Book

Radiotherapy for Non-Malignant Disorders

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Abstract

This volume discusses the general background, radiobiology, radiophysics and clinical applications of radiation therapy in the treatment of non-malignant diseases. Within 39 chapters, it documents the rationale and indications for the use of state-of-the-art radiotherapy for various non-malignant disorders of the CNS, head and neck, eye, skin and soft tissues, bone and joints, and the vascular system. In so doing, it draws attention to and elucidates the scope for application of radiotherapy beyond the treatment of malignancies. Both the risks and the benefits of such treatment are fully considered, the former ranging from minor clinical problems to life-threatening diseases. With the assistance of many tables and colored figures, the extensive data from clinical studies are presented in a well-structured and informative way. Each chapter concludes with a list of key points, allowing the reader to quickly comprehend the main facts. Since this approach offers an interdisciplinary perspective, this book will be of interest not only to radiotherapists but also to many other practitioners and medical specialists, for example orthopedists, surgeons, and ophthalmologists.

Chapters (29)

The unfavourable standing of radiotherapy for nonmalignant diseases among many members of the medical community rests on a few reports of severe radiation necrosis in patients treated in the 1920s and 1930s for various trivial conditions as exemplified by Cannon [3], who gave his paper the telling title “malignant irradiation for benign disease”.
The detrimental effects of exposure to ionising radiation are categorised into deterministic and stochastic effects [16]. It is well established that deterministic effects such as cataracts, skin erythema and radiation syndromes will only occur when a threshold dose is exceeded and that the severity of the damage is dose dependent. Special precautions have to be taken in interventional radiology (see, e.g., [37, 38]) to avoid skin damage. Stochastic effects, which are of a random or statistical nature, include carcinogenesis and hereditary effects. The severity of the stochastic effects is not affected by the dose. The probability of stochastic effects generally increases with dose, without a threshold in the low dose region.
Today we have an idea of what makes up an atom. The model of an atom has two main parts: the core (usually called the atomic nucleus), where most of the atomic mass is located, and a cloud of electrons surrounding it. The electrons move on orbits around the nucleus. These permitted orbits are also called electron shells and are named alphabetically with capital letters, starting with K. The atomic nuclei are made up of an integral number of protons and neutrons. While the protons carry a positive charge, the neutrons are electrically neutral. Electrons and protons carry the same charge, but of opposite sign. This charge is called the elementary charge, e: e=1.602×10−19 C. Since the number of negatively charged electrons is equal to the number of protons in the nucleus, the atom itself is electrically neutral.
Use of ionizing radiation is not strictly limited to the treatment of malignant disorders. Nowadays radiotherapy (RT) of benign or non-malignant diseases has much less impact on the daily clinical practice of most medical disciplines than RT for malignant tumors in radiation oncology. However, this distribution of professional activity was not always similar: at the beginning of the 20th century, and for almost 5 decades (1900–1950), there was no imbalance between benign and malignant indications: “radiation medicine” was often used as a noninvasive treatment in many disorders from various specialties in medicine, including surgery, internal medicine, gynecology, etc.
The use of radiotherapy (RT) for non-malignant disorders has a long tradition in Germany, but according to an international survey the clinical acceptance varies worldwide [19]; a low acceptance rate and level of professional practice have been observed in Anglo-American countries [31], as old fears of tumor induction are still not resolved [2, 3]. Moreover, legal restrictions (threat of malpractice), organizational and institutional reasons (availability of RT equipment only in cancer centers), and competing treatment options prevent a broader acceptance. Basic research on ionizing radiation for non-malignant diseases is developing slowly. Only a few prospective clinical studies have been systematically conducted to define dose-response curves and compare RT with other therapies [4, 20, 47], A first general patterns-of-care study (PCS) was conducted during the period of 1994-1996 to assess the clinical potential of these indications in Germany [42].
While modern indications for radiotherapy of skin cancers are well established, including the treatment of basal cell carcinoma, melanoma, Merkel cell tumors and cutaneous lymphomas, the use of ionizing radiation for non-malignant skin diseases has decreased considerably, because new and better systemic and local non-invasive and invasive treatment options have become available. Moreover, in many dermatological departments training and knowledge about using ionizing radiation have slowly faded away.
The digitopalmar contracture named after Guillaume Dupuytren (1832, 1834) [36, 37] and the corresponding digito-plantar contracture named after Georg Ledderhose (1897) [91] are fibrous, proliferative hyperplastic disorders of pre-existing connective tissue structures of the fascia of the fingers and palm or the toes and sole, respectively. However, in Morbus Dupuytren (MD) and Morbus Ledderhose (ML), the digitopalmar and digitoplantar changes are not just singular afflictions, but part of a systemic connective tissue disorder [41], which is confirmed by subtle biochemical changes and obvious ectopic fibrous deposits, which are located, for example, above the dorsal proximal interphalangeal joints (= knuckle pads), on the auricular helix, the hand wrist, the elbow and inside the penis (= Morbus Peyronie). These tissue changes are histologically identical, but all efforts to identify a single cause of this generalized disorder have failed, and numerous hypotheses about the disease onset and progression have been published, but a simple and straightforward explana tion is still missing.
Desmoids are rare benign neoplasms of the connective tissue that arise from the deep muscle fascia, aponeuroses, tendons and scar tissue [14, 19, 29]. The Anglo-American literature describes them as “aggressive fibromatosis” [14, 32]. The disease has been known since the 19th century: The terms desmoid and desmoidfibrom were coined by the famous German physiologist and comparative anatomist Johannes Müller (1801-1858) from Berlin in 1838 [56]. The name is derived from ancient Greek and indicates a band-like appearance. In 1832, the surgeon John McFarlane from Glasgow was the first to mention the entity in the English-speaking literature. First neoplasms in the abdominal walls of women who recently had given birth were described [34]. Later, similar tumors were found in other anatomic regions. The term fibromatosis was introduced for the first time by Arthur Purdy Stout from New York [76]. He stated that desmoids are masses of proliferated, scar-like tissue, which in spite of the fact of tissue infiltration rarely recur (which is not true today!) and do not become true malignant neoplasms.
A large number of publications in the last few years have shown the clinical efficacy of low dose radiotherapy in degenerative and painful joint diseases [25, 29, 30, 35, 38, 39, 45, 46, 55, 56, 59-62, 64]. However, there are only few studies which have obtained a higher level of evidence [46, 62]. One major reason is the inaccurate and imprecise definition of the treatment endpoint and the lack of using validated evaluation tools such as scores or examination schemes which encompass both subjective (patientrelated) and objective (observer-related) criteria for outcome analysis and follow-up [46,47]. In addition different stages of the disease (acute versus chronic type) may interfere with appropriate patient selection and radiotherapy indication.
The shoulder is a very complexly built human joint. Four parts compose the shoulder joint: the scapulohumeral, sternoclavicular, acromioclavicular and thoracoscapular joint component. Shoulder pain may be caused by several potential causes that are summarized by the term rotator cuff syndrome.
Humeral epicondylopathy (HEP) is a painful ensopathy or tendinitis of the elbow joint that is similar to the tendinopathies observed in the shoulder (rotator cuff syndrome, RCS; see Chap. 14) and the heel (heel spur syndrome, HSS; see Chap. 16). In these disorders usually the tendon insertion zones, sometimes also affecting the neighboring bursae and peritendineum of tendon(s), are involved in a chronic inflammatory process that induces a local and proximally or distally referred pain. Usually this results in impaired joint function with physical consequences for private, professional and sports activities [17, 28, 30]. Besides physical, physiotherapeutic and medical treatments, the use of low-dose radiotherapy (RT) may play an important role affecting the chronic refractory inflammatory process, especially when other treatments have been ineffective.
Painful heel spur (plantar fasciitis) is a major part of the heel spur syndrome. It is reportedly the most common cause of pain in the inferior heel and is estimated to account for 11% to 15% of all foot symptoms requiring professional care among adults [17]. The first description of the clinical picture in the literature came from Wood in 1812, but he incorrectly attributed it to tuberculosis [11, 68]. During the Civil War, another early citing by Zacharie in 1860 discussed a condition affecting the heel in which patients had “greater pain in the morning than after standing and walking one or two hours” [153].
