Biochemical and Cellular Characterization of New Radio-Resistant Cell Lines Reveals a Role of Natural Flavonoids to Bypass Senescence

Cancer is one of the main causes of death worldwide, and, among the most frequent cancer types, osteosarcoma accounts for 56% of bone neoplasms observed in children and colorectal cancer for 10.2% of tumors diagnosed in the adult population. A common and frequent hurdle in cancer treatment is the emergence of resistance to chemo- and radiotherapy whose biological causes are largely unknown. In the present work, human osteosarcoma (SAOS) and colorectal adenocarcinoma (HT29) cell lines were γ-irradiated at doses mimicking the sub-lethal irradiation in clinical settings to obtain two radio-resistant cellular sub-populations named SAOS400 and HT500, respectively. Since “therapy-induced senescence” (TIS) is often associated with tumor response to radiotherapy in cancer cells, we measured specific cellular and biochemical markers of senescence in SAOS400 and HT500 cells. In detail, both cell lines were characterized by a higher level of expression of cyclin-dependent kinase inhibitors p16INK4 and p21CIP1 and increased positivity to SAβ-gal (senescence-associated β-galactosidase) with respect to parental cells. Moreover, the intracellular levels of reactive oxygen species in the resistant cells were significantly lower compared to the parental counterparts. Subsequently, we demonstrated that senolytic agents were able to sensitize SAOS400 and HT500 to cell death induced by γ-irradiation. Employing two natural flavonoids, fisetin and quercetin, and a BH3-mimetic, ABT-263/navitoclax, we observed that their association with γ-irradiation significantly reduced the expression of p16INK4, p21CIP1 and synergistically (combination index < 1) increased cell death compared to radiation mono-alone treatments. The present results reinforce the potential role of senolytics as adjuvant agents in cancer therapy.

Prospecção científica e tecnológica de potenciais imunoterapias incluindo vacinas anticâncer com enfoque em osteossarcoma

Osteossarcoma (OS) é um tumor ósseo maligno, cujo sua terapêutica é realizada através da remoção cirúrgica associado a quimioterapia combinada, a qual incluem a utilização de medicamentos. Com intuito de verificar a importância da imunoterapia no cunho científico, foram realizadas pesquisas a fim de se confirmar a relevância que o estudo apresenta como inovação tecnológica. Para isso as bibliotecas de artigos do PubMed e Science Direct foram acessadas para a realização de uma prospecção científica, um quantitativo de 278 e 40 com as associações dos descritores “Bone Neoplasms AND cancer vaccines” e “Osteosarcoma AND cancer vaccines" foram obtidos, respectivamente. Em relação a prospecção tecnológica utilizou-se os mesmos descritores e as buscas foram realizadas no Google Patents selecionando os escritórios WO e BR quando necessário, com o uso dos descritores “bone neoplasms”, “osteosarcoma” e “cancer vaccines”, apresentando um total de 62.610, 20410 e 34337 patentes, respectivamente para o escritório WO. Já no escritório BR foram encontrados 687, 613 e 585 respectivamente. Dentre esses achados foi possível perceber que a busca por imunoterapias para OS é crescente, no entanto, o uso de vacinas para OS foi mais presente na prospecção científica do que na tecnológica, isso pode ser atribuído a tecnologia das vacinas terapêuticas serem recentes. A partir desses resultados pode-se concluir que o estudo forneceu dados de prospecção científico-tecnológico, que pode auxiliar no direcionamento de pesquisas, ressaltando a relevância da análise prospectiva tecnológica, como oportunidade de investir na propriedade intelectual como solução das necessidades sociais e econômicas.

