The Activation of PDGFRß on Mononuclear Stromal/Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment. An Immunohistochemical Study of Five Cases.

Due to the relatively high recurrence rate and the destructive nature of the tumor, the treatment of giant cell tumor is still a challenge. Denosumab appeared to be a promising candidate as a therapeutic drug. However, several studies have reported that tumors can recur during/after treatment with denosumab. Based on activated receptor tyrosine kinase signaling pattern of the stromal/tumor cells, a combination treatment with denosumab and sunitinib has recently been proposed to inhibit recurrences. This prompted us to investigate the PDGFRß expression of five denosumab treated cases using both primary and recurrent tumors during and after denosumab treatment. In addition, to recognise morphological changes, immunohistochemical analysis of H3F3A and PDGFRß was also performed. As an effect of denosumab treatment, the permanent absence of giant cells associated with severe to mild fibrosis was the most consistent morphological change, but H3F3A positive stromal/tumor cells were observed in all cases. Furthermore, an increased immunopositivity of PDGFRß in stromal/tumor cells was evident in all recurrent cases during denosumab treatment. Upon tumor recurrence (after the discontinuation of denosumab treatment) the intensity of PDGFRß immunostaining in stromal/tumor cells was restored/decreased. Our results confirm (for the first time) the activation of PDGFRß on mononuclear stromal/tumor cells at protein level as an effect of denosumab treatment, which has so far only been demonstrated by phosphoprotein array analysis (protein lysates). The decreased PDGFRß activity after the discontinuation of denosumab treatmeant and the increased PDGFRß activity during denosumab treatment underlines the need for denosumab and sunitinib combination therapy.

Extra-abdominal desmoid tumor fibromatosis: a multicenter EMSOS study.

BACKGROUND: Extra-abdominal desmoid tumor fibromatosis (DTF) is a rare, locally aggressive soft tissue tumour. The best treatment modality for this patient cohort is still object of debate. QUESTIONS/PURPOSE: This paper aimed to (1) to compare the outcomes of DTF after different treatment modalities, (2) to assess prognostic factors for recurrence following surgical excision, and (3) to assess prognostic factors for progression during observation. METHODS: This was a retrospective multicenter study under the patronage of the European Musculoskeletal Oncology Society (EMSOS). All seven centres involved were tertiary referral centres for soft tissue tumours. Baseline demographic data was collected for all patients as well as data on the diagnosis, tumour characteristics, clinical features, treatment modalities and whether they had any predisposing factors for DTF. RESULTS: Three hundred eighty-eight patients (240 female, 140 male) with a mean age of 37.6 (±18.8 SD, range: 3-85) were included in the study. Two hundred fifty-seven patients (66%) underwent surgical excision of ADF, 70 patients (18%) were observed without therapy, the residual patients had different conservative treatments. There were no significant differences in terms of tumour recurrence or progression between the different treatment groups. After surgical excision, younger age, recurrent disease and larger tumour size were risk factors for recurrence, while tumours around the shoulder girdle and painful lesions were at risk of progression in the observational group. CONCLUSION: Local recurrence rate after surgery was similar to progression rates under observation. Hence, observation in DTF seems to be justified, considering surgery in case of dimensional progression in 2 consecutive controls (3 and 6 months) and in painful lesions, with particular attention to lesions around the shoulder girdle.

Extracorporeal irradiation: biological reconstruction following tumor resection with a large bone defect / Extracorporalis irradiatio: nagy csontdefektussal járó tumorresectiót követo biológiai rekonstrukció.

