Ludwig Keilholz

Radiobiological mechanisms in inflammatory diseases of low-dose radiation therapy

Purpose: Whereas X-irradiation with high doses is established to exert pro-inflammatory effects, low-dose radiotherapy (LD-RT) with single fractions below 1.0 Gy and a total dose below 12 Gy is clinically well known to exert anti-inflammatory and analgesic effects on several inflammatory diseases and painful degenerative disorders. Experimental studies to confirm the effectiveness, the empirical dose and fractionation schemes, and the underlying radiobiological mechanisms are still fragmentary. Method: The anti-inflammatory efficiency of LD-RT was confirmed in several experimental in vitro and in vivo models. Results: In vitro studies revealed a variety of mechanisms related to the anti-inflammatory effect, in particular the modulation of cytokine and adhesion molecule expression on activated endothelial cells and leukocytes, and of nitric oxide (NO) production and oxidative burst in activated macrophages and native granulocytes. Conclusion: Inflammatory diseases are the result of complex and pathologically unbalanced multicellular interactions. It is, therefore, reasonable to assume that further molecular pathways and cellular components contribute to the anti-inflammatory effect of LD-RT. This review discusses data and models revealing aspects of the mechanisms underlying the anti-inflammation induced by low doses of X-irradiation and may serve as a basis for systematic analyses, necessary to optimize LD-RT in clinical practice.

Anti-inflammatory effect of low-dose X-irradiation and the involvement of a TGF-β 1 -induced down-regulation of leukocyte/endothelial cell adhesion

Purpose : Low-dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect, but the underlying radiobiological and immunological mechanisms remain elusive. In recent studies, we observed a reduced adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells (EC) after LD-RT (0.3-0.7 Gy). This shows that this treatment affects the initial steps of the inflammatory response. To explore the role of inflammatory mediators in this process, we investigated the expression of Transforming growth factor β 1 (TGF- β 1) and Interleukin 6 (IL-6) after LD-RT. Materials and Methods : EC were grown to subconfluence and irradiated with single-dose LD-RT. Twenty-hours after irradiation, EC were treated with IL-1 β for 4 h and then incubated with peripheral blood mononuclear cells (PBMC). Adherent PBMC were counted when using light microscopy. Expression of the cytokines TGF- β 1 and IL-6 was measured by ELISA, and mRNA levels were analysed by the RNAse-protection assay (RPA). Surface expression of E-selectin was quantified by flow cytometry. Results : A relative minimum of adhesion was observed after LD-RT between 0.3 and 0.7 Gy. This was paralleled by an expression maximum of TGF- β 1 and IL-6, as shown by protein and mRNA levels, respectively. Neutralization of TGF- β 1 by monoclonal antibodies, but not of IL-6, increased PBMC adhesion to EC nearly to control levels. In addition, fluorescence activated cell sorter (FACS) analysis of irradiated EC demonstrated a down-regulation of E-selectin in the same dose range. Conclusion : Low-dose X-irradiation between 0.3 and 0.7 Gy induced a relative maximum of TGF- β 1 production by stimulated EC. This results in a down-regulation of leukocyte/PBMC adhesion and may contribute to the anti-inflammatory effect of LD-RT.

Low-dose radiotherapy selectively reduces adhesion of peripheral blood mononuclear cells to endothelium in vitro☆

