High-dose carboplatin, thiotepa and cyclophosphamide (CTC) with peripheral blood stem cell support in the adjuvant therapy of high-risk breast cancer: a practical approach.

In 29 chemotherapy-naive patients with stage II-III breast cancer, peripheral blood stem cells (PBSCs) were mobilised following fluorouracil 500 mg m-2, epirubicin 90-120 mg m-2 and cyclophosphamide 500 mg m-2 (FEC) and granulocyte colony-stimulating factor (G-CSF; Filgrastim) 300 microgram s.c. daily. In all but one patient, mobilisation was successful, requiring three or fewer leucocytopheresis sessions in 26 patients; 28 patients subsequently underwent high-dose chemotherapy consisting of carboplatin 1600 mg m-2, thiotepa 480 mg m-2 and cyclophosphamide 6 g m-2 (CTC) followed by PBSC transplantation. Haemopoietic engraftment was rapid with a median time to neutrophils of 500 x 10(6) l(-1) of 9 days (range 8-10) in patients who received G-CSF after PBSC-transplantation; platelet transfusion independence was reached within a median of 10 days (range 7-16). Neutropenic fever occurred in 96% of patients. Gastrointestinal toxicity was substantial but reversible. Renal, neural or ototoxicity was not observed. Complications related to the central venous catheter were encountered in 64% of patients, with major vein thrombosis occurring in 18%. High-dose CTC-chemotherapy with PBSC-transplantation, harvested after mobilisation with FEC and G-CSF, is reasonably well tolerated without life-threatening toxicity and is a suitable high-dose strategy for the adjuvant treatment of breast cancer

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial

Background The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. Patients and methods Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF) ≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. Results Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C → T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H → T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). Conclusion PLD+C+H → T+H is feasible and results in lower early cardiotoxicity rates compared with A+C → T+

Do delays between diagnosis and surgery in resectable oesophageal cancer affect survival? a study based on West Midlands cancer registration data

This retrospective study investigates if delays between the diagnosis of cancer of the oesophagus and surgical resection influence long-term survival. Data held by the West Midlands Cancer Intelligence Unit on 800 patients who underwent oesophagectomy for a diagnosis of cancer of the oesophagus or oesophagogastric junction between 1995 and 2000 were reviewed. Six hundred and thirty-two patients treated with curative intention and who had not received neo-adjuvant treatment in the form of radio- or chemotherapy were included in the analysis. The time interval between histological diagnosis and surgical resection was stratified into four groups: less than 3, 3–6, 6–9 and more than 9 weeks. The Cox proportional hazard model was used to test for the independent effect of delays. The results showed no difference in long-term survival according to the delay between histological diagnosis and surgical resection. On multivariate analysis adverse prognostic factors were advanced age, incomplete resection and lymph node involvement. Patients with a longer delay had a higher rate of complete tumour resection suggesting that they were more appropriately selected for the surgical treatment approach. In conclusion we have found no evidence that shorter delays from the date of histological diagnosis to surgical resection are beneficial to long-term survival

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedule

Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis?

Negative effects on the progression of adenocarcinomas by hyperinsulinaemia and the insulin analogue glargine (A21Gly,B31Arg,B32Arg human insulin) have recently been suggested. Most actions of this insulin analogue have hitherto been explained by direct stimulation of growth potential of neoplastic cells and by its IGF-1 related properties. However, insulin-stimulated angiogenesis could be an additional factor involved in tumour progression and clinical outcomes associated with cancer. Five types of human adenocarcinoma (breast, colon, pancreas, lung and kidney) were evaluated for the presence of insulin receptors (IRs) on angiogenic structures. In an in vitro angiogenesis assay, various commercially available insulin compounds were evaluated for their potential to increase capillary-like tube formation of human microvascular endothelial cells (hMVEC). Insulin compounds used were: human insulin, insulin lispro (B28Lys,B29Pro human insulin), insulin glargine and insulin detemir (B29Lys[e-tetradecanoyl],desB30 human insulin). Insulin receptors were found to be strongly expressed on the endothelium of microvessels in all evaluated adenocarcinomas, in addition to variable expression on tumour cells. Low or no detectable expression of IRs was seen on microvessels in extratumoral stroma. Incubation with commercially available insulin compounds increased capillary-like tube formation of hMVEC in vitro. Our results suggest that all tested insulin compounds may stimulate tumour growth by enhancing local angiogenesis. Future studies need to confirm the association between insulin therapy in type 2 diabetes and tumour progressio