Összefoglaló. A malignus csonttumorok sebészi ellátása során kialakuló szegmentális csontdefektusok pótlása fontos szempont a végtagmegtartó sebészetben. Felnottkorban a megoldás rendszerint tumorprotézis beültetése, 10 évesnél fiatalabb gyermekeknél azonban ez nehezen alkalmazható módszer a kis csontméret és az igen magas várható szövodményarány miatt. A bemutatott, hazánkban még ritkán alkalmazott beavatkozás, a tumoros csontszegmentum mutét alatti sugárkezelése, visszaültetése megfelelo rekonstrukciós lehetoség a végtag funkciójának megtartása mellett, csökkentve a késobbi reoperációk, protézisrevíziók számát. Célkituzés: A hazánkban eddig az ismertetett módon végzett mutétek bemutatása, az eredmények összevetése nemzetközi irodalmi adatokkal. Módszer: Magyaroszágon eddig 12 alkalommal végeztünk végtagmegtartó mutétet malignus csonttumor miatt 12 évesnél fiatalabb gyermekeknél, és e mutétek során biológiai rekonstrukciós módszerként extracorporalis irradiatiót, autograft-reimplantatiót (ECRT, ECI) végeztünk. A mutétek mindegyike primer malignus csonttumor (Ewing-sarcoma 7 esetben, osteosarcoma 4 esetben, chondrosarcoma 1 esetben) miatt történt. Betegeink átlagéletkora 9 (3-12) év volt, az átlagos utánkövetési ido 32,5 (2-73) hónap. A felmérés során fizikális vizsgálat, valamint minden alkalommal röntgenfelvételek készítése történt, szükség esetén szövettani mintavétellel, vérelemzéssel vagy egyéb képalkotással kiegészítve. Eredményeinket nemzetközi irodalmi adatokkal hasonlítottuk össze. Eredmények: Lokális tumorkiújulást egyetlen esetben sem észleltünk, másik csontot érinto skip ('ugró') metastasis miatt egy alkalommal amputatiót végeztünk. A szövodmények tekintetében eredményeink megfelelnek a nemzetközi irodalomban leírtaknak. Két esetben jelentkezett szeptikus szövodmény (16,7%). A resectiós sík radiológiai átépülése 3-9 hónap alatt történt meg az esetek 60%-ában. Álízület, grafttörés, graft részleges elhalása miatt 3 esetben végeztünk reoperációt, kétszer újabb allograft felhasználásával, egy esetben pedig tumorprotézis beültetésével. Betegeink szubjektív véleménye a módszerrol pozitív, a legtöbb esetben megorizték jó fizikai aktivitásukat, az esetleges reoperációk ellenére végtagjukat terhelik, akár sporttevékenységet is végeznek. Következtetések: Vizsgálatunk alapján az extracorporalis irradiatio hasznos biológiai rekonstrukciós módszer 12 évesnél fiatalabb gyermekek esetében szegmentális csontdefektusok pótlására tumoros indikációval. A felmerülo szövodmények aránya alatta marad a hasonló korban beültetett tumorprotézisek szövodményarányainak, ideális esetben pedig több, további kiterjesztett mutét elkerülheto vele. Szövodmény esetén a késobbiekben tumorprotézis-beültetés mint végtagmegtartó vészmegoldás még mindig elvégezheto. Orv Hetil. 2020; 161(45): 1914-1919. INTRODUCTION: Reconstruction of massive segmental bone defects is a crucial point of limb salvage surgeries after malignant bone tumor resections. Megaendoprostheses implantation is a commonly used method for adult patients, but hardly usable for children below 12 years old, because of the small size of the host bone and multiple mechanic complications. OBJECTIVE: Extracorporeal irradiation and allograft reimplantation (ECRT, ECI) are promising methods for these young children for limb salvage, reducing the number of prostheses revisions, reoperations. METHOD: In Hungary, we performed limb salvage surgery for malignant bone tumor in 12 cases in children under 12 years old, using extracorporeally irradiated autografts as biological reconstruction. All cases were primary bone tumors (Ewing's sarcoma: 7, osteosarcoma: 4, chondrosarcoma: 1). The average age of our patients was 9 (3-12) years, the average follow-up was 32.5 (2-73) months. At follow-up, we performed physical examination, X-ray, and other imaging methods if they were necessary. Our results were compared to international publications. RESULTS: We observed no local recurrence, but in one case we had to perform above-knee amputation, due to a skip metastasis in the proximal tibia. The complication rates were similar to those reported in other papers. Septic complications were treated in two cases (16.7%). Total union of the resection lines was observed at 3-9 months in 60% of all cases. Reoperations were performed due to nonunion, or allograft fracture/partly desorganization in 3 cases, twice with new allograft, and with prostheses in one case. The subjective opinion of our patients is positive, they walk with full weightbearing, some of them do even light sporting activities. CONCLUSIONS: We found extracorporeal irradiation a useful and safe method for children under 12 years old for biological reconstruction after malignant bone tumor resection. Complication rate stays under the rate of growing prostheses complications, in optimal cases further radical, and extensive surgeries may be avoided. In the case of major complications, megaendoprostheses implantation later on is still an option as salvage procedure with limb salvage. Orv Hetil. 2020; 161(45): 1914-1919.

Prevalence and Clinical Features of Mazabraud Syndrome: A Multicenter European Study.

