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A. Kawai43, K. Kopeckova44, D. A. Krakorova45, A. Le Cesne46, F. Le Grange1, E. Legius47, A. Leithner48, A. Lopez Pousa49, J. Martin-Broto36, O. Merimsky50, C. Messiou51, A. B. Miah52, O. Mir53, M. Montemurro54, B. Morland55, C. Morosi56, E. Palmerini57, M. A. Pantaleo58, R. Piana59, S. Piperno-Neumann60, P. Reichardt61, P. Rutkowski62, A. A. Safwat63, C. Sangalli64, M. Sbaraglia19, S. Scheipl48, P. Schoffski65, S. Sleijfer66, D. Strauss67, K. Sundby Hall13, A. Trama68, M. Unk69, M. A. J. van de Sande70, W. T. A. van der Graaf66,71, W. J. van Houdt72, T. Frebourg73x, R. Ladenstein41z, P. G. Casali2,74z &

Introduction Bone metastases are frequent in patients with cancer. Electrochemotherapy (ECT) is a minimally invasive treatment. Preclinical and clinical studies supported the use of ECT in patients with metastatic bone disease (MBD). The purposes of this multicentre study are to confirm the safety and efficacy of ECT, and to identify appropriate operating procedures in different MBD conditions. Materials and methods 102 patients were treated in 11 Centres and recorded in the REINBONE registry (a shared database protected by security passwords): clinical and radiological information, ECT session, adverse events, response, quality of life indicators and duration of follow-up were registered. Results 105 ECT sessions were performed (one ECT session in 99 patients, two ECT sessions in 3 patients). 24 patients (23.5%) received a programmed intramedullary nail after ECT, during the same surgical procedure. Mean follow-up was 5.9 ± 5.1 months (range 1.5–52). The response to treatment by RECIST criteria was 40.4% objective responses, 50.6% stable disease and 9% progressive disease. According to PERCIST criteria the response was: 31.4% OR; 51.7% SD, 16.9% PD with no significant differences between the 2 criteria. Diagnosis of breast cancer and ECOG values 0–1 were significantly associated to objective response. A significant decrease in pain intensity and significant better quality of life was observed after ECT session at follow-up. Conclusion The results are encouraging on pain and tumour local control. ECT proved to be an effective and safe treatment for MBD and it should be considered as an alternative treatment as well as in combination with radiation therapy.

Chondroblastoma is one of the uncommon benign bone tumors, particularly when located in the mandibular condyle. Such a location makes its diagnosis difficult when based on only its clinical presentation and radiographic features. Herein the current report presents a case of chondroblastoma of the mandibular condyle: its clinical presentation, radiographic features, and immediate condylar reconstruction after resection. Additionally, the relevant literature is discussed to provide clinical recommendations for its diagnosis and treatment. Chondroblastoma has been reported so infrequently in the temporomandibular joint (TMJ), more common entities should first be considered in the differential diagnosis of masses in this location. Osteochondroma is the most frequent bone neoplasm in the TMJ. Since a correct diagnosis is difficult, additional tools, such as magnetic resonance imaging (MRI) and immunohistochemical analyses, should be used for diagnostics and surgical planning.

Aims Chondrosarcoma is the second most common primary sarcoma of bone: conventional chondrosarcoma accounts for 85% of all cases. Conventional chondrosarcoma may be central or peripheral. Most studies group central and peripheral chondrosarcomas together, although there is growing evidence that their clinical behaviour and prognosis differ. The aims of this study were to analyze any differences in characteristics between central and peripheral chondrosarcomas and to investigate the incidence and role of different syndromes. Methods Data from two international tertiary referral sarcoma centres between January 1995 and December 2018 were retrospectively reviewed. The study population consisted of 714 patients with surgically treated conventional chondrosarcoma of the pelvis and limbs. Results In patients with Ollier’s disease and Mafucci’s syndrome, 12/20 (60%) and 2/5 (60%) of malignancies, respectively, were in the limbs, most frequently in the proximal humerus, proximal tibia, and in the hands and feet. In patients with hereditary multiple exostosis (HME), 20/29 (69.0%) of chondrosarcomas were in the pelvis and scapula, specifically in the ilium in 13/29 (44.8%) and the scapula in 3/29 (10.3%). In central chondrosarcoma, survival of patients with Ollier’s disease and non-syndromic patients was the same (p = 0.805). In peripheral chondrosarcoma, survival among HME patients was similar (p = 0.676) in patients with tumours of the pelvis and limbs. Conclusion Both central and peripheral chondrosarcoma have specific characteristics. HME is frequently seen in patients with a peripheral chondrosarcoma, in whom tumours are commonly located in the ilium and scapula. The incidence of Ollier’s disease is uncommon in patients with a central chondrosarcoma. Disease-specific survival is equal in different subtypes after adjustment for histological grade. The local recurrence-free survival is the same for different locations and subtypes after adjustment for surgical margin. Cite this article: Bone Joint J 2021;103-B(5):984–990.

PURPOSE: A T1 sequence on routine baseline staging rectal magnetic resonance imaging (MRI) is thought to help detect bone lesions. Our primary aim was to evaluate the incidence of bone lesions encountered on baseline staging rectal MRI, particularly the prevalence of bone metastases. METHODS: This retrospective study included patients with rectal adenocarcinoma who underwent baseline rectal MRI at our institution between January 2010 and December 2017. The MRI report was reviewed for presence of bone lesions. When found, lesion type, presence of axial T1 non-fat-suppressed sequence, primary tumor T-stage, and presence of other organ metastases were recorded. In the absence of bone biopsy, the reference standard was follow-up imaging via computed tomography (CT), MRI, and/or positron emission tomography/CT (PET/CT) ≥ 1 year after the baseline MRI. The Wilcoxon rank-sum test and Fisher’s exact test were used to compare clinicopathologic data of patients with malignant or benign bone lesions. RESULTS: A total of 1,197 patients were included. 62/1197 patients (mean age 56.8 years (SD: 13.8), with 39 men) had bone lesions on baseline imaging, with 6 being bone metastases (0.5%, 95% CI: 0.2%–1.1%). Of the 6 patients with bone metastases, 5/6 had other metastases (i.e. liver, lung) at baseline. CONCLUSION: Bone metastases on baseline rectal MRI performed for rectal adenocarcinoma are extremely rare. Furthermore, bone metastases without other organ (i.e. liver, lung) involvement is extremely rare.

Background: Trans-arterial embolization (TAE) is a prom-ising less aggressive modality in either primary treatment or adjuvant to surgical management of bone tumors. The main aim is to induce necrosis and decrease bleeding and therefore facilitate resection. Palliation of compression manifestation of inoperable bone neoplasm is another indication of TAE. Frequent tumors selected to this modality include vascular tumors (particularly metastases), aneurysmal bone cysts (ABC), giant cell tumor (GCT), and osteosarcoma. Aim of Study: Our aim is to assess the role of embolization in management of bone tumors. Patients and Methods: The current study prospectively evaluated 33 patients (23 males and 10 females). Their age ranged from 9 to 69 years (mean age of 43.246±19.65). Extremities, hip, vertebrae, and skull were involved by variety of bony tumors. Sixteen patients were affected by primary osseous tumors, while 17 patients had metastases. A transar-terial embolization was done in all patients as a preoperative procedure in 15 patients, definite treatmentof primary benign inaccessible tumors in 6 patients, prebiopsy embolization in 6 patients, and as a palliative treatment in 6 patients. Results: Technical success was obtained in 30 out of 33 cases with percentage of 90.9%. All benign and primary malignant bony tumors showed technical success while, 82.4% of metastatic lesions did. Clinical success was achieved in 73.3% cases of first group, 83.3% of second group, 100% of third group and 66.7% of fourth group. Four patients (12.1%) showed no clinical improvement with 9% lost follow-up. Five out of 6 benign tumors showed clinical success (83.3%) as the sixth case lost follow-up (16.7%). Embolization of 9 of primary malignant lesions was clinically successful (90%), whereas 12 out of 17 metastatic lesions were improved clinically (70.6 %), 3 cases showed no clinical success (17.6%), and 2 cases were lost at follow-up (11.8%).Conclusion: A high consideration should be given totran-sarterialembolization in the algorithmic treatment strategy of bone tumors as it is much safer and effective tool when diminution of bleeding and compression manifestations is to be specifically aimed.

