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Atypical anorexia nervosa (AAN) has historically been underrecognized by clinicians due to traditional markers of low weight as indicative of malnutrition. Inadequate case identification can lead to treatment delays while placing children and adolescents with AAN at further risk of medical and psychiatric sequalae. The accompanying article in this journal issue examines the challenges of determining weight-based treatment goals for this population. In this commentary, we elaborate on this discussion and question the validity of weight stabilization as a treatment target in child and adolescent AAN. Furthermore, we address: (1) the role of weight and historical, variable, and stable growth curves in shaping treatment goals; (2) future growth targets, including numeric and remission targets; and; (3) the impact of weight stigma and implicit weight bias in clinical decision-making. We argue that target weights must take a secondary role in the treatment of AAN, shifting the focus to the mental, behavioural, and nutritional aspects of this disorder. In addition, we recommend that clinicians acknowledge and mitigate fears around weight gain and weight-based social rejection for young people and families in treatment.
L'anorexie mentale atypique (AMA) a été historiquement sous-reconnue par les cliniciens en raison des marqueurs traditionnels de poids faible comme indicateurs de malnutrition. L'identification de cas inadéquate peut mener à des retards de traitement tout en plaçant les enfants et les adolescents souffrant d'AMA à un risque accru de séquelles médicales et psychiatriques. L'article d'accompagnement dans ce numéro du journal examine les défis de la détermination des buts du traitement basé sur le poids pour cette population. Dans ce commentaire, nous élaborons cette discussion et questionnons la validité de la stabilisation du poids comme cible de traitement dans l'AMA chez les enfants et les adolescents. En outre, nous abordons (1) le rôle du poids et de la variable historique, et les courbes de croissance stable dans la définition des buts du traitement; (2) les cibles de croissance futures, y compris les cibles numériques et de rémission; et (3) l'effet de la stigmatisation liée au poids et du biais implicite lié au poids dans la prise de décision clinique. Nous soutenons que les poids cibles doivent jouer un rôle secondaire dans le traitement de l'AMA, en mettant l'accent sur les aspects mentaux, comportementaux et nutritionnels de ce trouble. De plus, nous recommandons que les cliniciens reconnaissent et atténuent les peurs de prendre du poids et du rejet social basé sur le poids pour les jeunes personnes et les familles en traitement.
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The purpose of this study was to conduct a literature review to examine micronutrient deficiencies in laparoscopic sleeve gastrectomy. We conducted a literature review using PubMed and Cochrane databases to examine micronutrient deficiencies in SG patients in order to identify trends and find consistency in recommendations. Seventeen articles were identified that met the defined criteria. Iron, vitamin B12 and vitamin D were the primary micronutrients evaluated. Results demonstrate the need for consistent iron and B12 supplementation, in addition to a multivitamin, while vitamin D supplementation may not be necessary. Additional prospective studies to establish a clearer picture of micronutrient deficiencies post-SG are needed.
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Gastrectomía/métodos , Laparoscopía/métodos , Micronutrientes/deficiencia , Calcio/sangre , Suplementos Dietéticos , Ferritinas/sangre , Ácido Fólico/administración & dosificación , Gastrectomía/efectos adversos , Humanos , Hierro/administración & dosificación , Deficiencias de Hierro , Obesidad/cirugía , Estudios Prospectivos , Estudios Retrospectivos , Vitamina B 12/administración & dosificación , Deficiencia de Vitamina B 12/epidemiología , Vitamina D/administración & dosificación , Deficiencia de Vitamina D/epidemiologíaRESUMEN
OBJECTIVE: The aim of the study was to determine abdominal and breast adipose tissue parameters on 18-fluorodeoxyglucose positron emission tomography/computed tomography (CT) that may serve as outcome predictors in breast angiosarcoma patients. MATERIALS: Women with breast angiosarcoma (n = 13) who underwent 18-fluorodeoxyglucose positron emission tomography/CT were identified. A control group was selected (n = 25). Abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) were assessed on unenhanced computed tomographies. Breast adipose tissue (BAT) volumes of the uninvolved breast were quantified. Metabolic activity of VAT, SAT, and BAT was calculated (standardized uptake value [SUV]). RESULTS: Breast angiosarcoma patients had higher metabolic activity of VAT compared with controls (SUV 0.93 ± 0.39 vs 0.64 ± 0.11, P = 0.044). Within the patient group, there were 6 deaths (46.2%). Patients who died had higher SAT activity (SUV 0.52 ± 0.24 vs 0.29 ± 0.06, P = 0.027) and higher BAT metabolic activity (SUV 0.48 ± 0.20 vs 0.27 ± 0.11, P = 0.045) compared with nondeceased patients. CONCLUSIONS: Patients with breast angiosarcoma have higher metabolic activity of VAT. Higher abdominal SAT and higher BAT metabolic activity of the uninvolved breast might predict mortality.
