Summary:Marrow-ablative chemo-radiotherapy followed by hematopoietic stem cell rescue from an allogeneic source improves outcomes for children with high-risk acute leukemia. The first effective pre-transplant preparative regimens consisted of high-dose cyclophosphamide (CY) and total body irradiation (TBI). Subsequent attempts have been made to improve leukemia-free survival, by adding other chemotherapy agents to these agents. In previous clinical studies of total body irradiation, etoposide, cyclophosphamide (TBI-VP-16-Cy) in adult allogeneic bone marrow transplantation, there has been a high incidence of severe regimen-related toxicity. In this study, we investigated the safety and efficacy of this combination in 41 children who received TBI (12-14 Gy), VP-16 (30 mg/kg), and CY (60 mg/kg × 2) and then either matched sibling or alternative donor transplants for acute leukemia. There was only one case of fatal regimen-related toxicity. The estimated 3-year event-free survival for patients with early or intermediate stage disease was 68% (53-88%). The estimated event-free survival of patients with advanced disease was 17% (5-59%). TBI-VP16-CY is safe in pediatric transplantation, and it has good efficacy for transplant recipients with less advanced disease. outcomes for both adults and children by augmenting the anti-leukemic activity of this combination. Increasing the TBI dose led to decreased relapse rates, but this was offset by increased treatment-related mortality. 3 Alternatively, many investigators sought improved preparative regimen efficacy, by incorporating supplemental chemotherapy agents such as busulphan, 4 cytarabine, 5 or etoposide. [6][7][8] Previous clinical studies of one of these novel regimens, total body irradiation, etoposide and cyclophosphamide combined with allogeneic bone marrow transplantation for adults with acute leukemia have yielded mixed results. [6][7][8] To assess the safety and efficacy of this combination in pediatric patients, we evaluated the outcomes of 41 children and adolescents who received allogeneic bone marrow transplants for acute leukemia after total body irradiation, etoposide and cyclophosphamide. Patients and methods EligibilityThe pediatric bone marrow recipients included in this analysis were treated between September 1990 and October 1998 at the University of Rochester Medical Center. Patients were followed until 1 April 1999. During this time, all patients between the ages of 1 and 19 years who were receiving their first sibling or unrelated donor bone marrow transplant, and had acute lymphoblastic leukemia (FAB classification 1 or 2) or acute undifferentiated leukemia, were treated with this regimen. Patients with AML in undelayed first remission with matched sibling donors were treated on Pediatric Oncology Group protocols and not included in this analysis. All other pediatric patients who received allogeneic bone marrow transplants for AML were treated with this regimen. Two patients receiving second transplants received this preparative regimen; differen...
Summary We have examined the effectiveness of photodynamic therapy against R3230AC rat mammary adenocarcinoma and human mesothelioma as xenografts in the same host. The results demonstrate that the xenografted human tumour is significantly more responsive to photodynamic treatment than the rodent mammary tumour. Studies also showed that the mesothelioma xenograft was fluence rate-and fluencedependent while the rat tumour exposed to the same conditions demonstrated neither of these dependencies. This disparity in response was not attributable to a difference in either whole-tumour uptake or subcellular distribution of the porphyrin photosensitiser. Analysis of the effects of visible irradiation on cytochrome c oxidase activity, measured in mitochondria prepared from tumours borne on hosts injected with photosensitiser, demonstrated that photoradiation-induced enzyme inhibition was significantly greater in mesothelioma than in R3230AC mammary tumour preparations. However, in parallel studies conducted in vitro, when photosensitiser and light were delivered to previously unperturbed mitochondria, rates of enzyme inhibition were not significantly different. Both tumours were established in long-term cell culture. While the uptake of porphyrin photosensitiser was equivalent in both cell lines, the R3230AC cells displayed a significantly greater photosensitivity than the mesothelioma cells. The data presented here demonstrate that the mechanisms that govern response to photodynamic therapy are complex, but in the case of these two xenografted tumours host response to therapy is not likely to play a significant role.Diffuse malignant mesothelioma (DMM) occurs on the serosal surfaces of the body. Induction of DMM is associated with prolonged exposure to asbestos fibres, followed by a latency period of 15-30 years before appearance of symptoms that support its diagnostic confirmation (Wagner et al., 1960;McDonald & McDonald, 1980;Muscat & Wynder, 1991 (Gomer & Dougherty, 1979;Woodburn et al., 1992). The light is usually delivered via fibre optics coupled to the output of a tuned dye laser. The resulting electronic excited state of the porphyrin retained in tumours initiates a photochemical reaction, which in turn forms the toxic oxygen species, singlet oxygen ('02) (Weishaupt et al., 1976;Gibson et al., 1984;Keene et al., 1986). Intracellular oxidative damage induced by '02 occurs in lipid-rich cellular structures, such as the plasma, mitochondrial and ribosomal membranes, where accumulation of PPS is greatest because of the hydrophobic nature of its 'active' components (Moan et al., 1982;Kessel & Cheng, 1985;Dougherty & Mang, 1987). The '02-induced damage leads to reduced cellular metabolism, morphological alterations, cytotoxicity and tumour necrosis (Hilf et al., 1986(Hilf et al., , 1987Berg & Moan, 1988 (1990) found that mesothelioma cells in culture were sensitive to PDT using PPS. Employing meta-tetrahydroxyphenylchlorin (mTHPP), Ris et al. (1993) found that a 3 day interval between sensitiser administration and...
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