Bone is the most common site of metastasis in metastatic castration-resistant prostate cancer (mCRPC), which is associated with pain and skeletal events. Radium-223 dichloride (Xofigo) is an alpha-emitting radioactive isotope that can specifically target bone lesions. Herein, we report the results of a retrospective analysis that documents our experience in the use of radium-223. Data from 63 patients (pts) with mCRPC who underwent radium-223 treatment from December 2015 to September 2017 were collected. Radium-223 (55 kBq/kg) was administered every 4 weeks for up to 6 cycles. The primary endpoint was OS. Radium-223 was administered as first line therapy in 11 pts, as second line in 19 pts, as third line in 16 pts and in successive lines in 17 pts; 42 pts out of 63 (67%) completed all six cycles. Within one month after the end of 6 cycles of radium-223, 15 pts out of 42 (35.7%) had achieved PR, 11 pts out of 42 (26.2%) had SD and 14 pts out of 42 (33.3%) had PD. Levels of pain decreased with progressive cycles of radium-223. After a minimum follow-up of 2 months and a maximum of 43 months, median OS was 15 months and median PFS was 8 months. The most frequent radium-223 related toxicity was low grade haematologic toxicity, predominantly G1-G2, that occurred halfway through treatment in about 75% of pts. The favourable results reported herein confirm that radium-223 can be considered well tolerated and effective in mCRPC, and is associated with significant decreases in pain. Bone is the most common site of metastasis in metastatic castration-resistant prostate cancer (mCRPC), which is associated with pain and skeletal events. Radium-223 dichloride (Xofigo) is an alpha-emitting radioactive isotope that can specifically target bone lesions. Herein, we report the results of a retrospective analysis that documents our experience in the use of radium-223. Data from 63 patients (pts) with mCRPC who underwent radium-223 treatment from December 2015 to September 2017 were collected. Radium-223 (55 kBq/kg) was administered every 4 weeks for up to 6 cycles. The primary endpoint was OS. Radium-223 was administered as first line therapy in 11 pts, as second line in 19 pts, as third line in 16 pts and in successive lines in 17 pts; 42 pts out of 63 (67%) completed all six cycles. Within one month after the end of 6 cycles of radium-223, 15 pts out of 42 (35.7%) had achieved PR, 11 pts out of 42 (26.2%) had SD and 14 pts out of 42 (33.3%) had PD. Levels of pain decreased with progressive cycles of radium-223. After a minimum follow-up of 2 months and a maximum of 43 months, median OS was 15 months and median PFS was 8 months. The most frequent radium-223 related toxicity was low grade haematologic toxicity, predominantly G1-G2, that occurred halfway through treatment in about 75% of pts. The favourable results reported herein confirm that radium-223 can be considered well tolerated and effective in mCRPC, and is associated with significant decreases in pain.

Cancer causes inflammation as it progresses through healthy tissue. The differentiation of tumoral growth from the surrounding inflammatory change is paramount in planning surgeries seeking to preserve function. This retrospective study aims at illustrating how a careful use of imaging (computed tomography (CT)/magnetic resonance imaging (MRI)) can help to draw the line between infiltration and inflammation. Out of 72 cases of parosteal osteosarcoma in our institution we selected 22 which had pretreatment imaging, and out of those, 14 that had both MRI and CT. Using Fisher’s exact test, we evaluated the performance of each technique on accurately diagnosing medullary tumor infiltration, using histological analysis as a gold standard. All cases (14/14) demonstrated medullary abnormality on MRI, but only 6/14 (42.9%) demonstrated abnormality on CT. The 8/14 cases with MRI abnormality but no CT abnormality (57.1%) showed inflammation with no tumoral cells present on histological analysis. In the cases where the two examinations showed medullary abnormality (6/14) histology demonstrated tumoral infiltration. MRI demonstrated high sensitivity and negative predictive value, but low specificity and low positive predictive value and accuracy (P=1). CT demonstrated high sensitivity, specificity, high positive and negative predictive values and accuracy (P = 0.000333). MRI is highly sensitive for the detection of medullary abnormality but lacks specificity for tumor invasion. Correlation with CT is recommended in all cases of positive MR to add specificity for tumors. The adequate use of the two imaging methods allows to differentiate between inflammatory change and tumoral infiltration in POS, relevant for surgical planning.

OBJECTIVE To determine an optimal time interval between amputation and initiation of adjuvant chemotherapy (TIamp-chemo) in dogs with appendicular osteosarcoma without distant metastases and whether TIamp-chemo was associated with outcome. ANIMALS 168 client-owned dogs treated at 9 veterinary oncology centers. PROCEDURES Data were collected from the dogs’ medical records concerning potential prognostic variables and outcomes. Dogs were grouped as to whether they received chemotherapy within 3, 5, 7, 10, 15, 20, 30, or > 30 days after amputation of the affected limb. Analyses were performed to identify variables associated with time to tumor progression and survival time after limb amputation and to determine an optimal TIamp-chemo. RESULTS Median TIamp-chemo was 14 days (range, 1 to 210 days). Median time to tumor progression for dogs with a TIamp-chemo ≤ 5 days (375 days; 95% CI, 162 to 588 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (202 days; 95% CI, 146 to 257 days). Median overall survival time for dogs with a TIamp-chemo ≤ 5 days (445 days; 95% CI, 345 to 545 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (239 days; 95% CI, 186 to 291 days). CONCLUSIONS AND CLINICAL RELEVANCE Findings indicated that early (within 5 days) initiation of adjuvant chemotherapy after limb amputation was associated with a significant and clinically relevant survival benefit for dogs with appendicular osteosarcoma without distant metastases. These results suggested that the timing of chemotherapy may be an important prognostic variable.

Introduction: Studies focusing on enchondroma and atypical cartilaginous tumour (ACT) of the pelvis are lacking. The purpose of this study was to verify possible clinical and radiological findings with regard to distinguishing enchondromas from ACT of the pelvis. In addition, this study analysed functional and oncological outcomes in patients with enchondromas or ACT of the pelvis treated with curettage or resection. Materials and methods: We retrospectively reviewed the medical records of 21 patients with confirmed enchondroma or ACT of the pelvis treated by curettage or resection from 1985 to 2018. The minimum follow-up was 18months. The relationship between clinical and radiological factors and tumour type or local recurrence was assessed using Fisher exact test and Mann–Whitney U test. Results: Endosteal scalloping (p = 0.039), tumour size (0.005) and age (0.006) were shown to statistically favour ACT over enchondroma; by contrast, enchondroma and ACT patients had no difference in pain frequency (p = 0.5528). All patients with enchondroma had no local recurrence; in contrast, local recurrence occurred in one patient with ACT, initially treated with resection. The patient with local recurrence had a disease progression with a higher histological grade than the original tumour. Patients treated with curettage had better functional outcomes than patients treated with resection (p = 0.001). Discussion: Endosteal scalloping, tumour size and age could be helpful in the differential diagnosis between enchondroma and ACT of the pelvis. In addition, our study showed that ACT of the pelvis can be safely treated with curettage due to a low risk of local recurrence and better functional results compared with resection. In case of recurrence, we suggest to treat these patients with resection for the risk of disease progression.

Bone and soft tissue sarcomas are uncommon tumors that can occur within the upper extremity as well as elsewhere within the body. However, certain histopathological subtypes have increased affinity for the upper limb and even certain sites within the arm and hand. Other benign masses and tumor mimics, such as infection and traumatic lesions, are more common and imaging appearances can sometimes overlap with malignant lesions making diagnosis difficult. In this article, we explore the current options for imaging of these lesions as well as typical imaging appearances of the more common upper limb tumors.

Technical advances in the last two decades have allowed rapid, high-resolution whole-body magnetic resonance imaging (WBMRI). MRI allows unparalleled visualization and detail in the imaging of bone marrow and surrounding soft tissues. The properties of nuclear magnetic resonance allow superb characterization of bone marrow constituents. WBMRI allows superb characterization of the different types of bone marrow and their natural evolution during the life cycle. Diffusion-weighted WBMRI is an exciting development that adds functional information to anatomical detail. The mainstay of WBMRI for bone marrow abnormalities to date has centered upon staging multiple myeloma and other hematologic bone marrow conditions, and as a valuable tool in quantifying skeletal metastases. Increasingly, WBMRI is being utilized in a variety of additional malignant and nonmalignant conditions. Due to the absence of ionizing radiation, WBMRI represents a valuable screening tool in areas such as malignant transformation in hereditary multifocal exostoses or for the development of ischemic marrow insult in at-risk patients. An additional novel area of use includes postmortem WBMRI for characterization of skeletal injuries. This article provides a state-of-the-art and current review of WBMRI of the bone marrow and highlights potential future areas of development. Level of Evidence: 5 Technical Efficacy Stage: 3 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2019;50:1687-1701.

ResumoOsteoma osteoide é um tumor ósseo benigno, mais frequente dos 10 aos 25 anos de idade e, em cerca de 80% dos pacientes, está associado a dor forte. O presente artigo descreve um paciente masculino apresentando claudicação, encurtamento do membro inferior direito e aumento de volume indolor da perna direita desde os 11 meses de idade. Os exames de imagem demonstraram lesão osteolítica contendo pequenas ossificações de permeio, envolvidas por espessamento cortical da diáfise da tíbia direita. As hipóteses diagnósticas de osteoma osteoide, de osteomielite crônica (abscesso de Brodie), de sarcoma de Ewing e de histiocitose de células de Langerhans foram levantadas. As culturas para microrganismos foram negativas e o exame histopatológico demonstrou osteoma osteoide. O presente relato expande o conhecimento sobre osteoma osteoide como causa de claudicação e discrepância de membros inferiores indolor em lactente. O diagnóstico diferencial precoce é importante, pois a exérese da lesão é curativa e previne sequelas futuras.

