RESUMO
BACKGROUND: Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) after surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined because the natural history of RP-LPS after treatment is poorly understood. This study evaluated the long-term risk of recurrence and disease-specific survival (DSS) for a cohort of patients with at least 10 years of progression-free survival (10yr-PFS) from their primary resection. METHODS: The prospective University of California, Los Angeles (UCLA) Sarcoma Database identified RP-LPS patients with 10yr-PFS after initial resection. The patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. The time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS. RESULTS: From 1972 to 2010, 76 patients with RP-LPS had at least 10 years of follow-up evaluation. Of these 76 patients, 39 (51%) demonstrated 10yr-PFS. The median follow-up period was 15 years (range 10-33 years). Among the 10yr-PFS patients, 49% (19/39) experienced a recurrence at least 10 years after surgery. Of those who experienced recurrence, 42% (8/19) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or perioperative treatment with radiation or chemotherapy. CONCLUSION: Patients who have primary RP-LPS treated with surgical resection ± multimodality therapy face a long-term risk of recurrence and disease-specific death unacknowledged by current surveillance imaging guidelines. Among the patients with 10yr-PFS, 49% experienced a recurrence, and 42% of those died of disease. These findings suggest a need for lifelong surveillance imaging for patients with RP-LPS.
Assuntos
Lipossarcoma , Neoplasias Retroperitoneais , Humanos , Estudos Prospectivos , Lipopolissacarídeos , Estudos Retrospectivos , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Retroperitoneais/cirurgia , Lipossarcoma/diagnóstico por imagem , Lipossarcoma/cirurgia , Lipossarcoma/patologia , Recidiva Local de Neoplasia/patologiaRESUMO
OPINION STATEMENT: The role of targeted therapy is firmly established for gastrointestinal stromal tumors (GISTs); other modalities for targeting this disease are necessary for recurrent and refractory disease. There are several lines of evidence pointing to an active role of the immune system in GIST. Preclinical and clinical studies revealed that the most common type of immune cell infiltration in GISTs is tumor-associated macrophages (TAMs). The mechanism of how TAMs sculpt the tumor microenvironment in GIST is not clear, but it seems that the presence of immunosuppressive regulatory T cells (Tregs) is correlated with the number of TAMs, thus linking macrophages to immunosuppression. CD3+ T cells and NK infiltrates are found in the GIST microenvironment and carry some prognostic value. In early clinical trials, there is evidence for an active role for immunotherapy in treating GIST patients. Moreover, preclinical evidence has indicated that combining TKIs with checkpoint blockers may be synergistic in murine GIST models. Overall, there is substantial preclinical and clinical evidence to support a role for immunoregulation in GIST and further studies will be important for the development of immunotherapies for GIST.
Assuntos
Tumores do Estroma Gastrointestinal/terapia , Imunoterapia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/imunologia , Humanos , Mesilato de Imatinib/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapia , Macrófagos Associados a Tumor/imunologiaRESUMO
BACKGROUND: There is conflicting evidence regarding the role of chemotherapy for high-grade soft tissue sarcoma (STS) in adults. We sought to characterize patterns of chemotherapy use, including multiagent and neoadjuvant chemotherapy, in the United States. PATIENTS AND METHODS: Using the National Cancer Database, we identified 19,969 adult patients who underwent surgical resection for primary high-grade STS from 2004 to 2016. Using logistic regression, we examined factors associated with overall, multiagent, and neoadjuvant chemotherapy use. RESULTS: Chemotherapy was administered to 22% (n=4,377) of the study population. Among patients treated using chemotherapy, 85% received multiagent treatment and 47% received neoadjuvant treatment. On multivariate analysis, factors associated with chemotherapy use included tumor size, depth, histology, and primary site; receipt of radiation treatment; younger age; higher patient income; and academic treatment facility. Factors associated with multiagent chemotherapy use included tumor histology, tumor primary site, and younger age. Factors associated with neoadjuvant chemotherapy use included tumor size, depth, margin status, and primary site; receipt of radiation treatment; higher patient income; academic treatment facility type; and distance to treatment facility. Treatment at a high-volume facility was the only factor associated with overall, multiagent, and neoadjuvant chemotherapy use. No significant temporal trend was seen in overall, multiagent, or neoadjuvant chemotherapy use. CONCLUSIONS: Overall chemotherapy use was low (22%). The variability in chemotherapy use was driven by clinical, patient, demographic, and facility factors. Among patients treated with chemotherapy, the use of multiagent chemotherapy was high (85%), and nearly half received neoadjuvant therapy. There was a discrepancy in the use of chemotherapy-including neoadjuvant and multiagent chemotherapy-between high- and low-volume treatment centers.