Osteoarthritis is a chronic, degenerative disorder of unknown cause characterized by the gradual loss of articular cartilage. It is the most prevalent disease in the western societies, with a worldwide distribution. As a cause of disability (such as walking and stair climbing) in the elderly in the west, osteoarthritis is second only to vascular diseases. Altogether 10%-15% of adults over 60 years have some degree of osteoarthritis, and with an aging population, it is becoming an increasingly important disease. Presently, most of our knowledge of the etiology and epidemiology of osteoarthritis is from observational studies. Very little is really known with certainty about the underlying mechanism(s) of osteoarthritis, why its course varies from person to person, and why it progresses rapidly in some, but not in others. Our diagnostic measures are based on clinical findings and clumsy radiological methods, and none of the current available therapeutic interventions are curative, but rather symptomatic. However, it is important to treat osteoarthritis effectively using a multidisciplinary approach tailored to the patient’s needs, and furthermore to develop robust outcome measures in order to assess the efficacy of any disease-modifying osteoarthritis treatment options in large-scale multicenter clinical trials.
The development and formation of non-neoplastic bone in and about soft tissues outside the skeleton are defined as ectopic bone formation or heterotopic ossification (HO). However, the various pathological and pathophysiological reasons and inducing clinical conditions for the development of HO outside the skeleton together with an ubiquitous occurrence of these ossifications in almost any body region have stimulated a variety of other clinical definitions, e.g., paraosteoarthropathy, myositis ossificans, neurogenic osteoma, panniculitis ossificans, fasciculitis ossificans, reactive mesenchymal proliferation or pseudo-malignant bone tumor [16].
Heterotopic or ectopic ossification is a biologic process in which new bone is formed in tissues that normally do not ossify (Fig. 19.1). The etiology of this disease can be discerned in the rare hereditary form and the more frequent acquired form.
Progress in medical care has improved the prognosis for patients with head and spinal cord injuries (HSCI) [28]. However, the clinical outcome may be compromised by various complications: these patients are at risk for urinary tract infections, thrombo-embolism, respiratory diseases and especially for the production of heterotopic bone or heterotopic ossification (HO), in the neighborhood of joints, preferentially the hips [27, 50, 54] (Table 20.1).
The pigmented villonodular synovitis (PVNS) is a very uncommon non-malignant, but proliferative disease, eventually with locally aggressive behavior, that can affect synovial-lined joints, bursae and tendon sheaths. PVNS is well characterized by a hyperplastic synovium of the affected joint, frequent and large effusions and para-articular bony erosions. The first physician ever to describe the lesion was the French surgeon Chassaignac in 1852 (1804–1879), but he overstated its biologic potential in referring to it as a “cancer of the tendon sheath.” It took almost 100 years for the first correct clinical description of PVNS as a distinct disease entity to be given by Jaffe and coworkers in 1941 [20]. They proposed the actual name and described the typical clinical and histological findings.
Langerhans’ cell histiocytosis (LCH) is a rare semimalignant disease in which an uncontrolled proliferation of Langerhans’ cells involves one or more body systems or tissues, leading to different clinical manifestations. Langerhans’ cell histiocytosis nowadays includes diseases previously designated as histiocytosis X, eosinophilic granuloma, Hand-Schüller-Christian syndrome or Abt-Letterer-Siwe disease. Langerhans’ cell histiocytosis usually is considered to be a typical disease of children; nevertheless, many adults are newly diagnosed, and the disease course in children can continue during their adult life. Primary isolated pulmonary Langerhans’ cell histiocytosis, especially in adults, seems to represent a special form of disease [24, 109, 116] requiring specialized (non-radiotherapeutic) treatment and is not addressed in this book chapter.
Hemangiomas are slowly growing benign vascular neoplasms derived from the endothelium of vessels. Subtypes include those with an increase of capillaries (capillary hemangioma) and those associated with an enlargement of blood channels (cavernous hemangiomas) as well as those of mixed type [12, 25, 89, 102, 110].
Aneurysmal bone cyst (ABC) is defined as a benign osteolytic bone lesion composed of blood-filled channels separated by fibrous septa. Another characteristic feature is the pathohistological evidence of bony trabeculation and osteoid and osteoclastlike giant cells [25]. The ABC was first described as a distinct histomorphologic disorder by Jaffe and Lichtenstein in 1942 [45]. The descriptive composite term “aneurysmal bone cyst” was introduced, with the first term “aneurysmal” introduced to point out an analogy to the arterial aneurysms and the second term “bone cyst” to emphasize their intraosseus localisation [5, 11, 13, 22, 45].
About 10% of neonates present with angioma in the first days or weeks of life. The main diagnostic and therapeutic problem is the correct differentiation of the various forms of vascular anomalies, which also defines the treatment strategy [21]. Especially the terms ‘hemangioma’ and Vascular malformation’ should be strictly separated from each other. Though both are caused by a disturbance in embryonic vessel development, vascular malformations already exist at the time of birth, while hemangiomas develop during the first days or weeks of life [19]. The initial clinical presentation can be very similar, so that exact history taking and clinical description are of great importance.
Graves’ disease-related eye signs are a complex of symptoms that describe the response of the eyes and surrounding orbital tissues to an inflammatory and autoimmune disorder related to thyroid disease. For this reason, the symptom entity is more accurately termed an orbitopathy rather than the more often used term of an ophthalmopathy.
Pseudotumor orbitae is a rare and uncommon disease including idiopathic benign inflammatory alterations with sudden onset of exophthalmus, reduced eye motility, swelling of soft tissue and heavy pain together with a tumor formation, which may even simulate a neoplastic process. In some situations, its masquerade as a neoplasm is so deceptive as to defy diagnosis until orbitotomy. In any case, a bioptic verification, if possible and assessable, is recommended. A localized inflammatory process with lymphocytic infiltration is often described histologically. However the pathologists sometimes report great difficulties in separating the lesion from a malignant non-Hodgkin’s lymphoma of the orbit. Because morphologic criteria alone may sometimes not allow distinguishing between benign and malignant disease, immunohistochemical examinations are necessary. Diagnosis has to be done using clinical examinations, characteristic CT or MR findings, intensive histologic analysis including immunohistochemic investigations.
A pterygium is a wing-shaped (in Greek, pteron means wing) or triangular structure of benign proliferation of the fibrovascular tissue originating from the bulbar conjunctiva, which grows invasively over months or years toward the center of the cornea, using the Bowman’s layer as a guiding structure and resulting in its destruction [10, 46]. Pterygia are nearly exclusively located nasally (92%), and simultaneous bilateral growth may be found in 4%–5%. Sequential bilateral ocular involvement may occur in up to one-third of patients with pterygia.
Intracranial arterio-venous malformations (AVM) are relatively uncommon, but increasingly recognized lesions that can cause serious neurological symptoms or death. Although AVM can initially present with hemorrhages or seizures, an increasing number is detected before symptomatic bleeding due to the recently developed imaging techniques. Over the last decades, the management of AVM has been widely modified due to the availability of neuronavigation and minimally invasive endoscopic surgery techniques, endovascular embolization and radiosurgery. As the management options have evolved, individual and combined modality treatment protocols have been developed in different institutions for the management of AVM. Besides preservation or improvement of neurological function, the main requirement for AVM treatment is the risk of bleeding. The main goal in AVM treatment is, therefore, the complete elimination of the nidus to cure the patient. Currently, it is well established that the entire nidus has to be removed or inactivated, respectively. Neither feeding arteries nor draining veins should be pursued beyond their points of attachment to the nidus to avoid unnecessary normal tissue damage [25]. Detailed information concerning the size, localization of the nidus, arterial feeders and venous drains is required for treatment planning as well as proof of lesions due to bleeding or atrophy or gliosis in the surrounding brain.