Chordoma is an uncommon bone neoplasm. Despite being considered a low-grade or benign bone tumor because of its histology, it is aggressive and locally invasive. It has a poor prognosis because it has a high rate of recurrence and is likely to be malignant. Chordoma is usually recurrent. Although its histology is considered a low-grade tumor or benign tumor, its behaviour of recurrence leads to a poor prognosis and higher likelihood of malignant tumors occurring. Chordoma is believed to emerge from transformed remnants of notochord and appears to favor the axial bone. The most commonly affected parts of chordoma are at the sacrum, vertebra, and skull base. The present gold standard for management of chordoma is a wide surgical resection. This article highlights recent practices and future directions for treatment. Keywords : chordoma, recurrent chordoma, treatment of chordoma DOI: 10.31524/bkkmedj.2019.02.019

Osteossarcoma (OSA) é o tumor ósseo primário mais observado em cães. Trata-se de uma neoplasia maligna que afeta a formação do osso, com comportamento clínico-biológico agressivo, crescimento rápido e altamente metastático. É mais observado em cães de meia idade, com porte grande ou gigante e, em geral, restringe-se à metáfise dos ossos longos do esqueleto apendicular. Foi atendido um cão Scottish Terrier macho de dez anos de idade que chegou com claudicação intermitente do membro torácico esquerdo (MTE), sensibilidade à palpação e edema de consistência firme na região cervicotorácica, sem nenhum histórico prévio de fraturas ou traumas. O diagnóstico definitivo de OSA fibroblástico escapular foi realizado com base na associação entre os achados clínicos, radiográficos, citológicos e histopatológicos. O tratamento utilizado foi a amputação do MTE, promovendo alívio da dor com pouca ou nenhuma perda da qualidade de vida.

Background Large, malignant bone tumors and revision limb salvage procedures often result in the resection of extensive lengths of the involved bone segment, leaving a residual segment of bone that may be too short to support a standard intramedullary stem for endoprosthetic reconstruction. Telescope allografting, in which an allograft is used to augment the remaining bone segment by telescoping it into the residual bone segment, was described for situations in which residual bone stock is insufficient after tumor resection or prosthetic revision. Apart from one study that first described the procedure [15], there are no other studies reporting the outcome of this telescopic concept for restoring bone stock. Questions/purposes For patients younger than 18 years who underwent the telescopic allograft technique to augment a short segment of the proximal femur after resection of bone sarcomas who also underwent endoprosthesis reconstruction of the distal femur, we asked: (1) What is the survivorship free from removal of the telescopic allograft and the endoprosthetic stem at 7 years after surgery? (2) What proportion of these reconstructions will heal to the host bone without delayed union or nonunion? (3) What is the functional outcome based on the Musculoskeletal Tumor Society (MSTS) score? Methods We retrospectively studied our institutional database and identified 127 patients younger than 18 years who underwent surgery for a primary malignant bone tumor of the distal femur between December 2008 and October 2018. After excluding 16 patients undergoing amputation and rotationplasty and 57 patients undergoing recycled autograft/allograft reconstruction, 54 patients who underwent primary or revision distal femur endoprosthesis reconstruction were identified. Among these patients, we considered 15 patients who underwent telescopic allograft augmentation of the femur for analysis. One patient was lost to follow-up before 2 years but was not known to have died, leaving 14 for analysis at a median (range) 49 months (24 to 136 months) of follow-up. The indications for telescopic allograft augmentation of the femur in our institution were a proximal femur length of less than 120 mm after resection or resection of more than two-thirds of the total length of the femur. Ten of 14 patients underwent telescopic allograft augmentation as a revision procedure (distal femur resorption in five patients, endoprosthesis stem loosening in three patients, implant fracture in one patient, and infection in one patient), and the remaining four patients underwent telescopic allograft augmentation as a primary limb salvage procedure for large malignant bone tumors of the distal femur. The histologic diagnosis in all patients was osteosarcoma. At the time of telescopic allograft augmentation and reconstruction, the median age of the patients was 14 years (7 to 18 years). The size and the type of bone allograft to be used (femoral shaft or proximal femur) was planned before surgery, with consideration of the extent of resection, level of osteotomy, diameter of the host bone at the osteotomy site, and approximate diameter of the endoprosthesis stem to be used. The segment of the cylindrical allograft used for telescoping was thoroughly washed, prepared, and impacted onto the native femur to achieve telescoping and overlap. Serial digital radiographs were performed once a month for the first 6 months after the procedure, every 2 months until 1 year, and then every 6 months thereafter. Two surgeons in the department (at least one of which was involved in the surgery) retrieved and reviewed clinical notes and radiographs to determine the status of the telescopic allograft and endoprosthesis stem. We defined delayed union as radiological union at the osteotomy site more than 6 months after the procedure without additional surgery; we defined nonunion as no radiological evidence of callus formation at the osteotomy site 9 months after the procedure, necessitating additional surgery. The reviewers did not disagree about the definition of healing time. None of the patients missed radiographic follow-up. Kaplan-Meier survivorship free from removal of telescopic allograft and the endoprosthesis stem at 7 years after surgery was estimated. Patient function was assessed using the 1993 version of the MSTS [9], as determined by chart review of the institutional database performed by one of the surgeons from the department. Results The survivorship free from removal of the telescopic allograft and endoprosthesis stem at 7 years after surgery was 80% (95% confidence interval 22% to 96%). The allograft united with the host bone in 100% (14 of 14) of the patients. Though 21% (3 of 14) had delayed union, no nonunions were seen. The median (range) MSTS score at the final follow-up interval was 27 (22 to 30). Conclusion Although this is a small group of patients, we believe that allograft segments help augment short bone stock of the proximal femur after long-segment resections, and the telescopic technique seems to be associated with a low proportion of nonunion or delayed union, which is one of the most common complications of allografts. Maintaining an adequate length of the proximal femur is important in preserving the hip, and this technique may be especially useful for young individuals who may undergo repeated revision procedures. Level of evidence Level IV, therapeutic study.

Background : Osteosarcomas are malignant neoplasms of bone tissue, with a high prevalence in dogs, especially in large and giant breeds. More commonly, such alterations affect the appendicular skeleton and, to a lesser extent, the axial skeleton. In order to obtain an accurate diagnosis, it is necessary to combine cytological and histopathological findings with clinical parameters, imaging exams and macroscopic findings. In the present study, we report a rare case of combined-type pelvic osteosarcoma with pulmonary metastasis in a dog. Case : A 5-year-old intact large male dog of mixed breed, was submitted to clinical care because of an increase in volume of the left perineal region. The cytological evaluation, performed without imaging exams, indicated that it was an undifferentiated sarcoma. An incisional biopsy defined the diagnosis as telangiectatic osteosarcoma, and with progressive clinical worsening, the patient died. Necroscopic examination revealed multiple nodules in the lungs and an irregular mass with a hard to friable consistency. The mass was intensely vascularised and extended craniodorsally from the left ischial tuberosity to the base of the renal fossa. Microscopically, the neoplasm was diagnosed as combined osteosarcoma, consisting of the osteoblastic, chondroblastic, and telangiectatic subtypes. Metastases with a predominance of the chondroblastic subtype were observed in the lungs. Discussion : This is the first report of combined-type canine osteosarcoma in the ischium. The case reported here is unusual, as there are few reports of canine osteosarcoma in the pelvic bones, and there is no concrete information regarding its histological appearance. Osteosarcoma is the most common bone neoplasm in dogs, representing up to 80% of the tumours found in such organs. In the present case, the dog was a large young adult with a higher probability of neoplasm development. A cytopathological examination is a diagnostic method with good sensitivity and specificity that can confirm osteosarcomas. However, in this case, the cytological diagnosis, performed without the information from the imaging exam, indicated that it was an undifferentiated sarcoma, given the impossibility of the architectural assessment of the lesion. Biopsy samples sent for histology may not be representative of the entire tumour, leading to misclassification of the histological type. Therefore, the evaluation of fragments from various sites of the lesions is recommended. Regarding the morphology of osteosarcomas, such neoplasms have the osteoblastic, chondroblastic, fibroblastic, telangiectatic, large cell, and poorly differentiated subtypes. With regard to tumours located in the axial skeleton, no studies have assessed the predominance of a particular morphological type, as well as the incidence of combined-type masses in dogs in this particular location. Such neoplasms are locally aggressive and have a high metastatic potential, with the lungs being the main location for implantation of neoplastic cells. There is no proven evidence of the correlation between morphological presentations and the presence of metastases from osteosarcomas in dogs. The histological type is not a predictive factor for the behaviour of the neoplasm. However, the anatomical location is considered as one of the factors with the greatest influence on the prognosis and metastatic potential. Rib masses are associated with a higher rate of metastases compared to others. The definitive diagnosis of osteosarcomas and its correct subclassification are of great importance in the prognosis of affected patients. These require an approach that considers the clinical findings, imaging examinations, and macroscopic and microscopic alterations. Keywords: bone, canine, cytopathology, histopathology, neoplasm. Titulo: Osteossarcoma pelvico metastatico em cao Descritores: canino, citopatologia, histopatologia, neoplasia, osso.

