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Background: The aim of this study was to evaluate the effect on the number of performed biopsies and costs associated with implementing positron emission tomography (PET) and computed tomography (PET/CT) with 16α-[(18)F]fluoro-17β-oestradiol (FES) or 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) as an upfront imaging test for diagnosing metastatic breast cancer (MBC) in comparison with the standard work-up in oestrogen receptor-positive women with symptoms., Methods: A published computer simulation model was adapted and validated. Three follow-up strategies were evaluated in a simulated cohort of women with primary breast cancer over a 5-year-time horizon: (1) the standard work-up, (2) upfront FES-PET/CT and (3) upfront FDG-PET/CT. The main outcome was the number of avoided biopsies to assess MBC. The costs for all three strategies were calculated based on the number of imaging tests and biopsies. The incremental cost-effectiveness ratio (ICER) to avoid a biopsy was calculated only based on the costs of initial imaging and staging tests., Results: The FES-PET/CT strategy decreased the number of biopsies by 39 ± 9%, while upfront FDG-PET/CT increased the number of biopsies by 38 ± 15% when compared with the standard work-up. Both PET/CT strategies reduced the number of imaging tests and false positives when compared with the standard work-up. The number of false negatives decreased only in the FES-PET/CT strategy. The ICER in the FES-PET/CT strategy per avoided biopsy was 12.1 ± 3.4 thousand Euro. In the FDG-PET/CT strategy, the costs were higher and there were no avoided biopsies as compared with the standard work-up, hence this was an inferior strategy in terms of cost effectiveness., Conclusions: The number of performed biopsies was lower in the FES-PET/CT strategy at an ICER of 12.1 ± 3.4 thousand Euro per biopsy avoided, whereas the application of the FDG-PET/CT did not reduce the number of biopsies and was more expensive. Whether the FES-PET/CT strategy has additional benefits for patients in terms of therapy management has to be evaluated in clinical studies.

Background: Isolated groups, such as first generation non-Western immigrants, are at risk for suboptimal utilisation of the health care system resulting in a worse outcome., Methods: From 1989 to 2007, all patients with stomach cancer were selected from the Comprehensive Cancer Centre North-East cancer registry. Associations between country of birth and patient, tumour and treatment characteristics were determined using χ(2) analysis. Relative survival analysis was used to estimate relative excess risk of dying according to country of birth (non-Western vs Western)., Results: After adjusting for confounding factors (patient, tumour and treatment related), the risk of dying was lower for first generation non-Western immigrants (relative excess risk 0.55, 95% confidence interval 0.43-0.70) compared with Western patients., Conclusion: Although the better survival of first generation non-Western immigrants with stomach cancer remains unexplained, it argues against accessibility problems within the Dutch health care system.

Favourable pharmacokinetics of the prodrug are essential for successful HSVtk/ganciclovir (GCV) suicide gene therapy. [(18)F]FHPG PET might be a suitable technique to assess the pharmacokinetics of the prodrug GCV noninvasively, provided that [(18)F]FHPG mimics the behaviour of GCV. Since membrane transport is an important aspect of the pharmacokinetics of the prodrug, we investigated the cellular uptake mechanism of [(18)F]FHPG in an HSVtk expressing C6 rat glioma cell line and in tumour-bearing rats. The nucleoside transport inhibitors dipyridamol, NBMPR and 2-chloroadenosine did not significantly affect the [(18)F]FHPG uptake in vitro. Thymidine and uridine significantly decreased [(18)F]FHPG uptake by 84 and 58%, respectively, but an enzyme assay revealed that this decline was due to inhibition of the HSVtk enzyme rather than membrane transport. Nucleobase transport inhibitors, thymine and adenine, caused a 58 and 55% decline in tracer uptake, respectively. In vivo, the ratio of [(18)F]FHPG uptake in C6tk and C6 tumours decreased from 3.0+/-0.5 to 1.0+/-0.2 after infusion of adenine. Thus, in our tumour model, [(18)F]FHPG transport exclusively occurred via purine nucleobase transport. In this respect, FHPG does not resemble GCV, which is predominantly taken up via the nucleoside transporter, but rather acyclovir, which is also taken up via the purine nucleobase carrier.

The specificity and sensitivity of the nested reverse transcriptase polymerase chain reaction (RT-PCR) on tyrosinase was studied, for the detection of micrometastases of malignant melanoma. The specificity was assessed in the blood of six healthy donors, four patients with non-melanoma cancers of which one patient was treated with granulocyte-colony stimulating factor. Lymph nodes of nine patients without malignant melanoma were tested and four cell lines of various other tumours. Six of the nine non-melanoma lymph nodes were positive in this assay. The sensitivity was tested in a spike experiment in vitro, using a melanoma cell line. The detection limit was ten melanoma cells per 10(7) peripheral blood lymphocytes.

