Feasibility and toxicity of chemoembolization for children with liver tumors.
(49/2226)
PURPOSE: To determine the feasibility, toxicity, and efficacy of hepatic arterial chemoembolization (HACE) in pediatric patients with refractory primary malignancies of the liver. PATIENTS AND METHODS: Six patients with hepatoblastoma (HB), three with hepatocellular carcinoma (HCC), and two with undifferentiated sarcoma of the liver were treated with HACE every 2 to 4 weeks until their tumors became surgically resectable or they showed signs of disease progression. All but one newly diagnosed patient with HCC had previously received systemic chemotherapy. RESULTS: All patients with HB and HCC responded to HACE, as measured by imaging studies and alpha-fetoprotein levels. Surgical resection (complete or microscopic residual disease) was feasible in five of 11 patients, and three patients remain alive with no evidence of disease. Elevated liver transaminase and bilirubin levels were seen after each one of the 46 courses of HACE. Other toxicities included fever, pain, nausea, vomiting, and transient coagulopathy. CONCLUSION: HACE is feasible, well tolerated, and effective in inducing surgical resectability of primary hepatic tumors in children. (+info)
Postirradiation aortic sarcoma demonstrated by magnetic resonance angiography.
(50/2226)
This is the first ever reported case of a radiation-induced aortic sarcoma. This patient had symptoms and signs initially interpreted as a pulmonary embolus. The extent of the disease was demonstrated with magnetic resonance imaging and magnetic resonance angiography, in particular, allowing rapid surgical intervention. (+info)
Effect of reresection in extremity soft tissue sarcoma.
(51/2226)
OBJECTIVE: To determine whether reresection affects survival in patients with inadequately resected, primary extremity soft tissue sarcoma. This study correlates reresection with local recurrence-free survival, metastasis-free survival, and disease-free survival. SUMMARY BACKGROUND DATA: Soft tissue sarcomas are rare neoplasms, with an incidence of approximately 6,000 per year in the United States. Because these tumors are rare and benign soft tissue tumors are common, many are initially thought to be benign and are excised without wide margins. METHODS: Patients who underwent treatment for primary tumors from July 1982 to June 1999 at a single institution were the subject of study. Two groups of patients were analyzed: those who underwent one definitive resection (one operation) and those whose tumors were previously resected and who were then referred for subsequent reresection (two operations). Patients were given adjuvant radiation or chemotherapy according to the standard of care. RESULTS: Of 1,092 patients with primary extremity soft tissue sarcoma underwent resection, 685 underwent definitive radical resection and 407 underwent reresection after undergoing excisional resection elsewhere. Median follow-up was 4.8 years. The 5-year disease-free survival rate of the definitive resection (one operation) group was 70%; that of the reresection (two operations) group was 88%. On multivariate analysis, reresection was adjusted and controlled for age, grade, depth, size, histology, and margins. Reresection remained a significant predictor of improved disease-free survival, even after these adjustments. To determine whether this difference was stage- or referral-biased, the patient population was divided by AJCC stage. In all stages there was a trend toward improved outcome; this was most marked for those with stage III disease (>5 cm, high-grade, and deep). CONCLUSIONS: Patients with extremity soft tissue sarcoma who undergo reresection with two "primary" operations have an improved survival compared with those who undergo one operation. The most plausible explanation, referral and selection bias, is questionable given the significance of reresection as a variable after adjusting for stage and other risk factors. This suggests that where indicated and possible, reresection should be liberally applied in patients with primary extremity soft tissue sarcoma. (+info)
The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.
(52/2226)
Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals. (+info)
A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors.
(53/2226)
GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors. Fourteen patients (13 evaluable for safety) received escalating doses of GEM231 at 20-360 mg/m2 (2.5-9 mg/kg). Tumor histologies included non-small cell lung cancer, renal cell cancer, sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13 microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II fever and fatigue at doses > or = 240 mg/m2. There was no treatment-related complement activation or thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses > or =160 mg/m2. Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative reversible transaminase elevation (three of three patients at 360 mg/m2 and three of six patients at 240 mg/m2 during weeks 3-10). One patient with colon cancer had stabilization of a previously rising carcinoembryonic antigen. Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested. (+info)
(F-18) fluorodeoxyglucose positron emission tomography as a predictor of pathologic grade and other prognostic variables in bone and soft tissue sarcoma.