Background Osteosarcoma is an aggressive and painful bone neoplasm in dogs. Previous studies have reported epidemiological associations suggesting that large body mass, long bone length and the genetics of certain breeds including the Rottweiler are associated with elevated osteosarcoma risk. However, these studies were often limited by selection bias and confounding factors, and have rarely offered insights into breed-associated protection for osteosarcoma. The current study includes 1756 appendicular and axial osteosarcoma cases presenting to VPG Histology (Bristol, UK) compared against a control population of 905,211 dogs without osteosarcoma from primary care electronic patient records in the VetCompass™ dataset. Methods and study design Retrospective, case-control study. Multivariable logistic regression analysis explored associations between demographic risk factors (including breed, chondrodystrophy, age, sex/neuter status, skull-shape, and body mass) and osteosarcoma of all anatomical sites. Results We identified several breeds with increased and reduced odds of osteosarcoma. At highest risk were the Rottweiler and Great Dane, with > 10 times the odds of osteosarcoma compared with crossbreds, and the Rhodesian Ridgeback, which has not featured in previous lists of at-risk breeds for osteosarcoma, and had an odds ratio of 11.31 (95% confidence interval 7.37–17.35). Breeds at lowest risk of osteosarcoma (protected breeds) included the Bichon Frise, the French Bulldog and the Cavalier King Charles Spaniel, all with odd ratios of less than 0.30 compared with crossbreds. Body mass was strongly associated with osteosarcoma risk; dogs over 40 kg exhibited osteosarcoma odds of 45.44 (95% confidence interval 33.74–61.20) compared with dogs less than 10 kg. Chondrodystrophic breeds had an osteosarcoma odds ratio of 0.13 (95% confidence interval 0.11–0.16) compared with non-chondrodystrophic breeds. Conclusions This study provides evidence of strong breed-associated osteosarcoma risk and protection, suggesting a genetic basis for osteosarcoma pathogenesis. It highlights that breeds selected for long legs/large body mass are generally overrepresented amongst at-risk breeds, whilst those selected for short leg length/small body mass are generally protected. These findings could inform genetic studies to identify osteosarcoma risk alleles in canines and humans; as well as increasing awareness amongst veterinarians and owners, resulting in improved breeding practices and clinical management of osteosarcoma in dogs.

Aims Bone tumours in children/young people are often associated with significant diagnostic delay, increasing the risk of amputation. The total diagnostic interval is a sum total of the patient and system interval. The HeadSmart campaign showed a national awareness campaign based on high quality evidenced based guidance halved time to diagnosis. We conducted a systematic review and meta-analysis to identify the core signs/symptoms and a public survey to understand public awareness of these symptoms. Methods Medline, Pubmed and Embase databases were searched from January 2005 – August 2015. Key words included ‘bone tumour(s)’, ‘bone neoplasm(s)’, ‘diagnosis’, ‘signs(s)’, ‘symptom(s)’, ‘presentation(s)’. All papers discussing bone tumour presentation were included. Pooled proportions (%) of children with each sign/symptom at diagnosis were estimated. A face-to-face opinion survey (n=1000; 475 males) was conducted by Ipsos MORI. Questions included perception of cancer risk, confidence in recognising signs/symptoms and urgency of seeking medical advice. Results The search strategy identified 15477 papers. 713 papers were reviewed in full; 11 met the inclusion criteria, describing the symptoms/signs at diagnosis in 1246 children. 29 symptoms/signs were recorded but only those that occurred in 2% or more of patients are reported. These were pain (76%), swelling (21%), fever (4%), history of trauma (3%), functional limitation (3%), palpable mass (3%), pain and swelling (2%), volume increase (2%), limp (2%) and pathological fracture (2%). Public awareness of the top 4 presenting symptoms of bone tumours were low. 23% of the public identified recurrent or persistent bone pain as a symptom of cancer; 27% identified swelling of bone or joint; 21% identified fever and 14% thought a slow recovery after injury or trauma could be a sign of cancer. Conclusions This is the first systematic review on paediatric bone tumours to our knowledge. It provides strong evidence of the common presentations and will form the basis of a new RCPCH endorsed clinical guideline on the assessment/investigation of suspected bone tumours. The results of the public awareness survey highlight low awareness which need to be tackled in order to drive earlier diagnosis. This will form key messaging in our new national awareness campaign called ChildCancerSmart.

Background: Osteosarcoma is a malignant neoplasm that occurs most often in long bones, with the head and neck region being rarely affected, accounting for less than 1% of all cancers in this region. Objective: To report a rare case of a large-extension osteosarcoma with emphasis on its clinical and diagnostic aspects. Case presentation: A 43-year-old woman presenting an intraoral exophytic lesion with involvement of other maxillofacial structures, such as nostril, zygoma and orbit. Despite the initial clinical diagnosis of actinomycosis, an incisional biopsy confirmed the histopathological diagnosis of osteosarcoma, showing a wide morphological variety. Conclusion: This case highlights the importance of clinical and histopathological findings for the correct diagnosis of osteosarcoma. Moreover, it shows that, although surgical resection is the primary treatment for this neoplasia, depending on the extent of the tumor and its proximity to vital anatomical structures, the most appropriate conduct is not always feasible. Introducción: El osteosarcoma es una neoplasia maligna que se presenta con mayor frecuencia en huesos largos, siendo raramente afectada la región de cabeza y cuello, lo que corresponde a menos del 1% de todos los cánceres de esa región. Objetivo: Reportar un caso raro de osteosarcoma a gran escala, con énfasis en sus aspectos clínicos y diagnósticos. Presentación del caso: mujer de 43 años que presenta una lesión intraoral exofítica con afectación de otras estructuras maxilofaciales, como fosa nasal, cigoma y órbita. A pesar del diagnóstico clínico inicial de actinomicosis, la biopsia incisional confirmó el diagnóstico histopatológico de osteosarcoma, presentando una amplia variedad morfológica. Conclusión: El caso clínico destaca la importancia de los hallazgos clínicos e histopatológicos para el correcto diagnóstico del osteosarcoma. Además, muestra que, si bien la resección quirúrgica es el tratamiento primario de esta neoplasia, dependiendo de la extensión del tumor y su proximidad a estructuras anatómicas vitales, el abordaje más adecuado no siempre es factible. Introdução: O osteossarcoma é uma neoplasia maligna que ocorre mais frequentemente em ossos longos, sendo a região da cabeça e pescoço raramente afetada, correspondendo a menos de 1% de todos os cânceres nessa região. Objetivo: Relatar um caso raro de osteossarcoma de grande extensão, com ênfase em seus aspectos clínicos e diagnósticos. Apresentação do caso: Mulher de 43 anos apresentando lesão exofítica intraoral com envolvimento de outras estruturas maxilofaciais, como narina, zigoma e órbita. Apesar do diagnóstico clínico inicial de actinomicose, a biópsia incisional confirmou o diagnóstico histopatológico de osteossarcoma, apresentando uma grande variedade morfológica. Conclusão: O caso clínico destaca a importância dos achados clínicos e histopatológicos para o diagnóstico correto do osteossarcoma. Além disso, mostra que, embora a ressecção cirúrgica seja o tratamento primário dessa neoplasia, dependendo da extensão do tumor e de sua proximidade com estruturas anatômicas vitais, a conduta mais adequada nem sempre é viável.

Primary sclerosing epithelioid fibrosarcoma (SEF) of bone is a rare and scarcely reported neoplasm. We document clinicopathological and molecular features of 9 additional cases. Five males and 4 females had a mean age of 39 years (14-71 years). Most tumors affected flat/irregular bones; only 3 cases involved a long bone. By radiology, it has characteristic radiographic features of a predominantly lytic expansile lesion with a sclerotic rim. Referring diagnoses were SEF (n = 2), low-grade osteosarcoma (n = 2), chondrosarcoma (n = 1), and chondromyxoid fibroma (n = 1). Histologically, five cases revealed classical morphology of SEF of soft tissue. Remaining cases were classified as hybrid SEF/low-grade fibromyxoid sarcoma, characterized by spindle or stellate cells, prominent stroma, and giant hyalinized areas. Various morphological deviations such as prominent vasculature (n = 3), osteoid-like material (n = 4), or parallel bone trabeculae (n = 2) were observed. Immunohistochemically, all cases showed diffuse and strong MUC4 expression. SATB2 was observed in 5/8 cases. Using FISH, EWSR1, and FUS rearrangements were detected in 4 cases and 1 case, respectively. EWSR1-CREB3L1 fusion was identified in 1 additional case by next-generation sequencing. Recurrence and metastasis were observed in 1 case and 2 cases, respectively. All but one patient were alive with disease for a mean interval of 31 months. SEF of bone is a relatively indolent sarcoma of adults, most commonly located in the flat/irregular bones. Due to overlapping histological features, it is often misdiagnosed as osteosarcoma or a chondroid tumor. Most SEF of bone exhibit EWSR1 rearrangements, but rare cases may harbor a FUS gene fusion.

Background Klippel-Trénaunay syndrome (KTS) is a complex congenital vascular disorder, typically accompanied by port-wine stains, varicose veins, and limb hypertrophy. This paper reports a rare and unusual clinical condition of periosteal reaction in a pediatric case of KTS. Although periosteal new bone formation is not rare in children, as is KTS, their dual occurrence or the presentation of the former due to KTS has not been previously documented. Our objective in this study is to highlight the potential association between periosteal new bone formation and KTS, as well as to help physicians consider this association when bone neoplasm has been ruled out. Case presentation A 7-year old girl, initially presented with a persistent mild swelling in her left shank, with no abnormalities in the X-ray of the tibiofibular. However, after a few consults and examinations, 7 weeks later, a 17 cm-long periosteal new bone formation along the left tibia and diffused dilated vessels in the left shank were revealed by the radiological examination. Not knowing the true nature of the fast-growing lesion in a typical case of KTS was worrying. Therefore, a core needle biopsy was performed. The test demonstrated a possible parosteal hemangioma. Following further investigation through an excisional biopsy, and a pathological analysis, hyperplasia of the bone tissues with no tumor cells was revealed. Thereafter, an elastic stocking treatment was prescribed. During the first two-year follow-up, recurrence of the mass or sign of progression of KTS was not observed. Conclusions Periosteal new bone formation is a potential manifestation of KTS. Based on the conclusive pathological results of the excisional biopsy, invasive examinations and surgeries could be avoided in future KTS-subperiosteal lesion manifestations.