Assuntos
Sarcoma , Adulto , Quimioterapia Adjuvante , Bases de Dados Factuais , Humanos , Terapia Neoadjuvante , Estudos Retrospectivos , Sarcoma/tratamento farmacológico , Sarcoma/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Ewing's sarcoma is a recalcitrant tumor greatly in need of more effective therapy. The aim of this study was to determine the efficacy of eribulin on a doxorubicin (DOX)-resistant Ewing's sarcoma patient derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma PDOX model was previously established in the right chest wall of nude mice from tumor resected form the patient's right chest wall. In the previous study, the Ewing's sarcoma PDOX was resistant to doxorubicin (DOX) and sensitive to palbociclib and linsitinib. In the present study, the PDOX models were randomized into three groups when the tumor volume reached 60 mm3 : G1, untreated control (n = 6); G2, DOX treated (n = 6), intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, Eribulin treated (n = 6, intravenous (i.v.) injection, weekly for 2 weeks). All mice were sacrificed on day 15. Changes in body weight and tumor volume were assessed two times per week. Tumor weight was measured after sacrifice. DOX did not suppress tumor growth compared to the control group (P = 0.589), consistent with the previous results in the patient and PDOX. Eribulin regressed tumor size significantly compared to G1 and G2 (P = 0.006, P = 0.017) respectively. No significant difference was observed in body weight among any group. Our results demonstrate that eribulin is a promising novel therapeutic agent for Ewing's sarcoma.
Assuntos
Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/administração & dosagem , Cetonas/administração & dosagem , Sarcoma de Ewing/tratamento farmacológico , Administração Intravenosa , Animais , Peso Corporal/efeitos dos fármacos , Doxorrubicina/farmacologia , Esquema de Medicação , Furanos/farmacologia , Humanos , Injeções Intraperitoneais , Cetonas/farmacologia , Camundongos , Camundongos Nus , Distribuição Aleatória , Sarcoma de Ewing/patologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer, resistant to conventional chemotherapy. A patient with high-grade USCS from a striated muscle was implanted orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3 : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, temozolomide (TEM) (25 mg/kg, p.o., daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance twice a week. TEM significantly inhibited tumor volume growth compared to the untreated control and the DOX-treated group on day 14 after treatment initiation: control (G1): 343 ± 78 mm3 ; DOX (G2): 308 ± 31 mm3 , P = 0.272; TEM (G3): 85 ± 21 mm3 , P < 0.0001. TEM significantly regressed the tumor volume compared to day 0 (P = 0.019). There were no animal deaths in any group. The body weight of treated mice was not significantly different in any group. Tumors treated with DOX were comprised of spindle-shaped viable cells without apparent necrosis or inflammatory changes. In contrast, tumors treated with TEM showed extensive tumor necrosis. The present study demonstrates the potential power of matching the patient with an effective drug and saving the patient needless toxicity from ineffective drugs.
Assuntos
Doxorrubicina/farmacologia , Medicina de Precisão , Sarcoma/tratamento farmacológico , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Sarcoma/metabolismo , Sarcoma/patologiaRESUMO
Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1-R. There was no significant body-weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1-R-GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first-line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1-R.
Assuntos
Doxorrubicina/administração & dosagem , Lipossarcoma/tratamento farmacológico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Salmonella typhimurium/fisiologia , Sarcoma/tratamento farmacológico , Idoso , Animais , Peso Corporal , Terapia Combinada , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Amplificação de Genes , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lipossarcoma/genética , Masculino , Camundongos , Distribuição Aleatória , Salmonella typhimurium/genética , Sarcoma/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.
Assuntos
Liases de Carbono-Enxofre/uso terapêutico , Doxorrubicina/uso terapêutico , Melanoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Animais , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Modelos Animais de Doenças , Docetaxel , Feminino , Indazóis , Camundongos , Camundongos Nus , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Taxoides/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general.