Most meningiomas are histologically benign and typically slow-growing lesions arising from the arachnoidal cap cells. They often occur in the arachnoidal granulations area next to the venous sinus. Meningiomas cause symptoms by extraaxial compression of the adjacent brain. The treatment of choice is surgical resection. Most meningiomas can be completely resected, but they have a high tendency for local recurrence, especially after subtotal surgical intervention. After complete resection, long-term disease-free survival can be achieved in 81% of the patients, with local tumor control of 96%. Relapses occurred from 4 to 17 years after the initial surgery intervention. Recurrence rates for patients after subtotal resection range from 17% to 100%. Radiation therapy after subtotal resection can achieve results comparable to those of complete resection [40].
Vestibular schwannomas (VS) or acoustic neuromas are benign tumors arising from Schwann cells of the vestibular branch of the eighth cranial nerve. The tumor was first described 1910 by Henschen, who provided evidence that it originates from the Schwann cells. Nevertheless, the term acoustic neuroma was commonly used. The National Institute of Health decided in 1992 in a Consensus Development Conference: “The term vestibular schannoma is preferred over acoustic neuroma as these tumors are composed of Schwann cells and typically involve the vestibular rather than the acoustic division of the eighth cranial nerve.” Therefore, we will use the term of VS, although acoustic neuroma is still more common in the literature.
Pituitary tumours grow slowly and are initially confined to the sella turcica. They may grow out of the sella and compress or destroy the optic chiasm, hypothalamus or surrounding bony structures. They are mostly benign and are associated with an immense diversity in their endocrine manifestations secondary to hormone excess or deficiency and ophthalmologic manifestations due to the mass effect of enlarging pituitary adenomas. Progress in the diagnostic examination of pituitary adenomas and advances in treatment of these tumours offer excellent prospects for a successful therapeutic outcome using a multidisciplinary approach. Therapeutic options for the treatment of pituitary adenomas have largely widened. Management by medical treatment, surgery or radiotherapy is possible. Treatment success depends on various factors, such as the tumour size, invasiveness, localisation, direction of growth or hormonal activity. The goals of pituitary adenoma therapy are to remove or to destroy the tumour, control hypersecretion and restore lost function without producing hypopituitarism or injury to surrounding normal tissue. There is therefore no doubt that the initial treatment for nonfunctional and hormonally active adenomas, except prolactinomas, is reserved to neurosurgery in operable patients [46, 68]. The reason is that surgical resection accomplishes these goals most rapidly, with prompt decompression of mass effects and improvement in pituitary function. In most cases, transsphenoidal or occasionally transethenoidal resection of the adenoma can be performed. Of particular interest was the development of microsurgical techniques, offering selective extraction of microadenomas [58]. For many pituitary adenomas, a major problem is the recurrent growth of tumours that are either primarily invasive or incompletely removed.
Trigeminal neuralgia (TN) is a disabling painful condition. It is characterized by sudden severe and intense attacks of stabbing or electrical-shock-like pain that are typically brief, lasting for a few seconds up to several minutes. TN pain is mostly unilateral, involving the innervation area of the trigeminal nerve. Each pain attack may come on spontaneously or be triggered by certain stimuli, usually in the affected areas of the face. Common triggers may include simple touch, talking, eating, drinking, chewing, tooth brushing and hair combing. In contrast, pinching or pressing these trigger points will not usually cause TN pain.
... Non-oncological radiotherapy can be used to treat several disorders and accounts for 20% of all treated patients in Germany [6][7][8]. ...
... Surgery is usually reserved for more advanced stages (Stage 3 Tubiana); the role of RT in the treatment of Dupuytren's disease tends to be rather preventive and prophylactic than curative. Thus, the goal is to avoid future functional impairment and a future need for surgery [6]. ...
... Medical treatment involves the use of drugs for oral treatment such as vitamin E, tamoxifen, and colchicine and for intralesional injection verapamil and collagenase. If drug therapy fails, surgery remains the best option, especially in the cases of severe curvature or angulation and erectile dysfunction [6]. The use of RT is considered indicated in earlystage disease with soft, noncalcified plaques. ...
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Despite being usually delivered in oncological patients, radiotherapy can be used as a successful treatment for several non-malignant disorders. Even though this use of radiotherapy has been scarcely investigated since the 1950s, more recent interest has actually shed the light on this approach. Thus, the aim of this narrative review is to analyze the applications of non-oncological radiotherapy in different disorders. Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. This review contains a narrative report and a critical discussion of non-oncological radiotherapy approaches. In conclusion, non-oncological radiotherapy is a safe and efficacious approach to treat several disorders that needs to be further investigated and used in clinical practice.
... The disease is a singular manifestation of a systemic connective tissue disorder including Dupuytrens contracture (DC) and Peyronies disease (PD), which affect the palmar fascia and tunica albugenia, respectively. These clinical manifestations are often bilateral and concomitant [1]. The cause of these diseases remains unknown [1,2]. ...
... These clinical manifestations are often bilateral and concomitant [1]. The cause of these diseases remains unknown [1,2]. ...
... The tissue changes in this family of diseases are histologically identical [1], with excessive proliferation of fibroblasts and myofibroblasts and dense bands of collagen in mature lesions [3]. LD tends to present with nodules affecting the medial and central aspect of the plantar aponeurosis, without typically progressing to a cord or cause a contracture as in DC. ...
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Ledderhose disease is a connective tissue disorder involving proliferation of fibrous tissue in the plantar fascia of the foot. Histologically identical manifestations exist in the hand (Dupuytren’s contracture) and penis (Peyronie’s disease), and collagenase injections are approved as a treatment in both, however not in Ledderhose, where the treatment of choice remains surgical resection. Surgery is associated with high rates of recurrence and need for further surgery, so alternative therapies should be sought. Due to their histological and physiological similarities, it is likely that therapies useful in Dupuytren’s and Peyronie’s would be useful in Ledderhose. Two previous case reports investigating collagenase injections for Ledderhose disease in adults have shown conflicting results; this study demonstrates the efficacy of collagenase injections in a paediatric patient at 1-year follow-up.
... Concerning the most clinical relevant endpoints pain relief, response, and analgetic effects, LD-RT is reported to result in a 33–100%, a 47–100%, and a 12–89% efficacy, respectively (Kutzner et al., 2003; Micke and Seegenschmiedt, 2004; Niewald et al., 2007; Adamietz et al., 2010; Betz et al., 2010; Heyd et al., 2010). Moreover, due to the low-doses used in actual clinical practice, radiogenic acute or chronic side effects were not observed in the treatment of inflammatory diseases (Seegenschmiedt et al., 2008). By contrast, LD-RT is still considered unfashionable in some (Anglo-American) countries due to elder reports on harmful side effects and increased mortality from leukemia and anemia (Cannon et al., 1959; Court-Braun Wm, 1965). ...
... Concepts and doses in clinical practice have been established empirically in the early twentieth century (von Pannewitz, 1933) recommending local treatment with single doses of 0.3–1.0 Gy in 4–5 fractions for acute and 1–3 fractions for chronic inflammatory disorders adding to a total doses of 3–5 Gy (acute) and 12 Gy (chronic), respectively (Seegenschmiedt et al., 2008). Typical clinical indication comprise degenerative disorders like rotator cuff syndrome (impingement of the shoulder joint), tennis/golfer’s elbow (Epicondylopathia humeri), painful heel spur (plantar fasciitis), exacerbated refractory, and painful osteoarthritis, or hyper-proliferative syndromes like Dupytren’s disease or the prevention of heterotopic ossification (Seegenschmiedt et al., 2004, 2008). ...
... The relationship between ionizing radiation and an inflammatory response displays a dichotomous character and greatly depends on the radiation dose/quality and immune cell types investigated. When compared to a high dose exposure with pronounced inflammatory promoting effects (Williams et al., 2003), low-dose irradiation (single doses ≤1.0 Gy) reveals anti-inflammatory properties (Seegenschmiedt et al., 2008; Rödel et al., 2012). This implicates the involvement of complex mechanisms differentially operating at different dose levels (Marples et al., 2004). ...
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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.
