RESUMO
The treatment of parathyroid hormone-related protein (PTHrP)-mediated hypercalcemia of malignancy includes treating the malignancy, intravenous fluids, and anti-resorptive therapies such as zoledronic acid or denosumab. PTHrP-mediated hypercalcemia has been reported in benign conditions such as systemic lupus erythematous (SLE) and sarcoidosis and appears to be responsive to glucocorticoids. We report a case of PTHrP-induced hypercalcemia due to a malignancy-low grade fibromyxoid sarcoma-that responded to glucocorticoid treatment. This is the first report of glucocorticoids controlling PTHrP-mediated hypercalcemia of malignancy. Immunohistochemistry of the surgical pathology localized PTHrP staining to the vascular endothelial cells within the tumor. Further studies are needed to elucidate the mechanism of glucocorticoid action in the treatment of PTHrP-mediated hypercalcemia of malignancy.
Assuntos
Hipercalcemia , Sarcoma , Humanos , Proteína Relacionada ao Hormônio Paratireóideo , Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Hipercalcemia/metabolismo , Glucocorticoides/uso terapêutico , Células EndoteliaisRESUMO
BACKGROUND: Expandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported. METHODS: We conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis. RESULTS: Thirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years. CONCLUSIONS: There is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic study.
Assuntos
Neoplasias Ósseas , Neoplasias Femorais , Criança , Humanos , Neoplasias Femorais/cirurgia , Desenho de Prótese , Estudos Retrospectivos , Implantação de Prótese/métodos , Falha de Prótese , Osteotomia , Resultado do Tratamento , Fatores de Risco , Fêmur/cirurgia , Reoperação , Neoplasias Ósseas/cirurgiaRESUMO
BACKGROUND: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? METHODS: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. RESULTS: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. CONCLUSION: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. LEVEL OF EVIDENCE: Level III, therapeutic study.
Assuntos
Sobreviventes de Câncer , Sarcoma , Neoplasias de Tecidos Moles , Criança , Humanos , Estados Unidos , Adolescente , Estudos Retrospectivos , Seguimentos , Qualidade de Vida , Fatores de Risco , Neoplasias de Tecidos Moles/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Extremidade InferiorRESUMO
BACKGROUND: Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. METHODS: Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. RESULTS: We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. CONCLUSIONS: Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.
Assuntos
Sarcoma/fisiopatologia , Neoplasias de Tecidos Moles/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Microambiente TumoralRESUMO
BACKGROUND: Acute hip fractures carry a high risk of morbidity and are associated with low vitamin D levels. Improvements in screening and treating low vitamin D levels may lead to lower fall rates and a lower likelihood of additional fragility fractures. However, patients with low vitamin D levels often remain unassessed and untreated, even after they experience these fractures. QUESTIONS/PURPOSES: We wished to determine whether a resident-led initiative can improve (1) screening for and (2) treatment of vitamin D deficiency in patients with acute hip fractures. METHODS: Our department initiated a housestaff-led, quality improvement project focused on screening and treating vitamin D deficiency in patients with acute hip fractures. Screening encompassed checking serum 25-hydroxyvitamin D level during the acute hospitalization, and treating was defined as starting supplementation before discharge when the serum 25-hydroxyvitamin D level was less than 30 ng/mL. To evaluate the efficacy of this program, an administrative database identified 283 patients treated surgically for an acute hip fracture between July 2010 and June 2014. This period included 2 years before program initiation (Year 1, n = 65 patients; Year 2, n = 61 patients), the initial program year (Year 3, n = 66 patients), and the subsequent program year (Year 4, n = 91 patients). Followup was extended to 6 weeks after treatment with 