Background Diffusion-weighted imaging (DWI) has been described to correlate with tumoural necrosis in response to preoperative chemotherapy for osteosarcoma. Objective To assess the accuracy of DWI in evaluating the response to neoadjuvant chemotherapy at the mid-course treatment of long-bone osteosarcoma and in predicting survival. Materials and methods We conducted a prospective single-centre study over a continuous period of 11 years. Consecutive patients younger than 20 years treated with a neoadjuvant regimen for peripheral conventional osteosarcoma were eligible for inclusion. Magnetic resonance imaging (MRI) with DWI was performed at diagnosis, and mid- and end-course chemotherapy with mean apparent diffusion coefficients (ADC) calculated at each time point. A percentage less than or equal to 10% of the viable residual tissue at the histological analysis of the surgical specimen was defined as a good responder to chemotherapy. Survival comparisons were calculated using the Kaplan-Meier method. Uni- and multivariate analyses with ADC change were performed by Cox modelling. This is an expansion and update of our previous work. Results Twenty-six patients between the ages of 4.8 and 19.6 years were included, of whom 14 were good responders. At mid-course chemotherapy, good responders had significantly higher mean ADC values (P=0.046) and a higher increase in ADC (P=0.015) than poor responders. The ADC change from diagnosis to mid-course MRI did not appear to be a prognosticator of survival and did not impact survival rates of both groups. Conclusion DWI at mid-course preoperative chemotherapy for osteosarcoma should be considered to evaluate the degree of histological necrosis and to predict survival. The anticipation of a response to neoadjuvant treatment by DWI may have potential implications on preoperative management.

There are conflicting reports regarding the outcome and effect of denosumab for distal radius giant cell tumor of bone (GCTB). The authors performed this study to evaluate the behavior of distal radius GCTB in relation to the type of treatment and the administration of denosumab. The files of 72 patients with distal radius GCTB treated from 1984 to 2018 were reviewed. Fourteen patients were administered denosumab. Surgical treatment consisted of curettage (25 patients) or resection (47 patients) and allograft or vascularized fibular head graft reconstruction. Median follow-up was 63.1 months (interquartile range [IQR], 35.5–107.1 months). The authors evaluated local recurrences, metastasis, function, and complications. The local recurrence rate was 30.6% at a median of 14.0 months (IQR, 10–19 months), with no difference between curettage and resection. The local recurrence rate was significantly higher in the patients who received denosumab. The metastasis rate was 9.7% at a median of 41.0 months (IQR, 15–114 months), with no difference regarding denosumab administration. Function was significantly better in patients after curettage. The complication rate was 25%; vascularized fibular graft reconstruction was associated with fewer complications. This study found that denosumab increases the risk of local recurrence after curettage, function is better after curettage, and vascularized fibular graft is the optimal reconstruction after resection of distal radius GCTB. [ Orthopedics . 2020;43(5):284–291.]

Rationale Patients with, or who develop, metastatic breast cancer have a 5-year relative survival of about 25%. Endocrine therapy clearly improves outcomes in patients with estrogen receptor-positive breast cancer. In the metastatic setting, the primary goal of treatment is to maintain long-term disease control with good quality of life. Rarely, exceptional responders achieve durable disease control, and potential cures cannot be ruled out. Patient concerns We report the case of a 39-year-old woman with primary breast cancer and associated synchronous bone metastases, who experienced a disease response of 12 years with hormonal therapy as maintenance after first line chemotherapy, with a good toxicity profile. Diagnosis The patient was diagnosed with estrogen receptor + human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer with synchronous bone metastases. Interventions This patient was treated with chemotherapy for 6 cycles as a first-line therapy following by endocrine treatment given as a maintenance therapy. Outcomes Our patient experienced a progression-free survival >12 years with an exceptionally good quality of life. Lessons Our anecdotal experience highlights the existence of exceptional responders among patients with hormone receptor-positive metastatic breast cancer, who achieve clinical remission and durable disease control with endocrine therapy. Being able to identify these patients could help in the selection of the best treatment option among the many available.

Patient: Female, 51-years-old Final Diagnosis: Choanal polyp with osseous metaplasia Symptoms: Nasal obstruction Medication:— Clinical Procedure: Combined surgical approach, endoscopic and trans-oral Specialty: Otolaryngology Objective: Rare co-existance of disease or pathology Background: Osseous metaplasia is a heterotopic normal bone in soft tissues. It is occasionally found in mucosal polyps of the external auditory canal, tongue, gut, stomach, nasal cavity, and uterus. Choanal polyp with osseous metaplasia originating from the lateral wall of the nasopharynx has not been previously reported. In fact, osseous metaplasia in nasal polyps represents a very uncommon histological finding with only 12 cases described in the literature. Case Report: We reported here, the clinical, radiological, and therapeutic management of a nasopharynx choanal polyp in a patient with severe nasal obstruction and rhinolalia history. Endoscopic examination of nasal cavities revealed a polypoid-like mass in the left nasal fossa, extending to the choanal area and nasopharynx. Computed tomography scan and contrast-enhanced magnetic resonance imaging confirmed the presence of a solitary and lobulated mass in the choanal area and nasopharynx. We performed the removal of the mass through careful hemostasis of left sphenopalatine artery using both transnasal and transoral paths, with no complications for the patient. Histopathological examination of the biopsy revealed a benign inflammatory polyp with osseous metaplasia. No recurrence was noted 24 months after surgery. Conclusions: The incidence of ossifying areas in nasal polyps is very low, with only 12 cases reported in the literature. Ossifying polyps originating from the lateral wall of nasopharynx has never been reported before. The use of a combined endoscopic and transoral surgical approach was shown to be reliable in terms of adequate exposure and visualization of the lesion, control of bleeding, and complete removal of the mass.

Aims: Osteoblastoma-like osteosarcoma is a rare variant of osteosarcoma (1% of all osteosarcomas), histologically similar to osteoblastoma. In the current World Health Organisation (WHO) classification, osteoblastoma-like osteosarcoma is classified within the group of conventional (high-grade) osteosarcomas. However, several published cases have been actually regarded as low-grade malignant tumours. As strict morphological criteria to distinguish between low- and high-grade lesions are not available, we reviewed our series of osteoblastoma-like osteosarcomas in the attempt to identify clinical and morphological features predictive of aggressiveness. Methods and results: We retrieved 15 cases of osteoblastoma-like osteosarcoma from the files of the Istituto Ortopedico Rizzoli. Patients received various treatments. Five patients developed metastasis and five patients developed local recurrences (all after incomplete surgery). Eleven patients were alive without disease, while four patients died of their disease. Statistical analysis revealed a statistically significant (P=0.048) lower disease-free survival in patients with areas of conventional (high-grade) osteosarcoma. Conclusions: With the important limitation of a small cohort of patients, the presence of areas of conventional (high-grade) osteosarcoma is the only parameter to predict the aggressiveness of osteoblastoma-like osteosarcoma.

Background: Osteosarcoma is the most common bone neoplasm found in the community but evaluation osteosarcoma cases in RSUD Dr. Soetomo has not been updated since 1995. Purpose : This study o osteosarcoma patient characteristic as well as therapy at Dr. Soetomo General Hospital in 2007 to 2016. It expects to show survival rates of osteosarcoma patient, so it can be a reference for searching the problems in the treatment of osteosarcoma cases and helps to decide treatment for osteosarcoma. Research Methods : Descriptive retrospective study, conducted on osteosarcoma patients at Dr. Soetomo General Hospital during 2007-2016 periods. Data were obtained from Ortho tumor patient database, and contacting them by phone or home visit. Results : Osteosarcoma patients was found mostly in 2015, while the least in 2008, with trend increasing by time. Majority of the patients came with advanced stage. Osteosarcoma treated mostly by amputation, either with or without chemotherapy. The survival rate in the first, second, or the fifth year was found lower than other references. Most common cause of mortality was the metastasis. Conclusion : Awareness of the society about the cancer sign of cancer and desire to use medical treatment as a priority is still low. This causes a low early detection rate of osteosarcoma and a high rate of metastatic cases because of inappropriate early treatment. Further socialization and increased awareness of medics about the suspicion of osteosarcoma are needed to improve the success rate of treatment as well as the survival rate.