... In line with that, the use of RT in the management of hyperproliferative non-cancerous disorders is controversially discussed and inadequately recognized by doctors from disciplines others than RT. However, long-term experiences impressively indicated a clinical benefit for patients (4,5). Accordingly, treatment with irradiation concepts not exceeding a single dose of 5 Gy and total doses of 30 Gy [low-or intermediate-dose RT (LD-RT)] is an established and effective modality in the management of a variety of non-cancerous inflammatory, degenerative, and hyperproliferative/fibroproliferative disorders (4)(5)(6). ...
... However, long-term experiences impressively indicated a clinical benefit for patients (4,5). Accordingly, treatment with irradiation concepts not exceeding a single dose of 5 Gy and total doses of 30 Gy [low-or intermediate-dose RT (LD-RT)] is an established and effective modality in the management of a variety of non-cancerous inflammatory, degenerative, and hyperproliferative/fibroproliferative disorders (4)(5)(6). The latter include, among others, heterotopic ossifications, symptomatic vertebral hemangiomas, Gorham-Stout syndrome, prophylaxis of keloid relapse after surgical excision (7), and, most prominent, palmar and plantar fibromatosis also known as Dupuytren disease (DD) and Ledderhose disease (LD) (8). ...
... Non-malignant indications for LD-RT comprise about 10-30% of all patient cases treated in most academic, public, and private RT facilities in Germany (4,9). In total, more than 50,000 patients per year are treated by LD-RT with the largest group suffering from painful degenerative musculoskeletal diseases, followed by symptomatic functional and hyperproliferative disorders with the latter to increase in numbers by 28.8% from 1999 to 2004 (8). ...
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.
... In line with that, the use of RT in the management of hyperproliferative non-cancerous disorders is controversially discussed and inadequately recognized by doctors from disciplines others than RT. However, long-term experiences impressively indicated a clinical benefit for patients (4,5). Accordingly, treatment with irradiation concepts not exceeding a single dose of 5 Gy and total doses of 30 Gy [low-or intermediate-dose RT (LD-RT)] is an established and effective modality in the management of a variety of non-cancerous inflammatory, degenerative, and hyperproliferative/fibroproliferative disorders (4)(5)(6). ...
... However, long-term experiences impressively indicated a clinical benefit for patients (4,5). Accordingly, treatment with irradiation concepts not exceeding a single dose of 5 Gy and total doses of 30 Gy [low-or intermediate-dose RT (LD-RT)] is an established and effective modality in the management of a variety of non-cancerous inflammatory, degenerative, and hyperproliferative/fibroproliferative disorders (4)(5)(6). The latter include, among others, heterotopic ossifications, symptomatic vertebral hemangiomas, Gorham-Stout syndrome, prophylaxis of keloid relapse after surgical excision (7), and, most prominent, palmar and plantar fibromatosis also known as Dupuytren disease (DD) and Ledderhose disease (LD) (8). ...
... Non-malignant indications for LD-RT comprise about 10-30% of all patient cases treated in most academic, public, and private RT facilities in Germany (4,9). In total, more than 50,000 patients per year are treated by LD-RT with the largest group suffering from painful degenerative musculoskeletal diseases, followed by symptomatic functional and hyperproliferative disorders with the latter to increase in numbers by 28.8% from 1999 to 2004 (8). ...
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Full-text available
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.
... On the contrary, low-dose radiation therapy (LD-RT: single doses < 1 Gy) modulates a variety of inflammatory processes and clearly reveals anti-inflammatory properties [2]. Although LD-RT is clinically used since decades for the treatment of non-cancerous inflammatory and degenerative diseases [3,4], underlying molecular mechanisms are far from being fully explored, at least in part because of their prominent discontinuous dose dependency and putative non (DNA)-targeted properties. ...
... Beside the very recent successes in exploring molecular and cellular mechanisms, low-dose radiotherapy of acute and chronic inflammatory diseases and painful degenerative joint disorders is a well accepted conservative treatment in Germany and other European countries [3,4]. It has been traditionally used in the clinical settings as early as 1898, when Sokoloff first reported on pain relieve in patients with arthritis treated with low-dose Xirradiation [108]. ...
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During the last decade, a multitude of experimental evidence has accumulated showing that low-dose radiation therapy (single dose 0.5-1 Gy) functionally modulates a variety of inflammatory processes and cellular compounds including endothelial (EC), mononuclear (PBMC) and polymorphonuclear (PMN) cells, respectively. These modulations comprise a hampered leukocyte adhesion to EC, induction of apoptosis, a reduced activity of the inducible nitric oxide synthase, and a lowered oxidative burst in macrophages. Moreover, irradiation with a single dose between 0.5-0.7 Gy has been shown to induce the expression of X-chromosome linked inhibitor of apoptosis and transforming growth factor beta 1, to reduce the expression of E-selectin and L-selectin from EC and PBMC, and to hamper secretion of Interleukin-1, or chemokine CCL20 from macrophages and PMN. Notably, a common feature of most of these responses is that they display discontinuous or biphasic dose dependencies, shared with "non-targeted" effects of low-dose irradiation exposure like the bystander response and hyper-radiosensitivity. Thus, the purpose of the present review is to discuss recent developments in the understanding of low-dose irradiation immune modulating properties with special emphasis on discontinuous dose response relationships.
... Arteriovenous malformations are the most common of the congenital vascular abnormalities, which are probably genetically determined. 13 Arteriovenous malformations are mostly found in the brain and rare in other organs such as lung and uterus. 14,15 Angiography, considered as the criterion standard defining the arterial and venous anatomy, is the most sensitive diagnostic procedure in AVMs. ...
... 14,15 Angiography, considered as the criterion standard defining the arterial and venous anatomy, is the most sensitive diagnostic procedure in AVMs. 13 Subsequently, angiography has been significantly improved so that it can be applied to forensic science. The use of postmortem angiography has increased significantly, as it enables the clear visualization of deep and narrow blood vessels in a corpse. ...
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This report presents a case of a 40-year-old woman who was found dead in her house. The examination of the body revealed no external injuries. The whole body was scanned by multi-detector-row computed tomography (CT) before autopsy, revealing massive hemorrhage in the right frontal extending into the ventricular system. At autopsy, the brain parenchyma was removed. Then CT angiography was carried on the isolated brain. Computed tomography angiography suggested a mass of irregular, tortuous vessels in areas of hemorrhage in the right frontal lobe of the brain. Finally, histological examination confirmed the result of CT angiography due to an arteriovenous malformation. Hence, postmortem CT angiography played an important role in diagnosis of the cerebral arteriovenous malformation that was responsible for a massive hemorrhage in the skull.
... Studie PLANET prokázala zvýšení četnosti konverzí u primárně neresekabilního metastatického postižení jaterní, při podávané kombinaci panitumumab s chemoterapií FOLFOX nebo Folfiri (23,24). Stejně tak i randomizovaná studie VOLFI potvrdila, že přidání panitumumabu k tripletu vedlo k signifikantně vyšší četnosti odpovědí (24,25 Klíčová slova: metastatický kolorektální karcinom, antiangiogenní terapie, VEGF. ...
... Key words: palliative radiotherapy, palliative care, radiotherapy, lung neoplasms, bone metastases, brain metastases, cervical cancer. (11,25) Remune™ Do studie bylo zařazeno 55 pacientů ze čtyř onkologických center -z Onkologického oddělení Nemocnice Nový Jičín (40 % nemocných), z Masarykova onkologického ústavu v Brně (36 %), z Ústavu radiační onkologie Nemocnice Na Bulovce v Praze (20 %) a z Onkologické a radioterapeutické kliniky FN Plzeň (4 %). U všech pacientů, jejichž věkové rozmezí se pohybovalo mezi 36 a 84 roky, probíhala onkologická léčba, ať už pomocí chemoterapie nebo radioterapie. ...
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In 2008, mutations in isocitric dehydrogenase 1 & 2 (mIDH 1 & 2) was first detected in glioblastoma multiforme (GBM) fromamong many types of solid tumour. Next year i.e. in 2009 acute myelogenous leukemia (AML) showed presence such mutation. mIDH 2 blocker enasidenib came into market for the first time for adult recurrent and relapsed AML in 2017. But mIDH 1 blocker ivosidenib (AG-120) is approved in 2019 in recurrent and relapsed AML. In the end 2019 it was approved for untreated adult AML. When it was in early phase trial it became eligible for special expanded access program as it showed encouraging results. Drug molecule's progress through preclinical and regulatory path is interesting. It is worthwhile to look into how it received market authorization while phase III trial was not over. Trial of both GBM and AML started in March 2014. Circumstances behind ivosidenib being first approved in adult recurrent and relapsed AML rather than in glioma where the mutation was first found are also discussed.
