RESUMO
BACKGROUND: Locally advanced (unresectable) or metastatic dedifferentiated liposarcoma (DDLPS) is a common presentation of liposarcoma. Despite established diagnostic and treatment guidelines for DDLPS, critical clinical gaps remain driven by diagnostic challenges, symptom burden and the lack of targeted, safe and effective treatments. The objective of this study was to gather expert opinions from Europe and the United States on the management, unmet needs and expectations for clinical trial design as well as the value of progression-free survival (PFS) in this disease. Other aims included raising awareness and educate key stakeholders across healthcare systems. MATERIALS AND METHODS: An international panel of 12 sarcoma key opinion leaders (KOLs) was recruited. The study consisted of two rounds of surveys with pre-defined statements. Experts scored each statement on a 9-point Likert scale. Consensus agreement was defined as ≥75% of experts scoring a statement with ≥7. Revised statements were discussed in a consensus meeting. RESULTS: Consensus was reached on 43 of 55 pre-defined statements across disease burden, treatment paradigm, unmet needs, value of PFS and its association with overall survival (OS), and cross-over trial design. Twelve statements were deprioritised or merged with other statements. There were no statements where experts disagreed. CONCLUSION: This study constitutes the first international Delphi panel on DDLPS. It aimed to explore KOL perception of the disease burden and unmet need in DDLPS, the value of PFS, and its potential translation to OS benefit, as well as the relevance of a cross-over trial design for DDLPS therapies. Results indicate an alignment across Europe and the United States regarding DDLPS management, unmet needs, and expectations for clinical trials. Raising awareness of critical clinical gaps in relation to DDLPS can contribute to improving patient outcomes and supporting the development of innovative treatments.
Assuntos
Consenso , Técnica Delphi , Lipossarcoma , Intervalo Livre de Progressão , Humanos , Lipossarcoma/terapia , Lipossarcoma/mortalidade , Lipossarcoma/patologia , Ensaios Clínicos como Assunto , Europa (Continente) , Projetos de PesquisaRESUMO
Bone sarcoma are infrequent diseases, representing < 0.2% of all adult neoplasms. A multidisciplinary management within reference centers for sarcoma, with discussion of the diagnostic and therapeutic strategies within an expert multidisciplinary tumour board, is essential for these patients, given its heterogeneity and low frequency. This approach leads to an improvement in patient's outcome, as demonstrated in several studies. The Sarcoma European Latin-American Network (SELNET), aims to improve clinical outcome in sarcoma care, with a special focus in Latin-American countries. These Clinical Practice Guidelines (CPG) have been developed and agreed by a multidisciplinary expert group (including medical and radiation oncologist, surgical oncologist, orthopaedic surgeons, radiologist, pathologist, molecular biologist and representatives of patients advocacy groups) of the SELNET consortium, and are conceived to provide the standard approach to diagnosis, treatment and follow-up of bone sarcoma patients in the Latin-American context.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Humanos , Osteossarcoma/diagnóstico , Osteossarcoma/patologia , Osteossarcoma/terapia , Guias de Prática Clínica como Assunto , Sarcoma/diagnóstico , Sarcoma/patologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/patologiaRESUMO
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
Assuntos
Sarcoma , Tropomiosina , Adulto , Fusão Gênica , Humanos , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases , Receptor trkA/genética , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológico , Sarcoma/genéticaRESUMO
Tenosynovial giant cell tumors (TGCT), are rare colony stimulating factor-1(CSF-1)-driven proliferative disorders affecting joints. Diffuse-type TGCT often causes significant morbidity due to local recurrences necessitating multiple surgeries. Imatinib mesylate (IM) blocks the CSF-1 receptor. This study investigated the long term effects of IM in TGCT. We conducted an international multi-institutional retrospective study to assess the activity of IM: data was collected anonymously from individual patients with locally advanced, recurrent or metastatic TGCT. Sixty-two patients from 12 institutions across Europe, Australia and the United States were identified. Four patients with metastatic TGCT progressed rapidly on IM and were excluded for further analyses. Seventeen of 58 evaluable patients achieved complete response (CR) or partial response (PR). One- and five-year progression-free survival rates were 71% and 48%, respectively. Thirty-eight (66%) patients discontinued IM after a median of 7 (range 1-80) months. Reported adverse events in 45 (78%) patients were among other edema (48%) and fatigue (50%), mostly grade 1-2 (89%). Five patients experienced grade 3-4 toxicities. This study confirms, with additional follow-up, the efficacy of IM in TGCT. In responding cases we confirmed prolonged IM activity on TGCT symptoms even after discontinuation, but with high rates of treatment interruption and additional treatments.