Assuntos
Neoplasias/microbiologia , Salmonella typhimurium , Sarcoma/terapia , Idoso , Animais , Linfócitos T CD8-Positivos , Doxorrubicina/uso terapêutico , Feminino , Proteínas de Fluorescência Verde/metabolismo , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Infecções por Salmonella , Salmonella typhimurium/patogenicidade , Sarcoma/microbiologiaRESUMO
Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fibrossarcoma/tratamento farmacológico , Infecções por Salmonella/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Fibrossarcoma/microbiologia , Humanos , Indazóis , Irinotecano/administração & dosagem , Masculino , Camundongos Nus , Pirimidinas/administração & dosagem , Distribuição Aleatória , Infecções por Salmonella/microbiologia , Salmonella typhimurium/fisiologia , Sulfonamidas/administração & dosagem , Temozolomida/administração & dosagem , Carga Tumoral/efeitos dos fármacosRESUMO
Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100â¯mm3: G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future.
Assuntos
Liases de Carbono-Enxofre/uso terapêutico , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Lipossarcoma/tratamento farmacológico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Idoso , Animais , Peso Corporal/efeitos dos fármacos , Liases de Carbono-Enxofre/farmacologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Humanos , Lipossarcoma/patologia , Masculino , Camundongos Nus , Piperazinas/farmacologia , Piridinas/farmacologia , Proteínas Recombinantes/farmacologiaRESUMO
Melanoma is a recalcitrant cancer. To improve and individualize treatment for this disease, we previously developed a patient-derived orthotopic xenograft (PDOX) model for melanoma. We previously reported the individual efficacy of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and recombinant methioninase (rMETase) for melanoma in the PDOX models of this disease. In the present study, we evaluated the efficacy of the combination of S. typhimurium A1-R with orally-administered rMETase (o-rMETase) for BRAF-V600E-negative melanoma in a PDOX model. Three weeks after implantation, 60 PDOX mouse models were randomized into six groups of 10 mice each: untreated control, temozolomide (TEM); o-rMETase; S. typhimurium A1-R; TEM + rMETase, S. typhimurium A1-R + rMETase. All treatments inhibited tumor growth compared to untreated control (TEM: p < 0.0001, rMETase: p < 0.0001, S. typhimurium A1-R: p < 0.0001, TEM + rMETase: p < 0.0001, S. typhimurium A1-R + rMETase: p < 0.0001). The most effective was the combination of S. typhimurium A1-R + o-rMETase which regressed this melanoma PDOX, thereby indicating a new paradigm for treatment of metastatic melanoma.
Assuntos
Antineoplásicos/uso terapêutico , Liases de Carbono-Enxofre/uso terapêutico , Melanoma/terapia , Pseudomonas putida/enzimologia , Salmonella typhimurium , Temozolomida/uso terapêutico , Administração Oral , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Liases de Carbono-Enxofre/administração & dosagem , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Humanos , Masculino , Melanoma/genética , Melanoma/microbiologia , Melanoma/patologia , Camundongos Nus , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Salmonella typhimurium/fisiologia , Temozolomida/administração & dosagemRESUMO
Our laboratory pioneered patient-derived orthotopic xenograft (PDOX) mouse models using surgical orthotopic implantation (SOI). PDOX models are patient-like, in contrast to the ectopic subcutaneous-transplant cancer models. In the present study, we demonstrate that an undifferentiated pleomorphic soft-tissue sarcoma (UPS-STS) PDOX model acquired bright RFP-expressing stroma through one passage in red fluorescent protein (RFP) transgenic mice, which upon passage to non-colored nude mice was non-invasively imageable. A PDOX nude mouse model of UPS-STS was established in the biceps femoris of nude mice. After the tumors grew to a diameter of 10 mm, the tumors were subsequently passaged to RFP transgenic mice, and after tumor growth were then passaged to non-transgenic nude mice. Tumors were divided into small fragments and transplanted in the biceps femoris at each passage. The OV100 Small Animal Fluorescence Imaging System and FV1000 laser scanning confocal microscope were used to image RFP fluorescence in the UPS-STS PDOX models. UPS-STS PDOX tumors, previously grown in RFP transgenic nude mice for only one passage, had very bright fluorescence and after passage to non-transgenic nude mice maintained the bright fluorescence and were non-invasively imageable. FV1000 confocal imaging revealed diffusely distributed bright RFP stromal cells in the PDOX tumor, both in RFP transgenic mice and after passage to non-transgenic mice. These results demonstrate a powerful method to make the PDOX UPS-STS model brightly fluorescent for non-invasive imaging, as well as for confocal microscopy of individual stromal cells associated with the tumor. The RFP-labeled UPS PDOX has the potential to rapidly screen for novel effective agents for individual patients, including stroma-targeting drugs, whereby the stromal cells are a visual target. J. Cell. Biochem. 