Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). This was a phase I dose escalation study of matuzumab at 400 and 800 mg weekly and 1200 mg every 3 weeks combined with ECX (epirubicin 50 mg m⁻², cisplatin 60 mg m⁻² on day 1 and capecitabine 1000 mg m⁻² daily). Patients were treated until disease progression, unacceptable toxicity or for a maximum of eight cycles. Twenty-one patients were treated with matuzumab at three different dose levels (DLs) combined with ECX. The main dose-limiting toxicity (DLT) was grade 3 lethargy at 1200 mg matuzumab every 3 weeks and thus 800 mg matuzumab weekly was the maximum-tolerated dose (MTD). Other common toxicities included rash, nausea, stomatitis and diarrhoea. Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab. Pharmacodynamic studies on skin biopsies demonstrated inhibition of the EGFR pathway. Objective response rates of 65% (95% confidence interval (CI): 43–82), disease stabilisation of 25% (95% CI: 11–47) and a disease control rate (CR+PR+SD) of 90% were achieved overall. The MTD of matuzumab in combination with ECX was 800 mg weekly, and at this DL it was well-tolerated and showed encouraging antitumour activity. At the doses evaluated in serial skin biopsies, matuzumab decreased phosphorylation of EGFR and MAPK, and increased phosphorylation of STAT-3.     

Testosterone implantation reduces the motor effects of cocaine

The abuse of anabolic-androgenic steroids noted in recent years has been correlated with an increased likelihood of abuse of other drugs, including cocaine. This research was designed to investigate whether manipulation of androgen levels would alter the unconditioned behavioral effects of cocaine. The influence of testosterone on the locomotor activating effect of oral cocaine was evaluated. Subjects were male gonadally intact and castrated Wistar rats, implanted s.c. with either placebo or 100mg testosterone 30-day pellets. Beginning 7 days after pellet implantation, each animal in the four subgroups randomly received 0, 20, 40 and 80mg/kg cocaine (once, each dose). Cocaine 80mg/kg significantly enhanced locomotor activity in all groups except the intact testosterone-treated group. Of the four groups, this subgroup would have the highest plasma level of testosterone. These data suggest that chronic exogenous androgen administration may reduce the behavioral effects of cocaine.     

Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience

Mycophenolate mofetil (MMF) is emerging as an effective agent for the treatment of both established rejection and primary rejection prophylaxis in solid-organ transplantation (Tx). However, little data is available on the use of MMF in the pediatric population. We therefore report on our experience with MMF in 21 pediatric heart transplant recipients. Data were obtained by retrospective chart review. Median age at time of review was 12.3 yr (range 11 months to 16.9 yr). Median age at Tx was 10.7 yr (range 55 days to 16.7 yr). MMF was started at a median of 4.3 months after Tx (range 1 day to 4.5 yr). At the time of MMF institution, all patients were concurrently on prednisone and azathioprine; 20 of these patients were also undergoing treatment with tacrolimus (median dose 0.18 mg/kg, range 0.03-0.64 mg/kg) and one with cyclo-sporin A (10 mg/kg). Azathioprine was discontinued at the time of commencing MMF. The average MMF dose was 40 +/- 14 mg/kg. The rationale for switching to MMF included rejection (International Society for Heart and Lung Transplantation [ISHLT] 3A/B), 66%; inability to wean steroids, 14%; ABO blood group donor-recipient mismatch, 10%; coronary artery disease (CAD), 5%; and side-effects of immuno-suppression, 5%. Of the patients switched for rejection, 93% demonstrated resolved or improving rejection. Both ABO donor-recipient mismatch patients were started on tacrolimus/MMF as primary therapy and had no significant episodes of rejection. Two patients had rejection classified as unchanged (one with CAD, one treated with addition of sirolimus prior to improvement). Corticosteroids were successfully discontinued in 28% of patients, and 20% are currently on a reduced dose. Fourteen per cent developed significant rejection while attempting to reduce the steroid dose. Steroid reduction has not yet been attempted in 38% of patients. The following side-effects were reported in 38% of the patients: diarrhea, 10%; gastrointestinal discomfort, 20%; and leukopenia, 20%. Dose reduction or temporary discontinuation was required in 63% of the patients who experienced side-effects (24% of the total number of patients). Opportunistic infections developed in 10% (cryptococcus, cytomegalovirus). Hence, MMF appears to be effective for treatment of rejection in the pediatric heart transplant population and has an acceptable side-effect profile. In addition, it may have a role in primary rejection prophylaxis and may facilitate a reduced steroid dosage or a steroid-free immunosuppression regimen.     

