Chapter

Review of Radiation Therapy for Palmar and Plantar Fibromatosis (Dupuytren and Ledderhose Disease)

Authors:
  • MVZ Strahlentherapie Osnabrück
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Abstract

Palmar fibromatosis and plantar fibromatosis, called Dupuytren disease and Ledderhose disease (DD, LD), respectively, are chronic inflammatory and hyperproliferative connective tissue disorders which involve the palmar fascia of the hand and the plantar fascia of the foot, where they produce nodules, cords, and contractures; in addition, the overlaying subcutaneous fat and skin layers can be affected. These digitopalmar and digitoplantar alterations are part of a deforming and progressive, irreversible condition and part of a systemic connective tissue disorder (Enzinger and Weiss 1995), which is characterized by typical biochemical changes and additional fibrous deposits located at the dorsal PIP joint (forming knuckle pads), on the ear helix, the hand wrist, the elbow, and the penis forming a penile angulation (Peyronie disease). Although the tissue changes appear to have some pathohistological similarities, many studies and research efforts to identify a single cause of this generalized disorder have failed so far (Tomasek et al. 1999; Rudolph and Vande Berg 1991). Although numerous hypotheses exist about the disease onset and progression, the specific role of mesenchymal stem cells, fibroblasts, and myofibroblasts and the correlation with the clinical development of DD and LD are still not conclusively answered (Rödel and Seegenschmiedt 2016).

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... Radiotherapy was also tested on DD because proliferating fibroblasts and myofibroblasts are radiosensitive and because radiation interferes with growth factors and inflammatory cytokines. Radiotherapy may slow disease progression at early stages when surgery is not an option [42], and research of its use is ongoing. There are other non-surgical treatments that are ineffective or deemed unsafe for clinical use [41]. ...
Thesis
The sense of touch is processed by the somatosensory system in which mechanoreceptors are the sensory neurons that translate mechanical stimuli into neural impulses by using specialized mechanoreceptive end organs. Pacinian corpuscles (PCs), located primarily in the hairless skin of the hands and feet, are the mechanoreceptor responsible for sensing low--amplitude, high--frequency vibrations (80-1000 Hz). In this thesis, I explored how vibrotactile perception is mediated by the PCs using a combination of computational modeling, benchtop experiments on donor tissue, and psychophysical tests. There are several mechanical models of the PC, and the first part of this thesis demonstrated that a multiphysics model of a single PC contained enough details to recapitulate the trend of observed discriminability of human subjects. We showed that discriminability of sinusoidal vibrations increases as the frequency difference between the pairs increase, and we found that complex waveforms with two frequency components were more difficult to discriminate and did not follow a discernible trend. Next, we investigated the effect that Dupuytren disease (DD) has on vibrotactile perception at frequencies within the PC's range. Dupuytren disease is a progressive hand disorder in which growth and densitification of fibrous tissue in the palms eventually causes the affected fingers to bend irreversibly. DD usually presents clinically after the age of 50, affects about 3 per 10,000 adults, and is associated with alterations to the size and the internal structure of PCs. By measuring vibrotactile sensitivity in healthy and DD subjects, we found that women are more sensitive to high--frequency vibrations than men and that men with DD may exhibit reduced sensitivity compared to men without DD. We also found that, for patients in which DD presents unilaterally, the finger with DD is less sensitive than the corresponding finger on the unaffected hand. These data may serve as a useful reference to future DD researchers and may facilitate development of novel diagnostic or prognostic protocols. Finally, we designed a system to measure the viscoelastic properties of the PC and tested isolated human cadaveric PCs from donors with and without DD to better understand how the mechanoreceptor's viscoelastic properties affect vibrotactile perception.
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Every year in Germany about 50.000 patients are referred and treated by radiotherapy (RT) for "non-malignant disorders". This highly successful treatment is applied only for specific indications like preservation or recovery of quality of life by means of pain reduction or resolution and / or an improvement of formerly impaired physical body function due to specific disease related symptoms. Since 1995, German radiation oncologists have treated non-malignant disorders according to national consensus guidelines; these guideline were updated and further developed over 3 years by implementation of a systematic consensus process to achieve national upgraded and accepted S2e clinical practice guidelines. Throughout this process international standards of evaluation were implemented. This review summarizes most of the generally accepted indications for the application of RT for non-malignant diseases and presents the special treatment concepts. The following disease groups are addressed: painful degenerative skeletal disorders, hyperproliferative disorders and symptomatic functional disorders. These state of the art guidelines may serve as a plattform for the daily clinical work; they provide a new starting point for quality assessment, future clinical research including the design of prospective clinical trials, and outcome research in the under-represented and less appreciated field of radiotherapy for nonmalignant disorders.
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Aim Radiotherapy was applied in our clinic to prevent the disease progression in early stage Dupuytren’s contracture. Initial response, long-term outcome, acute and late toxicity of the treatment were evaluated in a retrospective analysis. Patients and Method Between 1982 and 1993, 96 patients (142 hands) received orthovoltage radiotherapy, which consisted of 2 radiotherapy courses with daily fractionation of 5×3 Gy (total dose: 30 Gy) separated by a 6 weeks interval. The Dupuytren’s contracture was staged according to the classification of Tubiana et al. [38]. The initial evaluation was performed 3 months after completion of radiotherapy, while long-term outcome was analysed at last follow-up between February and April 1994. The mean follow-up was 6±2 (range 1 to 12) years. Fifty-seven patients with a follow-up of ≥5 (median 7,5; mean 9,5 to 12) years were separately evaluated for long-term outcome, i. e. prevention of disease progression. Acute and late treatment toxicity was assessed using the RTOG/EORTC criteria. Results According to stage, 130 (92%) cases remained stable at 3 months follow-up, 10 (7%) improved and 2 (1%) progressed. An objective reduction of symptomatic cords and nodules was achieved in 107 (75%) cases at 3 months follow-up. Moreover, 87% of the patients reported a subjective relief of symptoms. In long-term follow-up, only 16 of 142 (11%) cases had progressed according to stage. In the group with a minimum follow-up of 5 years (n=57), 44 (77%) patients experienced no progression, while 13 (23%) progressed inside (8 cases) or outside (5 cases) of the radiotherapy field. Many “failures” could have been avoided with appropriate choice of larger safety margins included in the treated portals, however, most failures were successfully managed by a second radiotherapy or hand surgery. Conclusion Radiotherapy prevents disease progression for early stage Dupuytren’s contracture. Thus, an otherwise necessary surgical procedure in adavanced stages of Dupuytren’s contracture can be avoided. Moreover, in case of disease progression despite radiotherapy a second radiotherapy or salvage operation is still feasible.
Article
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Dupuytren's disease (DD) is a type of fibromatosis which progressively results in the shortening and thickening of the fibrous tissue of the palmar fascia. This condition which predominantly affects white-northern Europeans has been identified since 1614. DD can affect certain activities of daily living such as face washing, combing hair and putting hand in a glove. The origin of Dupuytren's contracture is still unknown, but there are a number of treatments that doctors have come across throughout the years. Historically surgery has been the mainstay treatment for DD but not the only one. The objective is to make a structured review of the most recent advances in treatment of DD including the surgical and medical interventions. We have looked at the most relevant published articles regarding the various treatment options for DD. This review has taken 55 articles into consideration which have met the inclusion criteria. The most recent treatments used are multi-needle aponeurotomy, extensive percutaneous aponeurotomy and lipografting, injecting collagenase Clostridium histolyticum, INF-gamma and shockwave therapy as well as radiotherapy. Each of these treatments has certain advantages and drawbacks and cannot be used for every patient. In order to prevent this condition, spending more time and money in the topic is required to reach better and more consistent treatments and ultimately to eradicate this disease.
