Radiotherapy CT-based contouring atlas for non-malignant skeletal and soft tissue disorders: a practical proposal from Spanish experience.

OBJECTIVE: Interest in low-dose radiotherapy (LD-RT) for the symptomatic treatment of nonmalignant conditions, including inflammatory and degenerative disorders of the joints and para-articular soft tissues, has increased substantially in recent years. In the present document, we provide a CT-based contouring atlas to help identify and delineate the most common osteoarticular regions susceptible to LD-RT. METHODS: The clinical efficacy of LD-RT is supported by a large body of evidence. However, there is no consensus on the parameters for contouring the planning target volume (PTV). Moreover, 3D simulation and planning should be the standard of care even for nonmalignant disorders. For this reason, the present guidelines were prepared to help guide PTV contouring based on CT images, with the same quality criteria for patient immobilization, treatment simulation, planning and delivery as those routinely applied for cancer radiotherapy. RESULTS: PTV for radiotherapy requires precise identification of the target areas based on CT and other imaging techniques. Using a series of cases treated at our institution, we have defined the PTVs for each location on the simulation CT to establish the relationship between the image and the anatomical structures to be treated. We also specify the immobilization systems used to ensure treatment accuracy and reproducibility. CONCLUSIONS: This comprehensive atlas based on CT images may be of value to radiation oncologists who wish to use LD-RT for the symptomatic treatment of degenerative or inflammatory osteoarticular diseases. ADVANCES IN KNOWLEDGE: The recommendations and contouring atlas described in this article provide an eminently practical tool for LD-RT in non-malignant conditions, based on the same quality criteria recommended for all modern radiotherapy treatments in Spain.

A systematic review examining clinical markers and biomarkers of analgesic response to radiotherapy for cancer-induced bone pain.

INTRODUCTION: Cancer frequently spreads to bone, causing cancer-induced bone pain (CIBP) which affects quality of life. The best treatment is radiotherapy (XRT), but response is variable. The aim of this systematic review was to identify factors that predict analgesic response. MATERIALS AND METHODS: Using PRISMA guidelines, Medline (1946-2018), Embase Classic + Embase (1947-2018) and Cochrane (setup-2018) databases were searched. Eligible studies examined adult patients receiving external beam XRT for CIBP with clinical marker and/or biomarkers evaluated. RESULTS: Twenty-one studies (n = 4490) were included: Urinary markers in three studies (n = 357), genomic biomarkers in one study (n = 107), imaging techniques in five studies (n = 231) and demographics and disease parameters in eight studies (n = 4572). Quantitative sensory testing (n = 23) and physical activity and/or gait (n = 42) have been examined in one study each, while two studies have evaluated grade of spinal instability (n = 276). CONCLUSION: No predictors of analgesic response from XRT in CIBP were identified but several show promise.

Novel treatment of 99Tc-MDP improves clinical and radiographic results for patients with osteochondral lesions of the talus.

BACKGROUND: Management of osteochondral lesions of talus (OLT) remains controversial. 99Tc-MDP, a decay product of 99mTc-MDP which is widely used for bone scan, is effective in the clinical treatment of rheumatoid arthritis. The purpose of the study is to investigate the effects of 99Tc-MDP treatment on OLT. METHODS: In the clinical evaluation, 66 patients with a total of 83 lesions of OLT who failed appropriate non-operative treatment and surgery were retrospectively included and treated with intravenous injection of 99Tc-MDP and Chinese herbal fumigation (CHF). The effects of 99Tc-MDP and CHF on OLT were evaluated by the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Score (AOFAS), Visual Analog Scale (VAS), activities of daily living (Barthel Index), and MRI, 99mTc-MDP SPECT/CT and CT. Radiographic changes were also assessed by the transverse long diameter of the cyst on CT. RESULTS: At the last follow-up, AOFAS, VAS and Barthel Index improved significantly from 68.66±9.76, 3.05±0.34 and 85±8.31 to 85.4±8.31, 1.85±0.36 and 94.7±4.99 (P<0.01), respectively after one course treatment in 66 patients with OLT. Thirty one (31/66) patients had a second treatment course. Their AOFAS, VAS and Barthel Index also improved significantly after the mean follow-up of 7±2 (6-15) months. And the average diameter of the cysts decreased from 8.01±3.35 mm to 4.74±2.83 mm (P<0.01) in the 31 patients. CONCLUSIONS: The retrospective study indicates that a combination treatment of 99Tc-MDP and CHF is effective in pain relief and return of function in a short term of follow-up for patients with OLT. Our results suggest that the small cystic lesions with increased uptake of 99mTc-MDP on SPECT/CT can be well treated by 99Tc-MDP and CHF. This novel technique holds the potential to emerge as an effective conservative treatment for OLT without adverse effects. The level of evidence for 99Tc-MDP is medium for the number of patients and retrospective study.

