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BACKGROUND: Previous studies explored the prognostic value of pretreatment platelet count, fibrinogen, and d-dimer level in patients with several types of cancer, however, a comprehensive conclusion has not been reached in osteosarcoma patients. METHODS: PubMed, Web of Science, Embase, and CNKI databases were systematically searched for eligible studies up to May 09, 2023, and pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated to assess the prognostic impact of these indicators in osteosarcoma patients. RESULTS: Twelve studies from China consisting of 1682 patients were finally included. Our findings revealed that an elevated level of pretreatment platelet or d-dimer was associated with a worse outcome of overall survival (platelet: HRâ =â 1.63, 95% CI: 1.18-2.26, Pâ =â .003; d-dimer: HRâ =â 2.29, 95% CI: 1.58-3.31, Pâ <â .001). CONCLUSION: Based on current evidence, pretreatment platelet count and d-dimer level could be good prognostic biomarkers for Chinese osteosarcoma patients. However, future validation is also needed.
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Neoplasias Óseas , Productos de Degradación de Fibrina-Fibrinógeno , Fibrinógeno , Osteosarcoma , Osteosarcoma/sangre , Osteosarcoma/mortalidad , Humanos , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Recuento de Plaquetas , Fibrinógeno/análisis , Fibrinógeno/metabolismo , Pronóstico , Neoplasias Óseas/sangre , Neoplasias Óseas/mortalidad , Biomarcadores de Tumor/sangreRESUMEN
OBJECTIVE: To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy. METHODS: After retrospectively screening the data of 742 patients between January 2007 and July 2020, 50 patients aged 13 to 39 years with Enneking stage II disease were included in the study. Serum lipid levels, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein-α [Lp(a)], and apolipoprotein A1, B, and E (ApoA1, ApoB, and ApoE), and clinicopathological characteristics were collected before and after neoadjuvant chemotherapy. RESULTS: The mean levels of TC, TG, and ApoB were significantly increased following neoadjuvant chemotherapy (16%, 38%, and 20%, respectively, vs. pretreatment values; P<0.01). The mean levels of LDL-C and ApoE were also 19% and 16% higher, respectively (P<0.05). No correlation was found between the pretreatment lipid profile and the histologic response to chemotherapy. An increase in Lp(a) was strongly correlated with the Ki-67 index (R=0.31, P=0.023). Moreover, a trend toward longer disease-free survival (DFS) was observed in patients with decreased TG and increased LDL-C following chemotherapy, although this difference was not statistically significant (P=0.23 and P=0.24, respectively). CONCLUSION: Significant elevations in serum lipids were observed after neoadjuvant chemotherapy in patients with localized osteosarcoma. There was no prognostic significance of pretreatment serum lipid levels on histologic response to neoadjuvant chemotherapy. The scale of increase in serum Lp(a) might have a potential prognostic role in osteosarcoma. Patients with increased LDL-C or reduced TG after chemotherapy seem to exhibit a trend toward favorable DFS.
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Articulación de la Rodilla , Lípidos , Lipoproteínas , Terapia Neoadyuvante , Osteosarcoma , Humanos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/sangre , Osteosarcoma/patología , Masculino , Femenino , Estudios Retrospectivos , Adolescente , Adulto , Lípidos/sangre , Adulto Joven , Articulación de la Rodilla/patología , Lipoproteínas/sangre , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/sangreRESUMEN
BACKGROUND: Previous studies have shown that neutrophil-to-lymphocyte (NLR) ratio at diagnosis and early lymphocytes recovery on doxorubicin-based chemotherapy, may impact the outcome in patients with osteosarcoma (OST). This study aimed to evaluate the prognostic value of hemogram parameters in patients with OST treated with high-dose methotrexate and etoposide/ifosfamide (M-EI) chemotherapy. MATERIALS AND METHODS: We retrospectively analyzed the prognostic value of various hemogram parameters at diagnosis and during therapy in a large consecutive cohort of patients with OST included in the French OS2006 trial and treated with M-EI chemotherapy. RESULTS: A total of 164 patients were analyzed. The median age was 14.7 years (interquartile range [IQR]: 11.7-17). Median follow-up was 5.6 years (IQR: 3.3-7.7 years). Three-year event-free survival (EFS) and overall survival (OS) were 71.5% (95% confidence interval [CI]: 64%-78%) and 86.4% (95% CI: 80%-91%), respectively. In univariate analysis, blood count parameters at diagnosis and early lymphocyte recovery at Day 14 were not found prognostic of survival outcomes. By contrast, an increase of NLR ratio at Day 1 of the first EI chemotherapy (NLR-W4) was associated with reduced OS in univariate (p = .0044) and multivariate analysis (hazards ratio [HR] = 1.3, 95% CI: 1.1-1.5; p = .002), although not with EFS. After adjustment on histological response and metastatic status, an increase of the ratio NLR-W4 of 1 was associated with an increased risk of death of 30%. CONCLUSIONS: We identified NLR-W4 as a potential early biomarker for survival in patients with OST treated with M-EI chemotherapy. Further studies are required to confirm the prognostic value of NLR and better identify immune mechanisms involved in disease surveillance.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Óseas , Etopósido , Metotrexato , Osteosarcoma , Humanos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/mortalidad , Osteosarcoma/patología , Osteosarcoma/sangre , Femenino , Masculino , Adolescente , Estudios Retrospectivos , Niño , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Neoplasias Óseas/sangre , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Tasa de Supervivencia , Neutrófilos/patología , Estudios de Seguimiento , Linfocitos/patología , Ifosfamida/administración & dosificación , Francia/epidemiologíaRESUMEN
BACKGROUND: Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification. PATIENTS AND METHODS: Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients' individual risk of event. RESULTS: ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status [diagCPA hazard ratio (HR) = 3.5, P = 0.002 and 3.51, P = 0.012, for progression-free survival (PFS) and overall survival (OS)]. At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR = 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression. CONCLUSIONS: The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway.