... On the contrary, Low-Dose Radiation Therapy (LD-RT): single doses < 1 Gy) modulates a variety of inflammatory processes and clearly reveals anti-inflammatory properties 57 . Although LD-RT is clinically used for decades for the treatment of non-cancerous inflammatory and degenerative diseases [58][59] , underlying molecular mechanisms are far from being fully explored, in part It may be prudent to heed to …adaption after low dose exposures and activation of immune system by low doses of radiation along with the upregulation of antioxidant defense in the evaluation of harm to low dose radiation exposures. It appears reasonable to consider the existence of a threshold dose, below which organisms utilize low dose exposures for beneficial cellular and organ functions … (Mishra) 318 . ...
... Gy and a total dose of 3-12 Gy exerted anti-inflammatory and analgesic effects for painful degenerative disorders. Relatively low dose radiotherapy for joint inflammation was an effective and less toxic alternative to steroids and low dose chemotherapy drugs in treating arthritis and a variety of other chronic painful conditions 55,[58][59]63,69,73,[93][94][95][96][97][98][99] . ...
Chapter
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The health benefits from low dose ionizing radiation are many, that proceed beyond the benefits of preventing many diseases and prolonging lifespan or even reversing aging. Moderate doses of X-rays from 0.5-3.0 Gy were successfully used in the first half of the 20th century to treat many inflammatory and infectious diseases. Low dose radiation (LDR) may also be effective in treating viral infections such as hepatitis and HIV/AIDS, as well as difficult to treat infections like MRSA. A few cases of neurodegenerative disease (AD, PD) have responded to a series of brain CT scans. The addition of LDR to high dose radiotherapy or chemotherapy has significantly improved survival for non-Hodgkins lymphoma and other tumor types. The use of radioactive pads (Chapter 7) is also effective in treating a wide variety of health issues.
... 18,19 These data corroborate the notion that ionizing radiation has an impact in the immune system, with high doses promoting inflammation 20 and proinflammatory macrophages, 21 whereas lower doses lead to decreased inflammation. 22,23 Nevertheless, there is little information available regarding the impact of LDIR on monocytes and lymphocytes that contribute to atherosclerosis lesion formation in the first place. One study reported that in vitro irradiation of RAW264.7 monocytes/macrophages altered the binding of these cells to vascular cell adhesion molecule-1 (VCAM-1), 24 confirming a previous work demonstrating that LDIR reduced adhesion of monocytes to the endothelium. ...
Article
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Low dose ionizing radiation (LDIR) is known to have a protective effect on atherosclerosis in rodent studies, but how it impacts different cells types involved in lesion formation remains incompletely understood. We investigated the immunomodulatory response of different doses and dose-rates of irradiation in ApoE -/- mice. Mice were exposed to external γ rays at very low (1.4 mGy.h ⁻¹ ) or low (50 mGy.h ⁻¹ ) dose-rates, with cumulative doses spanning 50 to 1000 mGy. Flow cytometry of circulating cells revealed a significant decrease in pro-inflammatory Ly6C Hi monocytes at all cumulative doses at low dose-rate, but more disparate effects at very low dose-rate with reductions in Ly6C Hi cells at doses of 50, 100 and 750 mGy only. In contrast, Ly6C Lo monocytes were not affected by LDIR. Similarly, proportions of CD4 ⁺ T cell subsets in the spleen did not differ between irradiated mice and non-irradiated controls, whether assessing CD25 ⁺ FoxP3 ⁺ regulatory or CD69 ⁺ activated lymphocytes. In the aorta, gene expression of cytokines such as IL-1 and TGF-ß and adhesion molecules such as E-Selectin, ICAM-1, and VCAM-1 were reduced at the intermediate dose of 200 mGy. These results suggest that LDIR may reduce atherosclerotic plaque formation by selectively reducing blood pro-inflammatory monocytes and by impairing adhesion molecule expression and inflammatory processes in the vessel wall. In contrast, splenic T lymphocytes were not affected by LDIR. Furthermore, some responses to irradiation were nonlinear; reductions in aortic gene expression were significant at intermediate doses, but not at either highest or lowest doses. This work furthers our understanding of the impact of LDIR with different dose-rates on immune system response in the context of atherosclerosis.
... They suppose a pronounced inflammatory effect of a high-dose exposure 6 and an anti-inflammatory effect at low-dose irradiation (single doses 1.0 Gy). 7,8 The epidemiological studies of atomic bombing survivors and Chernobyl emergency and clean-up workers found longterm imbalance in Th1/Th2 responses shifted toward an inflammatory profile. [1][2][3][4][9][10][11] It is suggested [1][2][3][4][5]9 that doses in the range of 10 to 100 mGy lead to the prevalence of T1 helper subpopulation, while doses above 200 mGy switch to prevalence of T2 helper immune response. ...
Article
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The aim of the present study is to assess the effects of low-dose occupational exposure on T helper response. One Hundred five employees working in Nuclear Power Plant, Kozloduy, Bulgaria and control group of 32 persons are included in this investigation. Flow cytometry measurements of T-cell populations and subpopulations and natural killer T cells are performed and levels of G, A, and M immunoglobulins and interleukin 2 (IL-2), IL-4, and interferon γ were determined. The data interpreted with regard to cumulative doses, length of service, and age. The results of the present study are not enough to outline a clear impact of occupational radiation exposure on T helper populations. Nevertheless, the observed even slight trends in some lymphocyte’s populations and in cytokines profile give us the reason to assume a possibility of a gradual polarization of T helper 1 to T helper 2 immune response at dose range 100 to 200 mSv. The results of the present study indicate the need to perform a more detailed epidemiological survey including potential confounding and misclassifying factors and possible selection bias that could influence the results.
... a. der Glandula parotis) kann zu einer Xerostomie führen; früher war dies eine häufige Nebenwirkung der Strahlentherapie von Kopf-Hals-Tumoren. Der Nutzen der externen Bestrahlung ist für die Hypersalivation bei verschiedenen neurologischen Krankheitsbildern beschrieben [97][98][99][100][101]. Assouline et al. konnten bei einer Dosis von 20 Gy unter moderner 3D-konformaler Bestrahlungstechnik und maximaler Schonung des umliegenden Gewebes ein guter Therapieeffekt bei moderaten Nebenwirkungen zeigen [102]. ...
Article
A new and interdisciplinary S2k AWMF guideline for the treatment of obstructive sialadenitis has been published. There have been several technical achievements, for instance in the field of ultrasonography, via sialendoscopy, or by MR-sialography, that have increased the possibilities for diagnosis and treatment of patients with obstructive sialadenitis. In the past, the treatment of choice in case of unsuccessful medical treatment was a complete extirpation of the affected salivary gland. Nowadays, using a variety of modern treatment options (like sialendoscopy, or extracorporeal shock-waves lithotripsy sometimes combined with salivary duct incision), it is possible in most patients, especially in cases of sialolithiasis, to preserve the affected gland. A functional recovery after gland-sparing surgery is described but more data is needed to finally evaluate the long-time results. The new guideline describes all relevant steps to diagnose an obstructive sialadenitis and values all diagnostic tools critically. Finally, all recommendable therapy options are described and valued, too. © Georg Thieme Verlag KG Stuttgart · New York.
... pain relief, complete response and long-time analgesic effects, LD-RT in current clinical applications is reported to result in high response rates (>50–100%) without induction of radiogenic acute or chronic side effects (outlined in more detail in [8]). On the contrary , LD-RT is still considered unfashionable in some countries due to reports of harmful late effects and increased mortality from leukaemia and anaemia published in the 1960s [12] [13]. ...