Distal Tibia and Foot Involvement in a Patient With Waldenstrom's Macroglobulinemia.

Bone lesions are a rare presentation in Waldenstrom's macroglobulinemia patients. Although lytic bone lesions and generalized osteoporosis have been described variably in literature on Waldenstrom's macroglobulinemia patients, distal long bone and foot involvement has not been described to our knowledge. We report a patient with Waldenstrom's macroglobulinemia with IgM monoclonal spike, plasmacytic infiltration of bone marrow, and symptoms of foot pain, and found to have distal tibia and foot involvement. The symptoms of bone lesions in our patient were significantly improved with radiation treatment. The possibility of distal involvement of long bones in a clinically relevant presentation should be kept in mind in these patients.

Outcome After Radiation Therapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement.

PURPOSE: To characterize the efficacy and safety of radiation therapy in a contemporary Langerhans cell histiocytosis (LCH) cohort and to explore whether there are sites at higher risk for local recurrence. PATIENTS AND METHODS: Between 1995 and 2015 we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiation therapy. Patient demographics, treatment, and local failure were compared by site of lesion. RESULTS: Median age at radiation therapy was 35 years (range, 1.5-67 years). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4 Gy (range, 7.5-50.4 Gy). At a median follow-up of 45 months (range, 6-199 months), local recurrence or progression was noted in 5 of 46 lesions (11%). There were no local failures of the 31 bone lesions evaluated, whereas the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% confidence interval 32-83%; P=.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 patients (13%), all of whom were adults with multisystem disease. CONCLUSION: Radiation therapy is a safe and effective measure for providing local control of LCH involving the bone. Whereas bone lesions are well controlled with low doses of radiation, disease in other tissues, such as the skin and brain, may require higher doses of radiation or additional treatment modalities.

Low-Dose Radiation Therapy for Benign Painful Skeletal Disorders: The Typical Treatment for the Elderly Patient?

PURPOSE: To prospectively evaluate the short-term and long-term efficacy of low-dose radiation therapy (RT) for calcaneodynia, achillodynia, painful gonarthrosis, and painful bursitis trochanterica in elderly patients aged ≥70 years. METHODS AND MATERIALS: Between October 2011 and October 2013, patients aged ≥70 years with painful degenerative disorders of joints were recruited for a prospective trial. Single doses of 0.5 to 1.0 Gy and a total dose of 6.0 Gy per series were used. Pain was measured before and right after RT (early response) with a 10-point visual analogue scale. Additionally, pain relief was measured with the 4-point pain scale according to "von Pannewitz" immediately on completion of RT and during follow-up. We defined a good response as complete pain relief and markedly improved. RESULTS: A total of 166 evaluable patients with a mean age of 76.6 years (range, 70-90 years) with calcaneodynia (n=51), achillodynia (n=8), painful gonarthrosis (n=80), and painful bursitis trochanterica (n=27) were recruited. The mean visual analogue scale value before treatment was 6.38 and immediately upon completion of RT was 4.49 (P<.001). Concerning the von Pannewitz status immediately on completion of RT, 6 patients were free of pain, 56 were much improved, 47 reported slight improvement, and 57 experienced no change. After a median follow-up of 29 months, 109 patients could be reached for evaluation of follow-up results. Thirty-three patients were free of pain, 21 had marked improvement, 18 had some improvement, and 37 experienced no change. Therefore, a good response immediately on completion of RT could be achieved in 62 of 166 patients, and with the follow-up in 54 of 109 patients (P=.001). CONCLUSIONS: Low-dose RT is a very effective treatment for the management of painful degenerative disorders of joints in the elderly. Low-dose RT offers a low-risk, genuinely conservative, noninvasive therapeutic alternative for elderly patients.

Effects of low level laser therapy on inflammatory and angiogenic gene expression during the process of bone healing: A microarray analysis.