9.2% (26/282) of patients lost to followup. Eight patients were excluded owing to documented intolerance of vitamin D supplementation. There were no differences regarding patient demographics, fracture type, or treatment rendered across these 4 years. The primary endpoints were the proportion of patients screened and treated for vitamin D deficiency. The secondary endpoint was the continuation of vitamin D supplementation at the patient's 6 week followup, according to the patient's medication list at that visit. This analysis included all patients, assuming those lost to followup had not continued supplementation. ANOVA and chi-square tests were used to evaluate the differences in demographic data and in screening and treating rates. RESULTS: Screening for vitamin D deficiency improved after initiation of the resident-led quality improvement program, with screening performed for 31% of patients in Year 1 (20/65; odds ratio [OR], 0.44; 95% CI, 0.26-0.75), 20% of patients in Year 2 (12/61; OR, 0.24; 95% CI, 0.13-0.46), 46% of patients in Year 3 (30/66; OR, 0.83; 95% CI, 0.51-1.35), and 88% of patients in Year 4 (80/91; OR, 7.27; 95% CI, 3.87-13.7) (p < 0.001). Vitamin D supplementation was initiated for 33% of patients in Year 1 (21/63; OR, 0.5; 95% CI, 0.30-0.84), 28% in Year 2 (17/61; OR, 0.39; 95% CI, 0.22-0.68), 50% in Year 3 (32/64; OR,1.00; 95% CI, 0.61-1.63), and 76% in Year 4 (65/86; OR, 3.10; 95% CI, 1.89-5.06) (p < 0.001). At early postoperative followup, we saw substantial improvement in the proportion of patients who continued receiving vitamin D supplementation: Year 1, 12% (8/64; OR, 0.14; 95% CI, 0.07-0.30); Year 2, 15% (9/61; OR, 0.17; 95% CI, 0.09-0.35); Year 3, 26% (16/64; OR, 0.33; 95% CI, 0.19-0.59); and Year 4, 46% (40/86; OR, 0.87; 95% CI, 0.57-1.33) (p < 0.001). CONCLUSIONS: Implementation of a resident-led quality improvement program resulted in higher rates of screening and treating vitamin D deficiency for patients with acute hip fractures. Housestaff-based initiatives may be an effective way to improve care processes that target improvements in bone health.
Assuntos
Fraturas do Quadril/complicações , Deficiência de Vitamina D/diagnóstico , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Fraturas do Quadril/sangue , Humanos , Internato e Residência , Masculino , Programas de Rastreamento , Resultado do Tratamento , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológicoRESUMO
BACKGROUND: Current methods to identify infected tissue in periprosthetic joint infection (PJI) are inadequate. The purpose of this study was (1) to assess methylene blue-guided surgical debridement as a novel technique in PJI using quantitative microbiology and (2) to evaluate clinical success based on eradication of infection and infection-free survival. METHODS: Sixteen total knee arthroplasty patients meeting Musculoskeletal Infection Society criteria for PJI undergoing the first stage of 2-stage exchange arthroplasty were included in this prospective study. Dilute methylene blue (0.1%) was instilled in the knee before debridement, residual dye was removed, and stained tissue was debrided. Paired tissue samples, stained and unstained, were collected from the femur, tibia, and capsule during debridement. Samples were analyzed by neutrophil count, semiquantitative culture, and quantitative polymerase chain reaction (PCR). Clinical success was a secondary outcome. RESULTS: The mean age was 64.0 ± 6.0 years, and follow-up was 24.4 ± 3.5 months. More bacteria were found in methylene blue-stained vs unstained tissue-based on semiquantitative culture (P = .001). PCR for staphylococcal species showed 9-fold greater bioburden in methylene blue-stained vs unstained tissue (P = .02). Tissue pathology found 53 ± 46 polymorphonuclear leukocytes per high-power field in methylene blue-stained vs 4 ± 13 in unstained tissue (P = .0001). All subjects cleared their primary infection and underwent reimplantation. At mean 2-year follow-up, 25% of patients failed secondary to new infection with a different organism. CONCLUSION: These results suggest a role for methylene blue in providing a visual index of surgical debridement in the treatment of PJI.