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Grasa Abdominal/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/mortalidad , Hemangiosarcoma/diagnóstico por imagen , Hemangiosarcoma/mortalidad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Anciano , Anciano de 80 o más Años , Composición Corporal , Estudios de Casos y Controles , Femenino , Fluorodesoxiglucosa F18/administración & dosificación , Humanos , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND/OBJECTIVES: Oligometastatic sarcoma pulmonary metastases (PM's) are traditionally treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) is an effective, safe alternative to surgery that can achieve excellent local control (LC) with a favorable toxicity profile. METHODS: Patients treated with SBRT for sarcoma PM's from 2011 to 2016 at Massachusetts General Hospital and the University of Pennsylvania were included. Median dose was 50 Gy. Patients underwent computed tomography (CT) or positron emission tomography/CT Q3 months post-SBRT. RESULTS: 44 patients with 56 separate PM's were treated with SBRT. Median age was 59 (range 19-82). 82% received prior chemotherapy, 66% had prior pulmonary resections (range, 1-5 resections), and 32% received prior thoracic radiotherapy. Median lesion size was 2.0 cm (range, 0.5-8.1 cm). Median follow-up was 16 months and 25 months for patients alive at last follow-up. Overall survival at 12 and 24 months was 74% (95% confidence interval [CI], 67%-81%) and 46% (95% CI, 38%-55%). LC at 12 and 24 months was 96% (95% CI, 93%-98%) and 90% (95% CI, 84%-96%). LC and overall survival did not differ based on age, gender, histology, fractionation, lesion location, or size (P > .05). Three developed Common Terminology Criteria for Adverse Events version 4 grade-2 chest-wall toxicities; one had grade-2 pneumonitis. CONCLUSIONS: In the first multi-institutional series on SBRT for sarcoma PM's, SBRT has excellent LC and is well-tolerated. SBRT should be considered as an alternative/complement to resection.
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Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundario , Radiocirugia/métodos , Sarcoma/radioterapia , Sarcoma/secundario , Neoplasias de los Tejidos Blandos/radioterapia , Neoplasias de los Tejidos Blandos/secundario , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Radiocirugia/efectos adversos , Estudios Retrospectivos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: MicroRNAs are small, noncoding RNAs that regulate the expression of posttranslational genes. The presence of some specific microRNAs has been associated with increased risk of both local recurrence and metastasis and worse survival in patients with osteosarcoma. Pathologic fractures in osteosarcoma are considered to be more the manifestation of a neoplasm with a more aggressive biological behavior than the cause itself of worse prognosis. However, this has not been proved at the biological or molecular level. Currently, there has not been a microRNA profiling study of patients who have osteosarcoma with and without pathologic fractures that has described differences in terms of microRNA profiling between these two groups and their correlation with biologic behavior. QUESTIONS/PURPOSES: (1) In patients with osteosarcoma of the extremities, how do the microRNA profiles of those with and without pathologic fractures compare? (2) What relationship do microRNAs have with local recurrence, risk of metastasis, disease-specific survival, and overall survival in osteosarcoma patients with pathologic fractures? METHODS: Between 1994 and 2013, 217 patients were diagnosed and treated at our institution for osteosarcoma of the extremities. Patients were excluded if (1) they underwent oncologic resection of the osteosarcoma at an outside institution (two patients) or (2) they were diagnosed with an extraskeletal osteosarcoma (29 patients) or (3) they had less than 1 year of clinical follow-up and no oncologic outcome (local recurrence, metastasis, or death) (four patients). A total of 182 patients were eligible. Of those, 143 were high-grade osteosarcomas. After evaluation of tumor samples before chemotherapy treatment, a total of 80 consecutive samples were selected for sequencing. Demographic and clinical comparison between the sequenced and non-sequenced patients did not demonstrate any differences, confirming that both groups were comparable. Diagnostic samples from the extremities of 80 patients with high-grade extremity osteosarcomas who had not yet received chemotherapy underwent microRNA sequencing for an ongoing large-scale osteosarcoma genome profiling project at our institution. Six samples were removed after a second look by a musculoskeletal