... For decades an anti-inflammatory and analgetic effect of low-dose X-irradiation (LD-RT) has been well established in the treatment of a plethora of benign diseases and chronic degenerative disorders [1,2] with empirically identified single doses < 1 Gy to be most effective in the clinical setting [3][4][5]. Although the knowledge of the underlying cellular and molecular mechanisms is still at an early stage, a modulation of endothelial cell (EC) activity has already been proven to comprise a key element in the therapeutic effects of LD-RT [6]. ...
Article
Full-text available
A discontinuous dose response relationship is a major characteristic of the anti-inflammatory effects of low-dose X-irradiation therapy. Although recent data indicate an involvement of a variety of molecular mechanisms in these characteristics, the impact of reactive oxygen species (ROS) production to give rise or contribute to these phenomena in endothelial cells (EC) remains elusive. HUVEC derived immortalized EA.hy926 cells were stimulated by tumor necrosis factor-alpha (TNF-alpha, 20 ng/ml) 4 h before irradiation with doses ranging from 0.3 to 1 Gy. To analyse DNA repair capacity, phospho-histone H2AX foci were assayed at 1 h, 4 h and 24 h after irradiation. ROS production and superoxide dismutase (SOD) activity were analysed by fluorometric 2[prime],7[prime]-dichlorodihydrofluorescein-diacetate (H2DCFDA) and colorimetric assays. A functional impact of ROS on gammaH2AX production was analysed by treatment with the scavenger N-acetyl-L-cysteine (NAC). Irrespective of stimulation by TNF-alpha, EA.hy926 cells revealed a linear dose response characteristic of gammaH2AX foci detection at 1 h and 4 h after irradiation. By contrast, we observed a discontinuity in residual gammaH2AX foci detection at 24 h after irradiation with locally elevated values following a 0.5 Gy exposure that was abolished by inhibition of ROS by NAC. Moreover, SOD protein expression was significantly decreased at doses of 0.5 Gy and 0.7 Gy concomitant with a reduced SOD activity. These data implicate a non-linear regulation of ROS production and SOD activity in EA.hy926 EC following irradiation with doses < 1 Gy that may contribute to a discontinuous dose-response relationship of residual gammaH2AX foci detection.
... According to the literature, the relation between ionizing radiation exposure and inflammatory response seems to be dependent not only on the cell type analysed and radiation quality, but mainly on the delivered dose 58 . Low doses (maximum of 12 Gy at ≤ 1.0 Gy/fraction), usually applied in non-malignant disorders or received by normal tissues outside the tumour target volume, induce an anti-inflammatory phenotype, while higher doses (single doses ≥ 2 Gy, total doses ≥ 40 Gy) are reported to have a pro-inflammatory effect 59,60 . Most of the studies, aiming to reveal the role of irradiation on macrophage inflammatory status, are performed using in vitro or ex vivo mouse macrophages. ...
Article
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In order to improve the efficacy of conventional radiotherapy, attention has been paid to immune cells, which not only modulate cancer cell response to therapy but are also highly recruited to tumours after irradiation. Particularly, the effect of ionizing radiation on macrophages, using therapeutically relevant doses, is not well understood. To evaluate how radiotherapy affects macrophage behaviour and macrophage-mediated cancer cell activity, human monocyte derived-macrophages were subjected, for a week, to cumulative ionizing radiation doses, as used during cancer treatment (2 Gy/fraction/day). Irradiated macrophages remained viable and metabolically active, despite DNA damage. NF-kappaB transcription activation and increased Bcl-xL expression evidenced the promotion of pro-survival activity. A significant increase of pro-inflammatory macrophage markers CD80, CD86 and HLA-DR, but not CCR7, TNF and IL1B was observed after 10 Gy cumulative doses, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 expression decreased, suggesting the modulation towards a more pro-inflammatory phenotype. Moreover, ionizing radiation induced macrophage morphological alterations and increased their phagocytic rate, without affecting matrix metalloproteases (MMP)2 and MMP9 activity. Importantly, irradiated macrophages promoted cancer cell-invasion and cancer cell-induced angiogenesis. Our work highlights macrophage ability to sustain cancer cell activities as a major concern that needs to be addressed to improve radiotherapy efficacy.
... [14][15][16][17] In some historic series from the kilovoltage era, successful treatments were reported for a variety of entities, such as paronychium, furuncles, lymphadenitis, abscesses, parotitis, soft tissue infections/phlegmon, hidradenitis suppurativa, and osteomyelitis. 18 Historically, Heidenhain and Fried revealed that RT can be used for a spectrum of acute and chronic inflammation in clinical refractory stages, including acute lymphadenitis, hidradenitis suppurativa, soft tissue infections/phlegmon, osteomyelitis, pleuritis, and various abscesses (renal, gynecological, and perirectal). 19 Successful radiation treatments for infectious skin disorders, such as actinomycosis and pneumonia, have also been reported. ...
Article
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Mycetoma is a localized chronic subcutaneous infection caused by fungi. It is clinically characterized by a triad of tumefaction, sinuses, and discharge containing typical grains. Eumycetoma, a subtype, is characterized by a low cure rate. Long‐term medication and surgical excision are required to treat the infection. Radiotherapy, a less used modality of treatment, may provide a good salvage option for refractory eumycetoma. Herein, we present a case and a review of the literature of refractory eumycetoma of the foot where radiotherapy was used as a salvage treatment. In the present case, a dose of 17.5 Gy in five fractions was delivered, and the response was assessed as per the Response Evaluation Criteria in Solid Tumors 1.1, discharging grains status, and Dermatology Life Quality Index. The literature on the use of radiotherapy for mycetoma was found to be scanty. In the present case with radiotherapy, there was a partial radiological response, resolution of discharging grains, and improvement in the Dermatology Life Quality Index score. However, the benefit was short‐lived, but re‐irradiation and low‐dose radiotherapy resulted in sustained benefits until 15 months of follow up. The antiproliferative and anti‐inflammatory actions of radiotherapy can be exploited in the treatment of rare, medically difficult to treat mycetoma. This case report may serve as a basis for further evaluation.
... Among these promising candidates, X-ray has attracted most attention since Mr. Roentgen discovered this exciting radiation in the late 19 th century [188]. Considering the significant benefits in safety and precise examination, and importantly, almost limitless penetration capacity when compared to conventional optical imaging approaches, X-ray can be used as robust technique in radiotherapy and diagnosis with suitable dose of radiation for its extremely deep-tissue penetration (usually at 20-45 cm) in hospitals [189]. Until now, several inspiring radioactive or nuclear imaging modalities, such as computed tomography (CT) [190,191], positron emission tomography (PET) [192,193], single photon emission computed tomography (SPECT) [194,195] etc. have been widely applied in clinics as nuclear medical diagnostic techniques. ...
Article
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Currently, precision theranostics have been extensively demanded for the effective treatment of various human diseases. Currently, efficient therapy at the targeted disease areas still remains challenging since most available drug molecules lack of selectivity to the pathological sites. Among different approaches, light-mediated therapeutic strategy has recently emerged as a promising and powerful tool to precisely control the activation of therapeutic reagents and imaging probes in vitro and in vivo, mostly attributed to its unique properties including minimally invasive capability and highly spatiotemporal resolution. Although it has achieved initial success, the conventional strategies for light-mediated theranostics are mostly based on the light with short wavelength (e.g., UV or visible light), which may usually suffer from several undesired drawbacks, such as limited tissue penetration depth, unavoidable light absorption/scattering and potential phototoxicity to healthy tissues, etc. Therefore, a near-infrared (NIR) light-mediated approach on the basis of long-wavelength light (700-1000 nm) irradiation, which displays deep-tissue penetration, minimized photo-damage and low autofluoresence in living systems, has been proposed as an inspiring alternative for precisely phototherapeutic applications in the last decades. Despite numerous NIR light-responsive molecules have been currently proposed for clinical applications, several inherent drawbacks, such as troublesome synthetic procedures, low water solubility and limited accumulation abilities in targeted areas, heavily restrict their applications in deep-tissue therapeutic and imaging studies. Thanks to the amazing properties of several nanomaterials with large extinction coefficient in the NIR region, the construction of NIR light responsive nanoplatforms with multifunctions have become promising approaches for deep-seated diseases diagnosis and therapy. In this review, we summarized various light-triggered theranostic strategies and introduced their great advances in biomedical applications in recent years. Moreover, some other promising light-assisted techniques, such as photoacoustic and Cerenkov radiation, were also systemically discussed. Finally, the potential challenges and future perspectives for light-mediated deep-tissue diagnosis and therapeutics were proposed.