Assuntos
Artrite Infecciosa/cirurgia , Artroplastia do Joelho/efeitos adversos , Desbridamento/métodos , Azul de Metileno , Infecções Relacionadas à Prótese/cirurgia , Idoso , Artrite Infecciosa/diagnóstico , Artrite Infecciosa/etiologia , Feminino , Humanos , Articulação do Joelho/cirurgia , Prótese do Joelho , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Compressive osseointegration is a promising modality for limb salvage in distal femoral oncologic tumors. However, few studies have explored short-term survival rates in a large patient cohort of distal femur compressive endoprostheses or highlighted the risk factors for spindle failures. QUESTIONS/PURPOSES: We asked: (1) What is the frequency of compressive osseointegration spindle failure in distal femoral reconstructions? (2) What are the characteristics of rotational failure cases with distal femur compressive osseointegration endoprostheses? (3) What are the risk factors for mechanical and rotational failure of distal femur compressive osseointegration implantation? (4) What are other modalities of failure or causes of revision surgery, which affect patients undergoing distal femur compressive osseointegration implantation for oncologic reconstruction? METHODS: Between 1996 and 2013, 127 distal femoral reconstructions with the Compress(®) prosthesis were performed in 121 patients. During that time, 116 Compress(®) prostheses were implanted for aggressive primary tumors of the distal femur and/or failure of previous oncologic reconstruction. This approach represented approximately 91% of the distal femoral reconstructions performed during that time. Of the patients with prostheses implanted, four patients (four of 116, 3%) had died, and 37 (37 of 116, 32%) were lost to followup before 24 months. The median followup was 84 months (range, 24-198 months), and 71 patients (66% of all patients) were seen within the last 3 years. A retrospective chart review was performed to determine failure modality as defined by radiographs, clinical history, and intraoperative findings. Risk factors including age, sex, BMI, resection length, and perioperative chemotherapy were analyzed to determine effect on spindle and rotational failure rates. Survival analysis was determined using the Kaplan-Meier estimator. Differences in survival between groups were analyzed using the log rank test. Risk factors were determined using Cox proportional hazard modeling. RESULTS: Spindle survival at 5 and 10 years was 91% (95% CI, 82%-95%). Survival rates from rotational failure at 5 and 10 years were 92% (95% CI, 83%-96%); the majority of failures occurred within the first 2 years postoperatively and were the result of a twisting mechanism of injury. With the numbers available, none of the potential risk factors examined were associated with mechanical failure. The 5-year and 10-year all-cause revision-free survival rates were 57% (95% CI, 44%-67%) and 50% (95% CI, 36%-61%), respectively. CONCLUSIONS: Distal femur compressive osseointegration is a viable method for endoprosthetic reconstruction. Rotational failure is rare with the majority occurring early. No variables were found to correlate with increased risk of mechanical failure. More research is needed to evaluate methods of preventing mechanical and rotational failures in addition to other common causes of revision such as infection in these massive endoprosthetic reconstructions. LEVEL OF EVIDENCE: Level IV, therapeutic study.
Assuntos
Neoplasias Femorais/cirurgia , Fêmur/cirurgia , Osseointegração , Procedimentos de Cirurgia Plástica/efeitos adversos , Procedimentos de Cirurgia Plástica/instrumentação , Falha de Prótese , Implantação de Prótese/efeitos adversos , Implantação de Prótese/instrumentação , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Neoplasias Femorais/diagnóstico por imagem , Neoplasias Femorais/patologia , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Osteotomia , Modelos de Riscos Proporcionais , Desenho de Prótese , Reoperação , Estudos Retrospectivos , Fatores de Risco , Estresse Mecânico , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Ewing sarcoma peaks in incidence in adolescence. Infants <12 months old have rarely been reported. We aimed to compare clinical features, treatment, and survival of infants <12 months to those of older pediatric patients with Ewing sarcoma. PROCEDURE: We utilized the SEER database to identify patients <12 months of age diagnosed with Ewing sarcoma between 1973 and 2011. We used Fisher exact tests to compare clinical features and treatment modalities between these patients and patients aged 1-19 years. We used Kaplan-Meier methods to describe overall survival in these two groups. RESULTS: Of 1,957 patients in the cohort, 39 (2.0%) were diagnosed at <12 months of age. Infants had a different distribution of primary tumor sites, with lower extremity tumors under represented. Compared to older patients, infants were more likely to have soft tissue tumors (81.6% vs. 27.1%; P < 0.001); have primitive neuroectodermal tumor/Askin tumor (61.5% vs. 19.9%; P < 0.001); and have tumors <8 cm (81.0% vs. 53.2%; P < 0.014). Infants were less likely to receive radiation therapy (13.2% vs. 53.3%; P < 0.001). Infants were at increased risk for early death (P < 0.013 by Wilcoxon), though long-term overall survival was not different between age groups (P < 0.25 by log rank). CONCLUSIONS: Ewing sarcoma is rare in infants, with different clinical presentations and treatment approaches. These patients appear to be at higher risk for early death, but long-term survival is similar to older pediatric patients.
