Intraoperative electron boost radiation followed by moderate doses of external beam radiotherapy in limb-sparing treatment of patients with extremity soft-tissue sarcoma

PURPOSE: To analyze long-term prognosis and morbidity after limb-sparing treatment of patients with extremity soft-tissue sarcoma, with intraoperative electron boost radiotherapy (IOERT) followed by a moderate dose of external beam radiotherapy (EBRT). METHODS AND MATERIALS: A total of 153 patients who were treated in a single center from 1991 to 2004 were evaluated. Median IOERT dose was 15 Gy, mean EBRT dose 43 Gy (range, 40-50.4 Gy) in conventional fractionation (1.8-2 Gy). Median duration of follow-up was 33 months. Acute toxicity was assessed with Common Toxicity Criteria; late toxic effects were scored according to European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group criteria. RESULTS: Five-year overall survival and 5-year local control rates were 77% and 78%, respectively. Whereas tumor size, patient age, and EBRT dose did not significantly affect outcome, resection status and grading were significant for survival; resection status and IOERT dose were significant for local control. Extremity salvage until death or time of follow-up was achieved in 90% of our patients, 86% of whom showed excellent limb function without impairment in activities of daily life. Acute toxicity Grade 2-4 was observed in 23% and late toxicity Grade 2-4 in 17% of patients. CONCLUSIONS: Treatment with IOERT combined with moderate doses of external beam irradiation yields high local control and extremity preservation rates in resected extremity soft-tissue sarcoma.     

Target visualisation and microwave hyperthermia monitoring using nanoparticle-enhanced transmission ultrasound (NETUS)

Purpose: The aim of this study was to examine the feasibility of using nanoparticle-enhanced transmission ultrasound (NETUS) as an image-based monitoring modality for microwave hyperthermia treatment.

Methods: A dedicated transmission ultrasound imaging system was used to obtain acoustic projections and ultrasound computed tomography images. Initially, speed-of-sound based images were used to non-invasively monitor temperature changes in in vitro and ex vivo specimens, induced by a microwave needle-type applicator. Next, the hyperthermia acceleration ability of two ultrasound nanoparticles based contrast agents (iron oxide and copper oxide) was examined and visualised. Finally, a two-step image guided microwave therapeutic procedure using NETUS was investigated in a realistic breast mimicking phantom. First, the pathology simulating region borders were detected. Then, a microwave-induced temperature elevation was non-invasively monitored.

Results: The transmission ultrasound scanning system was able to detect temperature changes with a resolution of less than 0.5?°C, both in vitro and ex vivo. In accordance with previous studies, it was visually demonstrated that iron oxide nanoparticles expedite the heating process (p?Conclusions: NETUS can combine enhanced target visualisation with non-invasive thermometry and accelerated heating effect. Quantitative feedback, however, requires a tissue-specific calibration-curve. A proof of concept for microwave hyperthermia treatment monitoring using NETUS was established. The suggested methodology may potentially provide a non-invasive cost-effective means for monitoring thermal treatment of the breast.     

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia

Ataxia-telangiectasia (AT) is an autosomal recessive multisystent disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3–77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or α-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT. Received: 29 October 1998 Received in revised form: 5 February 1999 Accepted: 7 February 1999     

In vitro and in vivo antifungal activities of the eight steroid saponins from Tribulus terrestris L. with potent activity against fluconazole-resistant fungal pathogens

Antifungal activity of natural products is being studied widely. Saponins are known to be antifungal and antibacterial. We have isolated eight steroid saponins from Tribulus terrestris L. , namely TTS-8, TTS-9, TTS-10, TTS-11, TTS-12, TTS-13, TTS-14 and TTS-15. TTS-12 and TTS-15 were identified as tigogenin-3-O-β-D-xylopyranosyl（1→ 2）-[-β-D-xylopyranosyl（ 1 → 3 ） 3-β- D-glucopyranosyl （ 1 → 4 ）- 1- α-L-rhamnopyranosyl （ 1 → 2 ） 3-β-D-galactopyranoside and tigogenin-3-O-β-D-glucopyranpyranosyl（1→2）-[-β-D-xylopyranosyl（1→ 3）3-β-D-glucopyranosyl（1→4）-β-D-galactopyranoside, respectively. The in vitro antifungal activities of the eight saponins against six fluconazole-resistant yeasts, Candida albicans, Candida glabrata, Candida para psilosis , Candida tropicalis , Candida krusei , and Cryptococcus neo f ormans were studied using microbroth dilution assay. The results showed that TTS-12 and TTS-15 were very effective against several pathogenic candidal species and C. neoformans in vitro. It is noteworthy that TTS-12 and TTS-15 were very active against fluconazole-resistant C. albicans （MIC80 = 4.4, 9.4 mg/ml）, C. neoformans （MIC80 =10.7, 18.7 mg/ml） and inherently resistant C. krusei （MIC80 =8.8, 18.4 mg/ml）. So in vivo activity of TTS-12 in a vaginal infection model with fluconazole-resistant C. albicans was studied in particular. Our studies revealed TTS-12 also showed in vivo activities against fluconazole-resistant yeasts. In conclusion, steroid saponins TTS-12 and TTS-15 from Tribulus terrestris L. have significant in vitro antifungal activity against fluconazole-resistant fungi, especially TTS-12 also showed in vivo activity against fluconazole-resistant C. albicans.     