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Biomarcadores de Tumor , Neoplasias Óseas , ADN Tumoral Circulante , Osteosarcoma , Humanos , Osteosarcoma/genética , Osteosarcoma/sangre , Osteosarcoma/patología , Osteosarcoma/cirugía , Osteosarcoma/mortalidad , Osteosarcoma/diagnóstico , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Masculino , Femenino , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/sangre , Neoplasias Óseas/cirugía , Neoplasias Óseas/mortalidad , Adulto , Adolescente , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Estudios Prospectivos , Adulto Joven , Niño , Variaciones en el Número de Copia de ADN , Clasificación del Tumor , Persona de Mediana Edad , Secuenciación Completa del Genoma , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: This retrospective study investigated biomarkers that can reflect coagulation, inflammation, and lipid abnormalities: platelet-to-albumin ratio (PAR), platelet-to lymphocyte ratio (PLR), low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LDL-C/HDL-C), apolipoprotein B-to-apolipoprotein ratio (ApoB/ApoA1) whether may be viable prognostic predictors in children and adolescents with osteosarcoma. METHODS: The retrospective review has enrolled a total of 118 children and adolescent patients diagnosed with osteosarcoma. Analyses with a receiver operating characteristic (ROC) curve were performed to evaluate the optimal cut-off values and to compare the area under curves (AUC). Kaplan-Meier curves were used to visualize survival outcome and a Cox proportional hazards model were used to confirm independent prognostic factors. RESULTS: Osteosarcoma patients in high PAR group (> 4.41) and high ApoB/ApoA1 group (> 0.82) experienced significantly shorter overall survival compared with those in low PAR group (≤ 4.41) and low ApoB/ApoA1 group (≤ 0.82). In univariate and multivariable analyses, preoperative PAR and ApoB/ApoA1 were identified as independent prognostic factors for OS in children and adolescents with osteosarcoma. CONCLUSION: Preoperative PAR and ApoB/ApoA1 can be used as promising predictors in children and adolescents with osteosarcoma to help clinicians recognize patients with an increased risk of poor prognosis.
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Apolipoproteína A-I/sangre , Apolipoproteína B-100/sangre , Neoplasias Óseas/sangre , Osteosarcoma/sangre , Recuento de Plaquetas , Albúmina Sérica/análisis , Adolescente , Área Bajo la Curva , Biomarcadores/sangre , Niño , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Humanos , Recuento de Linfocitos , Masculino , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Pronóstico , Curva ROC , Estudios RetrospectivosRESUMEN
BACKGROUND: At present, no predictive factor has been validated for the early efficacy of neoadjuvant chemotherapy (NACT) in osteosarcoma. The purpose of this study was to investigate the significance of the neutrophil-to-lymphocyte ratio (NLR) in predicting the response to NACT in extremity osteosarcoma. METHODS: Pathological complete response (pCR) was used to assess the efficacy of NACT. Receiver operating characteristic (ROC) curves and the Youden index (sensitivity + specificity-1) were used to determine the optimal cut-off values of the NLR. Univariate and multivariate analyses using logistic regression models were conducted to confirm the independent factors affecting the efficacy of NACT. RESULTS: The optimal NLR cut-off value was 2.36 (sensitivity, 80.0%; specificity, 71.3%). Univariate analysis revealed that patients with a smaller tumour volume, lower stage, lower NLR and lower PLR were more likely to achieve pCR. Multivariate analyses confirmed that the NLR before treatment was an independent risk factor for pCR. Compared to patients with a high NLR, those with a low NLR showed a more than 2-fold higher likelihood of achieving pCR (OR 2.82, 95% CI 1.36-5.17, p = 0.02). CONCLUSION: The NLR is a novel and effective predictive factor for the response to NACT in extremity osteosarcoma patients. Patients with a higher NLR showed a lower percentage of pCR after NACT.
