Results of spot-scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: the Paul Scherrer Institut experience

PURPOSE: To assess the clinical results of spot scanning proton beam radiation therapy (PT) in the treatment of skull base chordomas and low-grade chondrosarcomas (CS). METHODS AND MATERIALS: Between October 1998 and October 2003, 29 patients (median age, 39 years) with chordomas (n = 18) and CS (n = 11) were treated at the Paul Scherrer Institut (PSI) with protons using the main 510-MeV cyclotron. Tumor conformal application of proton beams was realized by spot scanning technology. The median chordoma and CS dose was 74 and 68 cobalt Gy equivalent, respectively (cobalt Gy equivalent = proton Gy x 1.1). Median gross tumor volumes (GTV) were 16.4 mL (range, 1.8-48.1 mL) and 15.2 mL (range, 2.3-57.3 mL) for chordoma and CS, respectively. Late toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v3.0) grading system. The median follow-up time was 29 months (range, 6-68 months). RESULTS: Actuarial 3-year local control rates were 87.5% and 100% for chordoma and CS, respectively. We observed one surgical pathway and one marginal failure in patients with chordomas. No regional failure or distant metastasis was observed. At 3 years, actuarial PFS and OS for the entire cohort was 90% and 93.8%, respectively. Actuarial 3-year complication-free survival was 82.2%. Radiation-induced pituitary dysfunction was observed in 4 (14%) patients (CTCAE Grade 2). No patient presented with post-PT brainstem or optic pathways necrosis or dysfunction. In univariate analysis, age < or =40 years at the time of PT affected favorably on PFS (p = 0.09). CONCLUSION: Spot-scanning PT offers high tumor control rates of skull base chordoma and CS. These results compare favorably to other combined proton-photon or carbon ion irradiation series. Observed toxicity was acceptable. Younger age (< or =40 years) was a favorable prognostic factor of PFS. These preliminary results are encouraging but should be confirmed during a longer follow-up.     

Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener's granulomatosis and clinically related disorders.

In view of the supposed hypersensitivity, the elevated levels of IgE, and the occurrence of eosinophilia reported in Wegener's granulomatosis and related conditions, we studied the IgG subclass distribution of ANCA directed against a 29-kD serine protease and myeloperoxidase (MPO) in 41 untreated ANCA-positive patients with several forms of active vasculitis and/or glomerulonephritis. We found that both 29-kD ANCA and MPO ANCA were predominantly of the IgG1 and IgG4 subclass in all groups of patients. The additional presence of IgG3 subclass was associated with renal involvement. We compared the subclass distribution of ANCA with that of total IgG subclass levels, and with the IgG subclass distribution of antibodies to cytomegalovirus (CMV) as a persistent endogenous antigen and antibodies to tetanus toxoid (TT) as an exogenous recall antigen. Total levels of IgG4 were elevated in the majority of the patients together with elevated IgG1 levels. Antibodies to CMV and TT, however, had the same subclass distribution as found in normals and did not show enhanced IgG4 expression. ANCA belong predominantly to the IgG1 and IgG4 subclass, which may suggest that the production of ANCA is related to recurrent exposition to the antigen(s) involved, possibly as part of a hypersensitivity reaction.     

The quantitation of cell surface antigens by antibody-complement mediated cytotoxicity: application to murine leukemia virus-infected mouse cells.

51Cr-antibody-complement mediated cytotoxicity (ACC) can be used to quantify nanogram amounts of cell surface antigens. When pure antigen is available for calibration, inhibition of ACC by known amounts of antigen and by whole cells yields an estimate of the number of antigenic equivalents per cell. ACC is more suitable for this purpose than radioimmunoprecipitation assay. By ACC the number of antigenic equivalents of the oncornaviral proteins gp70 and p30 has been determined on the surface of various cells infected with Rauscher and Gross murine leukemia viruses.     

Norepinephrine and isoprenaline induced changes of peripheral blood flow acceleration caused by changes of cardiac inotropy

Summary In anesthetized dogs the norepinephrine (NE) and isoprenaline (ISO) (1–1024 ng/kg i.v.)-induced increase of maximum peripheral flow acceleration (celiac artery, cranial mesenteric artery, renal artery, and femoral artery) and the changes of the maximum first derivative of arterial pressure were compared with the increases of maximum ascending aortic flow acceleration and maximum first derivative of left ventricle pressure (LV dP/dt max).The maximum effect of each dose on maximum acceleration of flows (dF/dt max) and maximum first derivative of pressures (dP/dt max) occurred simultaneously for all variables. The effect was dose-dependent. Sensitivity was similar for NE (D₅₀:2256–512 ng/kg) and for ISO (D₅₀: 128–256 ng/kg).We demonstrated that other variables than inotropic action (heart rate, left ventricular end diastolic pressure and diastolic aortic pressure) played only a minor role in the increases of LV dP/dt max in our studies.In contrast with the uniform response of dF/dt max and dP/dt max, the reaction of peripheral vascular resistance varied. In particular in the gastrointestinal tract the resistance could either be increased (NE, D₅₀: 115 ng/kg) or decreased (ISO, D₅₀: 15 ng/kg). Gastrointestinal resistance was a more sensitive variable for catecholamine stimulation than dF/dt max and dP/dt max.The data show that under the present experimental conditions enhancement of peripheral flow acceleration induced by NE and ISO is due to increase of cardiac inotropy.Supported by the Foundation for Medical Research FUNGO     