BACKGROUND AND PURPOSE The anti-inflammatory effect of low-dose radiotherapy (LD-RT) still is not understood. The adhesion of leukocytes to endothelial cells (EC) of the vessel wall is the initial event of tissue invasion, and thus, crucially contributes to the regulation of inflammation. We investigated the influence of LD-RT on the adhesion process in vitro. MATERIALS AND METHODS Isolated peripheral-blood-mononuclear-cells (PBMC) were incubated with an activated murine endothelioma cell-line under shear conditions at 4 degrees C after irradiation with single doses between 0.1 and 10.0 Gy. Adherent cells were counted microscopically and compared to a non-irradiated control. In parallel, viability and expression of adhesion molecules, especially of L-selectin, and lineage-specific markers on the cell surface were determined by dye exclusion and cytofluorometry, respectively. Modulation of adhesion by soluble L-selectin was tested in the adhesion assay. RESULTS Radiation doses of 0.1-0.5 Gy reduced the adhesion of viable PBMC to EC in vitro by 70% of the control level 4 h after irradiation. Leukocytes showed a marked reduction of L-selectin expression after LD-RT. Soluble L-selectin can inhibit the adhesion of PBMC to EC. CONCLUSION The anti-inflammatory effect of LD-RT might, in part, be due to the reduction in the adhesion of PBMC to EC. This reduction in adhesion might be a consequence of the reduced expression of L-selectin on the surface of PBMC, and the inhibition of adherence by soluble L-selectin shed by PBMC in vitro.

In vitro apoptosis in peripheral blood mononuclear cells induced by low-dose radiotherapy displays a discontinuous dose-dependence

PURPOSE Cells undergoing apoptosis contribute to the regulation of activated mononuclear cells (Voll et al. 1997). Low-dose radiotherapy (LD-RT) is known to improve inflammatory symptoms, but the mechanism of action is still unclear. The aim of this study was to investigate the rate of apoptosis of peripheral blood mononuclear cells (PBMC) induced by LD-RT within the therapeutic dose range of anti-inflammatory RT. MATERIALS AND METHODS PBMC were isolated from venous blood of ten healthy volunteers and were irradiated with single doses between 0.1 and 3.0 Gy. Apoptotic nuclei were detected by flow cytometry after propidium iodide (PI) triton staining, and apoptotic cells were detected by annexin V/PI staining and cell scatter analysis. Since apoptotic cells display increased cytoplasmatic granularity and concomitant reduced cell size, they can be distinguished from viable cells in forward/side scatter (FSC/SSC) histograms. Apoptotic PBMC were further subtyped by double staining with annexin V and directly labelled monoclonal antibodies recognizing the lineage-specific surface markers CD4, CD8, and CD19, respectively. The apoptosis rate of irradiated cells was analysed in a time and dose dependent fashion and was compared to a sham-irradiated control. RESULTS After irradiation, a dose-dependent increase in apoptosis was observed, with a discontinuity (plateau or peak) between 0.3Gy and 0.7Gy in 9/10 donors (90%) and 59/80 samples (74%). 8/10 donors (80%) and 38/80 samples (47%) showed not only a discontinuous increase with a plateau but a relative maximum of apoptosis peaking within the dose range of 0.3 Gy and up to 0.7 Gy. CONCLUSION LD-RT induces a relative maximum of apoptosis in PBMC in the does range between 0.3 Gy and 0.7 Gy. This may contribute to its anti-inflammatory effect observed clinically.