pathologist who verified cellularity and quality of samples to be sequenced, leaving a total of 74 patients. Of these, two samples were removed as they were confirmed to be pelvic tumors in a second check after sequencing. The final study sample was 72 patients (11 patients with pathologic fractures and 61 without). Sequencing data were correlated with fractures and local recurrence, risk of metastasis, disease-specific survival, and overall survival through Kaplan-Meier analyses. RESULTS: Several microRNAs were expressed differently between the two groups. Among the markers with the highest differential expression (edgeR and DESeq algorithms), Hsa-mIR 656-3p, hsa-miR 493-5p, and hsa-miR 381-3p were upregulated in patients with pathologic fractures, whereas hsa-miR 363, hsa-miR 885-5p, and has-miR 20b-5p were downregulated. The highest differential expression fracture and nonfracture-associated microRNA markers also distinguished groups of patients with different metastasis risk, a well as different disease-specific and overall survival. Furthermore, the profile of pathologic fractures demonstrated a higher differential expression for microRNA markers that were previously associated with a higher risk of metastasis and lower survival rates in patients with osteosarcoma. CONCLUSIONS: In patients who have osteosarcoma, the microRNA profiles of those with pathologic fractures are different than of patients without pathologic fractures. The highest differential expression mircroRNA molecules in patients with pathologic fractures predict also higher risk of metastatic disease as well as worse disease-specific survival and overall survival. Furthermore, we found higher differential expression of microRNAs in the pathologic fracture group previously associated with poor prognosis. The higher risk of metastasis and poorer overall survival in patients with pathologic fractures is inherent to tumor aggressive biologic behavior. It is plausible that the fracture itself is not the direct cause of worse prognosis but another manifestation of tumor biologic aggressiveness. Identification of these molecules through liquid biopsies may help to determine which patients may benefit from surgery before fractures occur. The same technology can be applied to identify patterns of response to conventional chemotherapy, assisting in more specific and accurate systemic therapy. LEVEL OF EVIDENCE LEVEL: III, prognostic study.
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Neoplasias Óseas/genética , Fracturas Espontáneas/genética , Fracturas Espontáneas/mortalidad , MicroARNs/metabolismo , Osteosarcoma/genética , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Dietary restriction (DR), defined as reduced nutrient intake without malnutrition, is associated with longevity extension, improved glucose metabolism, and increased stress resistance, but also poor wound healing. Short-term preoperative DR followed by a return to normal feeding after surgery results in improved surgical outcomes in preclinical models. However, the effect of preoperative DR on wound healing and perioperative glucose homeostasis is currently unknown. Here, we tested the effects of two different preoperative DR regimens-protein restriction (PR) and methionine restriction (MR)-on wound healing and perioperative glucose homeostasis using an established murine model of wound healing in both nondiabetic and diabetic mice. MATERIALS AND METHODS: Surgical outcomes were tested using the McFarlane flap in nondiabetic and streptozotocin-induced diabetic mice. Short-term dietary preconditioning included 1 wk of PR or MR diet (1-2 wk) versus an isocaloric complete diet before surgery; all mice were returned to a complete diet postoperatively. Outcome measures of flap wound recovery included skin viability and laser Doppler imaging of flap perfusion and assessment of CD45+ cell infiltration. Glucose homeostasis was assessed by glucose tolerance testing and by perioperative glucose levels in the diabetic cohort. RESULTS: No significant differences were observed in percentage of viable skin, perfusion, or immune cell infiltration at 7-10 d after surgery in PR or MR mice compared with controls in healthy or diabetic mice. Preoperative glucose tolerance and postoperative glucose levels were however significantly improved by both PR and MR in diabetic mice. CONCLUSIONS: Short-term dietary preconditioning with PR or MR did not impair wound healing in nondiabetic or diabetic mice. However, both regimens reduced preoperative hyperglycemia in diabetic mice. Thus, brief preoperative dietary manipulations stand as strategies to potentially improve perioperative hyperglycemia with no deleterious effects on wound healing in mice.