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Neoplasias Óseas/sangre , Quimioterapia Adyuvante/mortalidad , Recuento de Leucocitos/estadística & datos numéricos , Terapia Neoadyuvante/mortalidad , Osteosarcoma/sangre , Adolescente , Biomarcadores de Tumor/sangre , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Extremidades , Femenino , Humanos , Modelos Logísticos , Linfocitos , Masculino , Neutrófilos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/mortalidad , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Osteosarcoma (OS) is solid tumors with high malignancy and incidence starting in the bones. OS pathogenesis has been proved to be closely associated with immune imbalance, and follicular helper T cells (Tfh) significantly affect host humoral immune homeostasis. However, there are few reports on the effect of Tfh cell activation on the prognosis of OS patients. Hence, this investigation on the changes in the proportion of peripheral blood Tfh cells in OS patients, and the relationship between their activity level and OS prognosis. We collected peripheral blood from patients with OS, benign bone tumor (BT group) and healthy subjects (Healthy group), respectively. The number of CD4+CXCR5+ Tfh cell in peripheral blood was measured by flow cytometry and correlation analysis between its activity and OS clinicopathological characteristics was carried out. The data showed that in comparison with the BT and Healthy groups, higher proportion and activation level of peripheral blood CD4+CXCR5+ Tfh cells in CD4+ T cells were found in the OS group. In OS patients, increases of the proportion and activity level of Tfh cells were associated with poorly differentiated OS and tumor metastasis. Additionally, Kaplan-Meier and Cox regression analysis showed a longer overall survival in patients with low proportion of peripheral blood CD4+CXCR5+ Tfh cells in CD4+ T cells, and their activation level may be a prognostic factor in OS patients. In conclusion, peripheral blood CD4+CXCR5+ Tfh cell activation in OS patients was associated with a poor prognosis. This study provided ideas for improving the clinical treatment of OS patients.
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Neoplasias Óseas , Osteosarcoma , Células T Auxiliares Foliculares , Adolescente , Adulto , Neoplasias Óseas/sangre , Neoplasias Óseas/inmunología , Neoplasias Óseas/mortalidad , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Masculino , Osteosarcoma/sangre , Osteosarcoma/inmunología , Osteosarcoma/mortalidad , Tasa de Supervivencia , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismoRESUMEN
BACKGROUND/AIM: Systemic inflammation responses have been associated with cancer development, progression and metastasis. Little is known about the risk of metastasis based on inflammatory-based scores in patients with osteosarcoma. PATIENTS AND METHODS: A total of 65 osteosarcoma patients without metastasis at presentation were enrolled in this retrospective study. All had been diagnosed histologically, and their laboratory data at the first visit were collected from medical records. The inflammation-based scores, tumor size, location, staging, pathological fracture, treatment methods, follow-up periods, and metastasis-free duration were evaluated. RESULTS: A multivariate Cox regression analysis revealed that a high platelet-lymphocyte ratio (PLR) >116 [hazard ratio (HR)=3.8, 95% confidence interval =1.5-9.3; p<0.01], and neutrophil count (NC) ≤4,030/µl (HR=4.5, 95%CI=1.7-12.3; p<0.01), were independent risk factors significantly associated with metastasis of osteosarcoma patients. CONCLUSION: The combination of a high PLR >116 and NC ≤4,030/µl before treatment was a useful inflammatory-based prognostic indicator for metastasis in patients with osteosarcoma.