118: 361-365, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Rastreamento de Células/métodos , Proteínas Luminescentes/biossíntese , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Sarcoma/metabolismo , Sarcoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Humanos , Proteínas Luminescentes/genética , Camundongos , Camundongos Nus , Camundongos Transgênicos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Sarcoma/tratamento farmacológico , Sarcoma/genética , Proteína Vermelha FluorescenteRESUMO
PURPOSE: Cell-based therapies such as concentrated bone marrow aspirate (BMA) with allograft and demineralized bone matrix (DBM) have been developed as a potential alternative to iliac crest bone graft (ICBG) in spinal fusion. BMA contains mesenchymal stem cells (MSCs) and growth factors that confer osteogenic and osteoinductive potential to osteoconductive scaffolds like allograft and DBM. It is well established that there is an age-related decline in bone marrow MSC population and efficacy. This might be problematic in spine arthrodesis when utilizing BMA derived from elderly patients as a fusion aide. The goal of this study was to describe the outcomes of concentrated BMA with allograft and DBM in elderly patients undergoing posterolateral and interbody lumbar fusion. METHODS: Thirty-one patients, age 65 and older, with a minimum of 12 months follow-up underwent combined primary posterolateral and transforaminal lumbar interbody fusion. Radiographic fusion, complications, reoperation rates and clinical outcomes were assessed. Multiple logistic regression analysis was used to examine the effects of variables such as patient age, gender, smoking, osteoporosis, Charlson co-morbidity index score, single versus multilevel fusion, length of hospital stay, and length of follow-up time on fusion outcome. RESULTS: The overall rate of a solid fusion (i.e. the concomitant presence of solid posterolateral and interbody fusion in a patient) was 83.9 % (26/31). Specifically, radiographic evidence of a successful posterolateral fusion was 83.9 % (26/31) while the radiographic evidence of a successful interbody fusion was 96.8 % (30/31). Using logistic regression analysis, none of the variables of interest had an association with non-solid unions. One (3.2 %) patient developed a seroma and one (3.2 %) patient developed clinical pseudarthrosis. None of the patients developed hardware-related complications or graft donor site morbidities. Five (16.1 %) patients required reoperation. Excellent or good results were achieved in 83.9 % of patients. CONCLUSIONS: Despite the concerns of reduced fusion potential in elderly patients, autologous concentrated BMA mixed with allograft and DBM in posterolateral and interbody fusions can achieve successful fusion rates with good clinical outcomes and low complication rates.
Assuntos
Transplante de Medula Óssea/métodos , Matriz Óssea/transplante , Transplante Ósseo/métodos , Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Feminino , Humanos , Ílio/transplante , Modelos Logísticos , Masculino , Estudos Retrospectivos , Transplante Autólogo , Transplante Homólogo , Resultado do TratamentoRESUMO
The use of image-guided percutaneous core needle biopsy (PCNB) to obtain tissue diagnosis of musculoskeletal lesions has become the standard of care in adult patients with a success rate of over 80%. Previous reports indicate a similar success rate in diagnosing pediatric solid tumors. In this large study, we analyzed >10 years of data in which PCNB was used for tissue diagnosis of musculoskeletal lesions in children; we evaluated the histopathologic accuracy, anesthetic requirements, and complications of these procedures. In 122 children, tissue diagnosis was successfully obtained in 82% of cases, and there were 0 complications associated with the procedure. There was a significantly higher PCNB diagnostic success rate in malignant lesions (93%). These data suggest that the use of PCNB is a safe and effective means of diagnosing musculoskeletal lesions in children.
