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1.
Br J Cancer ; 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734790

RESUMO

Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues and can occur almost anywhere in the body. Their rarity, and the heterogeneity of subtype and location, means that developing evidence-based guidelines is complicated by the limitations of the data available. This makes it more important that STS are managed by expert multidisciplinary teams, to ensure consistent and optimal treatment, recruitment to clinical trials, and the ongoing accumulation of further data and knowledge. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field. These guidelines are an update of the previous versions published in 2010 and 2016 [1, 2]. The original guidelines were drawn up by a panel of UK sarcoma specialists convened under the auspices of the British Sarcoma Group (BSG) and were intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. This iteration of the guidance, as well as updating the general multidisciplinary management of soft tissue sarcoma, includes specific sections relating to the management of sarcomas at defined anatomical sites: gynaecological sarcomas, retroperitoneal sarcomas, breast sarcomas, and skin sarcomas. These are generally managed collaboratively by site specific multidisciplinary teams linked to the regional sarcoma specialist team, as stipulated in the recently published sarcoma service specification [3]. In the UK, any patient with a suspected soft tissue sarcoma should be referred to a specialist regional soft tissues sarcoma service, to be managed by a specialist sarcoma multidisciplinary team. Once the diagnosis has been confirmed using appropriate imaging and a tissue biopsy, the main modality of management is usually surgical excision performed by a specialist surgeon, combined with pre- or post-operative radiotherapy for tumours at higher risk for local recurrence. Systemic anti-cancer therapy (SACT) may be utilised in cases where the histological subtype is considered more sensitive to systemic treatment. Regular follow-up is recommended to assess local control, development of metastatic disease, and any late effects of treatment.

2.
Br J Cancer ; 129(9): 1490-1499, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37684354

RESUMO

BACKGROUND: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer. METHODS: Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon's two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata. RESULTS: Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events. CONCLUSIONS: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials. CLINICAL TRIAL REGISTRATION: ISRCTN 60791336.


Assuntos
Hemangiossarcoma , Leiomiossarcoma , Sarcoma Sinovial , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Axitinibe/efeitos adversos , Leiomiossarcoma/tratamento farmacológico , Sarcoma Sinovial/induzido quimicamente , Sarcoma Sinovial/tratamento farmacológico , Hemangiossarcoma/induzido quimicamente , Hemangiossarcoma/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Inibidores da Angiogênese/uso terapêutico , Resultado do Tratamento
3.
Br J Cancer ; 128(12): 2307-2317, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37085598

RESUMO

BACKGROUND: Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. METHODS: Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). RESULTS: Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54-5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19-3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42-3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01-4.68, P = 0.04). CONCLUSIONS: This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.


Assuntos
Sarcoma , Hipóxia Tumoral , Humanos , Reprodutibilidade dos Testes , Prognóstico , Biomarcadores Tumorais/genética , Sarcoma/genética , Sarcoma/patologia , Hipóxia , Microambiente Tumoral
4.
Cancer Treat Rev ; 112: 102491, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36502615

RESUMO

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.


Assuntos
Tumor de Células Gigantes de Bainha Tendinosa , Qualidade de Vida , Humanos , Consenso , Tumor de Células Gigantes de Bainha Tendinosa/tratamento farmacológico , Tumor de Células Gigantes de Bainha Tendinosa/patologia
5.
Br J Radiol ; 93(1107): 20180883, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30943055

RESUMO

OBJECTIVE: Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS:: Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS:: Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION: Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE:: This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.


