Hyperthermic chest wall re-irradiation in recurrent breast cancer: a prospective observational study.

PURPOSE: To prospectively investigate the role of re-irradiation (re-RT) combined with hyperthermia (HT) in a contemporary cohort of patients affected by recurrent breast cancer (RBC). METHODS: Within the prospective registry HT03, patients with resected RBC and previous irradiation were included. Re-RT was applied to the recurrence region with doses of 50-50.4 Gy, with a boost up to 60-60.4 Gy to the microscopically or macroscopically positive resection margins (R1/R2) region. Concurrent HT was performed at 40-42 ℃. Primary endpoint was LC. Acute and late toxicity, overall survival, cancer-specific survival (CSS), and progression-free survival (PFS) were also evaluated. RESULTS: 20 patients and 21 RBC were analyzed. Median re-RT dose was 50.4 Gy and a median of 11 HT fractions were applied. Re-RT+HT was well tolerated, with three patients who experienced a grade (G) 3 acute skin toxicity and no cases of ≥G3 late toxicity. With a median follow up of 24.7 months, two local relapses occurred. Ten patients experienced regional and/or distant disease progression. Five patients died, four of them from breast cancer. PFS was favorable in patients treated with re-RT+HT for the first recurrence with doses of 60 Gy. A trend towards better CSS was found in patients with negative or close margins and after doses of 60 Gy. CONCLUSION: Full-dose re-RT+HT for RBC is well tolerated, provides good LC, and seems to be more effective when applied at the time of the first relapse and after doses of 60 Gy. The registry will be continued for validation in a larger cohort and with longer follow-up.

Air density correction in ionization dosimetry.

Air density must be taken into account when ionization dosimetry is performed with unsealed ionization chambers. The German dosimetry protocol DIN 6800-2 states an air density correction factor for which current barometric pressure and temperature and their reference values must be known. It also states that differences between air density and the attendant reference value, as well as changes in ionization chamber sensitivity, can be determined using a radioactive check source. Both methods have advantages and drawbacks which the paper discusses in detail. Barometric pressure at a given height above sea level can be determined by using a suitable barometer, or data downloaded from airport or weather service internet sites. The main focus of the paper is to show how barometric data from measurement or from the internet are correctly processed. Therefore the paper also provides all the requisite equations and terminological explanations. Computed and measured barometric pressure readings are compared, and long-term experience with air density correction factors obtained using both methods is described.

Oral tolerance in experimental autoimmune neuritis (EAN) of the Lewis rat. II. Adjuvant effects and bystander suppression in P2 peptide-induced EAN.

Experimental autoimmune neuritis (EAN) in Lewis rats serves as an animal model of human inflammatory demyelinating neuropathies. We previously demonstrated that EAN actively induced by immunization with bovine PNS-myelin can be suppressed by feeding of myelin. This myelin-specific oral tolerance (OT) was enhanced by coapplication of cholera toxin (CT).In the present study, EAN induced by immunization with a neuritogenic P2 peptide was completely prevented by precedent feeding of the peptide. Oral application of the P2 peptide mediated tolerance as efficient as did nasal administration. In contrast to OT by myelin, addition of CT completely prevented oral induction of tolerance to peptide-induced EAN, while adjuvant feeding alone did not modulate disease. As a possible immunological basis to explain the prevention of OT induction by CT, we identified a highly enhanced protein-specific in vitro proliferation of splenocytes from antigen/CT-fed animals compared to those of rats fed with the antigen only. The opposite effects of oral CT in combination with proteins versus myelin confirm our former assumption that CT augments myelin-induced tolerance by its binding to gangliosides present in the myelin but not in the P2 peptide solution, while free CT prevents the induction of OT. It is suggested that CT is a useful adjuvant for OT if coadministered with myelin, but requires chemical linkage to proteins to exert this function. Regulatory lymphocytes orally induced by feeding the protein keyhole limpet hemocyanine (KLH) slightly ameliorated peptide-induced EAN via bystander mechanisms, but injection of KLH in close proximity to the site of peptide-immunization was essential. The restriction of bystander suppression to that site in the lymphoid system where neuritogenic T cells are activated may limit the impact of OT as a bonafide treatment strategy in human autoimmune diseases and underscores the necessity to identify the autoantigens involved.

Role of TNF-alpha in high-dose antigen therapy in experimental autoimmune neuritis: inhibition of TNF-alpha by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis.

TNF-alpha has been implicated as a potentially detrimental cytokine in autoimmune disorders of the nervous system and has been reported to be elevated in antigen-specific therapy of experimental autoimmune neuritis (EAN) in vivo. To investigate the role of TNF-alpha in EAN in rats that had been subjected to antigen-specific therapy with human P2 protein, animals were cotreated with an anti-TNF-alpha neutralizing antibody and the effects of the antibody on disease determined. Using this strategy in adoptive transfer (AT-) EAN, antigen-induced T-cell apoptosis in inflamed sciatic nerve and in liver was reduced to levels observed in control animals indicating that TNF-alpha mediates antigen-induced apoptosis of inflammatory T-cells. Focal liver necrosis, which had been observed in earlier studies after antigen therapy in AT-EAN, was prevented by passive immunization with neutralizing anti-TNF-alpha antibody. Unexpectedly, neutralization of TNF-alpha only partly abolished the protective effect of antigen therapy on the overall disease course. This may indicate that inhibition of TNF-alpha exerts beneficial effects other than through T-cell apoptosis, or that some of the benefit of antigen therapy is mediated by other pathways. These results indicate that secretion of TNF-alpha during antigen therapy has the dual potential to mediate beneficial apoptosis of inflammatory T-cells in the inflammatory lesion and to induce liver damage as a severe side effect.