Radiotherapy in Early-Stage Dupuytren’s Contracture

Background and Purpose:In early-stage Dupuytren’s contracture, radiotherapy is applied to prevent disease progression. Long-term outcome and late toxicity of the treatment were evaluated in a retrospective analysis.Patients and Methods:Between 12/1982 and 02/2006, 135 patients (208 hands) were irradiated with orthovoltage (120 kV; 20 mA; 4-mm Al filter), in two courses with five daily fractions of 3.0 Gy to a total dose of 30 Gy; separated by a 6- to 8-week interval. The extent of disease was described according to a modified classification of Tubiana et al. Long-term outcome was analyzed at last follow-up between 02/2008 and 05/2008 with a median follow-up of 13 years (range, 2–25 years). Late treatment toxicity and objective reduction of symptoms as change in stage and numbers of nodules and cords were evaluated and used as evidence to assess treatment response.Results:According to the individual stages, 123 cases (59%) remained stable, 20 (10%) improved, and 65 (31%) progressed. In stage N 87% and in stage N/I 70% remained stable or even regressed. In more advanced stages, the rate of disease progression increased to 62% (stage I) or 86% (stage II). 66% of the patients showed a long-term relief of symptoms (i.e., burning sensations, itching and scratching, pressure and tension). Radiotherapy did not increase the complication rate after surgery in case of disease progression and only minor late toxicity (skin atrophy, dry desquamation) could be observed in 32% of the patients. There was no evidence for a second malignancy induced by radiotherapy.Conclusion:After a mean follow-up of 13 years radiotherapy is effective in prevention of disease progression and improves patients’ symptoms in early-stage Dupuytren’s contracture (stage N, N/I). In case of disease progression after radiotherapy, a “salvage” operation is still feasible.Hintergrund und Ziel:Im Frühstadium des Morbus Dupuytren wird die perkutane Radiotherapie eingesetzt mit dem Ziel, die weitere Progression der Erkrankung zu verhindern. In einer aktuellen retrospektiven Analyse wurden der Langzeiterfolg sowie die Nebenwirkungen untersucht.Patienten und Methodik:Im Zeitraum von 12/1982 bis 02/2006 wurden 135 Patienten mit 208 erkrankten Händen am Orthovoltgerät (120 kV; 20 mA; 4-mm-Al-Filter) in zwei Serien (6–8 Wochen Pause) mit je 5 × 3,0 Gy bis zu einer Gesamtdosis von 30 Gy bestrahlt. Die Klassifikation der Erkrankung erfolgte modifiziert nach Tubiana et al. Die Langzeitergebnisse wurden bei einer Nachsorgeuntersuchung zwischen 02/2008 und 05/2008 (mediane Nachbeobachtungszeit 13 Jahre; Spanne 2–25 Jahre) erhoben. Die Spätnebenwirkungen und das Therapieansprechen hinsichtlich der Veränderungen des Erkrankungsstadiums sowie der Anzahl der Knoten und Stränge wurden erfasst.Ergebnisse:Unter Berücksichtigung des Ausgangsstadiums zeigte sich bei 123 Händen (59%) eine Befundstabilität, 20 Hände (10%) verbesserten sich, während 65 Hände (31%) eine Verschlechterung im Stadium erlitten. Bei Patienten im Stadium N konnte bei 87% der Hände und im Stadium N/I bei 70% eine stabile Situation oder eine Stadienverbesserung erreicht werden. In fortgeschritteneren Stadien stieg das Progressionsrisiko auf 62% (Stadium I) bis 86% (Stadium II). 66% der Patienten berichten über eine anhaltende Symptomrückbildung. Die Radiotherapie führte nicht zu einer erhöhten Komplikationsrate nach einer bei Progression durchgeführten Operation; es zeigten sich nur geringgradige Spätnebenwirkungen (Hautatrophie oder Trockenheit mit Schuppung) bei 32% der Patienten.Schlussfolgerung:Auch nach einer medianen Nachbeobachtungszeit von 13 Jahren erweist sich die Radiotherapie als effektive Maßnahme zur Verhinderung einer weiteren Progression in den Frühstadien der Erkrankung (Stadium N und N/I). Im Fall einer Progression ist eine „Salvage“-Operation ohne erhöhte Nebenwirkungen möglich.

The Anti-Inflammatory Effect of Low-Dose Radiation Therapy Involves a Diminished CCL20 Chemokine Expression and Granulocyte/Endothelial Cell Adhesion