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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. 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. 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. 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.
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Keloids are benign diseases of the skin. Because of the high rate of relapses after operation often postoperative irradiation is used. Treatment modalities must be collected by Patterns of Care Studies before therapy advice may be given from DEGRO. Dates of investigations with questionnaire on mail of 250 radiotherapy institutions in Germany in 1997/2000 were collected to know therapy modalities, results and side effects. Keloids were irradiated in 101 institutions. During a time up to 35 years 1672 patients were irradiated, 880 patients had a follow-up. Mostly radiotherapy was applied soon postoperatively with kilovoltage radiotherapy or electrons 4-12 MeV fractionated 3-5 times a week and single doses of 2-3 Gy up to total doses of 10-20 Gy. 101 relapses were seen, the frequency of 11.4% is in the range of literature. Relapses were seen in the interval of some weeks up to 2 years after therapy. Side effects of irradiation were low, no malignant transformation was reported. Postoperative radiotherapy for keloids is applied in Germany mostly under equal conditions. This therapy offers effective relapse prophylaxis with nearly no side effects. A follow-up for 2 years is necessary to see outcome and relapses of irradiation.
Article
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Morbus Ledderhose (ML) is a rare hyperproliferative disorder of the plantar aponeurosis which is similar in its clinical course to Morbus Dupuytren (MD). We examined whether radiotherapy (RT) can effect symptoms and prevent disease progression. From June 1996 to December 2001, 25 patients (12 female/13 male) aged 9-76 (median: 56) years had radiotherapy (RT) for symptomatic ML. Follow-up (FU) was at least 1 year. 36 feet (16 right/20 left) were treated, as eleven patients had bilateral disease. Twelve (48%) patients had MD. There were 63 nodules (with 0,5-6,5 cm diameter) on all feet and 20 cords (with 1-4 cm length) on 13 (52%) feet prior to RT. 21 (84%) patients had one or more signs: 14 (56%) severe local pain, eight (32%) walking difficulties, twelve (48%) other symptoms, pressure or tension sensation. The RT field involved all nodules and cords plus safety margin. Two RT-series were applied (each 5 3 Gy in 1 week) separated by 8-12 weeks up to a total dose of 30 Gy. Evaluation was performed at the end of RT, after 3 and 12 months FU and in December 2002. The primary endpoint was prevention of disease progression and avoidance of surgery. Secondary endpoints were objective changes of morphological and functional parameters and patient's satisfaction measured on a visual analogue scale (VAS). With a median FU of 38 (12-67) months no patient experienced progression or underwent surgery: 11 of 36 (44%) feet had a reduced number (overall: -16) or size of nodules, 7 of 13 (54%) feet had a reduced number (overall: -9) or length of cords; gait was improved in six of twelve (50%) feet; pain was reduced or had completely disappeared in 9 of 15 (60%) feet, and other symptoms disappeared in 8 of 18 (44%) symptomatic feet. 20 (80%) patients regarded 28 of 36 (78%) treated feet as improved and 8 (22%) in stable condition. The median relative improvement stated by patients on the VAS was 50% (0-100%). Treatment side effects were minimal: During and within 3 months of the RT course only a slight erythema (CTC 1 degrees ) was seen in five treated lesions, while dry skin changes within the RT portal were observed in three cases (11%) in long term FU (> 12 months). Radiotherapy is effective in treating ML and may prevent otherwise necessary surgical interventions. Nodules, cords and symptoms regress, but long-term outcome of at least 5 years has to be awaited. Prospective phase III studies should confirm these results.
Article
Dupuytren’s contracture nodules, but not cords, contain myofibroblasts. These cells, which combine many electron microscopic, physiologic, and immunohistochemical characteristics of fibroblasts and smooth muscle cells, are probably the active force of contraction. Prominent myofibroblasts and intracellular microtubules correlate with increased likelihood of clinical recurrence after surgery. Tissue culture of cells derived from Dupuytren’s contracture myofibroblasts show consistently slower cell replication than from fibroblasts and show persistence of electron microscopic characteristics in early passages. Research in Dupuytren’s contracture myofibroblasts has been done on human tissue and so has clinical correlation. Myofibroblast presence may help to predict recurrence of disease and suggests that palmar skin should be excised when adherent to disease nodules. The theory of myofibroblasts helps explain why the open technique often succeeds, and why full thickness skin grafts inhibit recurrent contracture.
Article
Numerous studies support the idea that the myofibroblast is a key cell responsible for the tissue contraction in Dupuytren’s disease. In vitro models have been developed to study the underlying cellular basis of myofibroblast differentiation and contraction. Studies suggest that the growth factor TGF-β1 combined with mechanical stress can promote the differentiation of fibroblasts into myofibroblasts. Agonists, such as LPA and thrombin, can promote the contraction of myofibroblasts through specific intracellular signaling pathways that regulate levels of phosphorylated myosin light chain. Agents that can affect these intracellular signaling pathways hold promise as a means to decrease contraction of the myofibroblast and of the palmar fascia in Dupuytren’s disease. Finally, the recent finding that IFN-γ can suppress both the differentiation of the myofibroblast and the generation of contractile force, together with preliminary clinical results using IFN-γ, suggest the potential use of IFN-γ for nonsurgical therapy of Dupuytren’s disease. Future studies into the cellular basis of tissue contraction should provide alternative methods to improve management of Dupuytren’s contracture.
Chapter
For decades, a low-dose irradiation with X-rays has clinically been documented to exert a beneficial effect on hyperproliferative disorders like the Dupuytren disease (DD) and Ledderhose disease (LD). By contrast, experimental studies to unravel underlying cellular and molecular mechanisms are still at their early stages. Recent data, however, indicate the involvement of radiation-sensitive target cells like mitotic fibroblasts/myofibroblasts, induction of free radicals to impair proliferative activity of these cells, interference with growth factors and cytokines and a reduction of activated immune cells interacting with the inflammatory and proliferative processes. We here aim at briefly describing mechanisms contributing to a modulation of fibrogenic and inflammatory components upon exposure to ionizing radiation.
Chapter
Dupuytren’s contracture is associated with increasing age [1], sex (M gt; F) [1], diabetes mellitus [2,3], heavy alcohol consumptior [4], HIV infection [5], cigarette smoking [6], epilepsy [7] and Colles’ fractures [8], but rarely with rheumatoid arthritis [9]. Two important features of the palmar fascia of Dupuytren’s contracture are an increase in the number of fibroblasts [10], and an increase in the relative amounts of type III collagen [11]. It is likely that these phenomena are associated, as fibroblasts cultured at high density decrease type I collagen production and thus increase the relative amounts of type III collagen [12]. Changes in the glycosaminoglycan content can also be explained by high cell density [13].