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Recuento de Células Sanguíneas , Neoplasias Óseas/diagnóstico , Osteosarcoma/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Plaquetas/patología , Neoplasias Óseas/sangre , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Niño , Femenino , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/patología , Japón , Linfocitos/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/diagnóstico , Neutrófilos/patología , Osteosarcoma/sangre , Osteosarcoma/patología , Osteosarcoma/terapia , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: In recent years, numerous investigations have been conducted to determine the clinical significance and critical functions of vascular endothelial growth factor (VEGF) in various malignant cancers. The purpose of this meta-analysis was to comprehensively evaluate the prognostic and clinicopathological value of VEGF in patients with osteosarcoma. METHODS: We performed a systematic literature retrieval of available databases. Odds ratios (ORs) or standard mean difference (SMD) for clinicopathological parameters, hazard ratios (HRs) for overall survival and disease-free survival were calculated to assess the correlation between VEGF expression and prognosis in patients with osteosarcoma. RESULTS: A total of 22 studies with 1144 patients were included in our study. Pooled analyses showed that VEGF overexpression predicted worse overall survival (HR, 2.42; 95% CI, 1.87-3.11, p < 0.001) and disease-free survival (HR, 2.604; 95% CI, 1.698-3.995, p < 0.001), respectively. Furthermore, investigation regarding osteosarcoma clinicopathologic characteristics suggested that high VEGF expression was significantly associated with metastasis (OR, 4.39; 95% CI, 2.77-6.95; p < 0.001), clinical stage (OR, 0.73; 95% CI, 0.62-0.87; p < 0.001), and microvessel density (SMD, 3.33, 95% CI,1.57-5.10, p < 0.001), but not associated with tumor location, gender, age, local recurrence, and chemotherapy response. CONCLUSION: Our meta-analysis findings suggest that elevated VEGF expression may be a predictive biomarker for poor prognosis and adverse clinicopathological characteristics in patients with osteosarcoma.
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Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/mortalidad , Factores de Crecimiento Endotelial/análisis , Osteosarcoma/mortalidad , Factor A de Crecimiento Endotelial Vascular/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/metabolismo , Humanos , Osteosarcoma/sangre , Osteosarcoma/metabolismo , Pronóstico , Factores de Crecimiento Endotelial VascularRESUMEN
Osteosarcoma (OS) is a fast-progressing bone tumor with high incidence in children and adolescents. The main diagnostic methods for OS are imaging exams and biopsies. In spite of the several resources available for detecting the disease, establishing an early diagnosis is still difficult, resulting in worse prognosis and lower survival rates for patients with OS. The identification of novel biomarkers would be helpful, and recently, circulating microRNAs (miRNAs) have been pointed to as possible non-invasive biomarkers. In order to assess the effectiveness of miRNA research, we performed a systematic review to assess the potential role of circulating miRNAs as biomarkers for OS diagnosis. We performed a search in various databases-PubMed, LILACS (Literatura Latino-americana e do Caribe em Ciências da Saúde), VHL (Virtual Health Library), Elsevier, Web of Science, Gale Academic One File-using the terms: "Circulating microRNAs" OR "plasma microRNAs" OR "serum microRNAs" OR "blood microRNAs" OR "cell-free microRNAs" OR "exosome microRNAs" OR "extracellular vesicles microRNAs" OR "liquid biopsy" AND "osteosarcoma" AND "diagnostic". We found 35 eligible studies that were independently identified and had had their quality assessed according to Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) guidelines. Despite the useful number of publications on this subject and the fact that several microRNAs showed excellent diagnostic performance for OS, the lack of consistency in results suggests that additional prospective studies are needed to confirm the role of circulating miRNAs as non-invasive biomarkers in OS.
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Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , MicroARN Circulante/genética , Osteosarcoma/sangre , Osteosarcoma/genética , MicroARN Circulante/metabolismo , Humanos , Osteosarcoma/diagnóstico , Sesgo de Publicación , RiesgoRESUMEN
PURPOSE: To detect the expression level of hsa_circ_0005721 in osteosarcoma specimen and plasma of osteosarcoma patients, and to analyze the clinical significance of hsa_circ_0005721 as a diagnostic marker for osteosarcoma. METHODS: Expression levels of hsa_circ_0005721 in osteosarcoma specimen and osteosarcoma cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between hsa_circ_0005721 expression difference and overall survival in osteosarcoma was analyzed by Kaplan-Meier method. Expression level of hsa_circ_0005721 was stably downregulated in U-2OS and HOS cells by shRNA transfection. Proliferative potential in osteosarcoma cells regulated by hsa_circ_0005721 was assessed by colony formation and 5-Ethynyl-2'- deoxyuridine (EdU) assay. Differentially expressed hsa_circ_0005721 in the plasma of healthy controls, benign bone tumor patients and osteosarcoma patients was determined by qRT-PCR. The diagnostic capacity of hsa_circ_0005721 in osteosarcoma was examined by receiver operating characteristic (ROC) curves. RESULTS: hsa_circ_0005721 was upregulated in osteosarcoma specimen and osteosarcoma cell lines. High level of hsa_circ_0005721 predicted poor prognosis in osteosarcoma patients. In vitro experiments showed that knockdown of hsa_circ_0005721 suppressed proliferative ability in osteosarcoma cells. Compared with that in healthy controls and benign bone tumor patients, plasma level of hsa_circ_0005721 was higher in osteosarcoma patients. ROC curves demonstrated the diagnostic potential of hsa_circ_0005721 in osteosarcoma. CONCLUSIONS: hsa_circ_0005721 is upregulated in osteosarcoma samples, which acts as an oncogene responsible for aggravating the progression. hsa_circ_0005721 can be a promising diagnostic marker for osteosarcoma.