(54/2226)
Positron emission tomography (PET) can be used to measure tumor metabolism in sarcomas by measuring the standard uptake value (SUV) of (F-18) fluorodeoxyglucose (FDG). FDG-PET SUV has been shown to correlate with histological grade. We compared FDG-PET SUV in 89 bone and soft tissue sarcomas with histopathological features, including tumor grade, as well as with markers of cell proliferation and cell cycle regulatory gene expression that may be prognostically or therapeutically important. All patients had undergone PET before biopsy. Features evaluated included grade (National Cancer Institute for soft tissue or Mayo Clinic for bone), cellularity, and the number of mitoses per 10 400x fields. Deparaffinized, formalin-fixed sections were immunostained with antibodies to Ki-67 (MIB-1), p53 (DO7), p21WAF1 (EA10), and mdm-2 (1B10). For Ki-67, results were estimated as a percentage of positive cells. For p53 and mdm-2, only cases with >20% positive cells were considered to be overexpressing these proteins. For p21WAF1, only cases with <10% positive cells were considered to have lost normal p21WAF1 expression. Tumor S-phase percentage and ploidy were determined by flow cytometry. FDG-PET SUV was associated with histopathological grade, cellularity, mitotic activity, MIB labeling index, and p53 overexpression. No association was seen with p21WAF1, mdm-2, S-phase fraction, or ploidy. Tumor metabolism data acquired by FDG-PET may help ensure accurate grading and prognostication in sarcoma by guiding biopsy toward the most biologically significant regions of large masses. Further follow-up will be necessary to determine whether FDG-PET provides independent prognostic information. (+info)
Radiation-induced bone sarcoma following total body irradiation: role of additional radiation on localized areas.
(55/2226)
A 44-year-old patient who had had acute monoblastic leukemia developed an osteosarcoma of the pelvic bones 5 years after an allogeneic bone marrow transplant from his HLA-identical sister. He had additionally received superficial cutaneous radiation of the legs and pelvis, over the 3 weeks prior to total body irradiation (TBI), because of cutaneous leukemic lesions. The tumor was a fibrohistiocytomatous osteogenic sarcoma. The first lesion was in the right ilium, and a second lesion appeared 18 months later, symmetrically on the left ilium. Despite treatment, the patient died from metastases. At the time of diagnosis of radiation-induced sarcoma, the patient was free of leukemia and had several risk factors already reported to favor the development of solid tumors in stem cell recipients. These include acute leukemia, TBI and graft-versus-host disease. As he developed symmetrical lesions of the pelvic bone, and because of the histology of the radiation-induced tumor, we assumed that the additional radiation of the skin prior to TBI may have contributed to the pathogenesis of this malignant fibrous histiocytoma. Therefore, the risk/benefit ratio should be carefully considered in unusual indications. These patients should benefit from a close follow-up of the superimposed areas. (+info)
mdm2 mRNA level is a prognostic factor in soft tissue sarcoma.
(56/2226)
BACKGROUND: The oncogenic properties of murine double minute-2 (mdm2) protein over-expression, which mostly results from the interaction with the tumor suppressor p53, are well described and their negative impacts on the prognosis of affected patients is well characterized. However, clinical relevance of mdm2 mRNA expression is poorly investigated. MATERIALS AND METHODS: In this study, 65 soft tissue sarcoma (STS) samples were analyzed for mdm2 mRNA expression by a quantitative reverse transcription polymerase chain reaction (RT-PCR) approach using available validated ready-to-use assays based on the TaqMan technology (PE Applied Biosystems, Weiterstadt, Germany). Mdm2 data were correlated to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression calculated from the same sample. RESULTS: For patients with a mdm2/GAPDH mRNA ratio below 50 zmol/amol the survival was strikingly reduced in comparison to patients with a ratio of > or =50 (p = 0.0241). Multivariate Cox analysis showed that the difference in prognosis for patients with tumor stage 2 and 3 became even more pronounced between patients with a ratio of <50 zmol/amol and patients with a ratio of > or =50 (p = 0.0041; RR = 5.6). To test if the group with an mdm2 mRNA expression > or =50 is homogenous concerning the prognosis, the group was divided into three subgroups with values of 50 to <100, 100 to <500 and > or =500. The subgroup with values of 100 to <500 showed the best prognosis (p = 0.0164); whereas, the one with values of 50 to <100 showed the worst prognosis in this group and, in between, was the one with values of > or =500. After omitting patients of stage 1 and 4, the subgroup with values of 100 to <500 showed an even more striking best prognosis (p = 0.0015); the other subgroups remained in the same sequence. The risk of tumor-related death over 5 years was most conspicuous in patients with mdm2 mRNA expression <50 than in those with ratios of 100 to <500 displaying a 13.3-fold higher risk. In a comparison between mdm2 mRNA levels and P53 protein expression or p53 mutational status, no relationship was found. CONCLUSIONS: In our study, the mdm2 mRNA level appears to be an independent prognostic factor for STS patients, marking its role in STS genesis and as a potential factor for gene therapeutical approaches. (+info)