Article
Purpose: Palmar and plantar fibromatosis (PPF) is a progressive connective tissue disorder of the hand/foot that often leads to debilitating functional impairment. In Europe, orthovoltage radiation therapy (RT) has been demonstrated to prevent local disease progression for up to 80% of patients with early-stage PPF. There are limited data reporting outcomes for populations outside of Europe or using electron RT. Methods and materials: Between 2008 and 2013, 44 early-stage PPF cases received RT. RT fields involved clinically defined targets encompassing involved areas (skin changes, cords, nodules) with at least 1.5-cm margins. En face electrons (6-12 MeV) and bolus (0.5-1 cm) were selected individually. Outcomes are reported for patients who participated in an institutional review board-approved standardized questionnaire and chart review. Results: Thirty-three patients received 66 treatments (45 hands/15 feet and 6 reirradiations). Most frequent dose schemes were 21 Gy (3 Gy in 7 fractions) and 30 Gy (3 Gy in 10 fractions with 6- to 8-week breaks after 15 Gy). Median time to follow-up survey was 31 months. Disease progression at any location within or outside the RT treatment field occurred in 20 of 33 patients (61%). Fourteen of 60 sites (23%) developed in-field progression, but 4 sites were successfully reirradiated with final local control in 50 of 60 sites (83%). RT improved pretreatment symptoms of pain with strain at 30 of 37 sites (81%) and itch/burn sensations at 17 of 21 sites (81%). There were no reported grade ≥2 late toxicities even with reirradiation. Patient reported overall success with treatment was 31 of 33 patients (94%). Conclusion: PPF is a progressive disease. En face electron RT is an effective therapy that stabilizes or improves symptoms in the majority of patients. Reirradiation can be considered as a treatment option for in-field progression. Patients report minimal toxicity and a high rate of satisfaction with treatment.
Article
IntroductionPalmar and plantar fascial fibromatoses are benign hyperproliferative disorders of the deep fascia of the palm and sole. This study seeks to examine the role of radiotherapy in the management of fascial fibromatosis.Method Six consecutive cases of early-stage fascial fibromatosis treated with radiotherapy at the Adelaide Radiotherapy Centre between July 2008 and May 2011 were analysed. The results of the case series were compared with a systematic review of the literature.ResultsAll six cases regressed or showed a reduction of symptoms following radiotherapy. Treatment was well tolerated with minor toxicities. Median follow-up for the case series was 38.5 months. The systematic review identified seven studies describing the use of radiotherapy as primary treatment for fascial fibromatosis between 1946 and 2013. The literature indicates that radiotherapy can prevent disease progression and improve symptoms for early-stage disease, with low likelihood of significant toxicities.Conclusion Early results from our case series are consistent with the literature, showing that radiotherapy can provide an effective management option for patients with early-stage fascial fibromatosis, and justify consideration of radiotherapy as a primary treatment for early-stage disease.
Article
Im Frühstadium des Morbus Dupuytren wird die externe Radiotherapie mit dem Ziel eingesetzt, den progressiven Verlauf der Erkrankung zu verhindern. Eine aktuelle Langzeitverlaufskontrolle soll die Ergebnisse und Nebenwirkungen der Radiotherapie darstellen. Patienten und Methode: Wir untersuchten 99 Patienten (176 Hände), welche sich von 1982–1994 einer Radiotherapie an unserer Klinik unterzogen. Jeder Patient erhielt zwei Serien einer Radiotherapie mit jeweils 5 × 3 Gy (Gesamtdosis 30 Gy, 120 kV, 4 mm Al, Bestrahlungspause von 6–8 Wochen nach 15 Gy). Die Beugekontraktur wurde nach Tubiana et al. eingeteilt. Von Juli bis November 1999 erfolgte nach einer medianen Nachbeobachtungszeit von 10 Jahren (7–18 Jahre) eine Kontrolluntersuchung. Die Nebenwirkungen wurden nach den LENT-SOMA-Kriterien eingestuft. Ergebnisse: Im Stadium N blieben 84% und im Stadium N/I 67% stabil oder zeigten eine Regression. Dagegen stieg ab dem Stadium I die Progressionsrate auf 65% und im Stadium II auf 83% an. Eine “Salvage”-Operation erfolgte bei 29 Patienten, ohne dass Wundheilungsstörungen beobachtet wurden. Schlussfolgerung: Die Radiotherapie stellt in den Frühstadien (Stadium N, N/I) der Dupuytren'schen Kontraktur auch langfristig eine effektive und sichere Methode dar. Bei Therapieversagern ist eine spätere Operation möglich.
Article
The normal anatomy of the palmar fascia and histopathological changes occurring in Dupuytren's contracture are briefly described. The presenting signs are reviewed in 34 cases and correlated with these pathological and anatomical changes. The results of treatment by surgery alone are given and reasons for overall unsatisfactory outcome discussed. Two techniques of radiation treatment are described as well as the combined orthopaedic-radiotherapy policy practised. Roughly half the cases treated by radiotherapy alone obtain a satisfactory result. A combination of surgery and pre-operative radiotherapy is suggested for late cases, thereby lessening the chance of recurrence.
Chapter
Unter Dupuytren-Kontraktur (DK; Morbus Dupuytren, “Dupuytren’s disease”) versteht man eine Erkrankung der kollagenen Faserbündel des straffen Bindegewebssystems der Palmarseite der Hand. Es kommt zu einer Fibrose mit Knotenbildung und Umbauvorgängen, in deren Verlauf sich eine Verkürzung der Faserbündel mit einer Kontraktur der betroffenen Gelenke entwickelt.