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Biomarcadores de Tumor/análisis , Neoplasias Óseas/sangre , Neoplasias Óseas/química , Osteosarcoma/sangre , Osteosarcoma/química , ARN Circular/análisis , Biomarcadores de Tumor/genética , Neoplasias Óseas/diagnóstico , Humanos , Osteosarcoma/diagnóstico , ARN Circular/genética , Células Tumorales CultivadasRESUMEN
ABSTRACT: MicroRNA (miR)-26a-5p is an oncogene significantly associated with osteosarcoma. We try to evaluate expression of circulating miR-26a-5p in osteosarcoma patients and evaluate its significance.A total of 243 consecutive osteosarcoma patients and 96 healthy participates were enrolled. Circulating miR-26a-5p levels were evaluated by using real-time quantitative reverse transcription polymerase chain reactions (RT-PCR). The association between circulating miR-26a-5p level and survival outcomes was evaluated by univariate and multivariate analysis.Circulating miR-26a-5p levels in osteosarcoma patients was significantly higher than that of healthy volunteers (Pâ<â.05). Upregulated miR-26a-5p was significantly related to advanced cancer and metastasis (both Pâ<â.05). Moreover, patients with a high serum miR-26a-5p had a poorer overall survival than those with a low serum miR-26a-5p levels (Pâ<â.05). Circulating miR-26a-5p level also been showed as independent risk factor for osteosarcoma in multivariate analysis (hazard ratio [HR], 0.38; 95% confidence interval [CI]: 0.11-0.98; Pâ<â.01).Circulating miR-26a-5p was significantly upregulated in osteosarcoma patients and remarkably associated with poor prognosis, indicating that circulating miR-26a-5p might serve as a useful diagnostic and prognostic biomarker for osteosarcoma.
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Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/mortalidad , MicroARN Circulante/metabolismo , MicroARNs/metabolismo , Recurrencia Local de Neoplasia/epidemiología , Osteosarcoma/mortalidad , Adulto , Biomarcadores de Tumor/sangre , Neoplasias Óseas/sangre , Neoplasias Óseas/genética , Neoplasias Óseas/cirugía , MicroARN Circulante/sangre , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Biopsia Líquida , Masculino , MicroARNs/sangre , Recurrencia Local de Neoplasia/genética , Osteosarcoma/sangre , Osteosarcoma/genética , Osteosarcoma/cirugía , Estudios Retrospectivos , Medición de Riesgo/métodos , Regulación hacia Arriba , Adulto JovenRESUMEN
We report on a retrospective model-based assessment of the predictive value of translating antitumor drug activity from in vivo experiments to a phase I clinical study in cancer patients treated with the MDM2 inhibitor, HDM201. Tumor growth inhibition models were developed describing the longitudinal tumor size data in human-derived osteosarcoma xenograft rats and in 96 solid tumor patients under different HDM201 treatment schedules. The model structure describing both datasets captures the delayed drug effect on tumor growth via a series of signal transduction compartments, including a resistance component. The models assumed a drug-killing effect on both sensitive and resistant cells and parameterized to estimate two tumor static plasma drug concentrations for sensitive (TSCS) and resistant cells (TSCR). No change of TSCS and TSCR with schedule was observed, implying that antitumor activity for HDM201 is independent of treatment schedule. Preclinical and clinical model-derived TSCR were comparable (48 ng/mL vs. 74 ng/mL) and demonstrating TSCR as a translatable metric for antitumor activity in clinic. Schedule independency was further substantiated from modeling of clinical serum growth differentiation factor-15 (GDF-15) as a downstream marker of p53 pathway activation. Equivalent cumulative induction of GDF-15 was achieved across schedules when normalized to an equivalent total dose. These findings allow for evaluation of optimal dosing schedules by maximizing the total dose per treatment cycle while mitigating safety risk with periods of drug holiday. This approach helped guide a phase I dose escalation study in the selection of an optimal dose and schedule for HDM201.