Assuntos
Antineoplásicos/uso terapêutico , Tumor de Células Gigantes de Bainha Tendinosa/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Adulto , Austrália , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores de Fator Estimulador de Colônias/antagonistas & inibidores , Estudos Retrospectivos , Resultado do Tratamento , Estados UnidosRESUMO
Background: Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial. Patients and methods: Patients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup. Results: Among 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population. Conclusions: This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients. Trial registration: www.clinicaltrials.gov, NCT01343277.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Dacarbazina/administração & dosagem , Leiomiossarcoma/tratamento farmacológico , Lipossarcoma/tratamento farmacológico , Trabectedina/administração & dosagem , Administração Intravenosa , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Dacarbazina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Lipossarcoma/mortalidade , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Fatores de Tempo , Trabectedina/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. PATIENTS AND METHODS: Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. RESULTS: We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. CONCLUSIONS: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.
Assuntos
Neoplasias/patologia , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Adulto , Idoso , Animais , Estudos de Coortes , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias/métodos , Neoplasias/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: Patients with gastrointestinal stromal tumour (GIST) are often followed up after surgery with longitudinally repeated imaging examinations to detect recurrence early. Studies on follow-up of GIST patients are few, the optimal follow-up methods are unknown and the recommendations for follow-up vary in guidelines. METHODS: We reviewed the current evidence for follow-up of patients treated with surgery alone and of patients who were treated with adjuvant or neoadjuvant imatinib. RESULTS: Imaging of the abdomen and the pelvis with computerised tomography (CT) or magnetic resonance imaging (MRI) usually suffices, since metastases are uncommon at other sites. The frequency of imaging may be adjusted with the risk of recurrence with time. Very low risk GISTs are very frequently cured with surgery and usually require no regular follow-up after complete surgery, and annual CT of the abdomen and the pelvis for 5 years suffices for most patients with a low to intermediate risk for recurrence. Most high-risk patients are treated with imatinib for at least 3 years after surgery. CT or MRI may be carried out 6-monthly during adjuvant imatinib, 3 to 4-monthly during the 2 years that follow discontinuation of imatinib when the risk of recurrence is high, and then at 6-12 month intervals to complete 10 years of follow-up. Recurrence after the first 10 years of follow-up is infrequent. CONCLUSIONS: The follow-up schedules are best tailored with the risk of recurrence. The risk of recurrence should be estimated with the prognostic tools that consider the most relevant prognostic factors.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Tumores do Estroma Gastrointestinal/terapia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Quimioterapia Adjuvante , Terapia Combinada , Seguimentos , Tumores do Estroma Gastrointestinal/diagnóstico , Humanos , Mesilato de Imatinib , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico , Guias de Prática Clínica como Assunto , Tomografia Computadorizada por Raios X/métodosRESUMO
Elevated levels of the heme enzyme myeloperoxidase (MPO) are associated with adverse cardiovascular outcomes. MPO predominantly catalyzes formation of the oxidants hypochlorous acid (HOCl) from Cl(-), and hypothiocyanous acid (HOSCN) from SCN(-), with these anions acting as competitive substrates. HOSCN is a less powerful and more specific oxidant than HOCl, and selectively targets thiols; such damage is largely reversible, unlike much HOCl-induced damage. We hypothesized that increased plasma SCN(-), and hence HOSCN formation instead of HOCl, may decrease artery wall damage. This was examined using high-fat fed atherosclerosis-prone LDLR(-/-) mice transgenic for human MPO, with and without SCN(-) (10 mM) added to drinking water. Serum samples, collected fortnightly, were analyzed for cholesterol, triglycerides, thiols, MPO, and SCN(-); study-long exposure was calculated by area under the curve (AUC). Mean serum SCN(-) concentrations were elevated in the supplemented mice (200-320 µM) relative to controls (< 120 µM). Normalized aortic root plaque areas at sacrifice were 26% lower in the SCN(-)-supplemented mice compared with controls (P = 0.0417), but plaque morphology was not appreciably altered. Serum MPO levels steadily increased in mice on the high-fat diet, however, comparison of SCN(-)-supplemented versus control mice showed no significant changes in MPO protein, cholesterol, or triglyceride levels; thiol levels were decreased in supplemented mice at one time-point. Plaque areas increased with higher cholesterol AUC (r = 0.4742; P = 0.0468), and decreased with increasing SCN(-) AUC (r = - 0.5693; P = 0.0134). These data suggest that increased serum SCN(-) levels, which can be achieved in humans by dietary manipulation, may decrease atherosclerosis burden.
Assuntos
Peroxidase/genética , Placa Aterosclerótica/tratamento farmacológico , Tiocianatos/uso terapêutico , Animais , Dieta Hiperlipídica , Suplementos Nutricionais , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Placa Aterosclerótica/enzimologia , Tiocianatos/administração & dosagem , Tiocianatos/metabolismoRESUMO
BACKGROUND: There are limited data about the role of chemotherapy in patients with advanced chondrosarcomas. METHODS: The medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 participating institutions between 1988 and 2011 were reviewed. RESULTS: Median age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months [95% confidence interval (CI) 3-6.5]. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5-21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS. CONCLUSIONS: Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.