Assuntos
Bases de Dados Factuais , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: As patients with osteosarcoma become long-term survivors, increasing attention has turned to the burden of late effects. The goal of the current study was to describe the incidence, characteristics, and outcomes of secondary malignant neoplasms (SMNs) in this population. METHODS: Patients aged birth to 40 years at time of primary diagnosis with osteosarcoma and reported to the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2010 were eligible for inclusion in the cohort. Competing risks methods were used to estimate the cumulative incidence of SMNs and potential risk factors for developing an SMN. Standardized incidence ratios (SIR) and overall survival after an SMN were estimated. RESULTS: The SEER database included 3379 patients who were diagnosed with osteosarcoma as their first malignancy. Of these, 89 patients were diagnosed with an SMN. The cumulative incidence of any SMN was 2.1% (95% confidence interval [95% CI], 1.6%-2.7%) at 10 years, 4.0% (95% CI, 3.1%-5.1%) at 20 years, and 7.4% (95% CI, 5.6%-9.5%) at 30 years. The median time from the primary diagnosis to an SMN diagnosis was 6.0 years. The SIR for SMNs for survivors of osteosarcoma compared with the general population was 1.6 (95% CI, 1.0-2.5) for patients diagnosed with osteosarcoma from 1973 through 1985 and 4.7 (95% CI, 3.3-6.4) for patients diagnosed with osteosarcoma from 1986 through 2010, with a 34-fold increased risk of leukemia in this most recent era. The overall survival rate at 5 years for patients with SMNs after a diagnosis of osteosarcoma was 44.5%. CONCLUSIONS: Survivors of osteosarcoma are at an increased risk of developing SMNs compared with the baseline population, with an increased risk noted in patients treated in the more recent era.
Assuntos
Neoplasias Ósseas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Osteossarcoma/epidemiologia , Sobreviventes/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Programa de SEER , Estados Unidos/epidemiologia , Adulto JovemRESUMO
PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.
Assuntos
Neoplasias Ósseas , Óxidos N-Cíclicos , Indolizinas , Osteossarcoma , Compostos de Piridínio , Humanos , Animais , Camundongos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ensaios Antitumorais Modelo de Xenoenxerto , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Linhagem Celular Tumoral , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismoRESUMO
The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Humanos , Proteômica , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Translocação Genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Renais/genética , Cromatina/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cromossomos Humanos X/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína com Valosina/genéticaRESUMO
BACKGROUND: Although there is evidence suggesting that postoperative infection confers a survival benefit in osteosarcoma treated with resection and endoprosthetic reconstruction, there have been no prospective studies to date to support these findings. This secondary analysis of Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) study data examines the relationship between surgical site infection (SSI) and disease progression within 12 months after limb salvage surgery. METHODS: The PARITY trial was an international, multicenter, prospective randomized controlled trial of 604 patients who underwent resection of a lower-extremity bone tumor and endoprosthetic reconstruction. Our primary outcome was progression-free survival (PFS) at 1 year following surgery among the patients with osteosarcoma. Subgroup analyses by disease stage at presentation and infection severity were also performed. Cox proportional hazard models were employed to examine the association between clinical and tumor characteristics, SSI, and PFS. Kaplan-Meier analysis was used to determine the effect of SSI on PFS. RESULTS: The 274 PARITY patients with osteosarcoma were included in this secondary analysis. Thirty-two (11.7%) of the patients presented with metastasis at baseline; 53 (19.3%) of the patients developed an SSI. There was no difference in 1-year PFS between patients with and without SSI. There was no decreased risk of disease progression at 1 year in patients with localized disease at baseline who developed an SSI (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.64 to 2.28). Infection was associated with increased disease progression at 1 year in patients with baseline metastases (HR = 4.26; 95% CI = 1.11 to 16.3). CONCLUSIONS: No positive association was detected between postoperative infection and PFS at 1 year following surgery in this secondary analysis of prospective data. However, this analysis suggests infection could be a risk factor for early disease progression in patients with baseline metastases, and future investigations may better elucidate the association between disease burden and the host immune response to advance immunotherapeutic strategies for osteosarcoma. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Progressão da Doença , Salvamento de Membro , Extremidade Inferior/cirurgia , Intervalo Livre de Progressão , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/cirurgiaRESUMO
Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model.
RESUMO
The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.