Radio- and chemotherapy for the treatment of malignancies are often associated with significant toxicity. One approach to reduce the toxicity is the concomitant treatment with chemoprotective agents. This article reviews two sulfhydryl compounds, namely the agent WR-2721 (amifostine), a compound recently registered for use in human in many countries, and the natural occurring compound glutathione (GSH). GSH is not registered as a chemoprotective agent. WR-2721 is an aminothiol prodrug and has to be converted to the active compound WR-1065 by membrane-bound alkaline phosphatase. WR-1065 and GSH both act as naturally occurring thiols. No protective effect on the tumour has been found when these compounds are administered intravenously. There is even in vitro evidence for an increased anti-tumour effect with mafosfamide after pretreatment with WR-2721, and in vivo after treatment with carboplatin and paclitaxel. Randomized clinical studies have shown that WR-2721 and GSH decrease cisplatin-induced nephrotoxicity and that WR-2721 reduces radiation radiotherapy-induced toxicity. Side-effects associated with WR-2721 are nausea, vomiting and hypotension, GSH has no side-effects. An exact role of WR-2721 and GSH as chemoprotectors is not yet completely clear. Future studies should examine the protective effect of these drugs on mucositis, cardiac toxicity, neuro- and ototoxicity, the development of secondary neoplasms and their effect on quality of life.

The role of glutathione (GSH) in resistance to cisplatin (CDDP) was studied in a human small cell lung carcinoma cell line (GLC4) and a CDDP-resistant subline (GLC4-CDDP). In addition to studying the steady state of GSH, the kinetics of this defence system were also studied via the monitoring of the GSH status of the cells under continuous pressure of CDDP. GLC4-CDDP maintained its elevated GSH level whereas GLC4 (under pressure of CDDP) quickly synthesised GSH to about twice its initial level, corresponding with 80% of the GSH level of GLC4-CDDP. D,L-buthionine-S,R-sulphoximine (BSO) was used to analyse the role of GSH in resistance to CDDP. Pretreatment with BSO (48 h, 50 microM, GSH not detectable) increased the CDDP-induced cytotoxicity 2.8-fold in GLC4-CDDP and 1.7-fold in GLC4. In GLC4 no changes in the amount of platinum (Pt) bound to DNA could be observed after GSH depletion. Changes in formation of interstrand cross-links or the main Pt-containing intrastrand cross-link in digested DNA, the Pt-GG adduct, were also not observed. In GSH depleted GLC4-CDDP cells, an increase in the amount of Pt bound to DNA and in the Pt-GG adduct was observed. Pretreatment with BSO substantially reduced the repair of Pt bound to DNA in both cell lines. We conclude that an increased GSH level and GSH synthesis capacity were demonstrated in CDDP resistant cells. The observations after BSO treatment suggest two roles for GSH in CDDP resistance, namely that of a cytosolic elimination resulting in less DNA platination and a nuclear effect on the formation and repair of DNA platinum adducts.

In DNA digested samples of CDDP sensitive (GLC4) and an 11-fold resistant (GLC4-CDDP) hSCLC line, the CDDP induced DNA adducts Pt-GG (Pt-(NH3)2d (pGpG], Pt-AG (Pt-(NH3)2d (pApG], G-Pt-G (Pt-(NH3)2d (GMP)2) and Pt-GMP (Pt-(NH3)3d GMP), were measured with polyclonal antibodies. The total amount of platinum (Pt) bound to DNA was also measured but with the help of atomic absorption spectroscopy (AAS). An increased net formation in GLC4 compared with GLC4-CDDP is found for the total Pt bound to DNA, Pt-GG and Pt-AG adducts after a 2 h 100 microM CDDP treatment. No significant difference is detected in the net formation of the Pt-GMP and G-Pt-G adducts. A slow Pt-AG adduct formation, with a maximum reached 10 h after CDDP composition, is found for both cell lines. In the 22 h period after the 2 h 100 microM CDDP treatment, a significant removal in GLC4 is measured for the Pt-GG, Pt-AG and the Pt-GMP adducts. For GLC4-CDDP a significant removal is detected in the total Pt bound to DNA, the Pt-AG and the Pt-GMP adducts. The removal of the total Pt bound to DNA in GLC4-CDDP cannot be explained by an adduct measured with the immunochemical method. In conclusion, no evidence is found that CDDP resistance is based upon the repair of the Pt-GG, Pt-AG, G-Pt-G and Pt-GMP adducts.