Characterization of vortices using pulsed-wave Doppler ultrasound.

The detection and characterization of vortices from a Kaman vortex generator by means of a 20 MHz pulsed-wave Doppler ultrasound system were assessed. Measurements were made at different steady flowrates in a 10 mm internal diameter polyurethane tube, 14 mm distal to a circular cylinder of diameter 2 mm, placed across the tube inlet. The results were compared with those obtained with a two-component laser Doppler anemometer system. There was generally good agreement between the two techniques in the measurement of convective flow velocity, frequency of vortex shedding and the circulation velocity of the vortices. It is concluded that pulsed-wave Doppler ultrasound is a suitable technique for investigating vortical flow structures.

Characterisation of vortex shedding in vascular anastomosis models using pulsed Doppler ultrasound.

Vortex shedding at vascular anastomoses were investigated in vitro using a 20 MHz pulsed-wave Doppler velocimeter. Centreline velocity measurements were made at various axial distances in simplified polyurethane models of proximal and distal end-to-side anastomoses of angles 15, 30, 45, 60 and 80 degrees using pulsatile flow waveforms similar to those in femoropopliteal bypass grafts. The in-phase and quadrature Doppler signals were recorded and the maximum frequency waveform, averaged over 64 cycles, was obtained using short-time Fourier transform. A fourth-order Butterworth low-pass filter was employed to separate the vortex velocity signal from the convective velocity. The vortex signal envelope was calculated using a Hilbert transform method and the vortex amplitude was taken as the maximum of this envelope. The results show that higher vortex amplitude were found in the proximal anastomoses and under resting flow conditions. Although the vortex amplitudes generally increased with angles of anastomosis, they were found to be higher in the 60 degrees than in the 80 degrees proximal anastomosis. The vortex structures were investigated using spectrograms and these show prominent features at 40-50 Hz indicative of the short-duration oscillatory signals during the decelerative phase of systole expected from the passage of vortices. The study indicates that flow disturbances due to vortex shedding may be a common feature in femoropopliteal bypass grafts.

Modulation of experimental autoimmune neuritis in Lewis rats by oral application of myelin antigens.

Experimental autoimmune neuritis (EAN) in Lewis rats is a T cell-mediated disease and serves as an animal model of human inflammatory demyelinating neuropathies. EAN can be induced by immunization with complete bovine peripheral nerve myelin (BPM), the myelin protein P2 or its neuritogenic peptide, each emulsified in complete Freund's adjuvant (CFA). The present study evaluates the effect of oral tolerization with BPM or P2 protein on the development of actively induced EAN. Oral administration of BPM strongly suppressed clinical and histological signs of EAN subsequently induced by BPM/CFA, but feeding of P2 protein alone did not affect its course. In contrast, feeding of BPM did not mitigate the course of EAN subsequently induced by immunization with neuritogenic P2 peptide/CFA. Oral therapy with BPM after onset of myelin-induced EAN only slightly ameliorated the further course of disease, but significantly reduced lethality of this severe form of disease. The findings suggest that immunogenicity of the antigens fed determine strength of tolerance, that downregulation of EAN occurs at the site of immunization and not in the nerve, and that active suppression rather than specific anergization is operative in mediating resistance to EAN. However, only partial tolerance to myelin-induced EAN was achieved in naive animals by transfer of spleen/LN cells from rats orally tolerized with BPM. Although methodic factors may have limited the effect of the cells, the result is suggestive of some contribution of anergy to oral tolerance in the present model. Cholera toxin and LPS were identified as oral adjuvants for BPM and prolonged the state of tolerance. However, LPS exhibited proinflammatory properties if EAN was induced early after BPM/LPS-feeding. Thus, oral application of a mixture of myelin components in combination with cholera toxin may be a useful treatment for chronic inflammatory neuropathies considered autoimmune in nature.

Antigen therapy eliminates T cell inflammation by apoptosis: effective treatment of experimental autoimmune neuritis with recombinant myelin protein P2.

Exposure of T cells to their specific antigen normally results in proliferation, but in the presence of high and repeatedly administered doses of antigen, T cells may undergo apoptosis. Here we demonstrate that i.v. administration of as little as 100 microg of recombinant P2 protein twice daily completely prevents experimental autoimmune neuritis induced by adoptive transfer of neuritogenic P2-specific T cells or by immunization with the neuritogenic P2-peptide-spanning amino acids 53-78. Antigen treatment started after disease onset markedly ameliorated experimental autoimmune neuritis. The mechanism of action may be through programmed T cell death; a profound increase of the rate of apoptosis was seen in inflammatory foci of peripheral nerves and in the spleen. There was no cytokine switch by our Th1 cells after exposure to their specific antigen, but increased secretion of interferon gamma and tumor necrosis factor alpha was demonstrated. High antigen dose therapy using recombinant, pathogen-free protein may prove useful for the treatment of autoimmune inflammatory disorders of the nervous system.