Influence of cisplatin-use,age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: detailed symptom analysis of a randomised study comparing cisplatin-vindesine to gemcitabine

BACKGROUND: We previously reported that treatment of patients with symptomatic advanced non-small cell lung cancer with single agent Gemcitabine (GEM) resulted in a superior clinical-benefit response rate (RR) compared to cisplatin-based combination chemotherapy. We now report the detailed individual symptom control analysis, and the influence of cisplatin-use, age, performance status (PS) and duration of treatment. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m(2), days 1, 8 and 15) or cisplatin (100 mg/m(2), day 1) plus Vindesine (3 mg/m(2), days 1 and 15) (PV), both every 4 weeks. Scores of 9 symptoms were listed weekly by the patient on visual analogue scales. Improvement of a symptom was defined as 2 consecutive cycles of improvement over baseline. RESULTS: Baseline symptoms in the 169 patients were well balanced between the 2 arms (84 GEM, 85 PV). Both patients with objective response and disease stabilisation had clearly better symptom control than those with disease progression. Symptom control in both arms was similar for 'disease-specific' symptoms such as cough, dyspnea, pain or haemoptysis. Compared to PV, a significantly larger number of GEM-patients had better scores for 'constitutional' items such as anorexia (P=0.007), ability to carry on with daily activities (P=0.04) and overall impression of quality-of-life (P=0.008). Symptom control was very similar in younger (<65 years) versus older (>/=65 years) patients, and only slightly better in those with a Karnofsky PS >/=80% compared to those <80%. Most of the symptom improvement occurred in the first 3 cycles, with some further symptom improvement in the following cycles in the GEM-arm only. CONCLUSIONS: Both GEM and PV yield a symptom control rate much higher than expected by the objective tumour RR. GEM is equally effective in controlling 'disease-specific' symptoms, but superior in controlling 'constitutional' symptoms. Most of the symptom control was achieved during the first 3 cycles of treatment, with some further improvement thereafter in the GEM-arm only.     

Does the addition of glutamine to total parenteral nutrition have beneficial effect on the healing of colon anastomosis and bacterial translocation after preoperative radiotherapy?

Glutamine administration stimulates mucosal growth and preserves the morphology of the intestine. Theoretically, it could improve colonic anastomotic healing after radiotherapy (RT)-induced epithelial damage and mucosal atrophy induced by total parenteral nutrition (TPN). To investigate this issue, the rectosigmoid colon in male Wistar rats was irradiated to a total dose of 25 Gy. Five days after the end of RT, side-to-side anastomosis was constructed between the irradiated rectosigmoid and the nonirradiated caecum. Postoperatively, animals were divided in three groups: group I, normal diet orally; group II, TPN; group III, TPN enriched with 2% glutamine (Gln-TPN). All animals decreased in weight during RT and after surgery. Weight regain postoperatively was better in the orally fed animals in comparison with the parenterally fed animals (I vs. II and III; p < 0.01). Colonic anastomotic bursting pressure (BP) and bursting wall tension (BWT) were significantly less in group II in comparison with groups I and III (II vs. I and III; p < 0.01). BP and BWT were comparable in groups I and III. No significant differences were found between all the groups in gut bacterial translocation to the blood or to the mesenterical lymph nodes. Conclusively, Gln-TPN can play a role in counteracting the negative effect of food deprivation on the healing of irradiated colonic anastomoses. Postoperative Gln-TPN does not influence gut bacterial translocation in this rat model.     

Van Buchem disease: lifetime evolution of radioclinical features

Objective The purpose of this study was to evaluate the lifetime evolution of the radioclinical features in a large family with van Buchem disease.Design and patients The study population included 13 patients, ranging between 6 and 69 years. The evolution of the clinical features has been assessed by retrospective analysis of the clinical records of the patients. The age-related evolution of the cortical hyperostosis and defective modeling at the tubular bones was evaluated by morphometric analysis of hand films in 9 patients, compared with 9 control individuals. Progression of sclerosis of the craniofacial bones was evaluated by analysis of the skull radiographs of eleven van Buchem patients, taken at different age.Results and conclusions Radioclinical features, including sclerosis of the cranial and tubular bones and cranial nerve deficit, become more prominent in older patients. Defective modeling of tubular bones, cortical thickness and medullary width progress with age. Radioclinical abnormalities of van Buchem patients become more prominent in older patients, which suggests that the van Buchem gene is very actively involved in bone metabolism throughout life. Morphometric analysis of the plain films supports the hypothesis that the physiological function of the van Buchem gene is to inhibit bone formation and possibly to regulate bone remodeling.     