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Dieta con Restricción de Proteínas/efectos adversos , Hiperglucemia/dietoterapia , Metionina , Cuidados Preoperatorios , Cicatrización de Heridas , Animales , Diabetes Mellitus Experimental/complicaciones , Hiperglucemia/etiología , Masculino , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Myxoid liposarcoma (MLS) is a subtype of liposarcoma characterized morphologically by lipomatous differentiation with a myxoid stroma. The purpose of this study was to review clinical and pathological information for patients treated for MLS at our institution to better understand neoadjuvant and adjuvant therapy. MATERIALS AND METHODS: An institutional database of sarcomas was queried for patients who were treated for MLS at our institution between 1992 and 2013. Survival curves were constructed using Kaplan-Meier analysis, and univariate and multivariate statistics were performed using the Cox-proportional hazards model and using linear regression. RESULTS: A total of 85 patients with myxoid liposarcoma were identified. The mean and median histologic response rate to treatment for patients who received preoperative radiation therapy was 77.6%. Five-year disease-free survival, distant metastasis-free survival, local recurrence-free survival, and overall survival were 78.6% (95% CI: 67.8-86.1), 84.7% (95% CI: 74.5-91.0), 95.6% (95% CI: 86.9-98.6), and 87.5% (95% CI: 77.2-93.3) respectively. On univariate analysis, there was a trend towards higher necrosis or treatment response rates in patients who received concurrent chemotherapy, 84.7% (95% CI: 75.9-93.4) and 69.5% (95% CI: 55.1-83.8), p=0.061. Tumor size was associated with inferior disease-free and overall survival. Hazard ratio for disease-free survival is 1.08 (per cm) (95% CI: 1.01-1.16), p=0.019. CONCLUSIONS: Myxoid liposarcoma exhibits histological response to chemotherapy and radiation therapy. Tumor size appears to be greatest predictor of long-term disease control and overall survival. We were not able to show that chemotherapy provides a clinical benefit with regard to local control, disease-free survival, or overall survival. However, it is important to note that the selected usage of chemotherapy in the highest risk patients confounds this analysis. Further investigation is needed to help better determine the optimal use of chemotherapy in this group of patients.
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BACKGROUND: Several studies have identified prognostic factors for patients with chondrosarcoma, but there are few studies investigating the accuracy of computationally intensive methods such as machine learning. Machine learning is a type of artificial intelligence that enables computers to learn from data. Studies using machine learning are potentially appealing, because of its possibility to explore complex patterns in data and to improve its models over time. QUESTIONS/PURPOSES: The purposes of this study were (1) to develop machine-learning algorithms for the prediction of 5-year survival in patients with chondrosarcoma; and (2) to deploy the best algorithm as an accessible web-based app for clinical use. METHODS: All patients with a microscopically confirmed diagnosis of conventional or dedifferentiated chondrosarcoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) Registry from 2000 to 2010. SEER covers approximately 30% of the US population and consists of demographic, tumor characteristic, treatment, and outcome data. In total, 1554 patients met the inclusion criteria. Mean age at diagnosis was 52 years (SD 17), ranging from 7 to 102 years; 813 of the 1554 patients were men (55%); and mean tumor size was 8 cm (SD 6), ranging from 0.1 cm to 50 cm. Exact size was missing in 340 of 1544 patients (22%), grade in 88 of 1544 (6%), tumor extension in 41 of 1544 (3%), and race in 16 of 1544 (1%). Data for 1-, 3-, 5-, and 10-year overall survival were available for 1533 (99%), 1512 (98%), 1487 (96%), and 977 (63%) patients, respectively. One-year survival was 92%, 3-year survival was 82%, 5-year survival was 76%, and 10-year survival was 54%. Missing data were imputed using the nonparametric missForest method. Boosted decision tree, support vector machine, Bayes point machine, and neural network models were developed for 5-year survival. These models were chosen as a result of their capability of predicting two outcomes based on prior work on machine-learning models for binary classification. The models were assessed by discrimination, calibration, and overall performance. The c-statistic is a measure of discrimination. It ranges from 0.5 to 1.0 with 1.0 being perfect discrimination and 0.5 that the model is no better than chance at making a prediction. The Brier score measures the squared difference between the predicted probability and the actual outcome. A Brier score of 0 indicates perfect prediction, whereas a Brier score of 1 indicates the poorest prediction. The Brier scores of the models are compared with the null model, which is calculated by assigning each patient a probability equal to the prevalence of the outcome. RESULTS: Four models for 5-year survival were developed with c-statistics ranging from 0.846 to 0.868 and Brier scores ranging from 0.117 to 0.135 with a null model Brier score of 0.182. The Bayes point machine was incorporated into a freely available web-based application. This application can be accessed through https://sorg-apps.shinyapps.io/chondrosarcoma/. CONCLUSIONS: Although caution is warranted, because the prediction model has not been validated yet, healthcare providers could use the online prediction tool in daily practice when survival prediction of patients with chondrosarcoma is desired. Future studies should seek to validate the developed prediction model. LEVEL OF EVIDENCE: Level III, prognostic study.