BACKGROUND: Mazabraud syndrome is a rare disorder, characterized by the presence of fibrous dysplasia (FD) with associated intramuscular myxomas. Data are scarce on the prevalence, clinical features, and natural history of this disorder and outcomes. In this multicenter study, we evaluated a series of patients from 6 European centers. METHODS: All centers affiliated with the European Musculo-Skeletal Oncology Society (EMSOS) were invited to include data on all patients with Mazabraud syndrome who were seen between 1980 and 2015. The study investigated the prevalence of Mazabraud syndrome, the type, severity, and localization of FD lesions in relation to myxomas, the histopathology of myxomas, and results of GNAS-mutation analysis, when available. RESULTS: Thirty-two patients (22 female) from 6 centers were included. The prevalence of Mazabraud syndrome was 2.2% in the combined cohort of 1,446 patients with FD, and the syndrome was diagnosed at a mean of 10.1 years after diagnosis of FD. The myxomas were predominantly localized in the upper leg. Excision was performed in 20 patients, recurrence occurred in 6 of these patients (30%) at a median of 8.5 years (range, 1.9 to 16.0 years), and revision surgery was necessary in 5 (25%). High cellularity of myxomas was associated with recurrence (p < 0.05). A GNAS mutation was identified in the myxoma tissue of 5 (83%) of 6 patients with GNAS-mutation analysis. CONCLUSIONS: This study is the first, to our knowledge, to provide data on the prevalence of Mazabraud syndrome in a relatively large cohort. Although the outcomes of surgical resection were good, a quarter of the patients required revision surgery despite clear resection margins. High cellularity of myxomas was associated with recurrence. GNAS mutations were identified in 83% (5 of 6), emphasizing the shared origin of FD and myxomas. Our data show that patients with FD who have disproportionate complaints, irrespective of FD type, extent, or severity, should be investigated for the possible presence of myxomas. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

[Comparative functional outcome of reverse shoulder prostheses implanted on degenerative and oncological indications]. / Degeneratív és onkológiai indikációk alapján beültetett reverz vállprotézisek funkcionális kimenetelének összehasonlítása.

INTRODUCTION: Several methods (bone graft, endoprosthesis) are used to reconstruct proximal humerus resections due to primary and metastatic tumours. One of the new procedures is the replacement of the joint surfaces and the removed proximal humerus end with reverse shoulder prosthesis, optionally supplemented with bone implantation (composite procedure) in the hope of achieving better shoulder function. AIM: The aim of this study was to compare the shoulder function of the patient group operated by the above procedure with reverse prosthesis to a patient group operated by indication of degenerative shoulder disease (rotator cuff arthropathy). METHOD: The study involved 23 patients (13 men, 10 women) who were operated between 2012 and 2016 in our institution. Among them, 15 had rotator cuff arthropathy indication of reverse prosthesis, while in 8 cases, resection of the humerus and prosthesis implantation were performed due to tumour lesions. The average age of our patients was 62.5 years (17-82) and the average follow-up was 23.5 months (5-57). We performed physical examination, X-ray pictures on their operated arm, and data were recorded and analysed based on functional score systems. RESULTS: The level of postoperative pain was almost the same in the two groups, but only the rotator cuff arthropathy group needed pain medications. In line with our expectations, we received slightly lower values by each of the three scoring systems in case of tumorous patients. The tumorous patients were satisfied with the results achieved. CONCLUSIONS: Following proximal humerus resections, reversed prosthesis implantation with occasional bone allografts is a reliable method of reconstruction, which approaches available functions and reliability as compared to non-tumour-indicating patients. Orv Hetil. 2018; 159(45): 1838-1843.

[Epidemiology of soft tissue sarcomas in a university center in Hungary]. / A lágyrészszarkóma epidemiológiája egy hazai egyetemi centrumban.

Our aim was to investigate the rare malignant soft tissue sarcomas responsible for 1.5% of all malignant tumors, to compare our epidemiological data from the patient population of the Department of Orthopaedics, Semmelweis University, to data described in the international literature for soft tissue tumors. We reviewed 595 cases of primary soft tissue sarcomas treated between 1994 and 2014 and compared results to international data from the literature. Our results were similar to those found in the international literature: mean age, mild male predominance, the most common sarcoma subgroups, the superficial and deep sarcoma ratio, low and high grade sarcoma ratio, the ratio of patients with a primary lung metastasis. Compared to other European data we found significantly longer patient referral to centers (3.6 months in case of superficial sarcomas, 8 months in case of deep localization) which surprisingly had no substantial effect on average tumor size (superficial: 5 cm, deep: 10.5 cm). This corresponds with data from the literature. The long delay period in patients' request of medical service draws attention to difficulties in differential diagnosis in this rare type of tumor, delays in referring patients to a center, and the lack of consultation. We recommend that the required investigations be performed in a musculoskeletal oncology center where this type of cancer is treated.