Assuntos
Cordoma/terapia , Hipertermia Induzida/métodos , Terapia com Prótons/métodos , Sacro , Neoplasias da Coluna Vertebral/terapia , Idoso , Cordoma/diagnóstico por imagem , Cordoma/patologia , Terapia Combinada/métodos , Estudos de Viabilidade , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Eficiência Biológica Relativa , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/patologia , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
6.
BMC Cancer ; 16: 301, 2016 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-27154292

RESUMO

BACKGROUND: The optimal conduct of follow-up (FU) of patients with osteosarcoma is uncertain. In the absence of any formal validation of optimal timing and method of surveillance, guidance is provided by oncology societies' recommendations. FU is designed to detect either local recurrence or metastatic disease at a time when early treatment is still possible and might be effective. METHODS: We performed a retrospective analysis of 101 patients with high-grade extremity osteosarcoma in a single centre. Chest x-ray (CXR) was used as routine surveillance method; however patients with initial lung metastases or previous suspicious findings had computed tomography (CT) scans. RESULTS: With a median FU time of 30.7 months 34 patients relapsed. Relapse-free survival after 5 years was 61% (CI 52%; 73%), late relapses occurred in only two patients between 2 and 5 years of FU. Twenty-five of the 34 relapses were detected at routine FU appointments. All 8 local recurrences were noted clinically. Twenty-two patients had metastases confined to the lungs, either detected on CXR or CT. Thirty-two percent of patients with lung metastases only were salvaged successfully. CONCLUSIONS: Routine FU in high-grade osteosarcoma results in clinical detection of local relapse, and detection of lung metastases by CXR at a time when metastatectomy is possible. The optimal time interval for FU appointments is not known, however we recommend more frequent surveillance visits during the two years after treatment. We hypothesize that routine CT scans are not required and propose CXR for detection of lung metastases.


Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Osteossarcoma/diagnóstico por imagem , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Osteossarcoma/patologia , Radiografia Torácica , Tomografia Computadorizada por Raios X , Raios X
7.
J Pathol Clin Res ; 1(2): 106-12, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27499897

RESUMO

The reported incidence of local recurrence of peripheral atypical lipomatous tumours is highly variable and is likely to reflect the different inclusion criteria of cases, and the design of previous studies. We aimed to study the incidence of local recurrence of 90 cases of atypical lipomatous tumours and an additional 18 cases of de novo dedifferentiated liposarcoma. All tumours were diagnosed on the basis of MDM2 amplification: all patients had their first treatment in the same specialist sarcoma unit and were followed for a minimum of 60 months. The tumours were diagnosed between 1997 and 2009 and followed until the end of 2014. Seventy cases (78%) of atypical lipomatous tumours were located in the thigh (mean size 195 mm on presentation). Eight atypical lipomatous tumours (8.9%) recurred locally, of which 50% recurred after 60 months. The only two tumours with intralesional excisions recurred. Seven of the eight recurrent tumours were detected by the patient by self-examination. One case recurred a second time as a dedifferentiated liposarcoma. Seventeen per cent of the de novo dedifferentiated liposarcomas recurred within 60 months of presentation. Extending the study period revealed that atypical lipomatous tumour could recur up to 40 years after the first surgery. Furthermore, of 26 tumours that recurred in the extended study, 27% recurred more than once, and three of the seven that recurred more than once transformed into a dedifferentiated liposarcoma. We recommend that, following post-operative wound care, patients with atypical lipomatous tumour are referred back to their general practitioner for follow up, but that in the event of a suspected recurrence they have rapid access back to the specialist unit using a 'supported discharge' scheme. In the event of an intralesional excision and if a lesion recurs, patients are followed in a specialist unit at regular intervals: whether MRI scanning is a valuable means of monitoring such patients is unclear and requires an evidence base.