Chapter
Purpose: Several retrospective studies have shown that radiotherapy (RT) can prevent progression of Dupuytren’s disease (DD), but so far no dose-response relationship has been established. This chapter presents long-term results of our previously published prospective randomized trial comparing two different RT doses with a control group without RT. Methods: From January 1997 to December 2009 over 600 patients with DD were referred to our clinic for RT to prevent further disease progression. As of January 2011, 489 pts (291 males; 198 females) with at least five (range 5–13; mean 8.5) years follow-up (FU) were included in the analysis. Due to bilateral affliction, a total of 718 hands (sites) were evaluated. Overall 73% of all hands were affected, 230 (47%) on both hands; according to Tubiana’s classification, 470 (65.5%) hands had stage N (nodules/cords, no extension deficit), 124 (17%) had stage N/I (≤ 10° deficit), 106 (15%) had stage I (11–45° deficit), and 18 (2.5%) had stage II (46–90° deficit) or more. After clinical assessment and informed consent, patients could choose between observation only (83 patients with 122 affected hands) and RT (406 patients with 596 affected hands); all patients in the RT group were randomized into two different RT concepts: One group (207 patients with 303 affected hands) received 10 × 3 Gy (total 30 Gy) in 2 series of each 5 × 3 Gy separated by a break of 12 weeks; the other group (199 patients with 297 affected hands) received 7 × 3 Gy (total 21 Gy) in one series within 2 weeks. Orthovoltage RT (120 kV) was applied using standard cones and individual shielding of uninvolved areas of the palm. The relevant patient and disease parameters were equally distributed between control and both RT groups. The clinical evaluation (side effects, efficacy) was performed at 3 and 12 months after RT and at last follow-up (FU) in December 2010. Subjective (patient’s satisfaction) and objective parameters (palpation, measurements, and comparative photographs) were applied to assess the response. The primary endpoints were objective clinical progression and necessity of salvage surgery. Secondary endpoints were treatment of side effects and specific objective disease parameters (number and size of nodules, cords) and patient’s subjective satisfaction. Results: The acute radiogenic toxicity was low with 26.5% CTC grade 1 and 2.5% CTC grade 2; late effects, such as dry skin, were acceptable low with 14% LENT grade 1; no secondary cancer was observed in the long-term follow-up. After a minimum FU of >5 and a mean FU of 8.5 years, a total of 119 (16.5%) sites showed remission of nodules, cords or stage; 383 (53%) remained stable and 206 (29%) progressed and of those 97 (13.5%) required surgery. The progression rate in the control group (any progression 62%, surgery 30%) as compared to RT groups (21 Gy: 24%/surgery 12%; 30 Gy: 19.5%/surgery 8%) was significantly higher (p < 0.0001). Similarly, the overall and mean number of nodules, cords, and other changes decreased in the RT groups as compared to the progression in the control group (p < 0.01). Tubiana’s classification at last FU revealed a stage progression in the control group in 63 (52%) sites as compared to 64 (22%) and 49 (16%) in the 21 and 30 Gy RT group. There were 50 (8%) relapses inside and 114 (19%) outside the RT field in the RT group as compared to 52% and 28% potential relapses in the control group. Salvage surgery was possible without healing problems. Symptomatic relief was achieved in 4 (8%) sites of the control group as compared to 24 (21%) and 32 (26%) sites in the 21 and 30 Gy group, respectively. Uni- and multivariate prognostic factors for disease progression were smoking habit (trend), symptom duration prior to RT over 24 months, Dupuytren stage, extension deficit, and digital involvement (all p < 0.05). The most important independent factor was the implementation of RT as compared to the control without RT. Conclusions: RT is effective to prevent progression of Dupuytren’s disease; it reduces the necessity of hand surgery which is required due to disease progression at a minimum FU of 5 years. In addition, RT can reduce disease-related symptoms or helps to avoid their progression. Both RT protocols have been found to be effective and well tolerated, with slight advantage for the 30 Gy group as compared to 21 Gy group. Both acute and chronic side effects were well accepted and tolerated by the patients; so far no secondary malignancy was observed. From the radiobiologic background and rationale of radiotherapy, it appears possible not only to implement radiotherapy in the beginning of the disease process but also during active disease periods, e.g., for early relapses after surgical procedures. KeywordsRadiation therapy–Radiotherapy–Palmar fibromatosis–Controlled clinical trial–Prognostic factors–Long-term outcome–Non-malignant disorders–Benign disease
Chapter
Purpose: Use of radiotherapy (RT) for treating primary and recurrent plantar fibromatosis (Ledderhose disease, LD) has been reported in a few clinical studies. This chapter presents and analyzes for the first time the results of a long-term study. Initial results of our pilot study on a smaller number of patients with shorter follow-up have already been published (Seegenschmiedt 2007; Seegenschmiedt and Attassi 2003). Patients & Methods: From 01/1997 to 12/2009, 158 consecutive patients (91 males, 67 females; mean age 49, median 52, range 9–81 years) were referred for treatment. Ninety-four feet were unaffected and 222 feet affected (84 bilateral, 29 right, 25 left). Ninety-one patients (47 males, 44 females) received RT on 136 feet; 67 patients with 134 feet served as control w/o RT: prior to first contact all patients had growth or an increasing number of nodules (N) and cords (C); moreover, 88 (97%) had symptoms (S) within 6–12 months including pain (P), numbness (N), or other symptoms (O); 86 (95%) had walking difficulties (W) due to pain and/or used orthotics. Thirty-five feet (26%) had recurrent or progressive LD after one or more surgical procedures before RT. Orthovoltage RT (125–150 kV X-rays) was used in all cases with the exception of two adolescents (3 feet) who had megavolt electron beam RT due to more complex target volumes. RT was applied in 5 weekly fractions of 3 Gy repeated after a mean of 12 (range 10–15) weeks up to 30 Gy total dose; three patients (5 feet) received only one RT series. Primary endpoints were (a) prevention of progression (PP) and avoidance of surgery (AS). Secondary endpoints were number or size of nodules or cords, symptom relief including pain relief, function, subjective satisfaction using a linear analogue scale (LAS), and radiogenic side effects scored according to the Common Toxicity Criteria (CTC) and Late Effects Normal Tissue (LENT) scales. Results: In 01/2011, all patients (feet) with a minimum follow-up (FU) of 24 months were evaluated; mean FU was 68 (range 24–144) months. Six (7%) patients (11 (8%) feet) had progression and of those 5 (6%) patients (7 (5%) feet) had salvage surgery, one with longer healing period. Sixty feet (44%) remained stable and 65 (48%) feet regressed with regard to nodules, cords, or symptoms; of those, 35 feet achieved complete remission (CR) with freedom of all nodules, cords, and symptoms; 30 feet had partial remission (PR). Previous symptoms and dysfunction improved in up to 90% of all sites. Patients’ satisfaction improved by 3.2 points on the subjective symptom score in 81 (89%) patients. Acute side effects (CTC 1° or 2°) occurred in 29 (21%) or 7 (5%) feet. Chronic sequelae (LENT 1°: dryness or fibrosis of skin) occurred in 22 (16%) feet. No grade 3 acute or late side effects occurred. The control group without RT had significantly higher progression and surgical intervention rates. Multivariate analysis found recurrent LD, nicotine abuse, advanced and symptomatic disease as poor prognostic parameters. Conclusions: External beam RT is the most effective treatment both for primary and recurrent LD as compared to all published surgical results. After long-term follow-up (FU) of at least 2 years, only 6 (7%) patients (with 11 (8%) feet) had recurrent or progressive disease with only 5 (6%) patients (7 (5%) feet) requiring salvage surgery. As compared to the known outcome after surgery, RT reaches a high and long-term remission rate, causes much less side effects, is less impaired by relapses, and thus is highly cost-effective in the long-term management of LD. Although so far no cure is available for LD, the application of RT appears to be “best care” for primary early stage LD, while the potential role of RT for recurrent or progressive LD after completion of surgery has still to be defined in conjunction with foot surgeons in future prospective clinical trials. KeywordsRadiotherapy–Plantar fibromatosis–Morbus Ledderhose–Ledderhose Disease–Prognostic factors–Long-term outcome–Non-malignant disorders–Benign disease
Article
Plantar fibromatosis is a rare, hyperproliferative, benign lesion of the plantar aponeurosis with an unknown cause. Surgical treatment is associated with a high recurrence rate and risk of complications. The goal of this study was to determine the recurrence rate of plantar fibromatosis after plantar fasciectomy at the authors' institute during the past three decades and the factors associated with an increased risk for recurrence. The study group contained 27 patients with plantar fibromatosis, who underwent 40 operations on 33 feet, including 13 right (39 percent) and 20 left (61 percent) feet. The overall recurrence rate was 60 percent. Treating a primary lesion with total plantar fasciectomy was associated with the lowest (25 percent) and local resection of the lesion was associated with the highest recurrence rate (100 percent). There seemed to be a relation between the existence of multiple nodules in one foot and a higher recurrence rate. The recurrence of a primary lesion treated with fasciectomy combined with postoperative radiotherapy seemed to be lower in comparison with the recurrence rate after surgery only. Surgical treatment of plantar fibromatosis is associated with a high recurrence rate and indicated only when the lesions are highly symptomatic and conservative measures fail. Total plantar fasciectomy is the most successful treatment in this study, particularly for primary lesions. The role of postoperative radiotherapy should be evaluated further. A prospective multicenter study comparing different surgical procedures will be needed to determine the type of operation that most effectively eliminates plantar fibromatosis.