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Imidazoles/administración & dosificación , Modelos Biológicos , Osteosarcoma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Administración Oral , Adolescente , Adulto , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Masculino , Persona de Mediana Edad , Osteosarcoma/sangre , Osteosarcoma/genética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Pirroles/efectos adversos , Pirroles/farmacocinética , Ratas , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
BACKGROUND: In recent years, emerging studies have demonstrated critical functions and potential clinical applications of long non-coding RNA (lncRNA) in osteosarcoma. To further validate the prognostic value of multiple lncRNAs, we have conducted this updated meta-analysis. METHODS: Literature retrieval was conducted by searching PubMed, Web of Science and the Cochrane Library (last update by October 2, 2019). A meta-analysis was performed to explore association between lncRNAs expression and overall survival (OS) of osteosarcoma patients. Relationships between lncRNAs expression and other clinicopathological features were also analyzed respectively. RESULTS: Overall, 4351 patients from 62 studies were included in this meta-analysis and 25 lncRNAs were identified. Pooled analyses showed that high expression of 14 lncRNAs connoted worse OS, while two lncRNAs were associated with positive outcome. Further, analysis toward osteosarcoma clinicopathologic features demonstrated that overexpression of TUG1 and XIST indicated poor clinical parameters of patients. CONCLUSIONS: This meta-analysis has elucidated the prognostic potential of 16 lncRNAs in human osteosarcoma. Evidently, desperate expression and functional targets of these lncRNAs offer new approaches for prognosis and therapy of osteosarcoma.
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Neoplasias Óseas/sangre , Osteosarcoma/sangre , ARN Largo no Codificante/sangre , ARN Neoplásico/sangre , Biomarcadores de Tumor , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Osteosarcoma/genética , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Sesgo de PublicaciónRESUMEN
Gastrointestinal (GI) toxicosis is a common side effect of cytotoxic chemotherapy treatment in humans and dogs. Measurement of cytokeratin 18 (CK18), an intracellular structural protein released during epithelial apoptosis, and Alpha1-Antitrypsin (A1AT) in faeces provides a mechanism for evaluating damage to the intestinal mucosa secondary to cytotoxic chemotherapy. Our goal was to evaluate the clinical utility of plasma CK18 and faecal A1-AT levels as non-invasive biomarkers of cytotoxic chemotherapy induced GI toxicity. We conducted a prospective cohort study in dogs (N = 10) with osteosarcoma undergoing amputation followed by carboplatin chemotherapy. We hypothesized that plasma CK18 and faecal A1-AT levels would increase following carboplatin administration due to drug-induced GI epithelial damage/apoptosis, and that plasma CK18 and faecal A1-AT levels would correlate with severity of GI toxicity. Mean baseline plasma CK18 concentration was variable amongst patients; however, CK18 concentration prior to carboplatin chemotherapy treatment was not significantly different from CK18 levels after treatment. There was significant intra and inter-patient variability in mean faecal A1-AT levels at baseline. Mean A1-AT concentration did not change significantly from day 0 to day 21. Gastrointestinal toxicity was minimal; therefore, we were unable to determine the association of plasma CK18 and faecal A1-AT concentrations with development of GI toxicosis. In this study population, plasma CK18 and faecal A1-AT concentration were not clinically useful biomarkers for the detection of GI toxicosis secondary to carboplatin administration. Further prospective evaluation of CK18 and A1-AT as biomarkers of drug-induced GI toxicity is warranted in a larger cohort of dogs receiving cytotoxic chemotherapy. AVMA clinical trial registration number: AAHSD004827.
Asunto(s)
Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Enfermedades de los Perros/metabolismo , Queratina-18/sangre , Osteosarcoma/metabolismo , alfa 1-Antitripsina/análisis , Animales , Enfermedades de los Perros/sangre , Enfermedades de los Perros/tratamiento farmacológico , Perros , Heces/química , Osteosarcoma/sangre , Osteosarcoma/tratamiento farmacológicoRESUMEN
Results of ELISA investigation of the pretreatment sPD-1 and sPD-L1 content in blood serum of 133 bone neoplasms patients aged 6-70 years and 57 practically healthy control persons aged 12-70 years are described. In 14 patients the neoplasms were of a benign character, in 16 - borderline giant-cell bone tumor was diagnosed, and in 103 - malignant bone lesions including 39 osteosarcomas and 42 chondrosarcomas were revealed. The sPD-1 receptor concentrations in blood serum did not differ between control healthy persons and primary bone tumor patients, while serum sPD-L1 level in bone tumor patients was statistically significantly increased (p<0.0000001). By means of ROC curve construction a cut-off sPD-L1 level of 16.5 pg/ml was found that imposed 75,9% sensitivity and 75,4% specificity in relation to healthy control. However, the frequency of sPD-L1 levels exceeding 16.5 pg/ml was approximately similar in benign, borderline and malignant bone tumor patients. Analysis of the pattern of sPD-1 and sPD-L1 circulation in the peripheral blood of patients with the most prevalent malignant bone tumors - osteosarcoma and chondrosarcoma - demonstrated that in both sarcoma types sPD-L1 level was significantly higher than in control, but in patients with chondrogenic tumors the soluble ligand sPD-L1 dominates in the circulation, while in those with osteogenic tumors - sPD-1 receptor prevails. In particular, sPD-1 level is statistically significantly higher in patients with typical osteosarcoma than in those with typical chondrosarcoma (p=0.002437), and sPD-L1/sPD-1 concentration ratio in chondrosarcoma is highly significantly more than 2-fold higher than in osteosarcoma (0.81 and 0.35 respectively; p=0.000284). The sensitivity of sPD-L1 ≥16.5 pg/ml test in typical osteosarcoma patients' group comprised only 70.2%, and in those with typical chondrosarcoma - 84.6%. Serum sPD-1 and sPD-L1 concentrations in osteosarcoma and chondrosarcoma patients were not associated with the indices of tumor advancement, its histological grade, localization in the osseous system, and type of affected bone. Thus, it can be concluded that the ratio between circulating soluble forms of the receptor and the ligand of PD-1/PD-L signaling pathway differs between patients with chondrogenic and those with osteogenic tumors, sPD-L1 being diagnostically valuable mostly for chondrogenic bone neoplasms.