RESUMO
BACKGROUND: Failure of endoprosthetic reconstruction with conventional stems due to aseptic loosening remains a challenge for maintenance of limb integrity and function. The Compress(®) implant (Biomet Inc, Warsaw, IN, USA) attempts to avoid aseptic failure by means of a unique technologic innovation. Though the existing literature suggests survivorship of Compress(®) and stemmed implants is similar in the short term, studies are limited by population size and followup duration. QUESTIONS/PURPOSES: We therefore compared (1) the rate of aseptic failure between Compress(®) and cemented intramedullary stems and (2) evaluated the overall intermediate-term implant survivorship. METHODS: We reviewed 26 patients with Compress(®) implants and 26 matched patients with cemented intramedullary stems. The patients were operated on over a 3-year period. Analysis focused on factors related to implant survival, including age, sex, diagnosis, infection, aseptic loosening, local recurrence, and fracture. Minimum followup was 0.32 years (average, 6.2 years; range, 0.32-9.2 years). RESULTS: Aseptic failure occurred in one (3.8%) patient with a Compress(®) implant and three (11.5%) patients with cemented intramedullary stems. The 5-year implant survival rate was 83.5% in the Compress(®) group and 66.6% in the cemented intramedullary stem group. CONCLUSIONS: The Compress(®) implant continues to be a reliable option for distal femoral limb salvage surgery. Data regarding aseptic failure is encouraging, with equivalent survivorship against cemented endoprosthetic replacement at intermediate-term followup. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
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Neoplasias Ósseas/cirurgia , Osteossarcoma/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Próteses e Implantes , Adolescente , Adulto , Cimentação , Criança , Feminino , Neoplasias Femorais/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Osseointegração , Desenho de Prótese , Falha de Prótese , Implantação de Prótese/métodos , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: Malignancies of the mobile spine carry high morbidity and mortality. This study sought to examine factors associated with receipt of "standard" treatment and survival for patients with primary mobile spine tumors in the California Cancer Registry (CCR). METHODS: The CCR (1988 to 2016) data were obtained for patients with primary tumors of the mobile spine and at least 1-year follow-up. Sacrum/pelvis tumors were excluded. Age at diagnosis, sex, race, neighborhood socioeconomic status, insurance, Charlson Comorbidity Index, histologic diagnosis, stage at diagnosis, and treatment at a National Cancer Institute-designated Cancer Center (NCICC) were collected. Multivariate analyses were done to identify factors associated with all-cause mortality and receipt of "standard" treatment. RESULTS: Four hundred eighty-four patients (64% White, 56% low neighborhood socioeconomic status, and 36% privately insured) were included. Chordoma (37%) was the most common diagnosis. Only 16% had metastatic disease at presentation. Only 29% received treatment at an NCICC. Lower age, Charlson Comorbidity Index, less extensive stage of disease, and private insurance were associated with lower all-cause mortality (all P < 0.05). Medicaid/public insurance (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.13 to 2.41) and Medicare (HR, 1.80; 95% CI, 1.25 to 2.59) were associated with higher mortality compared with private insurance. Patients who received no known treatment (HR, 2.41; CI, 1.51 to 3.84) or treatment other than the "standard" (HR, 1.45; CI, 1.11 to 1.91) had higher mortality compared with those who received the standard protocols. A critical predictor of receiving the standard treatment protocol was being treated at an NCICC. If patients did not receive care at such institutions, they received optimal treatment only 40% of the time (HR, 0.5; P = 0.004). CONCLUSIONS: Receipt of defined "standard treatment" protocols was associated with care received at an NCICC and lower all-cause mortality in patients with primary osseous malignancies of the mobile spine. Patients with public insurance are vulnerable to worse outcomes, regardless of age, disease burden, or receipt of standard treatment. LEVEL OF EVIDENCE: III.
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Neoplasias Ósseas , Medicare , Idoso , Protocolos Clínicos , Humanos , Cobertura do Seguro , Medicaid , Classe Social , Estados UnidosRESUMO
The surgical management of sacro-iliac chondrosarcomas is challenging given their intimate relationship to the nerves and vessels of the pelvis. Osteotomies for en bloc excision can be challenging because of lack of visualization and high risk of injury to pelvic structures. The use of three-dimensional (3D) printed models helps conceptualize the tumor relative to the patient's anatomy. Coupled with stereotactic navigation, safe osteotomy planning and execution can be performed with avoidance of vital nerves and vessels. Very few cases have been reported demonstrating the successful use of these 2 modern technologies for en bloc excision of difficult tumors. We present our technique of using a 3D printed model and navigation for en bloc excision of a large sacro-iliac chondrosarcoma, supplemented with an intraoperative video.
