Retrospective study of management of uterine sarcomas at Oxford 1990-1998: role of adjuvant treatment

We report a retrospective study of 47 consecutive patients with uterine sarcoma treated at the Churchill Hospital in Oxford between 1990-1998. The mainstay of treatment was surgery with adjuvant chemotherapy and radiotherapy reserved for selected patients with early stage disease. Overall 1 and 2 year survival was 49% and 30% respectively compared with 73% and 55% in the group who received adjuvant chemotherapy/radiotherapy. Median survival was 11 months for the group as a whole compared to 32.9 months in the adjuvant therapy group. This is a retrospective review with small numbers and considerable selection bias, however, given the poor survival of patients with this disease, adjuvant treatment should be considered in future trials of patients with uterine sarcoma.     

Phase II study of the oxygen saturation curve left shifting agent BW12C in combination with the hypoxia activated drug mitomycin C in advanced colorectal cancer

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg(-1) over 1 h, followed by a maintenance infusion of 4 mg kg(-1) h(-1) for 5 h. MMC 6 mg m(-2) was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1-4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities--nausea/vomiting and vein pain--were mild and did not exceed CTC grade 2. Liver 31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity.     

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein α₁-acid glycoprotein (AAG), which may limit tissue availability. In this phase I–II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. Methods: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m² i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 μM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 μM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo. Received: 7 July 1999 / Accepted: 15 November 1999     

Hb Leiden-beta (0) thalassemia in a Chinese with severe hemolytic anemia

The first case of Hb Leiden (alpha2beta2 6 or 7 Glu---O)-beta (0) thalassemia in a young patient with chronic severe hemolytic anemia, which improved after splenectomy, is described. His parents were Chinese. The patient's blood showed no Hb A or normal beta chains when no blood transfusion was given. His mother was heterozygous for beta(0) thalassemia, and his father and brother had a trait for the unstable Hb Leiden. The Hb Leiden level of the father was 22.6% and that of the brother was 19.3%. It is probable that the abnormal hemoglobin in this Chinese family resulted from an independent gene mutation, unrelated to the one found in 2 Caucasian families reported earlier.     

The associations of hormone replacement therapy and preventive practices in minority women

OBJECTIVES: Minority women are less likely to use hormone replacement therapy (HRT), and the health characteristics associated with HRT use in this population are not well studied. We sought to examine the sociodemographic characteristics, health and preventive practices associated with HRT use among minority women. DESIGN: Survey SETTING: Inpatient and outpatient units of a teaching hospital. PARTICIPANTS: A convenience sample of 333 minority women aged 50 and above. VARIABLES: HRT use, demographic and lifestyle characteristics, and selected preventive practices. RESULTS: 14% of the study population, all minority women were using HRT. Regular exercise (p=0.03), and good perceived health status (p=0.02) were significant predictors of HRT use. None of the cancer screening measures studied were associated with HRT use. CONCLUSIONS: Only a small proportion of minority women were using HRT. Regular exercise and perceived good health were significant predictors of HRT use.     

Spirituality and treatment choices by South and East Asian women with serious mental illness

The purpose of this qualitative study is to investigate how South and East Asian immigrant women who have diagnoses of serious mental illness make treatment choices in relation to spirituality and to explore how gender, cultural beliefs, and spirituality intersect with the process of choice. The findings reveal that the process of spiritual choice includes three interrelated phases: (1) identifying contributing factors, (2) exploring spiritual resources and strategies, and (3) living with the choices. Variations among health beliefs and health care decisions are explained and services that women see as being helpful are identified.     