Article
To evaluate the efficacy of radiation therapy (RT) in the treatment of early stages of benign plantar fibromatosis (Morbus Ledderhose [ML]). From 2003 to 2008, 24 patients (33 sites) with a mean age of 52 years received RT for symptomatic ML. Prior to RT, 19 patients complained of pain and 15 had walking difficulties. 21 patients (28 sites) were irradiated with orthovoltage X-rays and three (five sites) received electron-beam irradiation. The RT protocol consisted of five weekly fractions of 3.0 Gy (15 Gy), repeated after 6 weeks to a total dose of 30 Gy in 20 patients (28 sites). In four patients (five sites), two single fractions of 4.0 Gy were applied, repeated at intervals of 4 weeks to total doses of 24-32 Gy. Primary study endpoints were the prevention of disease progression and the avoidance of a surgical intervention. Secondary endpoints were pain relief, improvement of gait, and patients' subjective satisfaction measured with a linear analog scale (LAS). After a median follow-up of 22.5 months, none of the patients experienced a progression of number and size of the lesions or the clinical symptoms. In eleven sites (33.3%) complete remission of cords or nodules occurred, in 18 (54.5%) a reduced number or size was noted, and four sites (12.1%) were unchanged. Pain relief was achieved in 13/19 patients (68.4%), and an improvement of gait abnormalities was noted in 11/15 patients (73.3%). The patients' subjective satisfaction measured by means of the LAS revealed a median improvement of 3.5 points in 22/24 patients (91.6%). Skin or soft tissues toxicities RTOG grade > 2 were not noted. RT is effective for treatment of the early stages of ML and may obviate the need for a surgical intervention. Long-term follow-up studies including a larger number of patients are required to define the role of RT in the management of this disorder.
Article
Limited indications for radiation treatment of benign dermatoses are presented in order to emphasize modern restrictions and techniques in the use of dermatologic radiation therapy and to promote measures of protection against stray radiation. The use of softer, less penetrating X rays, least effective doses and meticulous shielding are recommended. So done, radiation therapy offers an effective therapeutic alternative for conditions that do not respond to other forms of treatment.
Article
Dupuytren's contracture nodules, but not cords, contain myofibroblasts. These cells, which combine many electron microscopic, physiologic, and immunohistochemical characteristics of fibroblasts and smooth muscle cells, are probably the active force of contraction. Prominent myofibroblasts and intracellular microtubules correlate with increased likelihood of clinical recurrence after surgery. Tissue culture of cells derived from Dupuytren's contracture myofibroblasts show consistently slower cell replication than from fibroblasts and show persistence of electron microscopic characteristics in early passages. Research in Dupuytren's contracture myofibroblasts has been done on human tissue and so has clinical correlation. Myofibroblast presence may help to predict recurrence of disease and suggests that palmar skin should be excised when adherent to disease nodules. The theory of myofibroblasts helps explain why the open technique often succeeds, and why full thickness skin grafts inhibit recurrent contracture.
Article
In order to analyze the effect of various kinds of radiation on the terminal differentiation processes of fibroblasts in culture, both human skin and lung fibroblasts were irradiated with electromagnetic non ionizing as well as ionizing radiation in clonal and sparse mass culture systems. As analyzed by cell biological (cell type frequencies), biochemical (collagen synthesis) and molecular markers (expression of protein PIVa) human skin and lung fibroblasts are induced to differentiate prematurely into terminal postmitotic cells. Thus, both electromagnetic and ionizing radiation induce terminal differentiation in cultured cells. These data add some new aspects for the interpretation of radiation effects on cells, e.g., in clinical therapy, as well as for the development of normal tissue responses during early and late effects after radiotherapy.
Article
The etiology, symptomatology, clinical findings, course and staging of Dupuytren's contracture are discussed. Surgery is indicated from the second stage onwards; since pain very rarely occurs, it plays no role in establishing the indication for operation. The surgical techniques available are described. Conservative therapy has no influence on the course of the condition, while radiotherapy is inadmissible on account of its side effects. Physical therapy and physiotherapeutic pre-operative measures can improve the results of surgery.
Article
The cellular basis of contracture of the palmar fascia in patients who have Dupuytren disease involves the generation of intracellular force and the transmission of this force to the surrounding tissue. A specialized cell, the myofibroblast, supposedly generates this intracellular force. Recently published studies from our laboratory demonstrated that the cytoskeleton of the myofibroblast contains non-muscle myosin and not smooth-muscle myosin, suggesting that it utilizes a non-muscle contractile system. In addition, these studies identified the extracellular glycoprotein fibronectin, not the basal-lamina-specific glycoprotein laminin, at the surface of myofibroblasts, suggesting that the transmission of the intracellular force to the surrounding tissue also occurs by a non-muscle mechanism. Because of the lack of proteins that are specific to smooth muscle in the specialized cell in Dupuytren disease, we prefer the term specialized contractile fibroblast to describe this type of cell. To determine the mechanism by which the intracellular force may be transmitted to the surrounding tissue, we examined the ultrastructure of the connection of the cytoskeleton of the specialized contractile fibroblast to the surrounding extracellular matrix. By electron microscopy, extracellular filamentous material was identified at the surface of the specialized contractile fibroblast. These extracellular fibrils were found to be in close association with intracellular bundles of actin microfilaments, resulting in specialized transmembranous associations at the surface of the specialized contractile fibroblast. Bundles of filamentous extracellular material were found to extend from the surface of the specialized contractile fibroblast, connecting it with the surrounding matrix and also with adjacent specialized contractile fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
After a brief description of the characteristics of Dupuytren's disease the operative and conservative therapeutic measures are examined from both clinical and social medical aspects. It is shown in 154 patients with Dupuytren's contracture of the hands in various stages that an advance of this disease could usually be prevented by treatment with soft X-rays. A comparison of costs shows that this therapy is at least 11 times cheaper than a good operative procedure without follow-up treatment. For the patient it is highly important that only little time is lost in the outpatient compared with inpatient treatment. Loss of work-place, professional incapacity or inability to work because of Dupuytren's disease can be prevented with a probability bordering on certainty.
Article
Fibrosis is a common sequela of both cancer treatment by radiotherapy and accidental irradiation and has been described in many tissues including skin, lung, heart and liver. The underlying mechanisms of the radiation-induced fibrosis still remain to be resolved. In the present review we tried to illustrate the basic cellular mechanisms of radiation-induced fibrosis based on the newest findings arising from molecular radiobiology and cell biology. Based on these findings the cellular mechanism of radiation-induced fibrosis can be seen as a multicellular process involving various interacting cell systems in the target organ resulting in the fibrotic phenotype of the fibroblast/fibrocyte cell system.