The process of bone healing as well as the expression of inflammatory and angiogenic genes after low level laser therapy (LLLT) were investigated in an experimental model of bone defects. Sixty Wistar rats were distributed into control group and laser group (830nm, 30mW, 2,8J, 94seg). Histopathological analysis showed that LLLT was able to modulate the inflammatory process in the area of the bone defect and also to produce an earlier deposition of granulation tissue and newly formed bone tissue. Microarray analysis demonstrated that LLLT produced an up-regulation of the genes related to the inflammatory process (MMD, PTGIR, PTGS2, Ptger2, IL1, 1IL6, IL8, IL18) and the angiogenic genes (FGF14, FGF2, ANGPT2, ANGPT4 and PDGFD) at 36h and 3days, followed by the decrease of the gene expression on day 7. Immunohistochemical analysis revealed that the subjects that were treated presented a higher expression of COX-2 at 36h after surgery and an increased VEGF expression on days 3 and 7 after surgery. Our findings indicate that LLLT was efficient on accelerating the development of newly formed bone probably by modulating the inflammatory and angiogenic gene expression as well as COX2 and VEGF immunoexpression during the initial phase of bone healing.

Comparison of the Effects of Low-Level Laser Therapy and Ozone Therapy on Bone Healing.

This study aims to compare the effect of low-level laser therapy (LLLT) and ozone therapy on the bone healing. Thirty-six adult male Wistar albino rats were used for this study. Monocortical defects were shaped in right femur of all rats. Defects were filled with nano-hydroxyapatite graft. The animals were divided into 3 groups and each group was than divided into 2 subgroups. Then, LLLT with a diode laser was applied to the first group (G1), ozone therapy was applied to the second group (G2), and no treatment was applied to the third group as a control group (G3). Animals were sacrificed after 4th and 8th weeks and the sections were examined to evaluate the density of the inflammation, the formation of connective tissue, the osteogenic potential, and osteocalcin activity. As a result, there were no significant differences among the groups of 4 weeks in terms of new bone formation. In the immunohistochemical assessment, the number of osteocalcin-positive cells was higher in the laser group compared to the other group of 4 weeks; this difference was statistically significant in the LLLT and ozone groups (P < 0.05). Histomorphometric assessment showed that the new bone areas were higher in the LLLT and ozone groups; furthermore, there was a statistically significant difference in the LLLT in comparison with the control group at 8th week (P < 0.05). At the same time immunohistochemical assessment showed that osteocalcin-positive cells were considerably higher in G2 than G1 at 8th week (P < 0.05). The findings of this study may be the result of differences in the number of treatment sessions. Further studies are therefore needed to determine the optimal treatment modality.

Surgery or radiotherapy for the treatment of bone hydatid disease: a retrospective case series.

BACKGROUND: Currently, there is no accepted treatment for inoperable bone hydatid disease where medical treatment has proved ineffective. Alternative treatment strategies are therefore urgently needed. Radiotherapy may constitute a treatment option, but there is currently a lack of adequate evidence. This study sought to retrospectively assess the efficacy and safety of surgery or radiotherapy in the treatment of bone hydatid disease in patients attending a single hospital in China. METHODS: This was a retrospective case series analyzing clinical data from consecutive patients treated between January 2000 and December 2011. Patients with an Echinococcus sp infection were counselled about their disease and the potential treatment options, and made an informed decision between surgery and radiotherapy. All patients were followed up. The treatment outcome was observed in the two treatment groups based on the frequencies of relapse and complications, and self-evaluated patient satisfaction. RESULTS: Of 40 patients (age range 25-57 years), 24 opted for surgery and 16 for radiotherapy. Relapse occurred in 14 patients (58%) post-surgery and in three patients (21%) post-radiotherapy. Bone defects, limb movement disorders, and pain were reported in seven patients (29%) post-surgery, while two patients (13%) reported hardening of the irradiated region or a limb after radiotherapy. Titres of parasite-specific antibodies decreased significantly after radiotherapy but not after surgical intervention. Patient satisfaction was significantly higher in the radiotherapy group. CONCLUSION: This retrospective case series describes, for the first time, the clinical outcomes in a series of patients treated with radiotherapy for bone hydatid disease. Although no direct comparison between the treatment groups could be made due to methodological limitations of the study design, this study indicates that well-designed prospective randomized controlled clinical trials assessing radiotherapy may be warranted in patients with inoperable hydatid disease of the bones.

[Radiotherapy indications for non-malignant diseases in 2014]. / Indications non oncologiques de la radiothérapie : quelles indications en 2014 ?

This review updates the radiotherapy indications for non-malignant diseases, except those treated by radiosurgery. Since the last 2005 review, there have been no major changes in the indications: the prevention of heteropic bone formation and keloids remain classical indications, while the treatment of macular degeneration or the prevention of coronary restenosis are now past history. Nevertheless, the radiation treatment for benign diseases should have the same criteria as for malignant diseases: information of the patient on risks, benefits and treatment quality.