Asunto(s)
Antígeno B7-H1/sangre , Neoplasias Óseas/sangre , Condrosarcoma/sangre , Osteosarcoma/sangre , Receptor de Muerte Celular Programada 1/sangre , Adolescente , Adulto , Anciano , Antígeno B7-H1/genética , Estudios de Casos y Controles , Niño , Humanos , Ligandos , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/genética , Adulto JovenRESUMEN
The levels of sPD-1 and sPD-L1 were analyzed in blood serum of 132 patients (age 14-70 years) with primary bone tumors: osteosarcoma (N=39), chondrosarcoma (N=42), Ewing sarcoma (N=9), chordoma (N=12), giant-cell bone tumor (GCBT) (N=16), benign neoplasms (N=14) and in and practically healthy subjects (age 19-58 years; N=27). sPD-L1 levels in all studied bone neoplasms were significantly higher than in the control. Serum sPD-1 level in GCBT patients was significantly higher than in the control, benign neoplasms, chondrosarcoma, and chordoma patients, but did not differ from osteosarcoma group. sPD-1 concentration in Ewing sarcoma was significantly higher than in chordoma and chondrosarcoma, but did not differ from the control. sPD-1 level in chondrosarcoma patients was also lower than in osteosarcoma, Ewing sarcoma, and in the control. Both sPD-1 and sPD-L1 concentrations were not significantly associated with the type of affected bone, process localization, disease stage, tumor histological grade, patients' age and sex. These results suggest the possibility of using these biological markers for preliminary assessment of the character of the process in the bone.
Asunto(s)
Antígeno B7-H1/genética , Neoplasias Óseas/genética , Carcinoma de Células Gigantes/genética , Condrosarcoma/genética , Cordoma/genética , Osteosarcoma/genética , Receptor de Muerte Celular Programada 1/genética , Sarcoma de Ewing/genética , Adolescente , Adulto , Anciano , Antígeno B7-H1/sangre , Neoplasias Óseas/sangre , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Carcinoma de Células Gigantes/sangre , Carcinoma de Células Gigantes/inmunología , Carcinoma de Células Gigantes/patología , Estudios de Casos y Controles , Condrosarcoma/sangre , Condrosarcoma/inmunología , Condrosarcoma/patología , Cordoma/sangre , Cordoma/inmunología , Cordoma/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias/sangre , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Osteosarcoma/sangre , Osteosarcoma/inmunología , Osteosarcoma/patología , Receptor de Muerte Celular Programada 1/sangre , Sarcoma de Ewing/sangre , Sarcoma de Ewing/inmunología , Sarcoma de Ewing/patologíaRESUMEN
AIM OF STUDY: The present study was planned to analyze serum heme oxygenase-1 levels in osteosarcoma patients. MATERIALS AND METHODS: Twenty five histopathologically confirmed cases of osteosarcoma localized without metastasis of all the ages attending the Orthopedic Clinics were included in the study group and twenty five patients having musculoskeletal pain (age and sex matched) served as control. Five ml of venous blood was collected aseptically from antecubital vein and serum was be separated by centrifugation and analyzed the same day. Routine biochemistry investigations were performed as per standard enzymatic methods by autoanalyzer. Serum Heme oxygenase-1 was analyzed by enzyme-linked immunosorbent assay. RESULTS: In osteosarcoma patients, serum HO-1 levels were increased as compared to patients having musculoskeletal pain (P < 0.05). Workers have found that HO-1 induction in prostate cancer cell lines (PC3) cells restored the proliferation of osteoblasts, which was inhibited during co-culture with parental prostate cancer cell line PC3 cells. However, no concrete data are available on blood levels of HO in osteosarcoma. Major role of HO-1 is the protection against oxidative injury, additionally, it regulates cell proliferation, modulates inflammatory response and facilitates angiogenesis. CONCLUSION: Findings of the present study suggests that pharmacological agents that regulate HO activity or HO-1 gene silencing may become powerful tools for preventing the onset or progression of various cancers and sensitize them to anticancer therapies.
