Low Dose Radiation Therapy, Particularly with 0.5 Gy, Improves Pain in Degenerative Joint Disease of the Fingers: Results of a Retrospective Analysis.

Low-dose radiation therapy (LDRT) has been successfully established for decades as an alternative analgesic treatment option for patients suffering from chronic degenerative and inflammatory diseases. In this study, 483 patients were undergoing LDRT for degenerative joint disease of the fingers and thumb at the University Hospital Erlangen between 2004 and 2019. Radiotherapy was applied according to the German guidelines for LDRT. Several impact factors on therapeutic success, such as the age and gender, the number of affected fingers, the single and cumulative dose, as well as the number of series, were investigated. In summary, 70% of the patients showed an improvement of their pain following LDRT. No significant impact was found for the factors age, gender, the number of series or the cumulative dosage. Patients with an involvement of the thumb showed a significantly worse outcome compared to patients with an isolated affection of the fingers. In this cohort, patients receiving a single dose of 0.5 Gy reported a significantly better outcome than patients receiving 1.0 Gy, strongly suggesting a reduction in the total dose. In summary, LDRT is a good alternative treatment option for patients suffering from degenerative and inflammatory joint disease of the fingers.

DEGRO guidelines for the radiotherapy of non-malignant disorders. Part II: Painful degenerative skeletal disorders.

BACKGROUND AND PURPOSE: The purpose of this article is to summarize the updated DEGRO consensus S2e guideline recommendations for the treatment of benign painful degenerative skeletal disorders with low-dose radiotherapy. MATERIALS AND METHODS: This overview reports on the role of low-dose radiotherapy in the treatment of enthesiopathies (shoulder syndrome, trochanteric bursitis, plantar fasciitis, and elbow syndrome) and painful arthrosis (knee, hip, hand, and finger joints). The most relevant aspects of the DEGRO S2e Consensus Guideline Radiation Therapy of Benign Diseases 2014 regarding diagnostics, treatment decision, dose prescription as well as performance of radiotherapy and results are summarized. RESULTS: For all indications mentioned above, retrospective and some prospective analyses have shown remarkable effects in terms of pain relief. Nevertheless, the Level of Evidence (LoE) and the Grade of Recommendation (GR) vary: LoE 1b-4 and GR A-C. CONCLUSION: Low-dose radiotherapy for painful degenerative skeletal disorders is effective in the majority of the patients and therefore it may be a reasonable therapeutic alternative when simple and non-invasive methods have been used without persistent success. For all discussed entities, single fraction doses of 0.5-1.0 Gy and total doses of 3.0-6.0 Gy/series applied with 2-3 fractions per week are recommended.

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.

Calcifying tendonitis of the shoulder joint : predictive value of pretreatment sonography for the response to low-dose radiotherapy.

BACKGROUND AND PURPOSE: Calcifying tendonitis is a degenerative inflammatory joint disorder. Pain relief can be successfully achieved with low-dose radiotherapy. It is actually unknown which types of calcifying tendonitis respond to radiotherapy and which do not. The authors tried to get predictive objectives for the response to radiotherapy on the basis of different morphological patterns of calcifications evaluated by X-ray and ultrasound. PATIENTS AND METHODS: Between August 1999 and September 2002, a total of 102 patients with 115 painful shoulder joints underwent low-dose radiotherapy. At the beginning of radiotherapy, every shoulder joint was examined with a radiograph in two planes. In addition, sonography was performed before and during therapy. This examination was repeated 6 and 18 months after irradiation. Radiotherapy consisted of two series with a total dose of 6.0 Gy. 29 joints with calcifying tendonitis could be further divided using the sonographic and radiographic classification according to Farin and Gärtner, respectively. RESULTS: Pain relief was achieved in 94/115 joints (82%) at a follow-up of 18 months (median). A different response to radiotherapy was found using the sonographic classification of Farin: calcifying tendonitis type III (n = 18) responded well in contrast to a significantly worse result in type I (n = 11). The radiologic classification did not provide a predictive value. CONCLUSION: Sonographic classification of calcifying tendonitis is predictive for the outcome after radiotherapy. Especially patients with Farin type III calcification will benefit from low-dose radiotherapy.

Effect of total mesorectal excision on the outcome of rectal cancer after standardized postoperative radiochemotherapy: do randomized studies translate into clinical routine?

