High-grade osteosarcoma, a primary malignant bone tumour, is experiencing a global increase in reported incidence with varied prevalence. Despite advances in management, which include surgery and... Show moreHigh-grade osteosarcoma, a primary malignant bone tumour, is experiencing a global increase in reported incidence with varied prevalence. Despite advances in management, which include surgery and neoadjuvant chemotherapy often an unsatisfactory outcome is found due to poor or heterogeneous response to chemotherapy. Our study delved into chemotherapy responses in osteosarcoma patients and associated molecular expressions, focusing on CD95 receptor (CD95R), interferon (IFN)-γ, catalase, heat-shock protein (Hsp)70, and vascular endothelial growth factor (VEGF). Employing immunohistochemistry and Huvos grading of post-chemo specimens, we analysed formalin-fxed parafn-embedded (FFPE) osteosarcoma tissue of resected post-chemotherapy specimens from Dr. Soetomo General Academic Hospital in Surabaya, Indonesia (DSGAH), spanning from 2016 to 2020. Results revealed varied responses (poor 40.38%, moderate 48.08%, good 11.54%) and distinct patterns in CD95R, IFN-γ, catalase, Hsp70, and VEGF expression. Signifcant diferences among response groups were observed in CD95R and IFN-γ expression in tumour-infltrating lymphocytes. The trend of diminishing CD95R expression from poor to good responses, accompanied by an increase in IFN-γ, implied a reduction in the count of viable osteosarcoma cells with the progression of Huvos grading. Catalase expression in osteosarcoma cells was consistently elevated in the poor response group, while Hsp70 expression was highest. VEGF expression in macrophages was signifcantly higher in the good response group. In conclusion, this study enhances our understanding of immune-chemotherapy interactions in osteosarcoma and identifes potential biomarkers for targeted interventions. Show less
The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory... Show moreThe phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS. Show less
In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial... Show moreIn this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology. Show less
GCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclastlike giant cells, induced by neoplastic mononuclear cells expressing high-levels of... Show moreGCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclastlike giant cells, induced by neoplastic mononuclear cells expressing high-levels of the receptor activator of nuclear factor Kappa-B ligand (RANKL), a mediator of osteoclast activation. Although the mainstay of treatment is complete tumour removal with preservation of bone, therapy with denosumab, an inhibitor of RANKL, has been introduced for selected cases. Objectives: Denosumab-treated GCTB (DT-GCTB) was reported to show a wide spectrum of histological changes such as depletion of osteoclast-like giant cells and intralesional bone deposition, which may lead to diagnostic difficulties. We investigated clinicopathologic and molecular features of DT-GCTB, matched with pre-therapy samples. Participants: 21 cases were included (13 females, 8 males), aged 15 to 64 (median, 30 years). Results: DT-GCTB showed development of sclerotic neocortex and varying degrees of osteosclerosis radiographically. Marked depletion of giant cells, different degree of ossification, fibrosis, and proliferation of mononuclear cells was observed. Staining for H3.3G34W was positive in mononuclear cells in 19 cases (90.5%), while one negative case was positive for H3.3G34V. H3F3A G34W mutation was confirmed in 17 of 19 cases (89.5%), corresponding to nuclear staining with H3.3 G34W antibody. G34L mutation was detected in one G34W negative case, in which H3.3 G34V nuclear positive staining was observed, possibly due to cross-reaction. Conclusions: Post-therapy tumours still exhibit a similar mutation profile, while significantly differing from classic GCTB morphologically. Correlation with history of denosumab administration, awareness of features of DT-GCTB, IHC and molecular studies for histone H3 mutations are important in its assessment. Show less
It can be concluded from this thesis that high-grade osteosarcoma is at clinical, pathological and molecular level a heterogeneous disease. To treat high-grade osteosarcoma, neo-adjuvant... Show moreIt can be concluded from this thesis that high-grade osteosarcoma is at clinical, pathological and molecular level a heterogeneous disease. To treat high-grade osteosarcoma, neo-adjuvant chemotherapy should be combined with radical surgery, irrespective the localization. There are only 4 effective cytostatic agents for osteosarcoma treatment: methotrexate, doxorubicin, cis-platin and ifosfamide. Patients with pulmonary metastases should receive surgery in case of resectable disease, whereas the use of chemotherapy is not of proven value. Patients with irresectable metastatic osteosarcoma should be offered phase-I studies, because no response can be expected from other conventional cytostatic drugs. New drugs, such as the monoclonal antibody trastuzumab against HER2 is not supported by us, because we did not find this receptor on osteosarcoma cells. At molecular level, a disturbed Wnt signalling, an abnormal cell c ycle regulation and a disturbed p53/apoptotic pathway was present in osteosarcoma cells. The hypothesis is that failure of the mesenchymal stem cell to differentiate into the osteoblastic lineage, due to abnormal proliferation and lack of differentiation commitment results in chromosomal instability, which is the hallmark of osteosarcoma. In Patients with an inactive Wnt3a/_-catenin signalling the proteasome inhibitor bortezomib might be a candidate drug, to explore its suggested differentiation inducing properties. Show less
Mohseny, A.B.; Cai, Y.P.; Kuijjer, M.; Xiao, W.; Akker, B. van den; Andrea, C.E. de; ... ; Cleton-Jansen, A.M. 2012
Centrale chondrosarcomen zijn zeldzame kraakbeen-producerende tumoren die zich van oorsprong bevinden midden in het bot. Deze soort tumoren zijn op dit moment alleen te behandelen door middel van... Show moreCentrale chondrosarcomen zijn zeldzame kraakbeen-producerende tumoren die zich van oorsprong bevinden midden in het bot. Deze soort tumoren zijn op dit moment alleen te behandelen door middel van operaties. Dit kan zeer ingrijpend voor de pati_nt zijn (bijvoorbeeld bij een amputatie) en er is een kans dat de tumor weer terugkomt of dat er metastases ontstaan. In dit proefschrift is onderzoek gedaan naar de moleculaire en genetische veranderingen in deze tumoren. Hiermee hoopten we een beter inzicht te krijgen in het hoe en waarom van deze tumoren. Daarnaast hebben we gekeken of we factoren konden vinden die zouden helpen bij het voorspellen van de prognose van de betrokken pati_nten en of we mogelijk toekomstige doelwitten voor medicatie van deze tumoren kunnen vinden. Uit de resultaten behorende bij dit proefschrift zijn nieuwe invalshoeken voor verder onderzoek gekomen, bijvoorbeeld met betrekking tot het vaststellen van de diagnose en regelkringen betrokken bij de progressie naar tumoren met een slechtere prognose. Show less
