Clear surgical margins as a prognostic indicator for disease recurrence, with no impact on survival rates in patients with myxofibrosarcoma.

Myxofibrosarcoma presents an infiltrating growth pattern that results in a high tendency for local recurrence. Clear margin resection is challenging because of microscopic infiltration. The purpose of the present study was to analyze the overall and disease-free survival rates of patients with myxofibrosarcoma and the prognostic factors that determine both survival and disease recurrence. Among the 111 patients included in our study, the 5-year overall survival rate was 65.5%. An age of more than 65 years (hazard ratio [HR] 1.9 [95% confidence interval (CI) 1.4-5.6]; p < 0.001), a tumor size of more than 5 cm (HR 2.8 [95% CI 0.9-8.1]; p = 0.049) and the G3 tumor grade (HR 14.1 [95% CI 2.1-105.0]; p < 0.001) negatively affected overall survival. The 5-year recurrence-free survival rate was 49.4%. R1/R2-type resection (HR 2.4 [95% CI 1.0-5.6]; p = 0.048) had a detrimental effect on tumor recurrence. Clear margins had a positive impact on recurrence-free survival, but did not significantly affect overall patient survival, suggesting that other factors may play a more significant role in determining patient outcomes. A surgical margin of 2 mm was not sufficient to significantly influence the incidence of recurrence. Consequently, a wider surgical margin may be necessary to reduce the risk of myxofibrosarcoma recurrence.

Hand2 Immunohistochemistry in the Diagnosis of Paragangliomas and Other Neuroendocrine Neoplasms.

Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity.

Soft tissue sarcoma with ZC3H7B::BCOR fusion in a male mimicking low-grade fibromyxoid sarcoma - A case report.

Diagnosis of soft tissue tumors is often challenging, given the large number of entities, often with non-specific or overlapping morphology. Although morphology still plays an important part in diagnostic process, additional studies including immunohistochemistry and molecular genetics are often needed to arrive at correct diagnosis. We report a case of 61-year-old male with subcutaneous tumor in right hip area, that was surgically removed. The tumor was composed of uniform bland spindle cells in mild to moderately cellular myxoid nodules, with limited areas of collagenization and the diagnosis of low grade fibromyxoid sarcoma was made. The tumor recurred 3 years after the initial diagnosis and the new sample showed a high-grade round cell sarcoma with limited residual low-grade areas and non-specific immunoprofile after extended immunohistochemical work-up. Molecular analysis demonstrated ZC3H7B::BCOR fusion. Sarcomas with ZC3H7B::BCOR fusion occurring outside of uterus are exceedingly rare. A comprehensive review of previously published cases and a short discussion about classification of the entity is provided, together with data about morphology and immunoprofile of the lesions. The case also underscores the necessity of extended work up of soft tissue tumors with unusual immunohistochemical or morphological features in order to accurately assess their biological potential.

Proximal Tibia Tumour Location and Curettage Are Major Risk Factors of Local Recurrence in Giant Cell Tumour of Bone.

Giant cell tumour of bone (GCTB) is one of the most common local aggressive tumourous lesions with a wide variety of biological behaviour. However, there are no clear indicative criteria when choosing the type of procedure and the complication rates remain high, especially in terms of local recurrence. The purpose of the study was to (1) identify the main risk factors for local recurrence, (2) evaluate the recurrence-free survival in dependence on neoadjuvant denosumab use and the type of procedure, and (3) compare the functional outcomes after curettage and en bloc resection. The group included 102 patients with GCTB treated between 2006 and 2020. The mean age of patients was 34.4 years (15-79). The follow-up period was 8.32 years (2-16) on average. Local recurrence occurred in 14 patients (29.8%) who underwent curettage and in 5 patients (10.6%) after en bloc resection. Curettage was shown to be a factor in increasing recurrence rates (OR = 3.64 [95% CI: 1.19-11.15]; p = 0.023). Tibial location was an independent risk factor for local recurrence regardless of the type of surgery (OR = 3.22 [95% CI: 1.09-9.48]; p = 0.026). The recurrence-free survival rate of patients treated with resection and denosumab was higher compared to other treatments at five years postoperatively (p = 0.0307). Functional ability and pain as reported by patients at the latest follow-up were superior after curettage compared to resection for upper and lower extremity (mean difference: -4.00 [95% CI: -6.81 to -1.18]; p < 0.001 and mean difference: -5.36 [95% CI: -3.74 to -6.97]; p < 0.001, respectively). Proximal tibia tumour location and curettage were shown to be major risk factors for local recurrence in GCTB regardless of neoadjuvant denosumab treatment. The recurrence-free survival rate of patients treated with resection and denosumab was higher compared to other treatments. The functional outcome of patients after curettage was better compared to en bloc resection.

Outcomes of Intercalary Endoprostheses as a Treatment for Metastases in the Femoral and Humeral Diaphysis.