PURPOSE: To compare local control, disease-free survival and overall survival after postoperative radiochemotherapy with or without total mesorectal excision (TME) in a retrospective analysis. PATIENTS AND METHODS: Between 1993 and 2002, 103 patients with UICC stage II and III rectal cancer were treated by surgery and postoperative chemoradiation. Group B (n = 50; 1993-1998) were operated before TME era without using TME and group A (n = 53; 1998-2002) with TME; both groups received identical radiochemotherapy to a total dose of 50.4 Gy (median) and two courses of continuous 5-fluorouracil infusion. RESULTS: Patients in group A (TME) showed a significant improvement in 5-year disease-free survival (71.1%; 46.8%) and freedom from distant metastases (76.3%; 46.9%) and a marked improvement of local control (85.2%; 62.5%). Acute and late toxicity were significantly less frequent in group A. CONCLUSION: Radiochemotherapy cannot compensate an insufficient surgical procedure. These data confirm that TME is the standard. High outcome quality can be achieved in daily practice compared to results of randomized studies without patient selection.

Basics of Radiation Biology When Treating Hyperproliferative Benign Diseases.

For decades, low- and moderate-dose radiation therapy (RT) has been shown to exert a beneficial therapeutic effect in a multitude of non-malignant conditions including painful degenerative muscoloskeletal and hyperproliferative disorders. Dupuytren and Ledderhose diseases are benign fibroproliferative diseases of the hand/foot with fibrotic nodules and fascial cords, which determine debilitating contractures and deformities of fingers/toes, while keloids are exuberant scar formations following burn damage, surgery, and trauma. Although RT has become an established and effective option in the management of these diseases, experimental studies to illustrate cellular composites and factors involved remain to be elucidated. More recent findings, however, indicate the involvement of radiation-sensitive targets like mitotic fibroblasts/myofibroblasts as well as inflammatory cells. Radiation-related molecular mechanisms affecting these target cells include the production of free radicals to hamper proliferative activity and interference with growth factors and cytokines. Moreover, an impairment of activated immune cells involved in both myofibroblast proliferative and inflammatory processes may further contribute to the clinical effects. We here aim at briefly describing mechanisms contributing to a modulation of proliferative and inflammatory processes and to summarize current concepts of treating hyperproliferative diseases by low and moderate doses of ionizing radiation.

Reduced secretion of the inflammatory cytokine IL-1ß by stimulated peritoneal macrophages of radiosensitive Balb/c mice after exposure to 0.5 or 0.7 Gy of ionizing radiation.

Since the beginning of the 20th century, low dose radiotherapy (LD-RT) has been practiced and established as therapy of inflammatory diseases. Several clinical studies already have proven the anti-inflammatory effect of low doses of ionizing irradiation (LDR). However, further research is inevitable to reveal the underlying immune-biological mechanisms. Focus has been set on the modulation of activated macrophages by LDR, since they participate in both, initiation and resolution of inflammation. Here we examined with an ex vivo peritoneal mouse macrophage model how LDR modulates the secretion of the inflammatory cytokines IL-1ß and TNF-α by activated macrophages and whether the basal radiosensitivity of the immune cells has influence on it. Peritoneal macrophages of Balb/c mice responded to exposure of 0.5 or 0.7 Gy of ionizing irradiation (X-ray) with significant decreased release of IL-1ß and slightly, but not significantly, reduced release of TNF-α. Macrophages of the less radiosensitive C57BL/6 mice did not show this anti-inflammatory reaction. This was observed in both wild type and human TNF-α transgenic animals with C57BL/6 background. We conclude that only the inflammatory phenotype of more radiosensitive macrophages is reduced by LDR and that ex vivo and in vivo models with primary cells should be applied to examine how the immune system is modulated by LDR.

Immunomodulatory properties and molecular effects in inflammatory diseases of low-dose x-irradiation.

Inflammatory diseases are the result of complex and pathologically unbalanced multicellular interactions. For decades, low-dose X-irradiation therapy (LD-RT) has been clinically documented to exert an anti-inflammatory effect on benign diseases and chronic degenerative disorders. By contrast, experimental studies to confirm the effectiveness and to reveal underlying cellular and molecular mechanisms are still at their early stages. During the last decade, however, the modulation of a multitude of immunological processes by LD-RT has been explored in vitro and in vivo. These include leukocyte/endothelial cell adhesion, adhesion molecule and cytokine/chemokine expression, apoptosis induction, and mononuclear/polymorphonuclear cell metabolism and activity. Interestingly, these mechanisms display comparable dose dependences and dose-effect relationships with a maximum effect in the range between 0.3 and 0.7 Gy, already empirically identified to be most effective in the clinical routine. This review summarizes data and models exploring the mechanisms underlying the immunomodulatory properties of LD-RT that may serve as a prerequisite for further systematic analyses to optimize low-dose irradiation procedures in future clinical practice.