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Neoplasias Óseas/diagnóstico , Condrosarcoma/diagnóstico , Técnicas de Apoyo para la Decisión , Diagnóstico por Computador/métodos , Máquina de Vectores de Soporte , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Teorema de Bayes , Neoplasias Óseas/mortalidad , Neoplasias Óseas/terapia , Niño , Condrosarcoma/mortalidad , Condrosarcoma/terapia , Árboles de Decisión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Redes Neurales de la Computación , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Programa de VERF , Factores de Tiempo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
PURPOSE: Chordomas are malignant tumors arising from remnant notochordal tissue. Despite improved local control with preoperative/postoperative radiation therapy (RT), progression-free survival and overall survival (OS) remain poor in patients with high-risk features. Chordoma has been identified to express and activate platelet-derived growth factor receptor signaling. We conducted a phase 1 trial to identify the maximum tolerated dose (MTD), safety, and feasibility of nilotinib with RT as either preoperative or definitive treatment for patients with high-risk chordoma. METHODS AND MATERIALS: We recruited 23 patients with high-risk, nonmetastatic chordoma. High risk was defined as the presence of any of the following: local recurrence after surgery, previous intralesional resection, unplanned incomplete resection, unresectable or marginally resectable disease based on locally advanced stage, or declining surgery because of excessive morbidity. Patients were treated with nilotinib and concurrent RT to 50.4 Gy relative biological effectiveness (RBE) followed by surgery and postoperative RT to a cumulative dose up to 70.2 Gy RBE or definitively up to 77.4 Gy RBE without surgery. On completion of RT, patients were eligible to continue nilotinib until disease progression. RESULTS: In patients receiving nilotinib 200 mg twice daily with RT, 3 dose-limiting toxicities (DLT) occurred in 5 patients. One DLT was seen among 6 patients receiving nilotinib 200 mg daily with RT. Therefore, 200 mg daily was declared the maximum tolerated dose. Eleven additional patients received nilotinib with RT at the maximum tolerated dose, and 1 additional DLT occurred. The objective best response rate was 6% (1 of 18 patients, 95% confidence interval [CI], 0.1%-27%). The median progression-free survival was 58.15 months (95% CI, 39.10-∞). The median OS was 61.5 months (43.1-∞), and the 2-year OS rate was 95%. CONCLUSIONS: Nilotinib 200 mg/d with RT is safe and tolerated in patients with high-risk chordoma. Long-term follow-up is needed to understand whether nilotinib combined with RT, with or without surgery, adds greater improvement to progression-free survival or OS than with RT with or without surgery alone in patients with high-risk chordoma.
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Cordoma/tratamiento farmacológico , Cordoma/radioterapia , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Proton treatment slots are a limited resource. Therefore, we consider combined proton-photon treatments in which most fractions are delivered with photons and only a few with protons. We demonstrate how both modalities can be combined to optimally capitalize on the proton's ability to reduce normal tissue dose. METHODS: An optimal combined treatment must account for fractionation effects. We therefore perform simultaneous optimization of intensity-modulated proton (IMPT) and photon (IMRT) plans based on their cumulative biologically effective dose (BED). We demonstrate the method for a sacral chordoma patient, in whom the gross tumor volume (GTV) abuts bowel and rectum. RESULTS: In an optimal combination, proton and photon fractions deliver similar doses to bowel and rectum to protect these dose-limiting normal tissues through fractionation. However, proton fractions deliver, on average, higher doses to the GTV. Thereby, the photon dose bath is reduced. An optimized 30-fraction treatment with 10 IMPT fractions achieved more than 50% of the integral dose reduction in the gastrointestinal tract that is possible with 30 IMPT fractions (compared to 33% for a simple proton-photon combination in which both modalities deliver the same target dose). CONCLUSIONS: A limited number of proton fractions can best be used if protons hypofractionate parts of the GTV while maintaining near-uniform fractionation in dose-limiting normal tissues.
