients (39%). The addition of cetuximab to the combination of gemcitabine and oxaliplatin is well tolerated but does not increase response or survival in patients with metastatic pancreatic cancer.

An assessment of air toxics in Minnesota.

We used monitoring and modeling to assess the concentrations of air toxics in the state of Minnesota. Model-predicted concentrations for 148 hazardous air pollutants were from the U.S. Environmental Protection Agency Cumulative Exposure Project (1990 data). Monitoring data consisted of samples of volatile organic compounds, carbonyls, and particulate matter [Less than and equal to] 10 microm in aerodynamic diameter collected at 25 sites throughout the state for varying periods of time (up to 8 years; 1991-1998). Ten pollutants exceeded health benchmark values at one or more sites by modeling, monitoring, or both (including acrolein, arsenic, benzene, 1,3-butadiene, carbon tetrachloride, chromium, chloroform, ethylene dibromide, formaldehyde, and nickel). Polycyclic organic matter also exceeded the benzo[a]pyrene health benchmark value assumed to represent this class of pollutants. The highest modeled and monitored concentrations of most pollutants were near the center of the Minneapolis-St. Paul metropolitan area; however, many smaller cities throughout the state also had elevated concentrations. Where direct comparisons were possible, monitored values often tended to exceed model estimates. Upper-bound excess lifetime inhalation cancer risks were estimated to range from 2.7 [times] 10(-5) to 140. 9 [times] 10(-5) (modeling) and 4.7 [times] 10(-5) to 11.0 [times] 10(-5) (using a smaller set of monitored carcinogens). Screening noncancer hazard indices summed over all end points ranged from 0.2 to 58.1 (modeling) and 0.6 to 2.0 (with a smaller set of monitored pollutants). For common sets of pollutants, the concentrations, cancer risks, and noncancer hazard indices were comparable between model-based estimates and monitored values. The inhalation cancer risk was apportioned to mobile sources (54%), area sources (22%), point sources (12%), and background (12%). This study provides evidence that air toxics are a public health concern in Minnesota.

Identification of the endoplasmic reticulum targeting signal in vesicle-associated membrane proteins.

The vesicle-associated membrane proteins (Vamp(s)) function as soluble N-ethylmaleimide-sensitive factor attachment receptor proteins in the intracellular trafficking of vesicles. The membrane attachment of Vamps requires a carboxyl-terminal hydrophobic sequence termed an insertion sequence. Unlike other insertion sequence-containing proteins, targeting of the highly homologous Vamp1 and Vamp2 to the endoplasmic reticulum requires ATP and a membrane-bound receptor. To determine if this mechanism of targeting to the endoplasmic reticulum extends to other Vamps, we compared the membrane binding of Vamp1 and Vamp2 with the distantly related Vamp8. Similar to the other Vamps, Vamp8 requires both ATP and a membrane component to target to the endoplasmic reticulum. Furthermore, binding curves for the three Vamps overlap, suggesting a common receptor-mediated process. We identified a minimal endoplasmic reticulum targeting domain that is both necessary and sufficient to confer receptor-mediated, ATP-dependent, binding of a heterologous protein to microsomes. Surprisingly, this conserved sequence includes four positively charged amino acids spaced along an amphipathic sequence, which unlike the carboxyl-terminal targeting sequence in mitochondrial Vamp isoforms, is amino-terminal to the insertion sequence. Because Vamps do not bind to phospholipid vesicles, it is likely that these residues mediate an interaction with a protein, rather than bind to acidic phospholipids. Therefore, we suggest that a bipartite motif is required for the specific targeting and integration of Vamps into the endoplasmic reticulum with receptor-mediated recognition of specifically configured positive residues leading to the insertion of the hydrophobic tail into the membrane.

[Parenteral and enteral nutrition in palliative medicine]. / Parenterale und enterale Ernährung in der Palliativmedizin.

Artificial nutritional support does not alter the natural course in patients with malignant disease. The outcome of these patients is mainly determined by the type and stage of the underlying tumor. Progress of the underlying disease is often paralleled by malnutrition which in turn facilitates complications and may reduce survival and quality of life. Nutritional support can be applied to maintain body weight, immune function and quality of life. Enteral nutrition can be applied with a functioning gastrointestinal tract and has been proven to be superior compared to parenteral nutrition. Maintenance of intestinal mucosal function due to enteral substrate application prevents disruption of intestinal barrier function as well as the overgrowth of intestinal microorganisms. Using a step-by-step approach dietetic counselling in combination with augmented oral caloric intake should be the first measure. The next step to take is nutritional support by enteral tube feeding using formula diets. Parenteral feeding should only be used if other options to support caloric intake have failed.

Impact of obesity on neuropathic late complications in NIDDM.

OBJECTIVE: This cross-sectional study was aimed to investigate the isolated influence of obesity on peripheral sensorimotor and autonomic neuropathy in patients with long-term non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Ninety-one long-term NIDDM patients with a mean duration of 13.6 +/- 1.0 years and a mean age of 60.4 +/- 1.0 years were divided into two groups according to their body mass index (BMI) (lean with a BMI < 26.5: n = 41, age = 58.6 +/- 1.7 years, BMI = 23.7 +/- 0.3 kg/m2; and obese with a BMI > or = 26.5: n = 50, age = 61.9 +/- 1.2 years, BMI = 30.5 +/- 0.5 kg/m2). The two groups were not different in age, duration, gender, current parameters of glycemic control, number of smokers, cholesterol, triglycerides, and systolic and diastolic blood pressure. Neuropathic late complications were scrutinized by a standardized clinical examination that delivers a neuropathy score, pupillary autonomic neuropathy assessed by pupillometry, and cardiovascular autonomic neuropathy using a standardized test battery. RESULTS: One-way analysis of variance revealed that obese patients had poor results in the clinical neuropathy test (overall score in obese vs. lean: 71.1 +/- 2.9 vs. 80.6 +/- 3.0 points, 2P = 0.0266; 100 points were absolutely normal). This was particularly true for the discrimination perception (obese vs. lean: 67.0 +/- 4.0 vs. 81.7 +/- 3.3 points, 2P = 0.0073) and the reflex status (obese vs. lean: 57.4 +/- 4.0 vs. 71.8 +/- 4.3 points, 2P = 0.0164). Furthermore, obese patients had a poor result in the respiratory sinus arrhythmia (RSA) test, one of six autonomic function tests (RSA: obese vs. lean in average RSA percentile: 36.9 +/- 4.9 vs. 54.0 +/- 5.9%, 2P = 0.0264). CONCLUSIONS: Obesity influences sensorimotor and autonomic neuropathic late complications. The poor result in RSA in obesity may indicate an interrelation between pathogenesis of obesity and disorders of the respiratory and heart rhythm-generating control centers in the brain stem. Moreover, it could be due to intrathoracic fat deposits that alter lung mobility. Body mass control may be an important approach to reduce neuropathic complications. Beyond that, it seems necessary to control for body mass when comparing neuropathy in two groups of patients with NIDDM.