[Change of paradigm in the surgical treatment of metastatic diseases of bone. Part I. Bony metastases of the extremities and pelvis]. / Paradigmaváltás a csontmetasztázisok sebészetében. I. Végtagi és medencelokalizációjú áttétek.

According to the statistical data of tumor registries the incidence of cancer has increased in the last decade, however the mortality shows only a slight change due to the new and effective multimodal treatments. The aim of our overview article is to present the changes in the survival of the metastatic patients, and to demonstrate which factors influence their prognosis. The improvement of survival resulted in a more active surgical role both in metastases of the bone of the extremities and the pelvis. We present a diagnostic flow chart and current options for the reconstruction of the different regions of the bone and skeleton, and we will discuss their potential advantages, disadvantages and complications. It is evident that apart from the impending and pathological fracture surgery it is not the first choice of treatment but rather a palliative measure. The aim of surgery is to alleviate pain, to regain mobility and improve quality of life. If possible minimal invasive techniques are performed, as they are less demanding and allow fast rehabilitation for the patient, and they are solutions that last for a lifetime. In optimal conditions radical curative surgery can be performed in about 10 to 15 per cent of the cases, and better survival is encouraging. Orv Hetil. 2017; 158(40): 1563-1569.

[Contemporary management of bone tumors at Semmelweis University]. / Csonttumorellátás a Semmelweis Egyetem Ortopédiai Klinikáján.

The incidence of bone tumors is low therefore it is highly recommended to treat patients in specialized centers. In the late 70ies a bone tumor registry was initiated at the Department of Orthopedics of the Semmelweis University followed by the development of a specialized diagnostic unit and a bone cancer center. Several novel surgical procedures have been introduced, including the extremity-sparing surgery, leading to a significant improvement of the patients survival. This is fully supported by a specialized bone cancer oncoteam of experts. The 6000-sized registry and biobank now allows the development of translational research in this orphan tumor type.

[Resection and reconstruction in cases of musculosceletal soft tissue sarcomas]. / Sebészi radikalitás és rekonstrukciós lehetõségek végtagi lágyrészsarcomáknál.

Soft tissue sarcomas are rare, reaching some 1.5% of all malignant tumors. While formerly the surgical management of sarcomas almost exclusively consisted of amputation, in the recent years limb saving surgery has become the first choice of therapy. Negative factors affecting the survival rate are: histologically high-grade tumor, size and localization of the tumor, vascular invasion, extensive tumor necrosis, certain subgroups, local recurrence and oncologically positive surgical margin at the resection. Many modern reconstruction possibilities are essential for the safe limb saving surgery with wide surgical margins, such as bone allograft implantation, tumor endoprostheses reconstruction, vascular grafting and plastic surgery. There should always be an attempt to perform limb saving surgery, however life quality, life expectancy and survival are more important considerations influencing essentially the surgical method of choice. In our follow-up study no significant difference in recurrence rate was found between the group of patients with sarcomas requiring a complex reconstruction procedure and the group of those treated by only resection methods (32% versus 47%).

[Limb saving surgery in cases of bone sarcomas]. / Végtagmegtartó mûtétek csontsarcomáknál.

At the Orthopedic Department of Semmelweis University we operate an internationally recognized bone and soft tissue tumor center. Our specialty is the treatment of benign and malignant bone tumors, tumor-like lesions and surgery of soft tissue tumors. Our main aim, taking into account the appropriate oncologic radicality, is to create the conditions for the development of limb saving surgery. Limb saving surgery is an interdisciplinary activity both in diagnosis and in treatment. We have proper pathology, radiology and interventional radiology background for the fast and advanced pathomorphological and radiomorphological diagnosis of different tumors. Using modern chemotherapy, radiotherapy and other advanced cancer treatment protocols rapid access to oncology background is provided for children and adults as well, both primary and secondary bone tumors and soft tissue sarcoma cases of the extremities. The limb saving surgery after removal of the tumor is essentially a reconstructive surgery. Reconstructive surgery in childhood and younger ages mean mainly the biological solutions (vascularized autologus bone grafts and/or homologous bone graft), otherwise in elderly ages implantation of tumor endoprostheses has a greater significance. Furthermore, the final tumor surgery requires experienced abdominal surgeon, vascular surgeon and plastic surgeon to ensure the background as well. The professional background of our clinical practice is based on participating in international conferences and spending several months abroad in different big tumor centers. Over the past 15 years, several international cancer congresses were organized in Hungary by our Department.