A toxicokinetic study of inhaled ethylene glycol ethyl ether acetate and validation of a physiologically based pharmacokinetic model for rat and human

The solvents ethylene glycol monoethyl ether acetate (EGEEA) and ethylene glycol monoethyl ether (EGEE), at sufficiently high doses, are known to be rodent developmental toxicants, exerting their toxic effects through the action of their metabolite 2-ethoxyacetic acid (2-EAA). Thus risks associated with exposure to these compounds are best evaluated based on a measure of the internal dose of 2-EAA. The goals of the work reported here were to develop physiologically based pharmacokinetic (PBPK) models of EGEEA and EGEE for pregnant rats and humans. These models were used to identify human exposure levels (ppm in air) equivalent to the rat no observed effect level (NOEL) and lowest observed effect level (LOEL) for developmental effects (Hanley et al., 1984). We exposed pregnant Sprague-Dawley rats to concentrations of EGEEA corresponding to the NOEL and LOEL. Maternal blood, urine, and fetal tissue concentrations of EGEE and 2-EAA measured in these experiments were used to validate the rat EGEEA and EGEE models. Data collected by other researchers were used to validate the capabilities of the rodent EGEEA and EGEE models to predict the kinetics in humans. The models for estimating circulating blood concentrations of 2-EAA were considered valid based on the ability of the model to accurately predict 2-EAA concentrations in rat blood, urine, and fetal tissue. The human inhaled concentration equivalent to the rat NOEL for EGEEA (50 ppm) was predicted to be 25 ppm using the maternal blood average daily area under the curve (AUC) and 40 ppm using the maximum concentration achieved in maternal blood (C(max)). The human inhaled concentration equivalent to the rat LOEL for EGEEA (100 ppm) was determined to be 55 ppm using the maternal blood average daily AUC and 80 ppm using the maternal blood C(max).     

Intraabdominal hematoma following orchiectomy: a potential pitfall in using CT for staging of testicular cancer

Internal bleeding in patients undergoing orchiectomy for a malignant testicular tumor can cause a dissecting hematoma in the retroperitoneum. This mass may have the clinical appearance of an iliac fossa mass and may simulate metastasis on computed tomography (CT). This condition was seen in four of 486 orchiectomy patients who underwent postoperative staging with CT. One patient is described in detail.     

Immunologic identification of the cleavage products from the A alpha- and B beta-chains in the early stages of plasmin digestion of fibrinogen

Fragment X components (Mr 225,000 to 333,000) were distinguished on sodium dodecyl sulfate polyacrylamide gels. Western blotting with monoclonal antibodies to A alpha-chain segments demonstrated that the A alpha-chains of fibrinogen and the largest fragment X components (Mr 285,000-340,000) contained both A alpha 259-276 and A alpha 540-554. Fragment X components of Mr 270,000-285,000 contained A alpha 259-276 but lacked A alpha 540-554, whereas the smallest fragment X components (Mr 225,000-270,000) contained neither A alpha 540-554 nor A alpha 259-276. Studies of the small peptides generated during fragment X formation complemented the studies of the large molecules, by demonstrating peptides containing both A alpha 259-276 and A alpha 540-554 (Mr 41,600-41,800 and Mr 38,700-38,900), peptides containing A alpha 540-554 but not A alpha 259-276 (Mr 20,500-21,000 and Mr 17,300-17,500) and peptides containing only A alpha 259-276 (Mr 23,600-24,000 and Mr 20,500-21,000). Cleavage of B beta 1-42 from the amino terminal ends of the B beta-chains, measured with a specific radioimmunoassay, was linear until 1.6 moles per mole of fibrinogen had been released, and coincided with loss of the central and carboxy terminal A alpha-chain regions, i. e. A alpha 259-276 and A alpha 540-554. Based on present and previously reported data, a model is proposed for the evolution of the heterogeneous group of fragment X derivatives from fibrinogen with the simultaneous release of small peptides.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of an assay for in vivo human neutrophil elastase activity. Increased elastase activity in patients with alpha 1-proteinase inhibitor deficiency.

Leukocyte extracts contain enzymes that digest fibrinogen and release a fibrinopeptide A-containing fragment. This study was undertaken to identify the responsible proteinase and to characterize the fibrinopeptide A-containing fragment so that it could be used as an index of enzyme activity. Both the fibrinogenolytic activity and the release of the fibrinopeptide A-containing fragment mediated by the leukocyte extracts were shown to be due to human neutrophil elastase (HNE) by the following criteria: activity was completely blocked by a specific HNE inhibitor or by adsorbing HNE from the extracts with a monospecific antibody and reconstitution with purified HNE restored the ability to release the fibrinopeptide A-containing fragment. This fragment was not released by a variety of other proteinases or by HNE-inhibitor complexes indicating that, at least with respect to the enzymes tested, it is a specific product of HNE and its release requires the free enzyme. By separating the products of HNE digestion of fibrinogen using high performance liquid chromatography, identifying the immunoreactive fractions and subjecting them to amino acid analysis, the fragment was identified as A alpha 1-21, indicating an HNE cleavage site at the Val(A alpha 21)-Glu(A alpha 22) bond. The mean plasma A alpha 1-21 level was markedly higher in patients with alpha 1-proteinase inhibitor deficiency as compared to healthy controls (0.2 nM vs. 7.9 nM; P less than 0.0001), consistent with increased in vivo HNE activity in these individuals.