Background and Purpose:Low-dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect, however, the underlying molecular mechanisms are not fully understood. The manipulation of polymorphonuclear neutrophil (PMN) function and/or recruitment may be one mechanism. Chemokines contribute to this process by creating a chemotactic gradient and by activating integrins. This study aimed to characterize the effect of LD-RT on CCL20 chemokine production and PMN/endothelial cell (EC) adhesion.Material and Methods:The EC line EA.hy.926 was irradiated with doses ranging from 0 to 3 Gy and was co-cultured with PMNs from healthy donors either by direct cell contact or separated by transwell membrane chambers. CXCL8, CCL18, CCL20 chemokine and tumor necrosis factor-(TNF-)α cytokine levels in supernatants were determined by ELISA and adhesion assays were performed. The functional impact of the cytokines transforming growth factor-(TGF-)β1 and TNF-α and of the intercellular adhesion molecule-(ICAM-)1 on CCL20 expression was analyzed by using neutralizing antibodies.Results:As compared to CXCL8 and CCL18, CCL20 chemokine secretion was found to be exclusively induced by a direct cell-cell contact between PMNs and EA.hy.926 ECs in a TNF-α-dependent, but ICAM-1-independent manner. Furthermore, irradiation with doses between 0.5 and 1 Gy resulted in a significant reduction of CCL20 release which was dependent on TGF-β1 (p < 0.01). The decrease of CCL20 paralleled with a significant reduction in PMN/EA.hy.926 EC adhesion (p < 0.001).Conclusion:The modulation of CCL20 chemokine expression and PMN/EC adhesion adds a further facet to the plethora of mechanisms contributing to the anti-inflammatory efficacy of LD-RT.Hintergrund und Ziel:Eine niedrigdosierte Strahlentherapie (LD-RT) kennzeichnet eine entzündungshemmende Wirksamkeit, die zugrundeliegenden molekularen Mechanismen sind jedoch noch unvollständig aufgeklärt. Die Beeinflussung der Funktion oder Rekrutierung von polymorphkernigen neutrophilen Granulozyten (PMNs) könnte einen Mechanismus darstellen. Chemokine tragen zu diesem Prozess durch die Ausbildung eines chemotaktischen Gradienten und die Aktivierung von Integrinen bei. In dieser Studie wurde der Effekt der LD-RT auf die Expression des Chemokins CCL20 und die Adhäsion von PMNs an Endothelzellen (ECs) untersucht.Material und Methodik:Die EC-Linie EA.hy.926 wurde mit Dosen von 0–3 Gy bestrahlt und mit PMNs gesunder Spender, entweder in direktem Zell-Zell-Kontakt oder durch Transwell-Membran-Kammern getrennt, kultiviert. Die Konzentrationen der Chemokine CXCL8, CCL18, CCL20 und von Tumor-Nekrose-Faktor-(TNF-)α im Kulturüberstand wurden in einem ELISA bestimmt. Ein funktioneller Einfluss der Zytokine „transforming growth factor“-(TGF-)β1 und TNF-α sowie des „intercellular adhesion molecule“-(ICAM-)1 auf die CCL20-Expression wurde mittels neutralisierender Antikörper untersucht.Ergebnisse:Im Vergleich zu CXCL8 und CCL18 wurde die Sekretion des Chemokins CCL20 ausschließlich durch einen direkten Zell-Zell-Kontakt zwischen PMNs und EA.hy.926-ECs in einem TNF-α-abhängigen, jedoch nicht durch ICAM-1 vermittelten Prozess induziert. Eine Bestrahlung mit Dosen zwischen 0,5 und 1 Gy führte zu einer signifikanten TGF-β1-vermittelten Minderung der CCL20-Sekretion (p < 0,01). Neben der Reduktion von CCL20 konnte eine gleichzeitige signifikante Verminderung der Adhäsion von PMNs an EA.hy.926-ECs beobachtet werden (p < 0,001).Schlussfolgerung:Die Modulation der CCL20-Chemokin-Expression und der PMN/EC-Adhäsion stellt eine neuartige Facette der Mechanismen dar, die zur entzündungshemmenden Wirksamkeit der LD-RT beitragen.

The Induction of TGF-β1 and NF-κB Parallels a Biphasic Time Course of Leukocyte/Endothelial Cell Adhesion Following Low-Dose X-Irradiation