Low dose ionising radiation leads to a NF-κB dependent decreased secretion of active IL-1ß by activated macrophages with a discontinuous dose-dependency.

PURPOSE: Therapy with low doses of ionising radiation (X-rays) exerts anti-inflammatory effects. Little is known about whether and how low doses of X-ray treatment modulate the inflammatory phenotype of macrophages, especially the secretion of Interleukin-1beta (IL-1ß). MATERIALS AND METHODS: Macrophages were differentiated from human THP-1 monocytes, activated with lipopolysaccharide (LPS), treated with distinct low doses of X-rays, and co-activated with monosodium urate crystals (MSU) to induce inflammasome activation. Secretion of IL-1ß was analysed by an enzyme-linked immunosorbent assay (ELISA) and Western blot. Furthermore, we analysed the intracellular amounts of the serine/threonine protein kinase B (named: Akt), mitogen-activated protein kinase p38 (p38), the v-rel reticuloendotheliosis viral oncogene homolog A (RelA), and pro- and cleaved IL-1ß. RESULTS: Low dose X-rays led to decreased secretion of active IL-1ß in a manner discontinuous with dose which was most pronounced after 0.5 or 0.7 Gy. Passive release of lactate dehydrogenase (LDH) was not influenced by X-rays. The decreased secretion of IL-1ß correlated with reduced translocation of RelA, being part of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) complex, into the nucleus. After 0.5 or 0.7 Gy of X-rays, the intracellular protein amounts of up (p38) and downstream molecules (Akt) of NF-κB were reduced in activated macrophages, as were the pro- and cleaved forms of IL-1ß. CONCLUSIONS: Distinct low doses of X-rays induce an anti-inflammatory phenotype of activated macrophages by lowering the amount of secreted IL-1ß in a NF-κB dependent manner.

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.

Discontinuous induction of X-linked inhibitor of apoptosis in EA.hy.926 endothelial cells is linked to NF-κB activation and mediates the anti-inflammatory properties of low-dose ionising-radiation.

BACKGROUND AND PURPOSE: This study aimed to characterize a link between X-linked inhibitor of apoptosis protein (XIAP) expression, apoptosis induction, Nuclear Factor kappa B (NF-κB) activity and the anti-inflammatory properties of low-dose ionising-radiation (LD-RT). MATERIAL AND METHODS: EA.hy.926 endothelial cells (ECs) were irradiated with doses ranging from 0.3 to 3Gy, and subsequently stimulated by TNF-α, and XIAP expression was either detected by immunoblotting or TaqMan-PCR. Apoptosis was quantified by AnnexinV staining or by caspase 3/7 activity assays. NF-κB transcriptional activity was analysed by a luciferase reporter assay, secretion of Transforming Growth Factor beta 1 (TGF-ß(1)) and adhesion of peripheral blood mononuclear cells (PBMC) to EC were quantified using ELISA and adhesion assays. RESULTS: LD-RT of the activated EA.Hy.926 EC induces XIAP expression in a discontinuous manner with a relative maximum at 0.5Gy and 3Gy which parallels a discontinuity in apoptosis induction and caspase 3/7 activity. siRNA-mediated attenuation of XIAP resulted in an increased rate of apoptosis, a hampered NF-κB transcriptional activity and a diminished secretion of TGF-ß(1). As compared to control-siRNA treated cells, adhesion of PBMC to EC was increased in XIAP depleted EA.Hy.926 EC. CONCLUSION: The modulation of apoptosis, NF-κB activity and TGF-ß(1) by XIAP in irradiated and subsequent stimulated EC contributes to an impaired PBMC/EC adhesion and to the anti-inflammatory properties of LD-RT.

Activator protein 1 shows a biphasic induction and transcriptional activity after low dose X-irradiation in EA.hy.926 endothelial cells.

Low dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect. The underlying molecular mechanisms, however, are still a matter of actual research. We have recently shown that LD-RT of stimulated EA.hy.926 endothelial cells (EC) resulted in a biphasic DNA-binding and transcriptional activity of NF-kappaB in parallel with a biphasic course of leukocyte adhesion. Here we report, that following low dose X-irradiation, an increased activator protein 1 (AP-1) DNA-binding activity was observed in EC with a first relative maximum at 0.3 Gy as analysed by electrophoretic mobility shift assay. AP-1 activity then decreased at doses between 0.5 and 1 Gy and subsequently increased again at 3 Gy. This biphasic profile was confirmed on the transcriptional level by an AP-1 specific chemoluminescence reporter assay. In conclusion, the discontinuous dose response of AP-1 activation may add a further facet to the plethora of mechanisms contributing to the anti-inflammatory efficacy of LD-RT.