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Neoplasias Óseas/radioterapia , Cordoma/radioterapia , Neoplasias/radioterapia , Fotones/uso terapéutico , Terapia de Protones/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/métodos , Terapia Combinada/métodos , Fraccionamiento de la Dosis de Radiación , Humanos , Dosificación Radioterapéutica , Recto , SacroRESUMEN
Background Recent studies have suggested that the quantity and quality of adipose tissue and muscle, assessed on non-contrast computed tomography (CT), may serve as imaging biomarkers of survival in patients with and without neoplasms. Purpose To assess body composition measures that could serve as predictors of therapy response in patients with extremity soft tissue sarcomas treated with radiation therapy and surgery. Material and Methods The study was IRB-approved. Sixty patients had a history of extremity soft tissue sarcoma and underwent FDG-PET/CT prior to radiation therapy and surgical resection. Cross-sectional areas and CT attenuation (HU) of abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and psoas muscle were assessed on non-contrast CT. Clinical information on predictors of tumor recurrence and post-surgical wound infections were recorded. Cox proportional hazard models were used to determine longitudinal associations between body composition and tumor recurrence/wound infections. Results Twenty-three tumor recurrences occurred over a follow-up period of 43 ± 35 months. Higher SAT and lower psoas attenuation were associated with tumor recurrence which remained significant after adjustment for covariates ( P ≤ 0.01). There were 13 post-surgical wound infections. Higher VAT and SAT attenuation were associated with post-surgical wound infections ( P < 0.04); however, VAT attenuation lost significance after adjustment for covariates. Conclusion Abdominal adipose tissue and psoas muscle attenuation assessed on non-contrast CT may predict tumor recurrence and post-surgical infections in patients with extremity soft tissue sarcomas.
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Tejido Adiposo/diagnóstico por imagen , Composición Corporal , Recurrencia Local de Neoplasia/diagnóstico , Sarcoma/radioterapia , Sarcoma/cirugía , Tomografía Computarizada por Rayos X/métodos , Extremidades/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoma/diagnóstico por imagen , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Venous thromboembolism (VTE) is known to be independently associated with both orthopaedic surgery and malignancy. Patients undergoing surgery for musculoskeletal malignancies are at an increased risk for thromboembolic events. Although VTE can lead to serious morbidity and mortality, the potential complications of prophylactic anticoagulation call for a greater understanding of a patient's risk factors, as well as more rigorous guidelines for prophylactic anticoagulation regimens. The aims of this study were to 1) Analyze the rate of VTE in patients surgically treated for primary bone sarcoma; 2) Identify risk factors for VTE in patients with primary bone sarcoma; 3) Discuss the complications associated with prophylactic anticoagulation in patients with primary bone sarcoma. METHODS: This retrospective study identified all patients 18 years and older treated surgically at our institution for a primary bone sarcoma between 1990 and 2015. All patients with at least 90 days of post-operative follow-up from the index surgery were analyzed for occurrence of VTE. Those with an event were compared to those without to identify predictors of VTE. RESULTS: 21 patients (5.5%) had a clinically symptomatic, radiographically confirmed VTE within 90 days of index surgery (12 DVT, 9 PE). Higher preoperative white blood cell count (OR 1.15, 95% CI 1.01-1.29) and post-operative wound complications (OR 5.01, 95% CI 1.93-13.55) were found to be independent risk factors for VTE. No differences in terms of efficacy were found among medications. The risk of wound complications increased significantly in patients who received chemical prophylaxis (OR 2.21, 95% CI 1.00-4.87). CONCLUSIONS: Our patient population had a relatively low rate of VTE as compared to the literature. Preoperative white blood cell count (WBC) and post-operative wound complications were both found to be independently associated predictors for VTE in patients with primary bone sarcoma. An elevated WBC may reflect hemoconcentration which per se is prothrombotic in nature. Aggressive DVT prophylaxis may, counter intuitively, increase the risk of thromboembolic events due to prolonged immobilization and additional surgeries that usually occur when addressing postoperative wound complications such as postoperative hematoma and wound dehiscence that may relate to overanticoagulation. Prospective randomized trials comparing different medications in combination with compressive devices are needed to assess efficacy with the lowest complication profile. Simpler protocols may increase patient compliance to prophylactic treatment.