Assuntos
Biópsia Guiada por Imagem , Doenças Musculoesqueléticas/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Adolescente , Adulto , Biópsia por Agulha , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Doenças Musculoesqueléticas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Aurora kinases play important roles in cell division and are frequently overexpressed in human cancer. AMG 900 is a novel pan-Aurora kinase inhibitor currently being tested in Phase I clinical trials. We aimed to evaluate the in vitro activity of AMG 900 in a panel of 44 human breast cancer and immortalized cell lines and identify predictors of response. AMG 900 inhibited proliferation at low nanomolar concentrations in all cell lines tested. Response was further classified based on the induction of lethality. 25 cell lines were classified as highly sensitive (lethality at 10 nM of AMG 900 >10 %), 19 cell lines as less sensitive to AMG 900 (lethality at 10 nM of AMG 900 <10 %). Traditional molecular subtypes of breast cancer did not predict for this differential response. There was a weak association between AURKA amplification and response to AMG 900 (response ratio = 2.53, p = 0.09). mRNA expression levels of AURKA, AURKB, and AURKC and baseline protein levels of Aurora kinases A and B did not significantly associate with response. Cell lines with TP53 loss of function mutations (RR = 1.86, p = 0.004) and low baseline p21 protein levels (RR = 2.28, p = 0.0004) were far more likely to be classified as highly sensitive to AMG 900. AMG 900 induced p53 and p21 protein expression in cell lines with wt TP53. AMG 900 caused the accumulation of cells with >4 N DNA content in a majority of cell lines independently of sensitivity and p53 status. AMG 900 induced more pronounced apoptosis in highly sensitive p53-dysfunctional cell lines. We have found that AMG 900 is highly active in breast cancer cell lines and that TP53 loss of function mutations as well as low baseline expression of p21 protein predict strongly for increased sensitivity to this compound in vitro.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase A/antagonistas & inibidores , Ftalazinas/farmacologia , Proteína Supressora de Tumor p53/genética , Apoptose , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/genética , Aurora Quinase B/metabolismo , Aurora Quinase C/antagonistas & inibidores , Aurora Quinase C/genética , Aurora Quinase C/metabolismo , Neoplasias da Mama , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Expressão Gênica , Humanos , Mutação , Proteína Supressora de Tumor p53/metabolismoRESUMO
Chemotherapeutic induction of radiation recall (RR) is a rare event in which a chemotherapeutic agent given days to years after radiation therapy causes an inflammation reaction of the tissues within the irradiated area-"recalling" increased radiation effects to that area. In this unique case, a 14-year-old girl with a synovial sarcoma of the forearm was treated with neoadjuvant chemotherapy and radiation therapy. Gemcitabine was administered in an adjuvant setting inducing a RR reaction. The severity of the inflammation resulted in a forearm myositis secondarily causing a compartment syndrome that was treated with several prolonged courses of corticosteroids. The symptoms of RR and compartment syndrome have resolved 1 year postonset, although magnetic resonance imaging continues to show myositis and soft-tissue edema. This case highlights the need to maintain a heightened awareness to recognizing the signs and symptoms of RR and the potential severity of RR in pediatric cancer patients in conjunction with chemotherapeutic agents used more frequently in adults.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Síndromes Compartimentais/etiologia , Desoxicitidina/análogos & derivados , Radiodermite/complicações , Adolescente , Terapia Combinada , Desoxicitidina/efeitos adversos , Feminino , Humanos , Radiodermite/induzido quimicamente , Sarcoma Sinovial/terapia , GencitabinaRESUMO
BACKGROUND: Subjective, varying criteria identify "low-grade" dedifferentiation in well-differentiated/dedifferentiated liposarcoma (WD/DDLPS). The value of mitotic rate (MR) in defining DDLPS is not confirmed. We studied all patients with the resection of their primary or first recurrence retroperitoneal WD/DDLPS at our institution to determine the value of MR in diagnosing DDLPS and if MR associates with patient survival. DESIGN: Ninety-eight patients with retroperitoneal WD/DDLPS operated at our institution from January 1, 1989 to December 31, 2013 were included. Cases were defined as acellular (AC) WDLPS, LS0-4 (tumors with non-lipogenic areas and MR 0-4/10HPFs) or LS5+(non-lipogenic areas, MR≥5/10 HPFs) and graded using the French system. Kaplan-Meier survival estimates with log-rank test and multivariate Cox (mCox) analyses were performed. RESULTS: Follow-up was available on all patients (median 9.3 y, range 0.02-23.16 y). Kaplan-Meier demonstrated a significant ( P =0.004) difference in disease-specific survival (DSS) among the 3 groups. mCox demonstrated no difference in DSS between the AC and LS0-4 groups (HR 1.51; 95% CI 0.57-3.99, P =0.412) but significantly lower DSS in the LS5+group compared with the AC group (HR 2.68; 95% CI 1.07-6.71, P =0.035). The difference in DSS was not significant between grade 2 and 3 tumors ( P =0.094). DSS between MR 5-19/10 HPFs and MR20+/10 HPFs subgroups was significant ( P =0.007) but by mCox did not reach significance (HR 2.47; 95% CI 0.96-6.35, P =0.060). CONCLUSION: This study confirms that MR distinguishes DDLPS from WDLPS with non-lipogenic areas, also known as cellular WDLPS. For consistency in diagnosis and research, only WD/DDLPS with≥5 mitoses/10 HPFs should be considered DDLPS.