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Neoplasias Ósseas/cirurgia , Condrossarcoma/cirurgia , Imageamento Tridimensional/métodos , Neuronavegação/métodos , Osteotomia/métodos , Impressão Tridimensional , Humanos , Lasers , Masculino , Pessoa de Meia-Idade , Articulação Sacroilíaca/patologia , Articulação Sacroilíaca/cirurgia , Resultado do TratamentoRESUMO
Improvements in cancer treatment have led to prolonged survival and increased rates of cure. An estimated 14 million cancer survivors live in the United States. The cornerstones of cancer treatment, including radiation, chemotherapy, and surgery, give rise to a host of chronic health conditions, some of which affect the musculoskeletal system. As survivorship continues to improve, orthopaedic surgeons across all subspecialties will be tasked with managing these complications of treatment. This article reviews orthopaedic health concerns secondary to cancer treatment that are likely to present to orthopaedic surgeons for evaluation, such as osteoporosis, osteonecrosis, secondary malignancies, radiation-associated fractures, exercise tolerance, and perioperative evaluation.
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Antineoplásicos/efeitos adversos , Doenças Musculoesqueléticas/etiologia , Doenças Musculoesqueléticas/terapia , Neoplasias/terapia , Radioterapia/efeitos adversos , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Sobreviventes de Câncer/estatística & dados numéricos , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Fraturas Ósseas/terapia , Humanos , Doenças Musculoesqueléticas/diagnóstico , Doenças Musculoesqueléticas/prevenção & controle , Neoplasias/complicações , Osteonecrose/diagnóstico , Osteonecrose/etiologia , Osteonecrose/prevenção & controle , Osteonecrose/terapia , Osteoporose/diagnóstico , Osteoporose/etiologia , Osteoporose/prevenção & controle , Osteoporose/terapiaRESUMO
CASE PRESENTATION: A 33-year old man presented with a 25-cm lower extremity embryonal rhabdomyosarcoma with presumed extensive nodal metastasis on positron emission topography scan. Neoadjuvant chemotherapy and radiation provided minimal response. Following limb salvage resection and flap coverage, a prolonged postoperative infection occurred requiring intravenous antibiotics and wound care over 5 months. Given the infection, no postoperative radiation or chemotherapy was administered. Eight months following surgery, positron emission topography scan showed complete regression of local and nodal disease. The patient has remained in complete remission for more than 4 years. CONCLUSION: Postoperative wound infection leading to complete regression of embryonal rhabdomyosarcoma has not been reported. Stimulation of the innate and adaptive immune system through infectious elements is an area of ongoing immunotherapy research to improve sarcoma treatment outcomes.
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Rabdomiossarcoma Embrionário , Neoplasias de Tecidos Moles , Adulto , Humanos , Salvamento de Membro , Masculino , Terapia de Salvação , Neoplasias de Tecidos Moles/cirurgia , Infecção da Ferida Cirúrgica/terapiaRESUMO
BACKGROUND: While racial/ethnic survival disparities have been described in pediatric oncology, the impact of income has not been extensively explored. We analyzed how public insurance influences 5-year overall survival (OS) in young patients with sarcomas. METHODS: The University of California San Francisco Cancer Registry was used to identify patients aged 0-39 diagnosed with bone or soft tissue sarcomas between 2000 and 2015. Low-income patients were defined as those with no insurance or Medicaid, a means-tested form of public insurance. Survival curves were computed using the Kaplan-Meier method and compared using log-rank tests and Cox models. Causal mediation was used to assess whether the association between public insurance and mortality is mediated by metastatic disease. RESULTS: Of 1106 patients, 39% patients were classified as low-income. Low-income patients were more likely to be racial/ethnic minorities and to present with metastatic disease (OR 1.96, 95% CI 1.35-2.86). Low-income patients had significantly worse OS (61% vs 71%). Age at diagnosis and extent of disease at diagnosis were also independent predictors of OS. When stratified by extent of disease, low-income patients consistently had significantly worse OS (localized: 78% vs 84%, regional: 64% vs 73%, metastatic: 23% vs 30%, respectively). Mediation analysis indicated that metastatic disease at diagnosis mediated 15% of the effect of public insurance on OS. CONCLUSIONS: Low-income patients with bone and soft tissue sarcomas had decreased OS regardless of disease stage at presentation. The mechanism by which insurance status impacts survival requires additional investigation, but may be through reduced access to care.