Raman ratios on the repair of grafted surgical bone defects irradiated or not with laser (λ780 nm) or LED (λ850 nm).

This work aimed to assess biochemical changes associated to mineralization and remodeling of bone defects filled with Hydroxyapatite+Beta-Beta-tricalcium phosphate irradiated or not with 2 light sources. Ratios of intensities, band position and bandwidth of selected Raman peaks of collagen and apatites were used. Sixty male Wistar rats were divided into 6 groups subdivided into 2 subgroups (15th and 30th days). A standard surgical defect was created on one femur of each animal. In 3 groups the defects were filled with blood clot (Clot, Clot+Laser and Clot+LED groups) and in the remaining 3 groups the defects were filled with biomaterial (Biomaterial, Biomaterial+Laser and Biomaterial+LED groups). When indicated, the defects were irradiated with either Laser (λ780 nm, 70 mW, Φ∼0.4 cm(2)) or LED (λ850±10 nm, 150 mW, Φ∼0.5 cm(2)), 20 J/cm(2) each session, at 48 h intervals/2 weeks (140 J/cm(2) treatment). Following sacrifice, bone fragments were analyzed by Raman spectroscopy. Statistical analysis (ANOVA General Linear Model, p<0.05) showed that both grafting and time were the variables that presented significance for the ratios of ∼1660/∼1670 cm(-1) (collagen maturation), ∼1077/∼854 cm(-1) (mineralization), ∼1077/∼1070 cm(-1) (carbonate substitution) and the position of the ∼960 cm(-1) (bone maturation). At 30th day, the ratios indicated an increased deposition of immature collagen for both Clot and Biomaterial groups. Biomaterial group showed increased collagen maturation. Only collagen deposition was significantly dependent upon irradiation independently of the light source, being the amount of collagen I increased in the Clot group at the end of the experimental time. On the other hand, collagen I deposition was reduced in biomaterial irradiated groups. Raman ratios of selected protein matrix and phosphate and carbonate HA indicated that the use of biphasic synthetic micro-granular HA+Beta-TCP graft improved the repair of bone defects, associated or not with Laser or LED light, because of the increasing deposition of HA.

Comparing calvarial transport distraction with and without radiation and fat grafting.

The purpose of this study is to: a) assess transport distraction to reconstruct cranial defects in radiated and non-radiated fields b) examine adipose grafting's effect on the bony regenerate and overlying wound, and c) elucidate sources of bone formation during transport distraction osteogenesis. Twenty-three male New Zealand white rabbits (3 months; 3.5 kg) were used, 10 non-irradiated and 13 irradiated (17 treatment, 6 control) with a one-time fraction of 35 Gy. A 16 × 16 mm defect was abutted by a 10 × 16 mm transport disc 5 weeks after irradiation, and 11 animals were fat grafted at the distraction site. Latency (1 day), distraction (1.5 mm/day), and consolidation (4 weeks) followed. Fluorochromes were injected subcutaneously and microCT, fluorescence, and histology assessed. In distracted animals without fat grafting, bone density measured 701.87 mgHA/ccm and 2271.95 mgHA/ccm in irradiated and non-irradiated animals. In distracted animals with fat grafting, bone density measured 703.23 mgHA/ccm and 2254.27 mgHA/ccm in irradiated and non-irradiated animals. Fluorescence revealed ossification emanating from the dura, periosteum, and transport segment with decreased formation in irradiated animals. Transport distraction is possible for cranial reconstruction in irradiated fields but short-term osseous fill is significantly diminished. Adipose grafting enhances wound healing in previously irradiated fields but does not enhance ossification.

Effect of LLLT on autogenous bone grafts in the repair of critical size defects in the calvaria of immunosuppressed rats.