Background and Purpose:Low-dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect, but the knowledge of the underlying molecular mechanisms is still scarce. The authors have recently reported that transforming growth factor beta 1 (TGF-β1) essentially contributes to a reduced endothelial adhesion of mononuclear cells (PBMC) following LD-RT. Furthermore, TGF-β1 secretion was associated with the induction of the transcription factor nuclear factor kappa B (NF-κB). However, the time course of adhesion, TGF-β1 expression, and NF-κB activity following LD-RT has not been thoroughly investigated yet.Material and Methods:The human EA.hy.926 endothelial cell line (EA.hy.926 EC) was grown to 95% confluence. Immediately after stimulation with the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α), EA.hy.926 EC were irradiated with single doses ranging from 0.3 up to 3 Gy. Adhesion assays were performed 4, 12, and 24 h after irradiation. Nuclear extracts and culture supernatants were harvested after 4, 8, 12, 20, 24, 30, and 40 h. NF-κB DNA-binding activity was analyzed by electrophoretic mobility shift assays (EMSA) and TGF-β1 secretion by enzyme-linked immunosorbent assay (ELISA). The functional impact of TGF-β1 on the course of leukocyte/EC adhesion was analyzed by neutralizing TGF-β1 in parallel with stimulation/irradiation of the EA.hy.926 EC.Results:4 and 24 h after irradiation of EA.hy.926 EC in the dose range between 0.3 and 0.7 Gy, a reduced adhesion of PBMC compared to nontreated controls could be observed. However, 12 h after irradiation a relative maximum of adhesion (up to 30% increase) was seen at a dose of 0.3 Gy. TGF-β1 secretion and NF-κB DNA-binding activity displayed a similar biphasic kinetics of induction with a relative minimum 12 h after irradiation. Neutralization of TGF-β1 activity restored adhesion at 4 and 24 h after LD-RT of EA.hy.926 EC, but it did not influence leukocyte adhesion 12 h after irradiation.Conclusion:LD-RT of stimulated human EA.hy.926 EC is followed by a biphasic time course of NF-κB activity and an increased secretion of TGF-β1. The kinetics shows peak levels at 4–8 h and 24–30 h after LD-RT and results in a biphasic leukocyte/EC adhesion profile.Hintergrund und Fragestellung:Eine niedrig dosierte Strahlentherapie (LD-RT) zeigt klinisch einen antiinflammatorischen Effekt. Die zugrunde liegenden molekularen Mechanismen sind jedoch noch wenig untersucht. Die Autoren konnten kürzlich zeigen, dass “Transforming Growth Factor beta 1” (TGF-β1) zu einer verminderten Adhäsion von mononukleären Zellen (PBMC) an Endothelzellen nach LD-RT beiträgt. Dabei war die TGF-β1-Sekretion mit der Induktion des Transkriptionsfaktors “Nuclear Factor kappa B” (NF-κB) assoziiert. Die zeitliche Abhängigkeit der Adhäsion, der TGF-β1-Sekretion und der NF-κB-DNA-Bindungsaktivität nach LD-RT ist bisher allerdings kaum untersucht.Material und Methodik:Die humane Endothelzelllinie EA.hy.926 wurde bis zu 95% Konfluenz kultiviert. Sofort nach Stimulierung mit dem proinflammatorischen Zytokin Tumor-Nekrose-Faktor alpha (TNF-α) wurden die Zellen mit Einzeldosen zwischen 0,3 und 3 Gy bestrahlt. Nach 4, 12 und 24 h wurden dann Adhäsionsassays durchgeführt. Nukleäre Extrakte und Kulturüberstände wurden nach 4, 8, 12, 20, 24, 30 und 40 h gewonnen. Die Messung der NF-κB-DNA-Bindungsaktivität erfolgte mittels EMSA („Electrophoretic Mobility Shift Assay“), die TGF-β1-Sekretion wurde in einem ELISA („Enzyme-Linked Immunosorbent Assay“) bestimmt. Eine funktionelle Relevanz von TGF-β1 für den Verlauf der Leukozytenadhäsion wurde durch Behandlung mit neutralisierenden Antikörpern parallel zur Stimulation/Bestrahlung von EA.hy.926-Endothelzellen untersucht.Ergebnisse:4 und 24 h nach Bestrahlung aktivierter EA.hy.926-Endothelzellen war im Dosisbereich von 0,3 bis 0,7 Gy eine verminderte Leukozytenadhäsion im Vergleich zu einer unbehandelten Kontrolle zu beobachten. Überraschenderweise zeigte sich 12 h nach Bestrahlung ein relatives Adhäsionsmaximum (Anstieg um bis zu 30%) bei 0,3 Gy. Die TGF-β1-Sekretion und NF-κB-DNA-Bindungsaktivität wiesen eine vergleichbare biphasische Kinetik mit einem relativen Minimum 12 h nach Bestrahlung auf. Eine Neutralisation der TGF-β1-Aktivität führte zur Wiederherstellung der Adhäsion an EA.hy.926-Endothelzellen 4 und 24 h nach LD-RT, die gesteigerte Adhäsion 12 h nach Bestrahlung wurde hingegen nicht beeinflusst.Schlussfolgerung:Die LD-RT stimulierter humaner EA.hy.926-Endothelzellen führt zu einer biphasischen Zeitabhängigkeit der NF-κB-DNA-Bindungsaktivität und TGF-β1-Sekretion. Dabei zeigt die Kinetik relative Maxima nach 4–8 h und 24–30 h und resultiert in einem biphasischen Profil der Adhäsion von Leukozyten an die Endothelzellen.