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Lipoma , Lipossarcoma , Humanos , Índice Mitótico , Lipossarcoma/patologia , Lipoma/patologia , MitoseRESUMO
BACKGROUND: There is no consensus as to which surgical approach to the treatment of giant cell tumor of bone is most appropriate or which patients are at a higher risk for recurrence or metastasis. QUESTIONS/PURPOSES: Therefore, we asked: (1) Are there subsets of patients who are associated with a more recalcitrant disease course? And (2) are surgeons appropriately stratifying patients by identifying risk factors for increased local recurrence and pulmonary metastases? METHODS: We retrospectively reviewed the records of 230 patients with giant cell tumor of bone treated from 1980 to 2010, stratifying them by primary versus recurrent disease and by surgical treatment. From the records, we determined local recurrence, metastatic disease, and complications of treatment. The median follow up was 47 months (range, 0.1-312 months). RESULTS: Overall incidence of local recurrence was 10% and pulmonary metastasis was 2%. When stratified by surgical treatment, the incidence of local recurrence among patients undergoing intralesional curettage (12%) was greater than in those undergoing resection (2%). The incidence of local recurrence among primary tumors, independent of treatment, was 9%, whereas the incidence of local recurrence after treatment of recurrent lesions was 16%. The incidence of pulmonary metastases was similar, regardless of treatment or whether primary or recurrent. CONCLUSIONS: Our observations suggest there are subsets of patients with giant cell tumor of bone who are at higher risk of recurrence and should be clinically followed more closely. This should allow surgeons to provide patients with more informed expectations. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Assuntos
Neoplasias Ósseas/cirurgia , Curetagem , Tumor de Células Gigantes do Osso/cirurgia , Tíbia , Adolescente , Adulto , Idoso , Neoplasias Ósseas/patologia , Criança , Feminino , Neoplasias Femorais/cirurgia , Tumor de Células Gigantes do Osso/patologia , Humanos , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Rádio (Anatomia) , Estudos Retrospectivos , Neoplasias de Tecidos Moles/secundário , Adulto JovemRESUMO
The purpose of this study was to evaluate 18F-FLT PET/CT as an early prognostic imaging biomarker of long-term overall survival and disease-specific survival (DSS) in soft-tissue sarcoma (STS) patients treated with neoadjuvant therapy (NAT) and surgical resection. Methods: This was a 10-y follow-up of a previous single-center, single-arm prospective clinical trial. Patients underwent 18F-FLT PET/CT before treatment (PET1) and after NAT (PET2). Posttreatment pathology specimens were assessed for tumor necrosis or fibrosis and for Ki-67 and thymidine kinase 1 expression. Maximally selected cutoffs for PET and histopathologic factors were applied. Survival was calculated from the date of subject consent to the date of death or last follow-up. Results: The study population consisted of 26 patients who underwent PET1; 16 of the 26 with primary STS underwent PET2. Thirteen deaths occurred during a median follow-up of 104 mo. In the overall cohort, overall survival was longer in patients with a low than a high PET1 tumor SUVmax (dichotomized by an SUVmax of ≥8.5 vs. <8.5: not yet reached vs. 49.7 mo; P = 0.0064). DSS showed a trend toward significance (P = 0.096). In a subanalysis of primary STS, DSS was significantly longer in patients with a low PET1 tumor SUVmax (dichotomized by an SUVmax of ≥8 vs. <8; P = 0.034). There were no significant 18F-FLT PET response thresholds corresponding to DSS or overall survival after NAT at PET2. Conclusion:18F-FLT PET may serve as a prognostic baseline imaging biomarker for DSS in patients with primary STS.