The aim of this study was to evaluate the effects of low-level laser therapy (LLLT) on the bone repair of critical size defects (CSDs) filled with autogenous bone in the calvaria of immunosuppressed rats. A 5 mm-diameter CSD was created in the calvaria of 30 rats. The animals were divided into 5 groups (n = 6): Control (C)--the defect was filled with a blood clot; Dexamethasone (D)--dexamethasone treatment, and the defect was filled with a blood clot; Autogenous bone (AB)--dexamethasone treatment, and the defect was filled with autogenous bone; LLLT--dexamethasone treatment, and the defect received LLLT (660 nm; 35 mW; 24.7 J/cm(2)); and AB + LLLT--dexamethasone treatment, and the defect was filled with autogenous bone and received LLLT. All animals were euthanized at 30 postoperative days. Histometric and histological analyses were performed. The new bone area (NBA) was calculated as the percentage of the total area of the original defect. Data were analysed statistically (an analysis of variance and Tukey's test; P < 0.05). The AB + LLLT group showed the largest NBA of all groups (P < 0.05). The use of LLLT with AB effectively stimulated bone formation in CSDs in the calvaria of immunosuppressed rats.

Management of bone disease in multiple myeloma.

Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal complications that cause significant morbidity and mortality. Currently, bisphosphonates (BPs) are the mainstay for the treatment of myeloma bone disease. Zoledronic acid which has been found to be superior to clodronate, both in terms of reduction of skeletal-related events (SREs) and survival, and pamidronate are used for the management of myeloma-related bone disease. Patients with active disease (not in CR or VGPR) should receive BPs (especially zoledronic acid) even after two years of administration. Radiotherapy and surgical interventions can also be used for specific conditions, such as pathological fractures, spinal cord compression or uncontrolled pain. The better understanding of the biology of myeloma bone disease has led to the production of several novel agents, such as denosumab (targeting RANKL), sotatercept (activin-A antagonist) and romosozumab (targeting sclerostin) that appear very promising and have entered to clinical development.

Targeted radionuclide therapy--an overview.

Radionuclide therapy (RNT) based on the concept of delivering cytotoxic levels of radiation to disease sites is one of the rapidly growing fields of nuclear medicine. Unlike conventional external beam therapy, RNT targets diseases at the cellular level rather than on a gross anatomical level. This concept is a blend of a tracer moiety that mediates a site specific accumulation followed by induction of cytotoxicity with the short-range biological effectiveness of particulate radiations. Knowledge of the biochemical reactions taking place at cellular levels has stimulated the development of sophisticated molecular carriers, catalyzing a shift towards using more specific targeting radiolabelled agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides based on availability, the types of emissions, linear energy transfer (LET), and physical half-life. This article discusses the applications of radionuclide therapy for treatment of cancer as well as other diseases. The primary objective of this review is to provide an overview on the role of radionuclide therapy in the treatment of different diseases such as polycythaemia, thyroid malignancies, metastatic bone pain, radiation synovectomy, hepatocellular carcinoma (HCC), neuroendocrine tumors (NETs), non-Hodgkin's lymphoma (NHL) and others. In addition, recent developments on the systematic approach in designing treatment regimens as well as recent progress, challenges and future perspectives are discussed. An examination of the progress of radionuclide therapy indicates that although a rapid stride has been made for treating hematological tumors, the development for treating solid tumors has, so far, been limited. However, the emergence of novel tumor-specific targeting agents coupled with successful characterization of new target structures would be expected to pave the way for future treatment for such tumors.

International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease.

PURPOSE: The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease. METHODOLOGY: An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. RECOMMENDATIONS: Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

Radiation therapy for resistant sternal hydatid disease.

Hydatid disease is a zoonotic infectious disease for which there are known treatment procedures and effective antibiotics; however, there are resistant cases that do not respond to medication or surgery. We report a case diagnosed as hydatid disease of the chest wall and treated with radiation therapy (RT) after medical and surgical therapy had failed. In conclusion, RT represents an alternative treatment modality in resistant cases.

Effects of radial shock waves therapy on osteoblasts activities.

Radial shock waves therapy (RSWT) differs from extracorporeal shock waves therapy (ESWT) in that it produces a non-focused wave that is dissipated radially at the skin. Few studies have yet explored the effects of RSWT on bone tissue. Osteoblasts in culture flasks were studied by polymerase chain reaction after treatment with RSW (500 impulses, 0.05 mJ/mm(2)). An inhibited osteoblastogenesis was observed, with a statistically significant reduction in type 1 collagen, osterix, bone sialoprotein and receptor activator NF kappa ligand expression at 24 and 48 h, of osteocalcin at 24, 48 and 72 h, and osteopontin at 48 and 72 h. These findings show that RSWT is not indicated for treatment of delayed fracture union, pseudoarthrosis, and complex regional pain syndrome. The observed reduction in the receptor activator of nuclear factor-kB ligand/osteoprotegerin ratio suggests that it has an inhibiting effect on osteoclastogenesis, which could make it a useful tool for applications in proliferative diseases.