Highlights • Osteochondroma is a benign cartilaginous tumour that rarely affects the scapula. • We present a rare case of osteochondroma with winging of scapula, present in his fourth decade of life. • This symptomatic scapular osteochondroma exhibited positive radiological findings. • The patient was treated surgically and recovered fully, with no recurrence. • This report increases awareness of unusual osteochondroma sites and features., Introduction Osteochondroma, a type of cartilaginous tumour, is the most common benign tumour affecting the bone. These tumours usually arise around the knee, proximal humerus, and pelvis, but very rarely occur at the scapula. Osteochondromas are usually asymptomatic and uncomplicated, but must be treated by surgical resection. Presentation of case In this report, we present a rare case of a symptomatic scapular osteochondroma associated with scapular winging in a 30-year-old man. This tumour exhibited positive radiological findings and was treated surgically, leading to a complete resolution of the patient's symptoms with no history of recurrence. Discussion This case was unique because although the patient presented in his fourth decade of life, he had not noticed any signs indicative of lesional growth during adolescence and the maturation process. Additionally, this case was symptomatic and involved an unusual site. Conclusion By reporting this rare case of a ventral-side scapular osteochondroma that presented with scapular winging, we aim to increase the awareness of the unusual manifestations of osteochondroma, particularly atypical sites, signs, and symptoms. Furthermore, we have described the surgical treatment of this case in detail to assist other surgeons who face similar cases.

Background: Dedifferentiated chondrosarcoma (DDC) accounts for a small proportion of chondrosarcomas. They demonstrate aggressive behaviour with a high rate of local recurrence and systemic progression resulting in poor long-term survival rates. Due to its relatively low incidence, previous studies have grouped different histiotypes together to achieve adequate study numbers for analysis. Methods: This retrospective study examines the clinical course and the role of chemotherapy in the subgroup of patients with DDC where osteosarcoma is the predominant dedifferentiated component. Between 2000-2010, 21 patients were identified. Results: The mean age at presentation was 64 years (range 35-80 years). 12 patients were considered unfit for chemotherapy, whilst 2 patients declined chemotherapy. 5 patients received neoadjuvant chemotherapy, with less than 90% necrosis demonstrated in all these cases. 3 patients received post-operative chemotherapy. The median survival for the entire group was 9.5 months. In the 7 patients who received chemotherapy, the median survival was 17 months, and those who had chemotherapy had a greater median time to local recurrence. Conclusion: This study demonstrates that cytotoxic chemotherapy may be offered to appropriately selected patients.

Introducción: La neoplasia ósea es una patología que altera la homeostasis del hueso dependiendo de la benignidad o malignidad del proceso. El estudio imagenológico aporta una serie de información que es fundamental para el diagnóstico y tratamiento de esta patología. El objetivo del presente reporte es establecer las características imagenológicas de los pacientes atendidos en el Servicio de Imágenes del Hospital “Juan Tanca Marengo” con tumores óseos. Métodos: Se realizó un estudio observacional, en el que se registraron todos los casos con diagnóstico de neoplasias óseas atendidos en el Hospital “Juan Tanca Marengo“, en Guayaquil entre enero del 2006 a enero del 2008. Para el análisis estadístico se emplearon medidas de tendencia central. Resultados: Se incluyeron 100 casos, la edad promedio entre los pacientes con tumores óseos primarios fue menor que entre las metástasis (25.4 vs 32.8 años). Del grupo de pacientes con lesiones primarias fueron más frecuentes los del sexo masculino (56.0 vs 37.5%). La afectación cortical fue mayor entre pacientes con tumor óseo metastásico que entre tumores primarios (62.5 vs 39.3%). En las otras variables estudiadas no se presentaron diferencias significativas. Conclusión: La mayoría de las características imagenológicas no son exclusivas del tipo de lesión ósea (primaria o metastásica). Las características de edad y género ayudan a la orientación diagnóstica de las imágenes de las lesiones tumorales óseas.

Malignant transformation of giant cell tumor of bone (GCTB) without radiotherapy exposure is exceptionally rare, occurring in less than 1% of GCTBs. The safety and efficacy of denosumab in patients with GCTB was recently reported. We herein report a case of a benign recurrent GCTB with an H3F3A mutation that underwent secondary malignant transformation during treatment with denosumab. A 29-year-old woman underwent curettage of a GCTB of the left ischium in 2005. Ten years after the first surgery, the GCTB recurred locally. We started treatment with denosumab. During the first 5 months of treatment, we observed a demarcated area of osteosclerosis in the recurrent lesion, and the patient's clinical condition improved. At 6 months, however, the patient developed pain, and a rapidly growing mass was detected by computed tomography. An incisional biopsy was performed. Histologic analysis showed a high-grade osteosarcoma. The patient developed lung metastases and died soon after beginning chemotherapy. The mechanism of sarcomatous transformation of GCTB during denosumab therapy is unclear. These findings suggest that the scientific community should be aware of the possible malignant transformation of GCTB during denosumab treatment.

The present report illustrates a very rare case report of a foreign body granuloma of the foot associated with a 2-year period of a retained spongeous rubber foreign body after a penetrating injury. Because it appeared almost 2 years after the injury, the history of trauma was minimized, the foreign body had migrated from the plantar to the dorsal side of the foot, and the radiographic appearance resembled a malignant process, it was difficult to rule out the possibility of a malignant tumor. This case shows the weakness of magnetic resonance imaging in detecting spongeous rubber in the body. Also, a bone osteoblastic reaction to the foreign body has very rarely been noted. To the best of our knowledge, just 5 cases have been previously reported. Provided suspicion exists of previous trauma with an embedded foreign body, the differential diagnosis of a bone neoplasm should consider the possibility of a foreign body reaction. Biopsy proved to be the best diagnostic tool.

Dedifferentiated chondrosarcoma is defined by the presence of a low grade malignant cartilaginous component juxtaposed to a high grade malignant non-cartilaginous sarcomatous components. Only 4 cases in which the high grade component showed epithelial differentiation have been reported in the literature; three featured a squamous and the one a glandular epithelial component. Here we describe a case of dedifferentiated chondrosarcoma exhibiting epithelial “adamantinoma-like” basaloid features. The patient underwent wide resection of the proximal tibia and post-operative chemotherapy and died 8 months after the diagnosis due to lung and bone metastases.

Introduction: The purpose of our study is to verify possible clinical and radiological findings with regard to distinguishing enchondroma from atypical cartilaginous tumour (ACT). In addition, this study determined risk factors that are associated with local recurrence of enchondroma or ACT treated with curettage. Materials and methods: We retrospectively reviewed the records of 54 patients with enchondroma and 35 patients with ACT of the long bones treated by curettage between 1986 and 2015. The minimum follow-up was 18 months. The relationship between clinical and radiological factors and the tumour type or local recurrence was assessed using Chi-square test or Fischer exact test. Results: Endosteal scalloping (p = 0.004) and soft tissue extension (p = 0.017) were shown to statistically favour ACT over enchondroma; by contrast, pain (p = 0.034) was more frequent in enchondroma compared to ACT. All patients with enchondroma had no local recurrence; in contrast, local recurrence occurred in four patients with ACT (11%). Soft tissue extension (p = 0.049) and the diagnosis of ACT (p = 0.021) were associated with an increased risk of local recurrence. We had a disease progression in three of four patients with local recurrence, and these had higher histological grade than the original tumour. Discussion: Our data show that endosteal scalloping and soft tissue extension could be helpful in the differential diagnosis between enchondroma and ACT. We suggest following only those patients with ACT after surgery to identify any possible recurrence and, in case of recurrence, treat these patients with resection for the risk of disease progression.