How Does Ionizing Irradiation Contribute to the Induction of Anti-Tumor Immunity?

Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

Radiotherapy in early-stage Dupuytren's contracture. Long-term results after 13 years.

Background and Purpose:In early-stage Dupuytren’s contracture, radiotherapy is applied to prevent disease progression. Long-term outcome and late toxicity of the treatment were evaluated in a retrospective analysis.Patients and Methods:Between 12/1982 and 02/2006, 135 patients (208 hands) were irradiated with orthovoltage (120 kV; 20 mA; 4-mm Al filter), in two courses with five daily fractions of 3.0 Gy to a total dose of 30 Gy; separated by a 6- to 8-week interval. The extent of disease was described according to a modified classification of Tubiana et al. Long-term outcome was analyzed at last follow-up between 02/2008 and 05/2008 with a median follow-up of 13 years (range, 2–25 years). Late treatment toxicity and objective reduction of symptoms as change in stage and numbers of nodules and cords were evaluated and used as evidence to assess treatment response.Results:According to the individual stages, 123 cases (59%) remained stable, 20 (10%) improved, and 65 (31%) progressed. In stage N 87% and in stage N/I 70% remained stable or even regressed. In more advanced stages, the rate of disease progression increased to 62% (stage I) or 86% (stage II). 66% of the patients showed a long-term relief of symptoms (i.e., burning sensations, itching and scratching, pressure and tension). Radiotherapy did not increase the complication rate after surgery in case of disease progression and only minor late toxicity (skin atrophy, dry desquamation) could be observed in 32% of the patients. There was no evidence for a second malignancy induced by radiotherapy.Conclusion:After a mean follow-up of 13 years radiotherapy is effective in prevention of disease progression and improves patients’ symptoms in early-stage Dupuytren’s contracture (stage N, N/I). In case of disease progression after radiotherapy, a “salvage” operation is still feasible.Hintergrund und Ziel:Im Frühstadium des Morbus Dupuytren wird die perkutane Radiotherapie eingesetzt mit dem Ziel, die weitere Progression der Erkrankung zu verhindern. In einer aktuellen retrospektiven Analyse wurden der Langzeiterfolg sowie die Nebenwirkungen untersucht.Patienten und Methodik:Im Zeitraum von 12/1982 bis 02/2006 wurden 135 Patienten mit 208 erkrankten Händen am Orthovoltgerät (120 kV; 20 mA; 4-mm-Al-Filter) in zwei Serien (6–8 Wochen Pause) mit je 5 × 3,0 Gy bis zu einer Gesamtdosis von 30 Gy bestrahlt. Die Klassifikation der Erkrankung erfolgte modifiziert nach Tubiana et al. Die Langzeitergebnisse wurden bei einer Nachsorgeuntersuchung zwischen 02/2008 und 05/2008 (mediane Nachbeobachtungszeit 13 Jahre; Spanne 2–25 Jahre) erhoben. Die Spätnebenwirkungen und das Therapieansprechen hinsichtlich der Veränderungen des Erkrankungsstadiums sowie der Anzahl der Knoten und Stränge wurden erfasst.Ergebnisse:Unter Berücksichtigung des Ausgangsstadiums zeigte sich bei 123 Händen (59%) eine Befundstabilität, 20 Hände (10%) verbesserten sich, während 65 Hände (31%) eine Verschlechterung im Stadium erlitten. Bei Patienten im Stadium N konnte bei 87% der Hände und im Stadium N/I bei 70% eine stabile Situation oder eine Stadienverbesserung erreicht werden. In fortgeschritteneren Stadien stieg das Progressionsrisiko auf 62% (Stadium I) bis 86% (Stadium II). 66% der Patienten berichten über eine anhaltende Symptomrückbildung. Die Radiotherapie führte nicht zu einer erhöhten Komplikationsrate nach einer bei Progression durchgeführten Operation; es zeigten sich nur geringgradige Spätnebenwirkungen (Hautatrophie oder Trockenheit mit Schuppung) bei 32% der Patienten.Schlussfolgerung:Auch nach einer medianen Nachbeobachtungszeit von 13 Jahren erweist sich die Radiotherapie als effektive Maßnahme zur Verhinderung einer weiteren Progression in den Frühstadien der Erkrankung (Stadium N und N/I). Im Fall einer Progression ist eine „Salvage“-Operation ohne erhöhte Nebenwirkungen möglich.