Article
We studied 11 nodules from patients with Dupuytren's contracture to determine whether alpha-smooth muscle actin expression in Dupuytren's fibroblasts is related to the generation of contractile force. Tissue was placed into explant culture and fibroblast strains were obtained. The mean percent of cultured Dupuytren's fibroblasts expressing alpha-smooth muscle actin, as determined by immunofluorescence, was 14 +/- 8 and ranged from 1% to 26%. The ability of Dupuytren's fibroblasts to generate contractile force was determined by using a previously described collagen lattice contraction assay. We observed a significant positive correlation between the expression of alpha-smooth muscle actin and the generation of contractile force in cell strains of Dupuytren's fibroblasts. In addition, six fibroblast strains from palmar fascia of individuals undergoing carpal tunnel release were examined. In six strains of palmar fibroblasts the mean percent of cells expressing alpha-smooth muscle actin was 5 +/- 3 and ranged from 1% to 9%. Six Dupuytren's fibroblast strains, in which more than 15% of the cells expressed alpha-smooth muscle actin, were significantly more contractile than the palmar fibroblasts. These results suggest that Dupuytren's fibroblasts can acquire smooth muscle characteristics and that the acquisition of a smooth muscle-like phenotype correlates with increased contractility.
Article
Dupuytren contracture is a disease of the palmar fascia characterized by nodular fibroblastic proliferation; its etiology and pathogenesis are poorly understood. Growth factors are polypeptides that regulate cell growth and differentiation and extracellular matrix production. Platelet-derived growth factor is known to cause fibroblastic proliferation, and it may be involved in the pathogenesis of Dupuytren contracture. The purpose of this study was to determine if the gene for the B chain of platelet-derived growth factor is expressed in Dupuytren contracture. Tissue from patients who had Dupuytren disease was examined immunohistochemically with the 5B5 antibody, which is a marker for fibroblasts. Polymerase chain reaction, gel electrophoresis, Southern blotting, and in situ hybridization were also used to study gene expression in the tissue as well as in normal fascia, A172 cells, and MRC5 cells. Total cellular RNA was extracted from tissue and cells. Polymerase chain reaction was done with oligonucleotide primers complementary to a portion of the platelet-derived growth-factor-B and platelet-derived growth-factor-receptor genes. The platelet-derived growth-factor-B gene was expressed in all six specimens from the patients who had Dupuytren contracture as well as in the A172 cells, but not in the normal fascia lata or the MRC5 cells. These results were confirmed with Southern blotting of the products of the reaction with a platelet-derived growth-factor-B probe. The gene for the platelet-derived growth-factor receptor was expressed by all tissues and cells studied.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
In the early stage of the disease a group of patients was treated with radiotherapy, later another group with injections of superoxid-dismutase. The results of follow-up examinations 7 years after radiotherapy and 3 years after treatment with superoxid-dismutase respectively do not differ clearly from spontaneous course of Dupuytren's contracture grade one. At present we cannot recommend an alternative treatment for early stage Dupuytren's contracture.
Article
Plantar fibromatosis is a recognised form of Dupuytren's disease. Two cases are presented in which there were flexion contractures of the toes in the involved feet. This is an extremely rare form of this plantar affliction.
Article
Radiotherapy (RT) was given to prevent disease progression in early-stage Dupuytren's contracture. Initial response, long-term outcome, and treatment toxicity were evaluated. Between 1982 and 1993, 96 patients (142 hands) received orthovoltage RT, which consisted of two courses with daily fractionation of 5 x 3 Gy (total dose 30 Gy) separated by a 6-week interval. The extent of disease was staged according to the classification of Tubiana et al.. Initial evaluation was performed 3 months after completion of RT; long-term outcome was analyzed at last follow-up (i.e., between February and April 1994). The mean follow-up was 6 +/- 2 (range 1-12) years. Fifty-seven patients with a minimum follow-up of 5 (median 7.5; mean 9.5-12) years were separately evaluated for long-term outcome (i.e., prevention of disease progression). Acute and late treatment toxicity was assessed using the Radiation Therapy Oncology Group/EORTC criteria. According to stage, 130 cases (92%) remained stable at 3 months follow-up, 10 improved (7%), and 2 progressed (1%). An objective reduction of symptomatic cords and nodules was achieved in 107 cases (75%) at 3 months follow-up. Moreover, 87% of the patients reported a subjective relief of symptoms. In long-term follow-up, only 16 of 142 cases (11%) had progressed according to stage. In the group with minimum follow-up 5 years (n = 57), 44 patients (77%) experienced no disease progression, whereas 13 progressed (23%) inside [8 cases (14%)] or outside [5 cases (9%)] of the RT field. Most failures could have been avoided with appropriate choice of larger safety margins included in the treated portals; however, the failures outside were still amenable for another RT course. Radiotherapy is effective to prevent disease progression for early-stage Dupuytren's contracture. Thus, it helps to avoid an otherwise necessary surgical procedure which is performed in adavanced stages of Dupuytren's contracture.
Article
Dupuytren's disease is associated with contraction of specialized fibroblasts present in the diseased palmar fascia. Pharmacologic agents were evaluated for their ability to promote or inhibit contraction of Dupuytren's fibroblasts in vitro using a collagen lattice contraction assay. In the first part of the study, lysophosphatidic acid (LPA), serotonin, angiotensin II, and prostaglandin F2 alpha were tested for their ability to promote Dupuytren's fibroblast contraction. Lysophosphatidic acid was found to significantly promote Dupuytren's fibroblast contraction as compared with controls. This response to LPA is dose dependent, with a half-maximal response of 0.07 microM. Angiotensin II, serotonin, and prostaglandin F2 alpha at 1 mM, induced a significant amount of contraction as compared to controls, but the amount of contraction was at least six times less than that observed for LPA. In the second part of the study, prostaglandins E1 and E2 or the calcium blockers nifedipine and verapamil were tested for their ability to inhibit LPA-promoted contraction. It was found that both types of inhibitors partially block LPA-promoted contraction of Dupuytren's fibroblasts. The effect of the various pharmacologic agents on normal palmar fibroblasts was not evaluated. The focus of this study was to examine the regulation of contraction of Dupuytren's fibroblasts. This study demonstrates that LPA is a potent agonist of Dupuytren's fibroblast contraction and that this contraction can be inhibited by specific pharmacologic agents. These findings provide a rational basis for investigating further the clinical use of the calcium channel blockers nifedipine or verapamil and prostaglandins E1 and E2 to control Dupuytren's disease and possibly other fibrotic conditions.
Article
Radiotherapy was applied in our clinic to prevent the disease progression in early stage Dupuytren's contracture. Initial response, long-term outcome, acute and late toxicity of the treatment were evaluated in a retrospective analysis. Between 1982 and 1993, 96 patients (142 hands) received orthovoltage radiotherapy, which consisted of 2 radiotherapy courses with daily fractionation of 5 x 3 Gy (total dose: 30 Gy) separated by a 6 weeks interval. The Dupuytren's contracture was staged according to the classification of Tubiana et al. [38]. The initial evaluation was performed 3 months after completion of radiotherapy, while long-term outcome was analysed at last follow-up between February and April 1994. The mean follow-up was 6 +/- 2 (range 1 to 12) years. Fifty-seven patients with a follow-up of > or = 5 (median 7,5; mean 9,5 to 12) years were separately evaluated for long-term outcome, i.e. prevention of disease progression. Acute and late treatment toxicity was assessed using the RTOG/EORTC criteria. According to stage, 130 (92%) cases remained stable at 3 months follow-up, 10(7%) improved and 2 (1%) progressed. An objective reduction of symptomatic cords and nodules was achieved in 107 (75%) cases at 3 months follow-up. Moreover, 87% of the patients reported a subjective relief of symptoms. In long-term follow-up, only 16 of 142 (11%) cases had progressed according to stage. In the group with a minimum follow-up of 5 years (n = 57), 44 (77%) patients experienced no progression, while 13 (23%) progressed inside (8 cases) or outside (5 cases) of the radiotherapy field. Many "failures" could have been avoided with appropriate choice of larger safety margins included in the treated portals, however, most failures were successfully managed by a second radiotherapy or hand surgery. Radiotherapy prevents disease progression for early stage Dupuytren's contracture. Thus, an otherwise necessary surgical procedure in advanced stages of Dupuytren's contracture can be avoided. Moreover, in case of disease progression despite radiotherapy a second radiotherapy or salvage operation is still feasible.