Donati, Davide Maria/0000-0002-9170-0576; Campanacci, Laura/0000-0002-4734-6741; Bindiganavile Srinivas, Srimanth/0000-0003-0458-7331; MANFRINI, MARCO/0000-0003-2961-0171 WOS: 000399195300009 PubMed: 27995558 Background Intercalary reconstruction of tibial sarcomas with vascularized fibula autografts and massive bone allografts is reliable with predictable long-term results. However, inadequate data exist comparing free and pedicled vascularized fibula autografts in combination with a massive bone allograft in patients undergoing intercalary tibia reconstructions. Questions/Purpose Among patients undergoing large-segment intercalary allografting, we sought to compare supplemental free vascularized fibular autografts with supplemental pedicled vascularized fibular autografts, in terms of (1) oncologic results, (2) complications associated with surgery, (3) Musculoskeletal Tumor Society (MSTS) scores, and (4) surgical time. Methods Between 1994 and 2013, we treated 320 patients, younger than 40 years, with tibial sarcomas. Thirty-five patients (11%) underwent amputations. One hundred ninety-five patients (61%) were treated with intraarticular resection of the tibia, which constituted 104 tumor endoprostheses, 63 proximal tibia allograft prosthetic composites, 21 osteoarticular allografts, and seven arthrodeses with allografts. Ninety patients (28%) underwent joint-sparing intercalary reconstruction. Forty-one (13%) of these 90 patients were treated with allografts alone, two (1%) with vascularized fibula grafts, and 47 (15%) with intercalary allografts supplemented by autografts (free fibular autografts, 22 patients, 7%; pedicled fibular autografts, 25 patients, 8%). During the study period, we used free vascularized fibular autografts in association with massive bone allograft for a resection longer than 12 cm with a very small periarticular residual segment. The choice for using a pedicled fibula harvested in the ipsilateral leg initially was for patients having only diaphyseal resections and the indication was later extended to intraepiphyseal osteotomies with a small periarticular residual segment. The goals of this study are to present the long-term results in this group of patients and compare their results based on the type of vascularized fibula harvest. There were 33 male and 14 female patients with mean age of 14 +/- 6 years. The median followup was 84 months (range, 7-231 months). No patients were lost to followup before 1 year. Four patients died and were not available for followup after 18 months. The mean tibia resection length was 15 +/- 4 cm and mean length of the harvested vascularized fibula was 18 +/- 4 cm. Results Overall 5- and 10-year oncologic survival rates in this study were 87% +/- 5% and 83% +/- 6% respectively. With the numbers available, we observed no difference in survivorship free from death from disease between the study groups (85% +/- 8% [95% CI, 174-232 months] of the free vascularized group versus 82% +/- 8% [95% CI, 148-206 months] of the pedicled fibula graft group; p = 0.741). At last followup, 40 patients had no evidence of disease and seven had died of disease. Local recurrence was observed in two patients in the supplemental free vascularized fibula group and three patients in the supplemental pedicled vascularized fibula group, whereas metastases was observed in eight patients. With the numbers available, we observed no difference in the proportion of patients experiencing surgical complications between those treated with free vascularized fibula grafts and those treated with pedicled grafts (eight of 22 [36%] versus nine of 25 [36%] respectively; p = 0.605). With the numbers available, we observed no difference in mean MSTS scores between patients treated with free vascularized fibula grafts and those treated with pedicled grafts (24 +/- 9 versus 25 +/- 8; mean difference, 0.48; 95% CI, 0.54-4.6; p = 0.858). Mean surgical time was longer in the free vascularized fibula and massive bone allograft group at 9.4 +/- 1.7 hours compared with that of the pedicled vascularized fibula and massive bone allograft group at 5.7 +/- 1.3 hours (mean difference, 3.73 hours; 95% CI, 2.8-4.6 hours; p ae 0.001). Conclusions Intercalary reconstruction of tibia sarcomas with massive bone allografts supplemented with vascularized fibula grafts provide predictable results. Complications occur as expected in a biologic reconstruction, but are salvageable, preserving the original construct. The pedicled fibula can be an alternative to a free contralateral fibula for intraepiphyseal resections. Comparative technical ease, shorter surgical time, avoidance of additional microvascular anastomosis, and avoidance of surgery on the contralateral leg are notable advantages of pedicled vascularized fibula over free fibula grafts to supplement allografts when indicated in intercalary tibia resections. Italian Ministry of HealthMinistry of Health, Italy [RF-2010-2321501] This study was supported by Italian Ministry of Health (Grant Minsal RF-2010-2321501).

Osteoid osteoma and osteoblastoma are rare benign bone-forming tumors with very similar histological features. They are nowadays considered as two distinct entities. Progression of an osteoid osteoma to osteoblastoma is considered very rare with only a few cases reported in the literature. Herein we describe a case of an osteoid osteoma of the thoracic spine in a 29-year-old woman that was initially treated conservatively and progressed to osteoblastoma 5 years following the initial diagnosis. Imaging revealed an increase in the size of the spinal lesion that was surrounded by extensive paraspinal abnormal soft tissue that raised suspicion for sarcomatous transformation. The final diagnosis was established by CT-guided biopsy of both the bone lesion and the paraspinal soft tissue, which excluded malignancy and revealed an osteoblastoma surrounded by plasma cell-rich chronic inflammation. The patient then underwent wide surgical excision of the lesion and paraspinal soft tissue component that confirmed the diagnosis. Follow-up with MRI over the next 12 months was unremarkable, with no signs of recurrence or spinal instability. This unique presentation of an osteoblastoma has not been previously described. This case also demonstrates the importance of follow-up of osteoid osteomas that are treated conservatively.

Aims The purpose of this retrospective study was to differentiate between the MRI features of normal post-operative change and those of residual or recurrent disease after intralesional treatment of an atypical cartilage tumour (ACT)/grade I chondrosarcoma. Patients and Methods We reviewed the case notes, radiology and histology of 75 patients, who had been treated for an ACT/grade I chondrosarcoma by curettage, phenolisation and bone allografting between 1994 and 2005. The first post-operative Gd-enhanced MRI scan was carried out within one year of surgery. Patients had a minimum of two scans and a mean follow-up of 72 months (13 to 169). Further surgery was undertaken in cases of suspected recurrence. Results In 14 patients (18.6%) a second procedure was undertaken after a mean period of 59 months (8 to 114). Radio frequency ablation (RFA) was used in lesions of < 10 mm and curettage, phenolisation and bone grafting for those ≥ 10 mm. Only six of these (8% of total) had a histologically-proven recurrence. No increase in tumour grade was seen at time of recurrence. Conclusion Based on this study, we have been able to classify the post-operative MRI appearances into four groups. These groups differ in follow-up, and have a different risk of recurrence of the lesion. Follow-up and treatment vary for the patients in each group. We present a flow diagram for the appropriate and safe follow-up for this specific group of patients. Cite this article: Bone Joint J 2016;98-B:1674–81.

Background Zoledronic Acid is a bisphosphonate used in a 4-week schedule for the treatment of bone metastases. Some randomized trials supported its role also when administered every 12 weeks. Methods we performed a systematic review and a meta-analysis in order to evaluate the two different schedules in terms of skeletal morbidity rate (SMR), skeletal related events (SRE) and adverse events (AEs). Results our results showed a clinical difference favouring the 12-week schedule in terms of AEs (RR 1.17, 95% CI 1.06–1.29). No signifcant differences were found for SMR (RR 0.97, 95% CI 0.84–1.13) and SRE (RR 1.02, 95% CI 0.89–1.16). Conclusions Our findings support in clinical practice the 12-week schedule an alternative to the standard 4-week schedule in advanced breast and prostate cancer, in particular when the clinical comorbidities of the patients suggest a higher risk of renal failure or hypocalcaemia.

Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever. With timely diagnosis and treatment, this is a potentially curable disease. This report describes a unique case of Hodgkin lymphoma that presented with localized back pain without overt evidence of lymph node involvement. This nonclassic presentation offers a diagnostic challenge that emphasizes the importance of keeping a broad differential in an adolescent or young adult patient with lytic bone lesions.

Background: To describe the rate and predictors of pathologic fractures in benign neoplasms of the finger, as variables from prediction models for pathologic fractures of the long bones of the extremities are not necessarily applicable to the bones of the hand. Methods: In this retrospective chart review, 69 histologically confirmed neoplasms affecting the bones of the fingers, 49 phalanges and 20 metacarpals, were identified in patients presenting at 2 urban hospitals over a 24-year period. Different variables were studied as possible predictors of pathologic fractures. Results: Forty-nine percent of the tumors presented as a pathologic fracture. The small finger was independently associated with pathologic fractures compared to the other fingers. Tumors of the metacarpal bones were the least likely to fracture compared to other bones. Conclusions: Almost half of neoplasms affecting the bones of the fingers presented initially with a pathologic fracture, most commonly the small finger. Therefore, a lower threshold for surgical treatment of a bone neoplasm affecting the small finger may be reasonable.

Introduction: Chondroblastoma is a rare benign bone tumour that usually occurs in children and young adults. They are cartilaginous tumours arising in the epiphysis or apophysis of a long bone. The tumour is classified as benign, although rare cases of pulmonary metastases have been reported. The aims of this study were to describe clinical, radiographic characteristics of chondroblastoma; to analyse the local recurrence rate and complications associated with surgery. Material and methods: This retrospective study included 177 patients, who had been diagnosed with a chondroblastoma in extremity between 1990 and 2015. Results: The most common site was proximal tibia 20%, followed by proximal humerus 19%, proximal femur 18%, distal femur 16% and foot 15%. One patient has died of the disease and one patient is alive after being operated for lung metastases. There was local recurrence in 25/177 (14%) patients. The median time to local recurrence was 10 months (range 3–158 months). The most common site for local recurrence was proximal tibia (22.2%). The proximal femur was the location in 32/178 (18%) of the cases. 18/32 (56%) were in the greater trochanter and 14/32 (44%) in the femoral head. The mean age was lower in tumours located in femoral head when compared to the greater trochanter; 19.5 years and 13.9 years respectively (p = =0.004). Tumours located in greater trochanter were all curetted without further complications. Local recurrence was seen more often in femoral head tumours, though without statistical significance; 3/14 (21%) and none, respectively (p = =0.073). Conclusions: Chondroblastoma is a rare benign to intermediate grade bone tumour with a potential to metastasise. Femoral head chondroblastoma is rare, presenting 4.5% of all chondroblastoma cases. Around 50% of the chondroblastoma in femoral head. occur in patients with open growth plates. Keywords: Chondroblastoma, Bone neoplasm, Femur head, Growth plate