... Der Nutzen der externen Bestrahlung ist für die Sialorrhoe bei verschiedenen neurologischen Krankheitsbildern beschrieben, z. T. im randomisiert kontrollierten Ansatz [63][64][65][66][67][68][69]. Eine Bestrahlung kann auch nach zuvor erfolgloser Behandlung mit Botulinumtoxin die Hypersalivation mindern [70], und umgekehrt kann eine postradiogene Hypersalivation durch Injektion von Botuli numtoxin reduziert werden [71]. ...
Article
Zusammenfassung Die größten Speicheldrüsen sind die paarigen Gl. parotis und Gl. submandibularis. Der erwachsene Mensch produziert 1–1,5 l Speichel am Tag, die er regelmäßig abschluckt. Die häufigste Ursache eines vermehrten Speichelflusses mit einer Ansammlung von Speichel im Mund und Ausfluss (Sialorrhoe) ist eine Störung der Schluckfunktion. Seltener kann auch eine vermehrte Speichelsekretion, z. B. medikamentös bedingt, die Ursache sein. Eine Sialorrhoe beeinträchtigt die Lebensqualität erheblich und ist oft auch sozial stigmatisierend. Die Therapie umfasst konservative Maßnahmen wie die funktionelle Dysphagietherapie, orale oder transdermale Applikation von Anticholinergika sowie, in ausgewählten Fällen, invasive Therapien wie Bestrahlungen und Operationen. Seit 20 Jahren wird auch die lokale Injektion von Botulinumtoxin in die Speicheldrüsen erfolgreich therapeutisch eingesetzt. Durch die Zulassung von IncobotulinumtoxinA für die Behandlung von Kindern und Erwachsenen darf diese Maßnahme als Therapie der Wahl bei chronischer Sialorrhoe angesehen werden. Die Ergebnisse der Zulassungsstudien zeigen bei Kindern wie auch Erwachsenen eine hohe Effektivität und gute Verträglichkeit der Injektionsbehandlung.
... Only 3 schwannomas were located in the medial one third of the IAC in the area of the glial-Schwann cell junction. We concluded that cochleovestibular schwannomas may arise anywhere along the course of the axons of the eighth cranial nerve from the glial- Schwann sheath junction up until their terminations within the auditory and vestibular end organs., 1967; Neely et al., 1976; Curtin, 1984; Jia et al., 2008; Roche et al., 2008] and in textbooks [Kuhweide et al., 1996; Gunderson and Tepper, 2007; Bernstein and Berger, 2008; Seegenschmiedt et al., 2008]. To the best of our knowledge, there is no published evidence that supports this statement. ...
Article
Full-text available
The belief that cochleovestibular schwannomas arise from the glial-Schwann cell junction has repeatedly been quoted in the literature, although there is no published evidence that supports this statement. A systematic evaluation of the nerve of origin and the precise location of cochleovestibular schwannomas using our respective archival temporal bone collections was conducted. Forty tumors were within the internal auditory canal (IAC), while 10 were intralabyrinthine neoplasms. Of the 40 IAC schwannomas, 4 arose from the cochlear nerve, and 36 from the vestibular nerve. Twenty-one tumors clearly arose lateral to the glial-Schwann cell junction, while 16 tumors filled at least two thirds of the IAC, with the epicenter of the neoplasm located in the mid part or the lateral part of the IAC. Only 3 schwannomas were located in the medial one third of the IAC in the area of the glial-Schwann cell junction. We concluded that cochleovestibular schwannomas may arise anywhere along the course of the axons of the eighth cranial nerve from the glial-Schwann sheath junction up until their terminations within the auditory and vestibular end organs.
... Irradiation of the salivary glands (especially the glandula parotis) can lead to xerostomia; previously this was a common side effect of radiotherapy of head and neck tumors. The benefits of external irradiation have been described for hypersalivation in various neurological conditions (Borg and Hirst 1998;Andersen et al. 2001;Neppelberg et al. 2007;Postma et al. 2007;Seegenschmiedt et al. 2008). Assouline et al. (2014), were able to show a good therapeutic effect with moderate side effects at a dose of 20 Gy under modern 3D-conformal irradiation technique and maximum protection of the surrounding tissue. ...
Article
Full-text available
Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes to activate compensation mechanisms as long compliances are given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the EU. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long-lasting saliva reduction. Here, a phase III trial is completed for incobotulinum toxin A and, in the US, is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3D techniques to minimize tissue damage. Therapy effects and symptom severity have to be followed, especially in cases with underlying neurodegenerative disease.
... Der Nutzen der externen Bestrahlung ist für die Sialorrhoe bei verschiedenen neurologischen Krankheitsbildern beschrieben, z. T. im randomisiert kontrollierten Ansatz [62][63][64][65][66][67][68]. Eine Bestrahlung kann auch nach zuvor erfolgloser Behandlung mit Botulinumtoxin die Hypersalivation mindern [69], und umgekehrt kann eine postradiogene Hypersalivation durch Injektion von Botulinumtoxin reduziert werden [70]. ...
Article
Zusammenfassung Die größten Speicheldrüsen sind die paarigen Gl. parotis und Gl. submandibularis. Der erwachsene Mensch produziert 1–1,5 l Speichel am Tag, die er regelmäßig abschluckt. Die häufigste Ursache eines vermehrten Speichelflusses mit einer Ansammlung von Speichel im Mund und Ausfluss (Sialorrhoe) ist eine Störung der Schluckfunktion. Seltener kann die Ursache auch eine vermehrte Speichelsekretion, z. B. medikamentös bedingt, sein. Eine Sialorrhoe beeinträchtigt die Lebensqualität erheblich und ist oft auch sozial stigmatisierend. Die Therapie umfasst konservative Maßnahmen wir die funktionelle Dysphagietherapie, orale oder transdermale Applikation von Anticholinergika sowie, in ausgewählten Fällen, invasive Therapien wie Bestrahlungen und Operationen. Seit 20 Jahren wird auch die lokale Injektion von Botulinumtoxin in die Speicheldrüsen erfolgreich therapeutisch eingesetzt. Durch die Zulassung dieser Therapie durch die europäische Behörde darf diese Maßnahme als Therapie der Wahl bei ausgeprägter, therapieresistenter Sialorrhoe angesehen werden.
... As compared to a high-dose exposure (> 30 Gy) that is predominantly associated with inflammation-promoting effects (Williams et al. 2003), concepts including single doses of 0.5-5 Gy and total doses of 3-30 Gy (lowÀ/ intermediate-dose radiation therapy; here referred to as LD-RT) have been shown to ameliorate inflammation, to exhibit analgesic properties, and to impact on hyperproliferative benign diseases (Rodel et al. 2012b(Rodel et al. , 2017. Clinically these concepts are in use in a variety of non-cancerous inflammatory/degenerative disorders (see chapter ▶ "Radiotherapy for Inflammatory Diseases" and ▶ "Radiotherapy for Painful Skeletal Disorders" in this book) or among others in the treatment of fibro-proliferative diseases like Dupuytren's contractures for decades (Seegenschmiedt et al. 2008) (see chapter ▶ "Radiotherapy for Hyperproliferative Disorders" in ths book). As (chronic) inflammatory, degenerative, and hyperproliferative benign diseases are based on complex (patho)physiological, immunological, and cellular networks, it is tempting to hypothesize that the empirically documented benefit of lowÀ/intermediate-dose radiation therapy may originate from the interference with a multitude of inflammatory and immunological pathways including manifold cellular components. ...
... The effectivity of external radiotherapy has been described (in a partially controlled approach [63][64][65][66][67][68][69]) for sialorrhea seen in various neurological diseases. Subsequent to unsuccessful treatment with botulinum toxin, radiation can reduce sialorrhea [70] and, vice versa, post-radiogenic sialorrhea can be reduced by injections of BoNT [71]. ...