Article
Numerous studies support the idea that the myofibroblast is a key cell responsible for the tissue contraction in Dupuytren's disease. In vitro models have been developed to study the underlying cellular basis of myofibroblast differentiation and contraction. Studies suggest that the growth factor TGF-beta 1 combined with mechanical stress can promote the differentiation of fibroblasts into myofibroblasts. Agonists, such as LPA and thrombin, can promote the contraction of myofibroblasts through specific intracellular signaling pathways that regulate levels of phosphorylated myosin light chain. Agents that can affect these intracellular signaling pathways hold promise as a means to decrease contraction of the myofibroblast and of the palmar fascia in Dupuytren's disease. Finally, the recent finding that IFN-gamma can suppress both the differentiation of the myofibroblast and the generation of contractile force, together with preliminary clinical results using IFN-gamma, suggest the potential use of IFN-gamma for nonsurgical therapy of Dupuytren's disease. Future studies into the cellular basis of tissue contraction should provide alternative methods to improve management of Dupuytren's contracture.
Article
Since its discovery, radiation has been used to treat numerous ailments, including many benign conditions. The most susceptible disorders have included keloids, heterotopic bone formation, and, most recently, vascular restenosis. These disorders are proliferative in nature and fall under the category of excessive wound healing or scar formation after trauma. In addition, radiation has been used for its immunosuppressive quality, eg, in organ transplantation to suppress graft rejection and in the treatment of autoimmune diseases. In this article, we have chosen keloids as an archetype for radiation use with benign conditions; the radiation inhibition of vascular restenosis will be used as a prototype to explore a paradigm for the molecular and cellular basis of radiation treatment for selected benign disorders. Vascular restenosis is currently one of the new frontiers of radiation therapy and offers opportunities to explore the role of inflammatory or immune cell responses in benign conditions that lead to excessive fibrogenesis and require treatment. The pathophysiology of surgical wound healing has not been avidly studied in the radiobiologic laboratory setting. However, the paradigm we propose for the effectiveness of radiation treatment for benign conditions is based on the model offered by Clark. He describes three phases of molecular and cellular events in which an inflammatory phase precedes the fibrogenic phase, occurs within hours of injury, and continues for weeks. We postulate that the radiosensitive targets within the vascular milieu are the monocyte/macrophages that would otherwise act as the trigger for the induced cytokine cascade, leading to the myofibroblast being recruited from a quiescent to a proliferative phase, resulting in fibrogenesis.
Article
The most common cause of morbidity and mortality in the United States is vascular disease, which afflicts a wide spectrum of organs such as the heart (cardiovascular system), brain (cerebrovascular system), kidney (renal system), liver (hepatic system), and extremities (peripheral vascular system). The most common pathology of vascular diseases is occlusion. Percutaneous Transluminal Angioplasty (PTA) is currently the most common nonsurgical treatment for obstructive arteries. Unfortunately, the long-term effectiveness of PTA is limited by a high restenosis rate. Efforts to reduce post-PTA restenosis, including laser, mechanical atherectomy, intravascular stenting, and pharmacologic agents, have not been successful. With recent advances in the pathogenesis of restenosis, we have learned that the major problem is the intimal hyperplastic reaction in response to vessel injury. Encouraging animal data in the use of various radiotherapeutic approaches to prevent restenosis has led to a large number of multi-national, multicenter, randomized trials on coronary vascular systems. Because early results have been in favor of radiation therapy, and because the basic process of restenosis is similar for coronary and noncoronary vascular systems, many investigators extend the application of radiotherapy to the prevention of restenosis in peripheral vascular systems. However, the clinical scenarios are much different for peripheral vascular systems than for the coronary vascular system. This article discusses the current views of the pathophysiology of restenosis, major clinical trials, and perspectives on future studies. Experimental studies on animal models have documented the profound effects of endovascular brachytherapy in reducing restenosis caused by angioplasty and stenting. Early results of clinical trials are encouraging and confirm these positive results. Long-term follow-up data are needed to show that radiation does prevent, not merely delay, restenosis; Several areas of opportunity exist for both basic science research and clinical studies to enhance our knowledge of the pathophysiology. This would optimize the treatment strategy, maximizing the benefits and minimizing late complications.
Article
Benign diseases of the orbit can cause significant impairment of visual function through direct effects on the eye or supporting orbital tissues. Persistent moderate-to-severe inflammatory symptoms, diplopia, and visual loss may prompt therapeutic intervention. Low doses of external-beam irradiation (20 Gy in 2-Gy fractions) have an efficacy equivalent to corticosteroid medications in the treatment of both Graves' ophthalmopathy and orbital pseudotumor, with response rates of 50% to 80%. Appropriate patient selection, coordination with other medical subspecialties, and careful treatment planning are important in maximizing benefit from radiation therapy. In the case of Graves' ophthalmopathy, quantitative assessment of orbital disease severity and thyroid status as well as attainment of cross-sectional imaging should be performed before treatment. Patients whose thyroid disease is controlled but who have moderate-to-severe active orbital involvement can be offered orbital radiation therapy with a high likelihood of response. Stability of disease is generally obtained within 6 months; surgical correction of residual abnormalities may be required. For orbital pseudotumor, attainment of histological material before treatment is important in excluding benign or malignant systemic diseases, including malignant lymphoma. Genotypic abnormalities may exist in patients with reactive lymphoid hyperplasia, some of whom ultimately develop systemic lymphoma. Within the dose range recommended for treatment of Graves' ophthalmopathy and pseudotumor, late radiation effects on the retina or optic nerve should be nonexistent. Adequate lens shielding is required, however, to prevent cataract formation. This may require individualized treatment planning with computed tomography at the time of simulation. Pterygia recurrence after bare sclera excision occurs in at least 30% of cases, usually within 6 months of surgery. Radiation of the surgical bed using a strontium-90 source, beginning within 24 hours postoperatively, reduces the risk of recurrence substantially. Late scleral complications have been associated with large single-fraction treatments. To achieve maximal efficacy with minimal complications, fractionated treatment should be given by radiation oncologists experienced with the technique using sources calibrated by the National Bureau of Standards.