BACKGROUND: The purpose of this study was to evaluate the implant survival, functional score and complications of intercalary endoprostheses implanted for metastatic involvement of the femoral and humeral diaphysis. METHODS: The selected group covered patients with bone metastasis who were surgically treated with an intercalary endoprosthesis between 2012 and 2021. The functional outcome was evaluated with the Musculoskeletal Tumor Society (MSTS) scoring system, and complications were evaluated by using the failure classification for prosthetics designed by Henderson. RESULTS: The mean follow-up was 29.8 months. In our group of 25 patients with 27 intercalary endoprostheses (18 femurs, 9 humeri), there were 7 implant-related complications (25.9%), which were more common on the humerus (4 cases, 44.4%) than on the femur (3 cases, 16.7%). Only type II failure-aseptic loosening (5 cases, 18.5%)-and type III failure-structural failure (2 cases, 7.4%)-occurred. There was a significantly higher risk of aseptic loosening of the endoprosthesis in the humerus compared with that in the femur (odds ratio 13.79, 95% confidence interval 1.22-151.05, p = 0.0297). The overall cumulative implant survival was 92% 1 year after surgery and 72% 5 years after surgery. The average MSTS score was 82%. The MSTS score was significantly lower (p = 0.008) in the humerus (75.9%) than in the femur (84.8%). CONCLUSIONS: The resection of bone metastases and replacement with intercalary endoprosthesis has excellent immediate functional results with an acceptable level of complications in prognostically favourable patients.

New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRß Signaling.

Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of activated signaling proteins in fresh-frozen tumor samples and tumor-derived cell lines were determined using phosphoprotein arrays. Analysis of the obtained data revealed epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRß) as potential targets, but only the PDGFR inhibitor sunitinib caused a considerable decrease in stromal cell viability in vitro. Furthermore, in the case of a 17-year-old patient suffering from GCTB, we showed that the addition of sunitinib to the standard treatment of GCTB with the monoclonal antibody denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal cells in the tumor tissue. To summarize, the obtained data showed that a specific receptor tyrosine kinase (RTK) signaling pattern is activated in GCTB cells and plays an important role in the regulation of cell proliferation. Thus, activated RTKs and their downstream signaling pathways represent useful targets for precision treatment with low-molecular-weight inhibitors or with other types of modern biological therapy.

Improved osteosarcoma survival with addition of mifamurtide to conventional chemotherapy - Observational prospective single institution analysis.

PURPOSE: Conventional osteosarcoma is an orphan disease. Current treatment approaches include combining a three drug chemotherapy schedule and surgery. The 3- and 5-year event-free survival (EFS) in localized disease is roughly 65 and 60%, respectively. The registration study of mifamurtide reported survival benefit, but some methodological controversies have been insufficient for FDA market authorization in contrast to EMA. METHODS: prospective single centre survival analysis of a mifamurtide addition to conventional therapy in 23 patients over a 5.5 year enrolment period is reported and compared to a historical control of 26 patient with localized disease. Bias arising from observational methodology was addressed using Landmark analysis and time-dependent Cox models. Blood count dynamics were analysed during the treatment. RESULTS: The adverse event profile was as expected with no dose limiting toxicities. There were no local relapses observed, one patient died in the first complete remission due to doxorubicin cardiotoxicity, one patient had pulmonary metastatic relapse. The observed 3- and 5-year EFS was 87.4% (CI 72.4-100%) and 87.4% (CI 72.4-100%), progression free survival (PFS) was 92.9% (CI 80.3-100%) and 92.9% (CI 80.3-100%), overall survival was 94.1% (CI 83.6-100) and 80.7% (CI 58.3-100), respectively. Comparison to the historical control showed statistically significant better PFS for mifamurtide patients (Landmark analysis; p = 0.044). Risk of progression was 5-times lower for the mifamurtide group (Cox model; HR 0.21, p = 0.136). Only subtle differences in lymphocyte counts were observed across treatment. CONCLUSION: the PFS benefit of mifamurtide is reported herein. The addition of mifamurtide could be considered as a best treatment option for localized osteosarcoma.

Serial Xenotransplantation in NSG Mice Promotes a Hybrid Epithelial/Mesenchymal Gene Expression Signature and Stemness in Rhabdomyosarcoma Cells.

Serial xenotransplantation of sorted cancer cells in immunodeficient mice remains the most complex test of cancer stem cell (CSC) phenotype. However, we have demonstrated in various sarcomas that putative CSC surface markers fail to identify CSCs, thereby impeding the isolation of CSCs for subsequent analyses. Here, we utilized serial xenotransplantation of unsorted rhabdomyosarcoma cells in NOD/SCID gamma (NSG) mice as a proof-of-principle platform to investigate the molecular signature of CSCs. Indeed, serial xenotransplantation steadily enriched for rhabdomyosarcoma stem-like cells characterized by enhanced aldehyde dehydrogenase activity and increased colony and sphere formation capacity in vitro. Although the expression of core pluripotency factors (SOX2, OCT4, NANOG) and common CSC markers (CD133, ABCG2, nestin) was maintained over the passages in mice, gene expression profiling revealed gradual changes in several stemness regulators and genes linked with undifferentiated myogenic precursors, e.g., SOX4, PAX3, MIR145, and CDH15. Moreover, we identified the induction of a hybrid epithelial/mesenchymal gene expression signature that was associated with the increase in CSC number. In total, 60 genes related to epithelial or mesenchymal traits were significantly altered upon serial xenotransplantation. In silico survival analysis based on the identified potential stemness-associated genes demonstrated that serial xenotransplantation of unsorted rhabdomyosarcoma cells in NSG mice might be a useful tool for the unbiased enrichment of CSCs and the identification of novel CSC-specific targets. Using this approach, we provide evidence for a recently proposed link between the hybrid epithelial/mesenchymal phenotype and cancer stemness.