8.
Eur J Radiol ; 78(1): 30-40, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21247711

RESUMO

Uterine sarcomas are a group of rare tumours that provide considerable challenges in their treatment. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made post-operatively. Current staging systems have been unsatisfactory, although a new FIGO staging system specifically for uterine sarcomas has now been introduced, and may allow better grouping of patients according to expected prognosis. While the mainstay of treatment of early disease is a total abdominal hysterectomy, it is less clear whether routine oophorectomy or lymphadenectomy is necessary. Adjuvant pelvic radiotherapy may improve local tumour control in high risk patients, but is not associated with an overall survival benefit. Similarly there is no good evidence for the routine use of adjuvant chemotherapy. For advanced leiomyosarcoma, newer chemotherapy agents including gemcitabine and docetaxel, and trabectedin, offer some promise, while hormonal therapies appear to be more useful in endometrial stromal sarcoma. Novel targeted agents are now being introduced for sarcomas, and uterine sarcomas, and show some indications of activity. Non-pharmacological treatments, including surgical metastatectomy, radiofrequency ablation, and CyberKnife(®) radiotherapy, are important additions to systemic therapy for advanced metastatic disease.


Assuntos
Diagnóstico por Imagem , Sarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Histerectomia , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Sarcoma/patologia , Sarcoma/terapia , Neoplasias Uterinas/patologia
9.
Paediatr Drugs ; 10(2): 93-105, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18345719

RESUMO

The Ewing sarcoma family of tumors (ESFT) is one of the most common groups of malignancies arising in children, adolescents, and young adults up to approximately 25 years of age. It comprises Ewing sarcoma arising from bone and extraosseous Ewing sarcoma arising from soft tissues (which includes peripheral neuroectodermal tumors and Askin tumor arising from the chest wall). Ewing sarcoma is treated successfully in many cases by a combination of chemotherapy, surgery, and radiotherapy. A number of prognostic factors have been identified that can be used to stratify patients according to the risk of relapse, allowing optimization of treatment. These can be categorized as tumor-related factors (presence of metastases, tumor site, volume, lactic dehydrogenase level, chromosomal translocation type, presence of fusion transcripts in blood and bone marrow), treatment-related factors (local therapy, histologic response to chemotherapy, radiologic response to chemotherapy, chemotherapy regimen), and patient-related factors (gender, age). Newer chemotherapeutic agents are currently being investigated, and there is now increasing interest in the identification of molecular targets in ESFT that could be exploited therapeutically, which include the mammalian target of rapamycin (mTOR) and insulin growth factor-1 (IGF-1) receptor pathways.


Assuntos
Neoplasias Ósseas , Sarcoma de Ewing , Fatores Etários , Protocolos Antineoplásicos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/cirurgia , Terapia Combinada , Humanos , Pediatria , Prognóstico , Proteínas Quinases/fisiologia , Receptor IGF Tipo 1/fisiologia , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/cirurgia , Transdução de Sinais , Serina-Treonina Quinases TOR
10.
Cancer ; 112(7): 1585-91, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18278813

RESUMO

BACKGROUND: The efficacy of palliative chemotherapy was investigated in a large group of patients with advanced soft-tissue sarcomas (STS) treated on routine palliative protocols. METHODS: Patients with STS who had first-line chemotherapy for advanced and/or metastatic disease between 1991 and 2005 were identified from the Royal Marsden Hospital's sarcoma database. Patients with Ewing sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumor, and gastrointestinal stromal tumors were excluded from the study. RESULTS: In all, 488 patients (242 male, 246 female) fulfilled the study criteria. The median age was 49 years and the majority (83%) received chemotherapy for metastatic disease. The most common histologic subtypes were leiomyosarcoma (35%) synovial sarcoma (13%), liposarcoma (10%), and malignant fibrous histiocytoma (10%). In all, 61% received single-agent chemotherapy, usually doxorubicin. An objective response was reported in 33% of patients (53% in those with synovial sarcoma); 22% had stable disease and 45% derived 'clinical benefit' (objective responses + stable disease for >or= 6 months). Median duration of response was 9 months and median posttreatment overall survival (OS) was 12 months. In multivariate analysis, age <40 years, liposarcoma, and synovial histology were found to be positive, and bone involvement to be negative, independent prognostic factors. Patients treated with combination chemotherapy experienced longer OS than those treated with a single agent. CONCLUSIONS: Palliative chemotherapy may be beneficial in approximately half of patients with advanced STS. Synovial sarcoma and liposarcoma subtypes have a better prognosis. However, the overall poor outcome of these patients indicates the need to continue the search for more effective agents.