Objective: Hemipelvectomy is a complex surgery with a high complication rate. Here, we aimed to identify factors related to the onset of complications and calculate their impacts on hospital costs. Methods: We evaluated 31 consecutive patients who underwent hemipelvectomy between 1999 and 2015. We assessed the clinical and radiographic data to determine the patients’ demographic factors, tumor and surgical characteristics, and complications. The individual hospital stays and financial balances were assessed up to 6 months following the index surgery. Results: The overall complication rate was 61% (19/31). Infection was the most prevalent complication (36%). Immediate postoperative death occurred in 5/31 patients (16%); another 5 (16%) died after hospital discharge due to disease progression. Histological grade, previous surgery, and previous radiotherapy were not associated with complications or infection. Acetabular resections, bone reconstruction, and longer operative times were associated with infection, whereas older age, pelvic organ involvement, and comorbidities were associated with immediate postoperative death. Complications and infection were associated with 4.8- and 5.9-fold increases in hospital costs, respectively. Conclusions: Acetabular resection and bone reconstruction are important factors that increase short-term complication rates, infection rates, and hospital costs. Mortality was associated with older age and adjacent pelvic tumor progression. Level of Evidence: IV, case series. RESUMO Objetivo: Hemipelvectomia é uma cirurgia complexa associada a alta taxa de complicações. O objetivo foi identificar fatores relacionados a complicações e calcular o impacto sobre os custos hospitalares. Métodos: Avaliamos 31 pacientes consecutivos submetidos à hemipelvectomia entre 1999 e 2015. Analisamos dados clínicos e radiográficos para determinar variáveis demográficas, características do tumor e cirurgia, e complicações. A internação hospitalar individual e o balanço financeiro foram calculados até seis meses após a cirurgia principal. Resultados: A taxa de complicações foi de 61% (19/31). Infecção foi a complicação mais frequente (36%). Morte pós-operatória precoce foi observada em 5/31 pacientes (16%) e outros cinco (16%) morreram após alta hospitalar devido à progressão da doença. Grau histológico, cirurgia e radioterapias prévias não estiveram associadas com complicações ou infecções. Ressecções acetabulares, reconstruções ósseas e maiores tempos cirúrgicos estiveram associados com infecções, enquanto que mais idade, envolvimento de orgão pélvico e comorbidades estiveram associados com morte precoce. Complicações e infecções apresentaram aumento de 4,8-, e 5.9-vezes nos custos hospitalres. Conclusões: Ressecções acetabulares e reconstrução óssea são fatores importantes que aumentam as complicações, infecções e custos hospitalares. Mortalidade está associada com maior idade e progressão tumoral intrapélvica. Nível de Evidência IV, Série de casos.

The purpose of this study was to compare the efficacy of radiotherapy (RT) combined with transcatheter arterial chemoembolization (TACE) with RT alone for the treatment of bone metastases from renal cell carcinoma (RCC). We included in this retrospective study 25 RCC patients (28 bone metastases), who were treated with RT at our institution. Patients were divided into two groups: patients treated with RT alone (monotherapy group; n = 17) and those treated with RT combined with TACE (combined therapy group; n = 11). The administered median RT dose was 30 Gy in 10 fractions. Anti-cancer agents used in TACE were cisplatin (median dose, 50 mg) and carboplatin (median dose, 240 mg) for patients with reduced renal function. We evaluated the objective response, post-RT-skeletal-related event (PR-SRE)–free rate, and adverse events associated with treatment for each group. The objective response rates for bone metastases in the monotherapy and combined therapy groups were 33% and 82%, respectively (p = 0.009). The 2-year PR-SRE-free rate in the monotherapy and combined therapy groups was 41.8% and 100%, respectively (p = 0.009). The objective response and PR-SRE-free rates were significantly superior in the combined therapy than in the monotherapy group. There were no significant differences in adverse events or survival between the two groups. RT combined with TACE is a promising treatment for bone metastases from RCC, as it results in higher objective response, and PR-SRE-free rates compared with RT alone. • Skeletal-related events (SREs) are common in patients with bone metastases from renal cell carcinoma (RCC). • Radiotherapy (RT) provides pain relief in patients with bone metastases from RCC, but rarely achieves objective response. • Combination of RT with transcatheter arterial chemoembolization results in higher objective response and post-RT-SRE-free rates compared with RT alone and is a promising treatment for bone metastases from RCC, as it.

Does a rehabilitation protocol based on balance exercises using Serious Game improve walk performance in patients undergoing knee resection and reconstruction for bone primary tumor?. 30 patients undergoing modular prosthetic replacement, following a primary bone tumor, were consecutively enrolled. During each hospitalization a physiotherapy treatment was activated, included 25min training phase aimed postural and proprioceptive control. In order to better evaluate the walking speed at one-year post surgery in the study group, data were compared with a group of 22 patients treated in a previous period, called the control group, collected retrospectively. The control group differed only for the type of physiotherapy treatment offered. No statistically significant differences emerged from the two groups, regarding baseline characteristics. Walking speed in the study group was improved compared to the control group with a median difference of 0.22m/s (p = 0.022). A difference was also measured in the speed of centre mass, with a median reduction of 4.5mm/s (p = 0.005) in the study group, showing an improvement in postural control in stand-up position. Exercises aimed at recovering balance and Serious Game should be proposed in order to improve motor performance and postural control in the medium and long term.

Initial workup of malignant skeletal lesions includes obtaining a thorough clinical history, physical exam, imaging, and laboratory testing. Key findings that suggest underlying malignant bone pathology include the presence of hypercalcemia, history of pathologic fracture associated with a skeletal lesion, and locally aggressive behavior of a bone tumor on imaging. The optimal approach to patients with primary or metastatic bone neoplasm or a hematologic malignancy includes a multidisciplinary approach with a variety of subspecialists. Bone-modifying therapy including bisphosphonates and denosumab plays an important role in the management of pain related to metastatic malignancy of bone and multiple myeloma.

Objective: To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme. Patients and Methods: Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results: A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7–6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus. Conclusion: The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients. © 2018 The Authors BJU International

Aims The aim of this study is to assess outcomes of patients ≤12 years who undergo Stanmore noninvasive extendible endoprosthetic replacement of the distal femur (DF NIEPR). Patients and methods A total of 101 children (mean age 9.6 years) were included. All complications which required further surgery were recorded. Clinical and functional outcomes were evaluated with Musculoskeletal Tumor Society (MSTS) scores at a mean follow-up of 64 months (range 6-174). Results Thirty-one (30.7%) patients died at a mean of 33 months. Forty had prosthesis removed after a mean of 43 months (range, 7-103). Attaining of the full lengthening potential before skeletal maturity was the most frequent reason for revision surgery, particularly in those with smaller lengthening potential (P = 0.039). Implant survival rate for other causes was 61.7% at 5 years and 45.0% at 10 years. At final follow-up mean MSTS score was 26 (range, 13-29). Twenty-two (21.5%) patients had a final limb-length discrepancy (LLD) > 2 cm. Conclusions DF NIEPR produces a good functional outcome, with the prevention of major LLD at skeletal maturity in the majority of the cases. We suggest patient selection criteria to account for the stage of the disease due to the high cost of the NIEPR, and high percentage requiring revision, and a 60% mortality rate in those patients presenting with distant disease burden.

Background: High-grade bone osteosarcoma has a high relapse rate. The best treatment of local recurrence (LR) is under discussion. The aim of this study is to analyze LR patterns and factors prognostic for survival. Methods: LR diagnostic modality (clinical or imaging), pattern of recurrence, and post-LR survival (PLRS) were assessed. Results: Sixty-two patients were identified, with median age 21 years (range, 9–75 years), including 11 (18%) ≤15 years, 30 (48%) from 16 to 29 years; 21 (34%) were older. Patterns of relapse were LR only 58%, LR + distant metastases (DM) 42%. Seventy-nine percent of patients relapsed within 24 months, and diagnosis was clinical in 88%. LR treatment was surgery 85%, chemotherapy 55%, chemotherapy + surgery 45%. Surgical complete remission after LR (CR2) was achieved in 60% (LR 86%; LR + DM 23%). With a median follow-up of 43 months (range, 5–235 months), the five-year PLRS was 37%, significantly better for patients with longer LR-free interval (LRFI; ≤24 months 31% vs>24 months 61.5%, P=0.03), absence of DM (no DM 56%vs DM 11.5%, P=0.0001), and achievement of CR2 (no CR2 0%vs CR2 58.5%, P=0.0001). No difference was found according to age and chemotherapy (LR only: five-year PLRS: 53% without chemotherapy vs 58% with chemotherapy, P=0.9; LR + DM: five-year PLRS: 25% without chemotherapy vs 9% with chemotherapy, P=0.7). Conclusions: Early relapse is detected by symptoms in 90% of cases and associated with worse outcome. The achievement of CR2, not age, is crucial for survival. For patients with LR only, better survival was demonstrated, as compared with DM, and no improvement with chemotherapy after surgery was found.

Background Ewing sarcoma (ES) is the second most common bone tumor in adolescents and children. Staging workup for ES includes imaging and bone marrow biopsy (BMB). The effective role of BMB is now under discussion. Procedure A monoinstitutional retrospective analysis reviewed clinical charts, imaging, and histology of patients with diagnosis of ES treated at the Rizzoli Institute between 1998 and 2017. Results The cohort included 504 cases of ES of bone; 137 (27%) had metastases at diagnosis, while the remaining 367 had localized disease. Twelve patients had a positive BMB (2.4%). Eleven had distant metastases detected at initial workup staging with imaging assessment: six patients presented with bone metastases, five with both bone and lung metastases. Only one patient with ES of the foot (second metatarsus) was found to have bone marrow involvement with negative imaging evaluation (0.3%). Conclusions On the basis of our data, we suggest reconsidering the effective role of BMB in initial staging workup for patients with ES with no signs of metastases by modern imaging techniques. In metastatic disease, the assessment of the bone marrow status may remain useful to identify a group of patients at very high risk who could benefit from different treatment strategies.