Effects of gender and marital status on somatic symptoms of patients attending a mind/body medicine clinic.

To clarify the mechanisms of gender-related mind/body relationships, the authors analyzed the characteristics of 1,132 outpatients (848 women and 284 men) attending a mind/body medicine clinic. At entry in the program, the patients completed the Medical Symptom Checklist, Symptom Checklist-90 revised (SCL-90R), and Stress Perception Scale. Women reported 9 out of 12 symptoms (fatigue, insomnia, headache, back pain, joint or limb pain, palpitations, constipation, nausea, and dizziness) more frequently than the men did. Being a woman was a predictor of the total number of somatic symptoms endorsed. SCL-90R somatization scores were significantly higher in nonmarried women than in married women. Perceived stress ratings of family and health were higher in women than in men, despite the lower degree of perceived stress concerning work. Women, especially nonmarried women, were more likely to report somatic discomfort. Gender appears to be an important factor in relation to the report of somatic symptoms in stress-related conditions.     

Quinupristin-dalfopristin-resistant Enterococcus faecium on chicken and in human stool specimens

BACKGROUND: The combination of the streptogramins quinupristin and dalfopristin was approved in the United States in late 1999 for the treatment of vancomycin-resistant Enterococcus faecium infections. Since 1974, another streptogramin, virginiamycin, has been used at subtherapeutic concentrations to promote the growth of farm animals, including chickens. METHODS: To determine the frequency of quinupristin-dalfopristin-resistant E. faecium, we used selective medium to culture samples from chickens purchased in supermarkets in Georgia, Maryland, Minnesota, and Oregon and stool samples from outpatients. RESULTS: Between July 1998 and June 1999, samples from 407 chickens from 26 stores in four states were cultured, as were 334 stool samples from outpatients. Quinupristin-dalfopristin-resistant E. faecium was isolated from 237 chicken carcasses and 3 stool specimens. The resistant isolates from stool had low-level resistance (minimal inhibitory concentration [MIC], 4 microg per milliliter; resistance was defined as a MIC of at least 4 microg per milliliter). The resistant isolates from chickens in general had higher levels of resistance (MICs ranging from 4 to 32 microg per milliliter; MIC required to inhibit 50 percent of isolates, 8 microg per milliliter). CONCLUSIONS: Quinupristin-dalfopristin-resistant E. faecium contaminates a large proportion of chickens sold in U.S. supermarkets. However, the low prevalence and low level of resistance of these strains in human stool specimens suggest that the use of virginiamycin in animals has not yet had a substantial influence. Foodborne dissemination of resistance may increase, however, as the clinical use of quinupristin-dalfopristin increases.     

Some characteristics of the community practice of pathology in the United States. National Manpower Survey of 1987

An evaluation of 629 pathologists engaged in community hospital and private laboratory practice and representing 601 pathology practices of varying size shows surprising uniformity in the distribution of professional effort. On average, pathologists in community practice distribute their effort as follows: surgical pathology, 34.6%; autopsy pathology, 6.7%; cytology, 8.8%; clinical pathology, 18.0%; teaching, 6.0%; research and development, 2.3%; laboratory administration, 17.5%; hospital administration, 2.9%; and other, 3.2%. The average community pathologist is male, 52 years of age, and a graduate of an American medical school (60%). When surveyed in 1986, community pathologists worked an average of 50 hours per week and retired at an average age of 62 years.