A 4-methyl-substituted <Emphasis Type="Italic">meta</Emphasis>-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells

Purpose As a part of our efforts to develop a meta-iodobenzylguanidine (MIBG) analogue with improved characteristics for the diagnosis and treatment of neuroendocrine tumours, 3-[¹³¹I]iodo-4-methyl-benzylguanidine ([¹³¹I]MeIBG) has been developed. The purpose of this study was to evaluate [¹³¹I]MeIBG in vitro using the uptake-1 positive SK-N-SH neuroblastoma cell line and in vivo in normal mice and mice bearing human neuroblastoma xenografts.Methods The ability of SK-N-SH human neuroblastoma cells to retain [¹³¹I]MeIBG in vitro over a period of 4 days, in comparison to [¹²⁵I]MIBG, was determined by a paired-label assay. Paired-label biodistributions of [¹³¹I]MeIBG and [¹²⁵I]MIBG were performed in normal mice as well as in athymic mice bearing SK-N-SH and IMR-32 human neuroblastoma xenografts.Results Retention of [¹³¹I]MeIBG by SK-N-SH cells in vitro was increased by factors of 1.2, 1.5, 2.0, 2.5 and 3.1 compared with [¹²⁵I]MIBG at 8, 24, 48, 72 and 96 h, respectively. In normal mice, the uptake of [¹³¹I]MeIBG in the heart was similar to that of [¹²⁵I]MIBG at 1 and 4 h; in contrast, myocardial uptake of [¹³¹I]MeIBG was 1.6-fold higher than that of [¹²⁵I]MIBG (p<0.05) at 24 h. When mice were pre-treated with the uptake-1 inhibitor desipramine (DMI), the heart uptake of both tracers was reduced to about half that in untreated controls at 1 h post injection (p<0.05). The hepatic uptake of [¹³¹I]MeIBG was two- to threefold lower than that of [¹²⁵I]MIBG. On the other hand, blood levels of [¹³¹I]MeIBG were substantially higher (up to sixfold), especially at early time points. Uptake of [¹³¹I]MeIBG in heart and tumour at 1 h in the murine SK-N-SH model was specific and comparable to that of [¹²⁵I]MIBG. However, [¹³¹I]MeIBG uptake was 1.6- to 1.7-fold lower than that of [¹²⁵I]MIBG over 4–48 h. While the uptake of both tracers in IMR32 xenografts was similar, it was not uptake-1 mediated.Conclusion Introduction of a methyl group at the 4-position of MIBG seems to be advantageous in terms of higher tumour retention in vitro and lower hepatic uptake in vivo. However, the slower blood clearance of MeIBG may be problematic for some applications.     

Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-alpha

BACKGROUND: Salicylate was recently shown to provide protection against cisplatin nephrotoxicity in rats. We have demonstrated that enhanced tumor necrosis factor-alpha (TNF-alpha) production mediates, in part, cisplatin nephrotoxicity. The purpose of this study was to determine if the protective effects of salicylate were mediated through inhibition of TNF-alpha in vivo and to explore the mechanism of inhibition in vitro. METHODS: The effects of treatment with cisplatin alone and in combination with sodium salicylate in mice on renal function, histology, and gene expression were determined. The effects of cisplatin and salicylate on TNF-alpha expression, nuclear factor kappa B (NF-kappa B) activity, and apoptosis were determined in vitro using cultured murine proximal tubule cells. RESULTS: Salicylate significantly reduced both the functional and histologic evidence of cisplatin renal injury. Cisplatin increased the renal expression of TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule (ICAM)-1, heme oxygenase-1, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2). Treatment with sodium salicylate blunted the increase in TNF-alpha mRNA and also reduced serum TNF-alpha protein levels. Salicylate had little protective effect when administered with cisplatin to TNF-alpha-deficient mice. Cisplatin increased the degradation of I kappa B (I kappa B) in a time-dependent manner and also increased nuclear NF-kappa B binding activity. Salicylate inhibited I kappa B degradation and NF-kappa B binding activity in the presence of cisplatin. In addition, salicylate inhibited the cisplatin induced TNF-alpha mRNA increase in mouse proximal tubule epithelial (TKPT) cells. CONCLUSION: These results indicate that salicylate acts via inhibition of TNF-alpha production to reduce cisplatin nephrotoxicity. The inhibition of TNF-alpha production may be mediated via stabilization of I kappa B.