Solitary Plasmacytoma of The Sternal Stalk: A Case Report and Literature Review

Background: It has been reported that sternal neoplasms are a rare disease, accounting for about 1% of primary bone neoplasms, of which about 60% are malignancy, mostly occurring in the manubrium sternum. Case presentation: We reviewed a 77-year-old man with a solitary plasmacytoma of the sternal stalk presenting with pain in the anterior chest wall by examining a preoperative diagnosis of sternal manubrium malignant bone tumor. We performed extensive sternal manubrium tumor resection + bilateral partial costal cartilage resection + bilateral clavicular head resection + cervical lymph node dissection + thoracic reconstruction, and the postoperative recovery was perfect. Conclusion: We report a rare case of solitary plasmacytoma of the manubrium sternum successfully treated by extensive radical surgery for the manubrium tumor. Although rare, the disease should be identified, examined, and treated early to avoid serious complications.

Solitary Plasmacytoma of the Sternal Stalk: A Case Report and Literature Review.

Background: It has been reported that sternal neoplasms are a rare disease, accounting for about 1% of primary bone neoplasms, of which about 60% are malignancy, mostly occurring in the manubrium sternum.Case presentation: We reviewed a 77-year-old man with a solitary plasmacytoma of the sternal stalk presenting with pain in the anterior chest wall by examining a preoperative diagnosis of sternal manubrium malignant bone tumor. We performed extensive sternal manubrium tumor resection + bilateral partial costal cartilage resection + bilateral clavicular head resection + cervical lymph node dissection + thoracic reconstruction, and the postoperative recovery was perfect.Conclusion: We report a rare case of solitary plasmacytoma of the manubrium sternum successfully treated by extensive radical surgery for the manubrium tumor. Although rare, the disease should be identified, examined, and treated early to avoid serious complications.

Intraosseous schwannoma of inferior pubic ramus – A rare benign osseous neoplasm

Intraosseous schwannomas are a very rare subgroup of schwannomas. They account for <1% of all primary bone neoplasms. The mandible is the most commonly involved bone followed by the sacrum. We herein report a case of intraosseous schwannoma involving the inferior ramus and body of the pubic bone in a 43-year-old male who presented with a swelling in the right groin. On radiographs and computed tomography, it appeared as a mildly expansile, lytic, multiloculated lesion in the right pubic bone with a narrow zone of transition, sclerotic margins with areas of cortical breach, and a significant intra and extrapelvic soft-tissue component which did not show any areas of calcification. On magnetic resonance imaging, it appeared isointense to skeletal muscle on T1-weighted images, mildly hyperintense on T2-weighted images, and markedly hyperintense on short-tau inversion recovery images. The differentials considered on imaging were chondroid neoplasms such as chondromyxoid fibroma or low-grade chondrosarcoma, giant cell tumor, and plasmacytoma. However, biopsy and histopathology revealed an intraosseous schwannoma. The patient was operated and the lesion was excised in toto. Intraoperatively, the origin of the lesion was identified as the right obturator nerve. Post-operative, the patient recovery was uneventful and he was discharged.

Clinical and prognostic significance of the soluble form of the VISTA immunity control point in patients with primary bone tumors

The data of a comparative enzyme-linked immunosorbent assay of the content of the soluble form of the immunity checkpoint VISTA in the blood serum of 30 healthy donors (control group), 79 patients with primary malignant (osteosarcoma - 30, chondrosarcoma - 31, chordoma - 14) and 14 borderline (giant cell tumor) bone neoplasms are presented. In the general group of patients with malignant neoplasms of bones, the median sVISTA content in blood serum is statistically significant lower than in the control (p = 0.040). In patients with bone tumors and healthy donors over 18 years of age, there was a decrease with age in serum sVISTA levels. There were no significant differences in sVISTA concentration between patients with osteosarcoma, chondrosarcoma and healthy donors. Only in patients with chordoma were sVISTA levels statistically significant lower than in controls (p = 0.013). In the groups of patients with chondrosarcoma and osteosarcoma of the bone, there were no significant associations between the serum sVISTA content and the main clinical and morphological characteristics of the disease. In patients with osteosarcoma, no relationship was found between sVISTA levels and overall survival rates, while in patients with bone chondrosarcoma, there was a tendency towards a favorable prognosis with a high content of the marker in the blood serum.