[Radiotherapy for shoulder impingement]. / Bestrahlung beim Impingementsyndrom des Schultergelenks.

BACKGROUND AND PURPOSE: Up to now, degenerative shoulder diseases were summarized by the term "periarthritis humeroscapularis". Actual shoulder diseases can be differentiated etiopathologically according to a primary and secondary impingement syndrome. Narrowing of the subacromial space, which is caused by an osseous shape variant, leads to primary impingement. Secondary impingement develops, when the subacromial space is reduced by swelling tissue below the osseous shoulder roof. This study aimed for the exact diagnosis to indicate therapy and to classify the results according to the Constant score. PATIENTS AND METHODS: From August 1999 to September 2002, 102 patients with 115 shoulder joint conditions underwent radiation therapy (RT). All joints received two RT series (6 x 0.5 Gy/series) applied in two to three weekly fractions, totaling a dosage of 6.0 Gy (250 kV, 15 mAs, 1-mm Cu filter). The second RT course started 6 weeks after the end of the first. 115 shoulders were examined before RT, 6 weeks after the second RT course and, finally, during the follow-up from January to May 2003. RESULTS: Pain relief was achieved in 94/115 shoulder joints (82%) after 18-month follow-up (median). A significant difference existed between secondary impingement and primary/non-impingement according to response. Tendinosis calcarea, bursitis subdeltoidea, tendovaginitis of the long biceps tendon, and capsulitis adhaesiva responded well to therapy. CONCLUSION: Shoulder diseases of secondary impingement demonstrate a good response to RT. Less or no benefit was found in primary impingement syndrome or complete rotator cuff disruption and acute shoulder injuries, respectively.

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-)alpha cytokine levels in supernatants were determined by ELISA and adhesion assays were performed. The functional impact of the cytokines transforming growth factor-(TGF-)beta(1) and TNF-alpha 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-alpha-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-beta(1) (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.

Patterns of care in the radiotherapy of prostate cancer in Northern Bavaria 1998-2000.

PURPOSE: A patterns-of-care study of radiotherapy (RT) in prostate cancer was performed in Northern Bavaria, Germany, to characterize patient selection, treatment strategies and outcome for the time period 1998-2000. MATERIAL AND METHODS: Patients who received curative-intent radical or postoperative RT were identified from the databases of six centers (one university, five teaching/regional hospitals). Two centers treated < 20 patients and were excluded from further analysis. At the remaining four centers, 148 patients receiving radical RT and 134 undergoing postoperative RT were analyzed for pretreatment and RT characteristics and actuarial biochemical control (BC; ASTRO definition). RESULTS: All patients were treated with three-dimensional conformal external-beam techniques. In radical RT patients, cT- and cN-stages as well as the frequency of (neo)adjuvant hormonal therapy (53-91%) and RT to pelvic nodes (2-97%) and the mean total RT dose (64.8-71.0 Gy) varied significantly between centers. In postoperative RT, centers differed significantly in R-status, initial prostate-specific antigen (PSA) and nodal RT frequency (2-89%), whereas total RT doses were similar (62.3-64.8 Gy). After radical RT, 5-year BC was 68.6% and differed significantly between centers on univariate analysis. In a multivariate model, only total RT dose showed a trend toward an effect on BC. In postoperative RT patients, overall 5-year BC was 82.1%, and age and initial PSA were associated with BC on multivariate analysis. CONCLUSION: From 1998 to 2000, radical RT for prostate cancer at the Northern Bavarian centers now studied was performed with three-dimensional conformal technique to conservative total doses and selection criteria for postoperative RT were highly variable.

The induction of TGF-beta(1) and NF-kappaB 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-beta(1)) essentially contributes to a reduced endothelial adhesion of mononuclear cells (PBMC) following LD-RT. Furthermore, TGF-beta(1) secretion was associated with the induction of the transcription factor nuclear factor kappa B (NF-kappaB). However, the time course of adhesion, TGF-beta(1) expression, and NF-kappaB 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-alpha), 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-kappaB DNA-binding activity was analyzed by electrophoretic mobility shift assays (EMSA) and TGF-beta(1) secretion by enzyme-linked immunosorbent assay (ELISA). The functional impact of TGF-beta(1) on the course of leukocyte/EC adhesion was analyzed by neutralizing TGF-beta(1) 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-beta(1) secretion and NF-kappaB DNA-binding activity displayed a similar biphasic kinetics of induction with a relative minimum 12 h after irradiation. Neutralization of TGF-beta(1) 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-kappaB activity and an increased secretion of TGF-beta(1). 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.