Article
Full-text available
Botulinum neurotoxin (BoNT) is considered the treatment of choice for various symptoms and diseases such as focal dystonia and focal spas-ticity. The effects of BoNT on the salivary glands have also been known for years, but their use was limited because of a lack of approval studies. Now the indication of sialorrhea is approved in some countries for incobotulinumtoxinA, such as the USA and Europe, and therapy could also become the treatment of choice. According to the pivotal study, a dose of 100 units of incobotulinumtoxinA, which is divided into the parotid and submandibular glands, is recommended. RimabotulinumtoxinB is approved in the USA only. To define the value of this therapy, we must consider anatomy, physiology, and available therapies. Therapy includes conservative measures such as functional dysphagia therapy, oral or transdermal application of anticholinergics, and, in selected cases, radiotherapy and surgical procedures. A combination of different approaches is optional. On the basis of the evidence and clinical experience, BoNT injections will be the first line of pharmacotherapy for chronic sialorrhea.
... The effectivity of external radiotherapy has been described (in a partially controlled approach [63][64][65][66][67][68][69]) for sialorrhea seen in various neurological diseases. Subsequent to unsuccessful treatment with botulinum toxin, radiation can reduce sialorrhea [70] and, vice versa, post-radiogenic sialorrhea can be reduced by injections of BoNT [71]. ...
Article
Full-text available
Botulinum neurotoxin (BoNT) is considered the treatment of choice for various symptoms and diseases such as focal dystonia and focal spasticity. The effects of BoNT on the salivary glands have also been known for years, but their use was limited because of a lack of approval studies. Now the indication of sialorrhea is approved in some countries for incobotulinumtoxinA, such as the USA and Europe, and therapy could also become the treatment of choice. According to the pivotal study, a dose of 100 units of incobotulinumtoxinA, which is divided into the parotid and submandibular glands, is recommended. RimabotulinumtoxinB is approved in the USA only. To define the value of this therapy, we must consider anatomy, physiology, and available therapies. Therapy includes conservative measures such as functional dysphagia therapy, oral or transdermal application of anticholinergics, and, in selected cases, radiotherapy and surgical procedures. A combination of different approaches is optional. On the basis of the evidence and clinical experience, BoNT injections will be the first line of pharmacotherapy for chronic sialorrhea.
... a. der Glandula parotis) kann zu einer Xerostomie führen; früher war dies eine häufige Nebenwirkung der Strahlentherapie von Kopf-Hals-Tumoren. Der Nutzen der externen Bestrahlung ist für die Hypersalivation bei verschiedenen neurologischen Krankheitsbildern beschrieben [97][98][99][100][101]. Assouline et al. konnten bei einer Dosis von 20 Gy unter moderner 3D-konformaler Bestrahlungstechnik und maximaler Schonung des umliegenden Gewebes ein guter Therapieeffekt bei moderaten Nebenwirkungen zeigen [102]. ...
Article
Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation.Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes in order to activate compensation mechanisms as long compliances is given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the E. U. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Here, a phase III trial is completed for Incobotulinum toxin A and, in the U. S., is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3 D techniques to minimize tissue damage. Therapy effects and symptom severity has to be followed, especially in cases with underlying neurodegenerative disease. © Georg Thieme Verlag KG Stuttgart · New York.
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Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This reduces social interaction chances and burdens daily care. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, and saliva aspiration. Therefore, a multidisciplinary S2k guideline was developed. Diagnostic tools such as fiberoptic endoscopic evaluation of swallowing and videofluoroscopic swallowing studies generate important data on therapy selection and control. Especially traumatic and oncologic cases profit from swallowing therapy programmes in order to activate compensation mechanisms. In children with hypotonic oral muscles, oralstimulation plates can induce a relevant symptom release because of the improved lip closure. In acute hypersalivation, the pharmacologic treatment with glycopyrrolate and scopolamine in various applications is useful but its value in long-term usage critical. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Surgical treatment should be reserved for isolated cases. External radiation is judged as ultima ratio. Therapy effects and symptom severity has to be followed, especially in neurodegenerative cases. The resulting xerostomia should be critically evaluated by the responsible physician regarding oral and dental hygiene. © Georg Thieme Verlag KG Stuttgart · New York.
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Langerhans cell histiocytosis (LCH) is a rare semimalignant disease involving uncontrolled clonal proliferation of Langerhans cells, i.e. abnormal cells deriving from bone marrow and capable of migrating from skin to lymphnodes. LCH can involve one or more body systems or tissues, leading to different clinical manifestations. The disease is part of a group of clinical syndromes called histiocytoses characterized by pathologic proliferation of histiocytes (a former term for dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.
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Thesis
Il est bien établi que l’exposition aux fortes doses de rayonnements ionisants favorise le développement de l’athérosclérose, une pathologie inflammatoire chronique qui affecte la paroi des vaisseaux de gros et moyens calibres. Cependant les mécanismes biologiques des faibles doses de rayonnements ionisants sur cette pathologie sont moins bien documentés. Plusieurs travaux ont néanmoins mis en évidence que dans un contexte d’athérosclérose, l’exposition aux doses faibles pouvait, contrairement aux doses fortes, entrainer une réponse en faveur d’une modulation de l’inflammation et une hausse de la stabilité des plaques d’athérome (Le Gallic et al. 2015a; T. G. Ebrahimian et al. 2017; Mancuso, Pasquali, Braga-TanakaIII, et al. 2015; Mitchel et al. 2011). Ces études suggèrent que la dose et le débit de dose sont déterminants dans la survenue de cette réponse adaptative. L’objet de cette thèse est donc d’étudier les mécanismes adaptatifs immunomodulatoires mis en jeu dans l’athérosclérose après exposition à des doses faibles et modérées. A cette fin, l’évaluation de l’impact de la dose et du débit de dose dans cette réponse a été étudiée, puis les mécanismes immunitaires précoces et leurs conséquences à long terme sur la pathologie athéromateuse ont été explorés. Une première approche expérimentale a été réalisée sur un modèle de souris prédisposées à l’athérosclérose (ApoE-/-) exposés à des doses faibles et modérées d’irradiations γ à débit de doses chroniques et aiguës. Nous avons ainsi pu observer que les populations immunitaires ont une réponse non linéaire en fonction de la dose et dépendante du type cellulaire étudié. Les populations monocytaires pro-inflammatoires étaient diminuées à l’ensemble des doses tandis que des populations pro-inflammatoires lymphocytaires étaient diminuées uniquement à très faible dose et débit de dose. Dans un second temps, une autre approche expérimentale sur un modèle ApoE-/- fut dédiée à l’étude des mécanismes précoces post-irradiations (24 heures et 10 jours) sur principalement la polarisation des macrophages ainsi que les conséquences tardives sur le phénotype des plaques. Ainsi, 24 heures après irradiation, nous avons constaté une régulation à la hausse de gènes à action anti-inflammatoire (Chil-3 et Retnla) ainsi qu’une augmentation concomitante de la sécrétion eninterleukine-10 chez les macrophages de type M2. Concernant les études à long terme, nous n’avons pas observé de modifications par rapport à la stabilité des plaques d’athérome, néanmoins, la teneur en macrophages intra plaques était significativement abaissée à la plus forte des doses appliquées. Par ailleurs la proportion en monocytes spléniques était significativement augmentée après 100 jours, laissant entrevoir une hausse possible du stockage splénique des monocytes à long terme enclenchée par l’irradiation. L’ensemble de ces résultats confirme l’occurrence d’un mécanisme adaptatif immunomodulatoire à doses faibles et modérées dans le contexte de l’athérosclérose. Cette réponse est néanmoins dépendante du type cellulaire étudié et a des conséquences différentes en fonction de la dose et du débit de dose étudié. De plus, lors de l’application d’une dose modérée, nous avons mis en évidence la présence d’un mécanisme adaptatif observé plusieurs mois après irradiation au niveau de la plaque d’athérome et au niveau du système immunitaire.
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