Assuntos
Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Paliativos , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Taxa de Sobrevida
11.
Clin Cancer Res ; 9(14): 5101-12, 2003 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-14613987

RESUMO

PURPOSE: To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS). EXPERIMENTAL DESIGN: SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h. CONCLUSIONS: SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.


Assuntos
Biomarcadores Tumorais/farmacocinética , Hipóxia/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Neoplasias/metabolismo , Nitroimidazóis/farmacocinética , Adulto , Idoso , Biomarcadores Tumorais/efeitos adversos , Cromatografia Líquida de Alta Pressão , Feminino , Radioisótopos de Flúor , Meia-Vida , Humanos , Hipóxia/diagnóstico , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Nitroimidazóis/efeitos adversos
12.
Clin Cancer Res ; 8(7): 2323-35, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12114437

RESUMO

PURPOSE: Tumor hypoxia is associated with poor prognosis and a more malignant tumor phenotype. SR-4554, a fluorinated 2-nitroimidazole, is selectively bioreduced and bound in hypoxic cells. We present validation studies of SR-4554 as a noninvasive hypoxia marker detected by fluorine-19 magnetic resonance spectroscopy ((19)F MRS) in the P22 carcinosarcoma, a tumor with clinically relevant hypoxia levels. EXPERIMENTAL DESIGN: Tumor-bearing female severe combined immunodeficient mice received SR-4554 at 180 mg/kg. Pharmacokinetic studies of parent SR-4554 in plasma and tumors were performed using high-performance liquid chromatography-UV. Total SR-4554 (parent SR-4554 and bioreduction products) was monitored in tumor by (19)F MRS using a 4.7 T spectrometer, with continuous acquisition for up to 5 h. A parameter of total SR-4554 retention, the 3-h (19)F retention index ((19)FRI) was determined. Tumor pO(2), assessed polarographically, was decreased (5 mg/kg hydralazine or 100 mg/kg combretastatin A-4 phosphate) or increased [1 l/min carbogen (5% CO(2), 95% O(2)) plus 500 mg/kg nicotinamide], and the corresponding (19)FRI was measured. RESULTS: Comparative HPLC-UV- and MRS-derived assessments of parent and total SR-4554, respectively, indicated that concentrations of total SR-4554 consistently exceeded parent SR-4554, the differential increasing with time. This indicates formation and retention of SR-4554 bioreduction products in tumor, confirming the presence of hypoxia. The (19)FRI was higher in hydralazine- and combretastatin-treated animals compared with unmodulated animals (P = 0.004 and 0.15, respectively) and animals receiving carbogen and nicotinamide (P = 0.0001 and 0.005, respectively). Significant correlations were demonstrated between mean (19)FRI and polarographic pO(2) parameters (P < 0.002). CONCLUSIONS: Retention of hypoxia-related SR-4554 bioreduction products can be detected in the clinically relevant P22 tumor by (19)F MRS, and the (19)FRI correlates with polarographically measured pO(2). These findings support the use of SR 4554 as a noninvasive hypoxia marker.


Assuntos
Biomarcadores Tumorais , Hipóxia/diagnóstico , Espectroscopia de Ressonância Magnética/métodos , Neoplasias Experimentais/diagnóstico , Nitroimidazóis , Animais , Biomarcadores Tumorais/farmacocinética , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Feminino , Radioisótopos de Flúor , Hipóxia/metabolismo , Camundongos , Camundongos SCID , Transplante de Neoplasias , Neoplasias Experimentais/metabolismo , Nitroimidazóis/farmacocinética , Oxigênio/metabolismo , Polarografia , Ratos , Distribuição Tecidual
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