Met expression is an independent prognostic risk factor in patients with oesophageal adenocarcinoma

Oesophageal adenocarcinoma is an aggressive malignancy with propensity for early lymphatic and haematogenous dissemination. Since conventional TNM staging does not provide accurate prognostic information, novel molecular prognostic markers and potential therapeutic targets are subject of intense research. The aim of the present study was to study the prognostic significance of Met, the hepatic growth factor (HGF) receptor and a possible target for therapy in comparison to cyclooxygenase-2 (COX-2). Tumour sections from 145 consecutive patients undergoing intentionally curative surgery for oesophageal adenocarcinoma were immunohistochemically analysed for Met and COX-2 expression. Clinicopathological data were prospectively collected for all patients. Patients with high Met expression had significantly reduced overall and disease-specific 5-year survival rates (P⩽0.001 and P⩽0.001, respectively) and were more likely to develop distant metastases (P=0.002) and local recurrences (P=0.004) compared to patients with low Met expression. High COX-2 expression tended to be correlated with poor long-term survival but this did not reach statistical significance. Expression of Met was recognised as a significant and independent prognostic factor by stage-specific analysis and multivariate analysis (relative risk=2.3; 95% CI=1.3–4.1). These findings support the importance of Met in oesophageal adenocarcinoma and support the concept of Met tyrosine kinase inhibition as (neo-) adjuvant treatment

Non-solvolytic synthesis of aqueous soluble TiO2 nanoparticles and real-time dynamic measurements of the nanoparticle formation.

Highly aqueously dispersible (soluble) TiO2 nanoparticles are usually synthesized by a solution-based sol-gel (solvolysis/condensation) process, and no direct precipitation of titania has been reported. This paper proposes a new approach to synthesize stable TiO2 nanoparticles by a non-solvolytic method - direct liquid phase precipitation at room temperature. Ligand-capped TiO2 nanoparticles are more readily solubilized compared to uncapped TiO2 nanoparticles, and these capped materials show distinct optical absorbance/emission behaviors. The influence of ligands, way of reactant feeding, and post-treatment on the shape, size, crystalline structure, and surface chemistry of the TiO2 nanoparticles has been thoroughly investigated by the combined use of X-ray diffraction, transmission electron microscopy, UV-visible (UV-vis) spectroscopy, and photoluminescence (PL). It is found that all above variables have significant effects on the size, shape, and dispersivity of the final TiO2 nanoparticles. For the first time, real-time UV-vis spectroscopy and PL are used to dynamically detect the formation and growth of TiO2 nanoparticles in solution. These real-time measurements show that the precipitation process begins to nucleate after an initial inhibition period of about 1 h, thereafter a particle growth occurs and reaches the maximum point after 2 h. The synthesis reaction is essentially completed after 4 h.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Fatigue and physical disability in patients with multiple sclerosis: a structural equation modeling approach

Although fatigue is one of the most common and disabling symptoms in patients with multiple sclerosis (MS), its pathogenesis is still poorly understood and it is difficult to treat. The aim of the current study was to test the assumptions of a cognitive-behavioral model that explains fatigue and physical disability in MS patients, by comparing this approach with a more traditional biomedical approach. Structural equation modeling was applied to a sample of 262 MS patients. Neither the cognitive-behavioral, nor the biomedical model showed an adequate fit of our data. The modification indices supported an integration of both models, which showed a better fit than those of the separate models. This final model, is notable for at least three features: (1) fatigue is associated with depression and physical disability, (2) physical disability is associated with disease severity and fatigue-related fear and avoidance behavior, and (3) catastrophic interpretations about fatigue, fueled by depression, mediated the relationship between fatigue and fatigue-related fear and avoidance behavior. Our results suggest that an integrated approach, including the modification of catastrophic thoughts about fatigue, would be beneficial in the treatment of fatigue in MS patients