Article
The benign mesenchymal diseases, for which radiation is often quite effective in halting progression or achieving complete and permanent resolution, include neoplastic and nonneoplastic processes (eg, giant cell tumor of bone to keloid). Radiation oncologists have been reluctant to employ radiation in the management of patients with benign disease for several reasons: (1) the small but nonzero risk of late appearance of radiation-induced malignant tumors; (2) were radiation subsequently required to be employed in the same region of the body for treatment of a separate and independent neoplasm, the radiation dose might have to be reduced to an ineffective level; and (3) nonmalignant tissue changes that might appear at quite remote times and complicate healing of surgical wounds. Currently a liberalization of the use of radiation is in progress because of the clinical seriousness of many benign processes for which radiation yields a major therapeutic benefit. This reassessment of radiation oncology in the United States has been stimulated by the much wider application of radiation for patients with a wide spectrum of benign diseases in several European countries. This article considers the major indications and the expected outcomes from radiation treatment of benign mesenchymal diseases. For benign neoplasms that are locally progressive, the radiation dose is usually in the range 50 to 60 Gy administered at 1.8 to 2.0 Gy/fraction, five fractions per week. The response is characteristically quite slow, and the long-term local control probability is high (80%). Further, the response probability is not sensitive to lesion size, in contrast to malignant tumors of the mesenchymal tissues. For the nonneoplastic processes managed in some instances by radiation, the doses recommended are usually in the range of 6 to 12 Gy as single-dose or 20 to 25 Gy as fractionated dose irradiation. The efficacy of such treatment tends to be equal to or less than that noted for the benign neoplastic diseases.
Article
The problem of restenosis after coronary angioplasty remains a major limiting factor of the procedure. Intracoronary stenting has led to a modest reduction in the frequency of this event. In the early 1990s, the effectiveness of ionizing radiation combined with balloon angioplasty and stenting was first convincingly demonstrated in animal models of restenosis. Small feasibility studies and two randomized trials have, in general, supported the promise of these initial preclinical studies in the prevention of restenosis. Much remains to be learned about the application of radiation for this therapy. This article reviews the current status of preclinical and clinical investigation of this therapy.
Article
Over a 4-year period 63 patients (75 hands) with Dupuytren's nodules were treated with a series of injections with the steroid triamcinolone acetonide directly into the area of disease. The purpose of this study was to determine whether intralesional injections of triamcinolone acetonide could produce softening and flattening in nodules of Dupuytren's disease as seen in the intralesional injections of hypertrophic scars and keloids. After an average of 3.2 injections per nodule 97% of the hands showed regression of disease as exhibited by a softening or flattening of the nodule(s). Although some patients had complete resolution of the nodules, most experienced definite but incomplete resolution of the nodules in the range of 60% to 80%. Although a few patients did not experience recurrence or reactivation of the disease in the injected nodules or development of new nodules, 50% of patients did experience reactivation of disease in the nodules 1 to 3 years after the last injection, necessitating 1 or more injections. The findings of this study indicate that the intralesional injection of nodules of Dupuytren's disease with triamcinolone acetonide may modify the progression of the disease.
Article
Radiotherapy (RT) can prevent progression of Dupuytren's contracture (DC). It is unknown whether there is a dose response and which dose is sufficient. Herein, the 1-year results of a prospective randomized trial are presented which compared two different RT dose concepts with each other. 129 patients (67 males; 62 females) were entered in this study: 69 had bilateral and 60 uni-lateral involvement of DC accounting for 198 irradiated hands. According to Tubiana's classification, 73 hands had Stage N (nodules/cords, no extension deficit = flexion deformity), 61 had Stage N/I (< or = 10 degrees deficit), 59 had Stage I (11-45 degrees deficit), and 5 had Stage II (46-90 degrees deficit) DC. Prophylactic RT was randomly delivered; in Group A, 63 patients (95 hands) received 10 x 3 Gy (total dose, 30 Gy) in 2 series (5 x 3Gy) separated by 8 weeks; in Group B, 66 patients (103 hands) received 7 x 3 Gy (total dose, 21 Gy) in 1 series within 2 weeks. Orthovoltage RT (120 kV) was applied using standard cones and individual shielding of uninvolved areas of the palm. Relevant patient and disease parameters were equally distributed in both groups. Evaluation (toxicity, efficacy) was performed at 3 and 12 months after RT. Subjective (patient's opinion) and objective parameters (palpation, measurements, and comparative photographs) were applied to assess treatment response. Minimum follow-up (FU) was 1 year. Acute toxicity was minimal, but slightly more pronounced in Group B. Seventy-six (38%) hands developed skin reactions CTC 1 degrees (A, 30; B, 46); and 12 (6%) had skin reactions CTC 2 degrees (A, 4; B, 8). Chronic side effects were limited to dryness, desquamation, skin atrophy, and change of sensation (LENT 1 degrees ) in 9 (5%) sites without differences between the two groups. At 3 and 12 months after RT, subjective and objective reduction of symptoms, nodules, and cords occurred in both groups (p < 0.01) with no differences between the groups: in Group A, 55 (56%) sites regressed, 35 (37%) remained stable, and 7 (7%) progressed, whereas in Group B, 55 (53%) regressed, 39 (38%) remained stable, and 9 (9%) progressed at 12 months FU (NS). Overall and mean number of nodules, cords, and skin changes decreased at 3 and 12 months. The "treatment failure" rate at 1 year was 16 of 198 (8%), but only 4 (2%) sites required hand surgery for disease progression. Seven of 60 patients with unilateral DC received prophylactic RT for the initially uninvolved, contralateral hand due to progression of DC. Both prophylactic RT concepts have been well accepted and tolerated by patients. Within the first year, they were equally effective to prevent further disease progression of DC and obtain considerable symptomatic improvement. Although 1-year results suggest similar response rates for both treatment groups, long-term FU of > 5 years has to be awaited for final assessment and recommendation of an optimized RT treatment schedule.
Article
In early stage Dupuytren's contracture radiotherapy was applied to prevent disease progression. Long-term results and late toxicity of this treatment were evaluated in a retrospective analysis. Between 1982 and 1994, 99 patients (176 hands) received orthovoltage radiotherapy, which consisted of two courses with 5 x 3 Gy (total dose: 30 Gy, daily fractionated; 120 kV, 4 mm Al), separated by a 6 to 8-week pause. The Dupuytren's contracture was staged according to the classification of Tubiana et al. The long-term outcome was analyzed at last follow-up between July and November 1999. The median follow-up was 10 years (range 7-18 years). Late toxicity was assessed using the LENT-SOMA criteria. In Stage N 84% and Stage N/I 67% of cases remained stable. 65% of the cases in Stage I and 83% in Stage II showed progressive nodules and cords. In case of progression we saw no complications after a second radiotherapy or salvage operation. Radiotherapy effectively prevents disease progression for early stage Dupuytren's contracture (Stage N, N/I). Moreover, in case of disease progression despite radiotherapy salvage surgery is still feasible.
Article
The incidence of plantar fibromatosis (PF) is unknown. Sometimes PF tends to recur repetitively after surgical treatment. In our institute we have used postoperative radiotherapy in an attempt to diminish the change on recurrence. The Dutch Network and National Database for Pathology (PALGA) was consulted to establish the incidence of plantar fibromatosis (PF). Data from 9 patients (11 feet) with PF referred to our institute for recurrent disease were analyzed and the role of postoperative radiotherapy in prevention of recurrence was studied. An average of 1.2 operations for PF was performed per 100,000 citizens yearly in the Netherlands. Twenty-six operations were performed and postoperative radiotherapy was used in 6 cases. Plantar fasciectomy was associated with the lowest recurrence rate. After microscopically incomplete excision or excision of early recurrence (< or =6 months) alone all tumors recurred, while recurrence was rarely observed after adjuvant radiotherapy. However, radiotherapy was associated with significantly impaired functional outcome in 3 cases. Plantar fibromatosis is relatively rare. Plantar fasciectomy seems to be the operation of choice. Although effective in decreasing the recurrence rate, adjuvant radiotherapy should be used very selectively because of its serious side effects.