Micelle-Associated Protein in Epoetin Formulations: A Risk Factor for Immunogenicity?

PURPOSE: An upsurge of pure red cell aplasia (PRCA) cases associated with subcutaneous treatment with epoetin alpha has been reported. A formulation change introduced in 1998 is suspected to be the reason for the induction of antibodies that also neutralize the native protein. The aim of this study was to detect the mechanism by which the new formulation may induce these antibodies. METHODS: Formulations of epoetin were subjected to gel permeation chromatography with UV detection, and the fractions were analyzed by an immunoassay for the presence of epoetin. RESULTS: The chromatograms showed that Eprex/Erypo contained micelles of Tween 80. A minute amount of epoetin (0.008-0.033% of the total epoetin content) coeluted with the micelles, as evidenced by ELISA. When 0.03% (w/v) Tween 80, corresponding to the concentration in the formulation, was added to the elution medium, the percentage of epoetin eluting before the main peak was 0.68%. CONCLUSIONS: Eprex/Erypo contains micelle-associated epoetin, which may be a risk factor for the development of antibodies against epoetin.     

Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway

Synthetic alkyl-lysophospholipids (ALPs) represent a new class of anti-tumor agents that target cell membranes and induce apoptosis. However, the exact mechanisms by which ALPs exert these effects remain unclear. Here, we investigated in the epithelial carcinoma cell lines A431 and HeLa the effect of three clinically relevant ALPs [Et-18-OCH3 (Edelfosine), HePC (Miltefosine) and D-21266 (Perifosine)] on the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB survival pathway. We found that growth factor-induced Akt/PKB activation in these cells is dependent on PI3K and that all three ALPs inhibited this pathway in a dose-dependent manner. We further showed that inhibition of the PI3K-Akt/PKB pathway by wortmannin or ALPs is associated with activation of the pro-apoptotic SAPK/JNK pathway. Inhibition of the PI3K-Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis.     

Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial

OBJECTIVES: After transurethral resection, the local and systemic side effects of Bacillus Calmette-Guerin (BCG) instillations were assessed during a 6-week induction course followed by 3 weekly maintenance instillations at 3, 6, 12, 18, 24, 30 and 36 months to determine if BCG toxicity increases over time. METHODS: 487 patients who received BCG in a multicenter phase III trial were included. Side effects were divided into 5 different treatment periods: the first 6 weeks induction, months 3 and 6, month 12, the second year, and the third year. RESULTS: 99 (20.3%) patients stopped BCG due to side effects. 72 (14.8%) stopped due to local side effects, including 59 for BCG induced cystitis, 33 during the first 6 months. 46 (9.4%) stopped due to systemic side effects: 23 due to fever, 19 within 6 months, and 15 due to general malaise, 12 within 6 months. 68% who stopped due to side effects did so during the first 6 months. The percent stopping after 6 months due to local side effects does not increase and actually decreases for systemic side effects. CONCLUSIONS: The majority of local and systemic side effects are seen already during the induction and the first half-year of maintenance. During further maintenance BCG toxicity does not increase and instillations are generally well tolerated.     

Endotracheal colonization at birth is associated with a pathogen-dependent pro- and antiinflammatory cytokine response in ventilated preterm infants: a prospective cohort study

The possible association between mediators of inflammation such as cytokines and perinatal colonization of the respiratory tract remains unclear. This prospective cohort study evaluated endotracheal colonization in 141 ventilated preterm infants at birth. The relation with cytokine response in the airways and C-reactive protein (CRP) in umbilical blood was investigated. Of the 141 preterm infants enrolled in this study, 37 (26%) were colonized. In addition to traditional pathogens (61%), commensal species (26%) and Mycoplasmataceae (13%) were isolated. Both the pro-inflammatory cytokines IL-1 beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha as well as the antiinflammatory IL-10 are increased in colonized patients in a dose-dependent manner, with the strongest response in neonates colonized with Gram-negative organisms. There was no antimicrobial IL-12p70 response in colonized infants. Commensal flora is associated with the same inflammatory response as traditional pathogens. Although the umbilical cord blood CRP level was significantly higher in neonates with endotracheal colonization, it was highest in those colonized with Gram-negative organisms but still close to normal limits. Microorganisms in the endotracheal fluid of ventilated preterm infants are associated with a pathogen-specific and dose-dependent cytokine response in the airways and systemic CRP response.