Giant Cell Tumor of the Femoral Head: A Case Report and Review of the Literature

Introduction: Giant cell tumors (GCTs) of the bone are uncommon primary bone neoplasms that occur mainly in the epiphysis of long bones. GCT of the femoral head is rarely encountered. Case Report: We report a rare case of GCT of the femoral head in a 20-year-old female. The patient presented with pathological fracture. The patient underwent total hip arthroplasty (THA). The aim of this paper is to present a case study with pathological fracture of the femoral head and to report the results of a literature review. Conclusion: The treatment of choice for GCT of the proximal femur is a hip arthroplasty with either a standard THA for small confined tumors or endoprosthesis insertion for more extensive tumors. Joint preserving procedures have a high revision rate (47.06%). Denosumab has been tried as a neoadjuvant treatment with some success in certain cases. Keywords: Giant cell tumor, pathological fracture, arthroplasty.

Analysis of the Density Characteristics of Giant Cell Bone Tumors Treated with Denosumab According to CT Findings

Background: Giant cell tumor of bone (GCTB) is a relatively common benign bone tumor, accounting for 4–9.5 % of all primary bone neoplasms. Localization of GCTB is one of the most important differential diagnostic criteria, since the tumor affects certain parts of the skeleton. Until now, surgical treatment was considered the method of choice in the treatment of GCTB. However, in recent years, denosumab, a genetically engineered drug, has been widely used to treat this tumor. Denosumab treatment of GCTB prevents further tumor progression and reduces tumor size. Histological examination of the surgical specimen is undoubtedly the most objective method for assessing the effectiveness of the treatment. However, it is sometimes necessary to get information regarding the effectiveness of conservative therapy.Purpose: To analyze the density characteristics of denosumab-treated GCTB using CT densitometry.Material and methods: The study included 15 patients aged 28–59 years with histologically verified giantcell tumor, who received denosumab treatment followed by surgery. Tumor structure was assessed before starting denosumab therapy, after 3 and 6 courses of denosumab therapy.Results: Changes in the density parameters (the mean tumor density, standard deviation of density, increase in the median tumor density and standard deviation of density, index of the relative density of the tumor) measured by CT images were analyzed. These changes were statistically significant in GCTB patients before initiating therapy with denosumab, and after 3 and 6 courses of denosumab therapy.Conclusion: Thus, CT densitometry is a useful tool for assessing the density characteristics of the tumor in GCS patients treated denosumab.

Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations

The diagnosis of benign and malignant soft tissue and bone neoplasms is a challenging area of surgical pathology, due to the large number, rarity, and histologic diversity of tumor types. In recent years, diagnosis and classification has been aided substantially by our growing understanding of recurrent molecular alterations in these neoplasms. Concurrently, the role of diagnostic immunohistochemistry has also expanded, with the development of numerous biomarkers based on underlying molecular events. Such biomarkers allow us to infer the presence of these events and can therefore substitute for other ancillary molecular genetic techniques (e.g., fluorescence in situ hybridization, polymerase chain reaction, and next-generation sequencing). In this review, we discuss a range of biomarkers currently available for these neoplasms, highlighting the accuracy, staining characteristics, and interpretation pitfalls of each antibody. These include immunohistochemical antibodies that represent reliable surrogates for the detection of gene fusions (e.g., STAT6, CAMTA1, FOSB, DDIT3) and more recently described breakpoint-specific antibodies (e.g., SS18-SSX, PAX3/7-FOXO1). Additionally, discussed are markers that correlate with the presence of gene amplifications (e.g., MDM2, CDK4), deletions (e.g., SMARCB1, SMARCA4), single nucleotide variants (e.g., G34W, K36M), aberrant methylation (H3K27me3), and increased expression as discovered through gene expression profiling (e.g., MUC4, DOG1, ETV4, NKX2.2, NKX3.1).