High-dose regimes containing etoposide, carboplatin and an oxazaphospharine can salvage 30 -40% of patients with relapsed or refractory male germ cell tumours (GCTs). The additional benefit of paclitaxel in such high-dose therapy has not been tested. Between March 1995 and November 2002, 36 male GCT patients were treated with Carbop-EC-T (paclitaxel 75 mg m À2 , etoposide 450 mg m À2 , carboplatin AUC 10 on days À7, À5 and À3 and cyclophosphamide 60 mg kg À1 on days À5 and À3) followed by peripheral blood stem cell infusion (day 0). The 1-year overall survival rate for all patients is 67% (median follow-up 29 months). For the 24 patients with cisplatin-sensitive disease, the 1-year overall and event-free survivals are 88 and 64%, respectively. For those with cisplatin refractory or absolutely refractory disease, the 1-year overall survival is 25%. In all, 12 patients relapsed at a median duration of 5 months, 11 of whom have died. There were also six treatment-related deaths, five associated with pneumonitis. Pulmonary toxicity has been reported with paclitaxel in other high-dose regimes. Since altering our protocol so that paclitaxel is infused over 24 h with steroid prophylaxis, only one of 18 patients (13 testicular GCTs and five other tumour types) has had a treatment-related death. Our results suggest that Carbop-EC-T may enable a greater proportion of patients with relapsed and refractory GCTs to enter long-term remission.

In man gymnemic acid is able to abolish the sweet taste. Also in man, the neural correlate of that effect is a disappearance of the response to sweet stimuli in the taste nerves, as indicated by the observations of Diamant et al. (1965). Although a variety of other mammals also show neural responses to sweet-tasting compounds, the corresponding effect of gymnemic acid has not been demonstrated. This study presents chorda tympani proper nerve recordings from the chimpanzee before and after gymnemic acid. On the chimpanzee tongue, application of 2 ml gymnemic acid (3-10 mg X ml-1 for 3-4 min) completely abolished the taste responses to 0.0035 M acesulfam-K, 0.0018 M aspartame, 0.015 M D-tryptophan, 0.02% monellin, and 0.02% thaumatin, reduced by 75% the response to 0.3 M sucrose, and by 50% that of 0.76 M xylitol. No decrease was recorded in the responses to 0.001 M quinine, 0.1 M NaCl, 0.02 and 0.04 M ascorbic acid, 0.02 and 0.04 M citric acid. The response to the sweeteners recovered with time and the recovery was complete or nearly complete after one and a half hours. It was also found that after application of 2 ml miraculin, 3 mg X ml-1 for 3 min to the tongue the neural response to acids was about 1.5 times as large as before. Gymnemic acid applied before miraculin prevented this enhancement and gymnemic acid after miraculin depressed the enhancement by miraculin of the response to citric and ascorbic acid.

3586 Background: CYT-6091 is the first tumor-targeted nanomedicine formulation designed to safely deliver an API that itself is not approved for systemic administration due to unacceptable toxicity. CYT-6091, consisting of tumor necrosis factor-α (TNF) covalently linked to pegylated colloidal gold nanoparticles, has been safely administered in preclinical models, demonstrating an increased T1/2 compared to native TNF, a documented trafficking of nanoparticles to tumor, and no hypotension, the known DLT for TNF. Methods: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients. Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 μg/m2 of TNF, up to 600 μg/m2. Vital signs were monitored and blood samples were drawn over 48 h. The primary endpoint of the study was to determine the MTD for CYT-6091. Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Twenty-nine patients were treated. Even at the lowest dose (50 μg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50–600 μg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen. T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 μg/m2, respectively (published T1/2 for native TNF is ∼27 minutes). In the 28 patients eligible for response assessment, there was 1 PR (100 μg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies. Conclusions: CYT-6091 is well tolerated at doses up to 600 μg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned. [Table: see text]

We present retrospectively our experience in the use of high-dose chemotherapy and haematopoietic stem cell support (HSCS) for refractory gestational trophoblastic neoplasia (GTN) Occasional patients with gestational trophoblastic neoplasia (GTN) will have an incomplete response to conventional chemotherapy or will relapse from remission. There have been several case reports of high-dose chemotherapy (HDC) and haematopoietic stem cell support (HSCS) in patients with refractory GTN (Collins et al, 1991;Giacalone et al, 1995;Lotz et al, 1995;Nagatoshi et al, 1996;Chou et al, 1997;van Besien et al, 1997;Aoki et al, 1999;Knox et al, 2002). The results have been mixed and no clear prognostic scoring system has been developed to identify which patients may benefit from HDC. MATERIALS AND METHODSIn all, 11 patients with refractory or relapsing GTN were treated with HDC and HSCS at three supraregional trophoblast centres (Charing Cross Hospital, London, UK, Weston Park Hospital, Sheffield, UK and Waikato Hospital, New Zealand)

3603 Background: CYT-6091, a nanotherapeutic manufactured by covalently linking tumor necrosis factor-a (TNF) onto the surface of 30 nm particles of pegylated colloidal gold, avoids uptake by the reticuloendothelial system (RES) and distributes primarily to solid tumors. In tumor bearing mice, CYT-6091 shows little to no uptake by the RES and increases intra-tumor TNF levels 10-fold. Electron micrographs show the accumulation of gold nanoparticles in tumors, with few particles in healthy tissue. In dogs with naturally occurring cancers and healthy rabbits, CYT-6091 caused fever but no hypotension, the known DLT for TNF. Methods: CYT-6091 is being tested in a phase I open label trial in solid tumor, advanced stage disease patients. Patients (n=3/dose), admitted to the NIH Clinical Center ICU, receive two IV injections of CYT-6091 on day 0 and 14. Doses start at 50 μg/m2 of TNF and increase by 50 μg/m2 increments to 300 μg/m2. Vital signs are monitored and blood samples are drawn over 48 hours. The primary endpoint of the study is to determine the MTD for CYT-6091. Secondary endpoints include PK, disease response (staged 45 days post treatment), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Seven patients have been treated to date. The three treated with the lowest dose (50 μg/m2) exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the seven patients treated with 50, 100 or 150 μg/m2 showed a DLT hypotensive response, and blood chemistries and urinalysis were not significantly different following treatment. PK estimates for the TNF T1/2, administered as CYT-6091, are 117, 145 and 127 minutes for 50, 100 and 150 μg/m2, respectively. Electron micrographs of tumor biopsies and adjacent healthy tissue show as much as a 10-fold increase in the number of gold nanoparticles in tumors from 5 of 6 patients compared to adjacent healthy tissue. Conclusion: These observations are the first definitive demonstration in man of the tumor targeting of a systemically administered, colloidal gold-based nanomedicine. No significant financial relationships to disclose.