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Neoplasias Óseas/cirugía , Procedimientos Ortopédicos/efectos adversos , Complicaciones Posoperatorias , Sarcoma/cirugía , Tromboembolia Venosa/diagnóstico , Adulto , Neoplasias Óseas/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Sarcoma/patología , Tromboembolia Venosa/etiología , Adulto JovenRESUMEN
PURPOSE: To conduct phase 1 and 2 trials with photon intensity modulated radiation therapy and intensity modulated proton therapy (IMPT) arms to selectively escalate the retroperitoneal sarcoma preoperative radiation dose to tumor volume (clinical target volume [CTV] 2) that is judged to be at a high risk for positive margins and aim to reduce local recurrence. We report on the IMPT study arm in phase 1. METHODS AND MATERIALS: Patients aged ≥18 years with primary or locally recurrent retroperitoneal sarcoma were treated with preoperative IMPT, 50.4 GyRBE in 28 fractions, to CTV1 (gross tumor volume and adjacent tissues at risk of subclinical disease) with a simultaneous integrated boost to CTV2 to doses of 60.2, 61.6, and 63.0 GyRBE in 28 fractions of 2.15, 2.20, and 2.25 GyRBE, respectively. The primary objective of the phase 1 study was to determine the maximum tolerated dose to CTV2, which will be further tested in the phase 2 study. RESULTS: Eleven patients showed increasing IMPT dose levels without acute dose limiting toxicities that prevented dose escalation to maximum tolerated dose. Acute toxicity was generally mild with no radiation interruptions. No unexpected perioperative morbidity was noted. Eight months postoperatively, one patient developed hydronephrosis that was treated by stent with ureter dissected off tumor and received 57.5 GyRBE. Retained ureter(s) was (were) subsequently constrained to 50.4 GyRBE without further problem. With an 18-month median follow-up, there were no local recurrences. CONCLUSIONS: IMPT dose escalation to CTV2 to 63 GyRBE was achieved without acute dose limiting toxicities. The phase 2 study of IMPT will accrue patients to that dose. Parallel intensity modulated radiation therapy phase 1 arm is currently accruing at the initial dose level. Ureters that undergo a high dose radiation and/or surgery are at risk for late hydro-ureter. Future studies will constrain retained ureters to 50.4 GyRBE to avoid ureteral stricture.
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The development of multidrug resistance (MDR) in cancer cells to chemotherapy drugs continues to be a major clinical problem. MicroRNAs (miRNA, miR) play an important role in regulating tumour cell growth and survival; however, the role of miRs in the development of drug resistance in osteosarcoma cells is largely uncharacterized. We sought to identify and characterize human miRs that act as key regulators of MDR in osteosarcoma. We utilized a miR microarray to screen for differentially expressed miRs in osteosarcoma MDR cell lines. We determined the mechanisms of the deregulation of expression of miR-15b in osteosarcoma MDR cell lines, and its association with clinically obtained tumour samples was examined in tissue microarray (TMA). The significance of miR-15b in reversing drug resistance was evaluated in a mouse xenograft model of MDR osteosarcoma. We identified miR-15b as being significantly (P < 0.01) downregulated in KHOSMR and U-2OSMR cell lines as compared with their parental cell lines. We found that Wee1 is a target gene of miR-15b and observed that transfection with miR-15b inhibits Wee1 expression and partially reverses MDR in osteosarcoma cell lines. Systemic in vivo administration of miR-15b mimics sensitizes resistant cells to doxorubicin and induces cell death in MDR models of osteosarcoma. Clinically, reduced miR-15b expression was associated with poor patient survival. Osteosarcoma patients with low miR-15b expression levels had significantly shorter survival times than patients with high expression levels of miR-15b. These results collectively indicate that MDR in osteosarcoma is associated with downregulation of miR-15b, and miR-15b reconstitution can reverse chemotherapy resistance in osteosarcoma.
