Pharmacogenetics of the Primary and Metastatic Osteosarcoma: Gene Expression Profile Associated with Outcome.

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. In recent decades, OS treatment has reached a plateau and drug resistance is still a major challenge. Therefore, the present study aimed to analyze the expression of the genes related to pharmacogenetics in OS. The expression of 32 target genes in 80 paired specimens (pre-chemotherapeutic primary tumor, post-chemotherapeutic primary tumor and pulmonary metastasis) obtained from 33 patients diagnosed with OS were analyzed by the real-time PCR methodology. As the calibrators (control), five normal bone specimens were used. The present study identified associations between the OS outcome and the expression of the genes TOP2A, DHFR, MTHFR, BCL2L1, CASP3, FASLG, GSTM3, SOD1, ABCC1, ABCC2, ABCC3, ABCC5, ABCC6, ABCC10, ABCC11, ABCG2, RALBP1, SLC19A1, SLC22A1, ERCC1 and MSH2. In addition, the expression of the ABCC10, GGH, GSTM3 and SLC22A1 genes were associated with the disease event, and the metastasis specimens showed a high expression profile of ABCC1, ABCC3 and ABCC4 genes and a low expression of SLC22A1 and ABCC10 genes, which is possibly an important factor for resistance in OS metastasis. Therefore, our findings may, in the future, contribute to clinical management as prognostic factors as well as possible therapeutic targets.

Influence of body composition assessed by computed tomography on mortality in older adults undergoing hematopoietic stem cell transplantation.

BACKGROUND: The incidence of most hematologic malignancies increases with age. Hematopoietic stem cell transplantation (HSCT) provides a potentially life-prolonging or curative option for many patients in this scenario. Limited data assessed from computed tomography (CT) images are available on muscle mass and density outcomes after HSCT. We evaluate the influence of body composition on morbidity and mortality in older adults undergoing HSCT. METHODS: Retrospective longitudinal study conducted with 50 patients ≥ 60 years old undergoing HSCT. Body composition was assessed by chest CT (CCT), and treatment-related mortality, graft-vs-host disease (GVHD), neutrophil grafting, and overall survival were analyzed. RESULTS: 148 HSCT patients were evaluated; 50 patients were eligible: 60% with autologous and 40% with allogeneic transplantation. Body mass index in patients was (female: 26.9 ± 4.7 kg/m2 ; male: 30.1 ± 4.9 kg/m2 ) - autologous and, (female: 24.3 ± 5.1 kg/m2 ; male: 26.4 ± 2.0 kg/m2 ) - allogeneic. In the autologous group, we found a positive association between age and death risk, with 63.5% increased risk of death (P = 0.006), and also Karnofsky Performance Score, with a 11.9% decrease in death risk (P < 0.001). A negative association between muscle radiodensity and death risk was observed in patients who received an allogeneic transplantation, with a risk decrease of 20.1% (P = 0.032). We found a positive association between the fourth thoracic vertebra muscle area and radiodensity and risk of acute GVHD (P = 0.028). CONCLUSION: Body composition assessed by CCT showed the importance of radiodensity for better prognosis.

Epidemiological characteristics of patients with pelvic tumors submitted to surgical treatment.

OBJECTIVE: Describe the epidemiological profile of patients with primary or secondary neoplastic lesions in the pelvis who required a surgical procedure such as hemipelvectomy. METHODS: This study retrospectively evaluated 69 patients located in the database of a São Paulo educational institution, subject to surgical hemipelvectomy treatment between January 1990 and December 2013. All patients had previous diagnosis of bone tumor (primary or metastatic) in the pelvis (ilium, ischium, pubis, and/or sacrum). RESULTS: Analyzing the data obtained in this study, it was observed that these are partly similar to those found in the literature, with primary bone malignancies as the main diagnosis; general injuries affecting the pelvic area I (pelvic bone) and its most frequent complication, infection. The differences are mainly due to rarity of the bone tumors evaluated in this study, and the type of surgical procedure in question, which is even more unusual. CONCLUSION: Building a picture that conveys the reality of each diagnosis and that indicates which characteristics of these patients would better resemble an absolute or relative indication for the realization of hemipelvectomy is harder by the rarity of these cases.

OBJETIVO: Traçar o perfil epidemiológico dos pacientes com lesões neoplásicas na pelve, primárias ou secundárias, para as quais foi necessário procedimento cirúrgico do tipo hemipelvectomia. MÉTODOS: Foram avaliados, retrospectivamente, 69 pacientes localizados no banco de dados de uma instituição de ensino de São Paulo, submetidos a tratamento cirúrgico tipo hemipelvectomia entre janeiro de 1990 e dezembro de 2013. Todos os pacientes apresentavam diagnóstico prévio de tumor ósseo (primário ou metastático) na pelve (ílio, ísquio, púbis e/ou sacro). RESULTADOS: Ao analisar os dados obtidos no presente estudo, observou-se que esses são em parte semelhantes aos encontrados na literatura mundial, apresentam como principal diagnóstico as neoplasias malignas ósseas primárias. Em geral, as lesões acometeram a zona I pélvica (osso ilíaco) e a complicação mais frequentemente observada foi a infecção. As diferenças encontradas são devidas principalmente à raridade dos tumores ósseos avaliados nesses estudos e ao tipo de procedimento cirúrgico em questão, esses ainda mais incomuns. CONCLUSÃO: Construir um panorama que transmita a realidade de cada diagnóstico e indique quais as características que esses pacientes apresentam que mais se aproximariam como indicações relativas ou absolutas para o procedimento de hemipelvectomia encontra na raridade desses casos o seu maior obstáculo.