Asunto(s)
Neoplasias Óseas/enzimología , Hemo-Oxigenasa 1/sangre , Osteosarcoma/enzimología , Adolescente , Adulto , Fosfatasa Alcalina/sangre , Antioxidantes/metabolismo , Biomarcadores de Tumor/sangre , Neoplasias Óseas/sangre , Neoplasias Óseas/patología , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Osteosarcoma/sangre , Osteosarcoma/patología , Pronóstico , Adulto JovenRESUMEN
Traditionally, circular RAN hsa_circ_0008035 was proven to function as a tumor inhibitor in gastric cancer. Nevertheless, much less was known about hsa_circ_0008035 in osteosarcoma (OSA). This project was undertaken to assess the role of hsa_circ_0008035 in OSA. Hsa_circ_0008035 level in serum of OSA patients, OSA tissues and cell lines were measured by reverse transcription-quantitative PCR. After downregulation or overexpression of hsa_circ_0008035, cell proliferation, apoptosis and migration were tested in MG63, SAOS-2 or hFOB1.19 cells. Meanwhile, the expression level of miR-375 was analyzed. The binding between hsa_circ_0008035 and miR-375 was confirmed using bioinformatics and luciferase assay. Subsequently, the effects of miR-375 inhibition on MG63 cell growth and migratory potential were reevaluated. Eventually, the activating status of Notch pathway was assessed by Western blot. Our results demonstrated that hsa_circ_0008035 was overexpressed in serum of OSA patients, OSA tissues and cells. Silencing hsa_circRNA_0008035 impeded OSA cell growth and migration, while hsa_circ_0008035 facilitated cell behaviors of hFOB1.19 cells. Additionally, hsa_circ_0008035 negatively modulated miR-375 expression. Meanwhile, miR-375 inhibition overturned the suppressive effects of silencing hsa_circRNA_0008035 on OSA cell behaviors. Furthermore, silencing hsa_circ_0008035 perturbed Notch pathway by adjusting miR-375 expression. In conclusion, silencing hsa_circRNA_0008035 exerted repressive function on OSA cell growth and migration and Notch pathway by accelerating miR-375.
Asunto(s)
Movimiento Celular/genética , Proliferación Celular/genética , Silenciador del Gen , MicroARNs/metabolismo , Osteosarcoma/genética , Osteosarcoma/patología , ARN Circular/metabolismo , Regulación hacia Arriba/genética , Adolescente , Secuencia de Bases , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Osteosarcoma/sangre , ARN Circular/sangre , ARN Circular/genética , Receptores Notch/metabolismo , Transducción de Señal , Adulto JovenRESUMEN
Hu14.18K322A is a humanized anti-GD2 monoclonal antibody with a single point mutation that reduces complement-mediated cytotoxicity, with a maximum tolerated dose (MTD) of 60 mg/m2 daily for 4 days in children with recurrent/refractory neuroblastoma. We report additional results of a Phase 1 trial to determine the MTD and safety profile of hu14.18K322A in patients with osteosarcoma, and of an alternative schedule of weekly hu14.18K322A administration in patients with neuroblastoma or osteosarcoma. Eligible patients with recurrent/refractory osteosarcoma received hu14.13K22A daily x4 every 28 days in a Phase 1 traditional 3 + 3 dose escalation design. Additional patients with osteosarcoma were then enrolled to receive hu14.18K322A once weekly for 4 weeks per course. Patients with recurrent/refractory neuroblastoma were also enrolled on the weekly schedule at 50 mg/m2/dose. Six patients with osteosarcoma treated on the daily schedule received a median of 2 (range 1-6) courses; the recommended daily dose was established as 60 mg/m2. Three patients had stable disease (SD) as best overall response. Five patients (3 neuroblastoma, 2 osteosarcoma) enrolled on the weekly schedule received a median of 1 (1-3) course; 2 achieved SD as best overall response. Pain, fever, hematologic toxicities, hyponatremia, and ocular/visual abnormalities were common toxicities among both schedules. Dose-limiting toxicities attributed to hu14.18K322A included anorexia and fatigue (n = 1). Pharmacokinetic profiles were similar between daily and weekly schedules. The recommended dose for patients with osteosarcoma receiving daily hu14.18K322A x4 is 60 mg/m2. Patients receiving the weekly schedule experienced similar pharmacokinetics and toxicity profile as the daily schedule.