Epicondylopathia humeri (EPH) and peritendinitis humeroscapularis (PHS): evaluation of radiation therapy long-term results and literature review

BACKGROUND The effectiveness of radiotherapy (RT) for degenerative inflammatory disorders has been clinically documented in historical studies, but long-term follow-up and assessment with objective criteria are still not available. PATIENTS AND METHODS From 1986 to 1991, 200 consecutive patients with symptomatic epicondylopathia humeri (EPH, n = 104) and peritendinitis humeroscapularis (PHS, n = 96) were referred to our clinic. All patients were refractory to conventional therapy prior to irradiation. One hundred fifty-six patients with 192 sites (due to bilateral symptoms) received a full treatment course and were available for long-term follow-up, i.e. 83 patients with 93 elbows and 73 patients with 89 shoulders. The treatment response was evaluated with regard to pain symptoms grouped into five categories (pain at strain, pain at night, persistent pain during daytime, pain at rest and morning stiffness) and four grades (none, mild, moderate and severe) and with regard to established orthopedic scores (Morrey score and Constant and Murley score). The analysis was performed before and 6 weeks after RT and at last follow-up. All joints received two RT series applied in three weekly fractions (EPH, 6 x 1 Gy (total 12 Gy); PHS, 6 x 0.5 Gy (total 6 Gy)). The second RT series started 6 weeks after the first RT series. The minimum follow-up was 1 year for both groups and the mean follow-up reached 4 years (range 1-8 years). RESULTS Fifty elbows (43 patients) and 44 shoulders (39 patients) achieved complete pain relief in all pain categories; 24 elbows and 28 shoulders substantially improved, i.e. had only minor symptoms. Thus, 74 elbows and 72 shoulders responded to RT. Nineteen elbows (17 patients) had surgery after RT due to persisting symptoms or subjective dissatisfaction; 17 shoulders (12 patients) were non-responders and five of those were operated on; seven elbows and one shoulder were completely free of pain after surgery. The mean Morrey score improved by 18 points (from 78 to 96) and the mean Constant and Murley score improved by 48 points (from 18 to 66). Two cases worsened according to the Morrey score and one case worsened according to the Constant and Murley score. Bi- and multivariate analysis revealed two factors with negative prognostic value on treatment outcome, i.e. EPH, long symptom interval prior to RT and long-term immobilization with plaster (P < 0.05) and PHS, long symptom interval prior to RT and lack of pain intensification during the first RT course (P < 0.05) were poor prognostic factors. CONCLUSION RT is highly effective for refractory EPH and PHS. Structured pain scores and quantitative orthopedic scores are important for evaluation. Prognostic factors for outcome can be established. Due to minimal side effects and low costs, RT represents an excellent treatment compared to conventional methods of treatment and surgery in the chronic disease.