EWING'S SARCOMA: EPIDEMIOLOGY AND PROGNOSIS FOR PATIENTS TREATED AT THE PEDIATRIC ONCOLOGY INSTITUTE, IOP-GRAACC-UNIFESP.

OBJECTIVE: To outline the epidemiological profile and prognosis for Ewing's sarcoma in the Brazilian population. MATERIAL AND METHODS: The medical records of 64 patients with intraosseous Ewing's sarcoma who were treated at the Pediatric Oncology Institute, IOP-GRAACC-Unifesp, between 1995 and 2010, were retrospectively evaluated. RESULTS: The statistical analysis on the data obtained did not correlate factors such as sex, trauma, pathological fracture and time taken for case diagnosis with the treatment outcome. Factors such as initial metastasis, lung metastasis, tumor site, age, recurrence and type of surgery showed results corroborating what has been established in the literature. CONCLUSION: The prognosis in cases of Ewing's sarcoma was mainly influenced by the presence of metastases at the time of diagnosis.

MAPK7 and MAP2K4 as prognostic markers in osteosarcoma.

Osteosarcoma is a class of cancer originating from the bone, affecting mainly children and young adults. Cytogenetic studies showed the presence of rearrangements and recurrent gains in specific chromosomal regions, indicating the possible involvement of genes located in these regions during the pathogenesis of osteosarcoma. These studies investigated expression of 10 genes located in the chromosomal region involved in abnormalities in osteosarcoma, 1p36, 17p, and chromosome 19. The purpose of this study was to investigate the expression profile of genes located in regions involved in chromosomal rearrangements in osteosarcoma. We used quantitative real-time polymerase chain reaction to investigate the expression of 10 genes located in 1p36.3 (MTHFR, ERRFI1, FGR, E2F2), 17p (MAPK7, MAP2K4), and chromosome 19 (BBC3, FOSB, JUND, and RRAS), in 70 samples taken from 30 patients (30 prechemotherapy, 30 postchemotherapy, and 10 metastases specimens) and 10 healthy bones as a control sample. The most interesting results showed a strong association between the expression levels of MAPK7 and MAP2K4 genes and clinical parameters of osteosarcoma. Overexpression of these genes was significantly associated to a poor response to treatment (P = .0001 and P = .0049, respectively), tumor progression, and worse overall survival (P = .0052 and P = .0085, respectively), suggesting that MAPK7 and MAP2K4 could play an important role in osteosarcoma tumorigenesis. Thus, these genes could be good markers in assessing response to treatment and development of osteosarcoma.

Bone deposition, bone resorption, and osteosarcoma.

Bone deposition and bone resorption are ongoing dynamic processes, constituting bone remodeling. Some bone tumors, such as osteosarcoma (OS), stimulate focal bone deposition. OS is the most common primary bone tumor in children and young adults. A complex network of genes regulates bone remodeling and alterations in its expression levels can influence the genesis and progression of bone diseases, including OS. We hypothesized that the expression profiles of bone remodeling regulator genes would be correlated with OS biology and clinical features. We used real-time PCR to evaluate the mRNA levels of the tartrate-resistant acid phosphatase (ACP5), colony stimulating factor-1 (CSF1R), bone morphogenetic protein 7 (BMP7), collagen, type XI, alpha 2 (COL11A2), and protein tyrosine phosphatases zeta 1 (PTPRZ1) genes, in 30 OS tumor samples and correlated with clinical and histological data. All genes analyzed, except CSF1R, were differentially expressed when compared with normal bone expression profiles. In our results, OS patients with high levels of COL11A2 mRNA showed worse overall (p = 0.041) and event free survival (p = 0.037). Also, a trend for better overall survival was observed in patients with samples showing higher expression of BMP7 (p = 0.067). COL11A2 overexpression and BMP7 underexpression could collaborate to OS tumor growth, through its central role in bone remodeling process.

Prognostic factors and outcomes for osteosarcoma: an international collaboration.

We aimed to evaluate the prognostic significance of traditional clinical predictors in osteosarcoma through an international collaboration of 10 teams of investigators (2680 patients) who participated. In multivariate models the mortality risk increased with older age, presence of metastatic disease at diagnosis, development of local recurrence when the patient was first seen, use of amputation instead of limb salvage/wide resection, employment of unusual treatments, use of chemotherapeutic regimens other than anthracycline and platinum and use of methotrexate. It was also influenced by the site of the tumour. The risk of metastasis increased when metastatic disease was present at the time the patient was first seen and also increased with use of amputation or unusual treatment combinations or chemotherapy regimens not including anthracycline and platinum. Local recurrence risk was higher in older patients, in those who had local recurrence when first seen and when no anthracycline and platinum were used in chemotherapy. Results were similar when limited to patients seen after 1990 and treated with surgery plus combination chemotherapy. This large-scale international collaboration identifies strong predictors of major clinical outcomes in osteosarcoma.