The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: a case-control study of infertile women

BACKGROUND: A case-control study was designed to determine the possible association between chronic exposure to dioxins and polychlorinated biphenyls (PCBs), and the occurrence of endometriosis. The study group consisted of 42 infertile endometriosis cases and 27 mechanical infertile controls, both groups attending one of the collaborating Centres for Reproductive Medicine, enrolled between 1996-1998. METHODS: Exposure assessment to dioxin-like compounds was determined through CALUX (chemical-activated luciferase gene expression)-bioassay to measure dioxin-like total toxic equivalents (dioxins and co-planar PCBs), whereas non-co-planar PCBs were determined through chemical analysis. RESULTS: No association was found between median dioxin-like total toxic equivalents (TEQ) and the occurrence of endometriosis in infertile women [cases (n = 34): 29; controls (n = 27): 24; NS]. When patients were subdivided based on an arbitrary cut-off value of 100 pg TEQ/g serum lipids, no statistically significant association between very high exposure to dioxin-like compounds and endometriosis was found [crude odds ratio (OR) = 4.33; confidence interval (CI) 0.49-38.19; NS]. After adjusting for body mass index, and alcohol consumption, the risk increased slightly to OR = 4.6 (CI 0.48-43.62; NS). There was no confounding by age, ovulatory dysfunction, caffeine intake, smoking or exposure to non-co-planar PCBs. CONCLUSIONS: The study results showed no statistically significant association between exposure to dioxin-like compounds and the occurrence of endometriosis in infertile women.     

Autoantibodies against small nucleolar ribonucleoprotein complexes and their clinical associations

Sera from patients suffering from systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) have been shown to contain reactivities to nuclear components. Autoantibodies specifically targeting nucleolar antigens are found most frequently in patients suffering from SSc or SSc overlap syndromes. We determined the prevalence and clinical significance of autoantibodies directed to nucleolar RNA-protein complexes, the so-called small nucleolar ribonucleoprotein complexes (snoRNPs). A total of 172 patient sera with antinucleolar antibodies were analysed by immunoprecipitation. From 100 of these patients clinical information was obtained by chart review. Autoantibodies directed to snoRNPs were detected not only in patients suffering from SSc and primary Raynaud's phenomenon (RP), but also in patients suffering from SLE, rheumatoid arthritis (RA) and myositis (PM/DM). Antibodies against box C/D small snoRNPs can be subdivided in antifibrillarin positive and antifibrillarin negative reactivity. Antifibrillarin-positive patient sera were associated with a poor prognosis in comparison with antifibrillarin negative (reactivity with U3 or U8 snoRNP only) patient sera. Anti-Th/To autoantibodies were associated with SSc, primary RP and SLE and were found predominantly in patients suffering from decreased co-diffusion and oesophagus motility and xerophthalmia. For the first time autoantibodies that recognize box H/ACA snoRNPs are described, identifying this class of snoRNPs as a novel autoantigenic activity. Taken together, our data show that antinucleolar patient sera directed to small nucleolar ribonucleoprotein complexes are found frequently in other diseases than SSc and that categorization of diagnoses and clinical manifestations based on autoantibody profiles seems particularly informative in patient sera recognizing box C/D snoRNPs.     

Localization of dopamine D2 receptor mRNA with non-radioactive in situ hybridization histochemistry.

A digoxigenin-labeled antisense 42-mer oligonucleotide was used for the localization of the dopamine D2 receptor mRNA in the rat brain. The digoxigenin label was identified with alkaline phosphatase conjugated sheep-anti-digoxigenin. In good analogy with the known terminal fields of the dopaminergic system, various nuclei throughout the brain were labeled. Positive in situ hybridization signals were also found in dopamine cell groups of the substantia nigra and ventral tegmental area and in regions where a dopaminergic innervation is controversial, like the cerebellar cortex and the hippocampus. The non-radioactive in situ hybridization procedure described, shows the localization of the dopamine D2 receptor mRNA with a very high contrast and an optimal histological resolution.     

Physiological responses to asynchronous and synchronous arm-cranking exercise

The purpose of this study was to examine mechanical efficiency (ME) and physiological responses during asynchronous (the pedal arms oriented in opposing directions) arm-cranking exercise (AACE) and compare these responses to those obtained during synchronous (the pedal arms oriented in the same direction) arm-cranking exercise (SACE). Ten male subjects participated in the study and performed two exercise tests, one AACE and the other SACE in counter-balanced order. Each test consisted of submaximal (30, 60 and 90 W) and maximal exercise. At 30 W, gross ME was significantly lower during SACE compared to AACF, whereas at 60 W and 90 W no differences between the two types of exercise could be observed. We found that at lower power output levels the flywheel mass and its moment of inertia may have induced more body movements for compensation, which may have been more pronounced during SACE than during AACE. At higher levels of power output this flywheel mass-effect was less, which explained the lack of differences in ME at these levels. Physiological responses to maximal AACE or SACE exercise were not significantly different. The results indicated that there were no differences in physiological responses to AACE and SACE exercise at higher exercise intensities. However, at lower levels of power output ME seemed to decrease, most likely as a result of the flywheel-mass effect, which was more pronounced during SACE.