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Neoplasias Óseas/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , MicroARNs/biosíntesis , Osteosarcoma/metabolismo , ARN Neoplásico/biosíntesis , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Osteosarcoma/genética , Osteosarcoma/patología , Proteínas Tirosina Quinasas/biosíntesis , Proteínas Tirosina Quinasas/genética , ARN Neoplásico/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND OBJECTIVES: We sought to examine our outcomes with advanced preoperative and intraoperative radiation therapy (XRT) combined with aggressive en bloc surgical resection of retroperitoneal sarcoma (RPS) as a strategy to minimize the risk of local recurrence (LR). METHODS: From 2003 to 2013, 46 patients with RPS received preoperative XRT followed by radical en bloc surgical resection, with or without intraoperative electron radiation therapy (IOERT). Clinical and pathologic variables predictive of LR and distant recurrence (DR) were evaluated. RESULTS: Thirty-seven patients had primary tumors and 80% were intermediate grade or higher. All patients received preoperative XRT to a median dose of 50.4 Gy and underwent complete (R0/R1) tumor resection, and 16 patients received IOERT. After a median follow-up of 53 months, 33 (72%) patients were disease-free, and there were 8 (17%) DRs, 2 (4%) abdominal recurrences outside of the XRT field, and 5 (10.9%) LRs. High tumor grade and recurrent disease at presentation were the only factors associated with higher rates of recurrence. CONCLUSIONS: Excellent local control can be achieved with a coordinated strategy of preoperative (±intraoperative) XRT combined with aggressive en bloc surgical resection of RPS, but systemic failure remains a problem for higher-grade tumors.
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Neoplasias Retroperitoneales/radioterapia , Neoplasias Retroperitoneales/cirugía , Sarcoma/radioterapia , Sarcoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Electrones , Femenino , Humanos , Cuidados Intraoperatorios/métodos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Cuidados Preoperatorios/métodos , Neoplasias Retroperitoneales/patología , Estudios Retrospectivos , Sarcoma/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Multi-drug resistance (MDR) remains a significant obstacle to successful chemotherapy treatment for osteosarcoma patients. One of the central causes of MDR is the overexpression of the membrane bound drug transporter protein P-glycoprotein (P-gp), which is the protein product of the MDR gene ABCB1. Though several methods have been reported to reverse MDR in vitro and in vivo when combined with anticancer drugs, they have yet to be proven useful in the clinical setting. RESULTS: The meta-analysis demonstrated that a high level of P-gp may predict poor survival in patients with osteosarcoma. The expression of P-gp can be efficiently blocked by the clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 system (CRISPR-Cas9). Inhibition of ABCB1 was associated with reversing drug resistance in osteosarcoma MDR cell lines (KHOSR2 and U-2OSR2) to doxorubicin. MATERIALS AND METHODS: We performed a meta-analysis to investigate the relationship between P-gp expression and survival in patients with osteosarcoma. Then we adopted the CRISPR-Cas9, a robust and highly efficient novel genome editing tool, to determine its effect on reversing drug resistance by targeting endogenous ABCB1 gene at the DNA level in osteosarcoma MDR cell lines. CONCLUSION: These results suggest that the CRISPR-Cas9 system is a useful tool for the modification of ABCB1 gene, and may be useful in extending the long-term efficacy of chemotherapy by overcoming P-gp-mediated MDR in the clinical setting.
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Antibióticos Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Sistemas CRISPR-Cas , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Edición Génica/métodos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Humanos , Osteosarcoma/metabolismo , Osteosarcoma/patología , TransfecciónRESUMEN
Achieving negative surgical margins can be challenging for skull base and spinal/paraspinal sarcomas. Data shows that pre- or post-operative radiation therapy improves local control. Delivery of sufficient dose of radiation can be difficult because of the proximity to normal organs/tissues that are sensitive to radiation therapy and therefore dose-limiting. A comprehensive literature search was conducted using PubMed search engine. The scarcity of prospective, randomized data limits the ability to generate definitive treatment recommendations. J. Surg. Oncol. 2016;114:564-569. © 2016 Wiley Periodicals, Inc.