Assuntos
Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Condrossarcoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Condrossarcoma/mortalidade , Condrossarcoma/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , PrognósticoRESUMO
BACKGROUND: This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabectedin in young and elderly patients with recurrent advanced soft tissue sarcoma (STS). METHODS: Data from 350 adults with STS treated in five phase II trials with trabectedin were divided in the younger (<60 years; n=267) and the older cohort (≥60 years; n=83). RESULTS: The response rate did not differ with age (younger: 10.1% vs elderly 9.6%). No significant differences were found in median progression-free survival (PFS) in younger (2.5 months) and older (3.7 months) cohort with a comparable PFS rates at 3 (45.1% vs 55.1%) and 6 months (29.5% vs 36.4%). Similar median overall survival was observed in both cohorts (13.0 vs 14.0 months). Reversible neutropenia and aspartate aminotransferase/alanine aminotransferase elevation were the most common abnormalities. A higher incidence of grade 3/4 neutropenia (43.6% vs 60.2%) and fatigue (6.3% vs 14.4%) was observed in older patients. In 24 patients aged ≥70 years, no significant differences in efficacy or safety outcomes were found. CONCLUSION: This analysis demonstrated that trabectedin is a feasible treatment in young and elderly patients with STS, with meaningful clinical benefits and an acceptable safety profile, essential in palliative treatment of elderly patients.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/mortalidade , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: There are no data regarding the management of advanced soft-tissue sarcoma (STS) in elderly patients. PATIENTS AND METHODS: We retrospectively reviewed the charts of patients ≥75 years old diagnosed with metastatic or unresectable STS between 1991 and 2011 in 11 French and American centers. RESULTS: The study included 361 patients. Of these, 223 patients (62%) received systemic therapy, whereas 123 patients (34%) were managed with best supportive care (BSC) only. Patients who received BSC were more likely to be ≥80 years, with performance status (PS) ≥ 2, Charlson comorbidity score ≥ 10, and metastatic disease. The median progression-free survival of patients treated with systemic therapy was 4 months (95% CI: 2.9-5.1). Thirty-six patients (16%) stopped chemotherapy because of toxicity. Median overall survival (OS) of patients managed with specific therapy was 10.9 months (95% CI: 8.3-13.5) versus 5.3 months (95% CI: 3.6-7.1) for patients managed with BSC (P = 0.001). On multivariate analysis, age ≥ 80 years, PS ≥ 2, and number of metastatic sites were the only independent factors associated with OS. CONCLUSION: A high proportion of elderly patients with advanced STS were denied chemotherapy. Further efforts are needed to define better the optimal care for fit and unfit elderly patients with STS.
Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Cuidados Paliativos , Estudos Retrospectivos , Sarcoma/mortalidade , Sarcoma/secundário , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTP(n)) of therapy to the TTP(n)(-1) with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials. PATIENTS AND METHODS: This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials. RESULTS: One hundred and forty-two (51%) patients received one prior line and 137 ≥ 2 lines. The median TTP(n) was 2.8 months (range 0.2-26.8), whereas the median TTP(n)(-1) was 4.0 months (0.3-79.5). The median GMI was 0.6 (0.0-14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1-1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04). CONCLUSIONS: A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Terapia de Salvação , Sarcoma/metabolismo , Sarcoma/mortalidade , Sarcoma/patologia , Trabectedina , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. PATIENTS AND METHODS: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped>14 days before starting BIIB021. RESULTS: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 µmol and the mean AUC was 2.9 µmol h. Cmax>1.5 µmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. CONCLUSIONS: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.
Assuntos
Adenina/análogos & derivados , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Piridinas/uso terapêutico , Adenina/efeitos adversos , Adenina/farmacocinética , Adenina/farmacologia , Adenina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18 , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Piridinas/efeitos adversos , Piridinas/farmacocinética , Piridinas/farmacologia , Resultado do TratamentoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Lipossarcoma/tratamento farmacológico , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Lipossarcoma/patologia , Lipossarcoma/cirurgia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Mutação , Piridinas/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Éxons/genética , Humanos , Niacinamida/análogos & derivados , Compostos de Fenilureia , SorafenibeRESUMO
BACKGROUND: Gastrointestinal stromal tumors (GISTs) and desmoid tumors (DTs) are two rare mesenchymal tumor. Anecdotal reports of individuals with both diseases led us to make the hypothesis that the association is a nonrandom event as the probability would be extremely low to observe such cases if they were independent events. PATIENTS AND METHODS: We evaluated the existence of patients with GIST and DT in a large multicenter cohort at 10 institutions in the United States, Australia and Europe. Data on gender, age at diagnosis, KIT, PDGFRA, CTNNB1 mutation status and follow-up time after diagnosis were collected. RESULTS: We identified 28 patients diagnosed with both tumors. DT was diagnosed after GIST in 75% of patients and concomitantly in 21%. In only one case (4%), GIST was diagnosed after DT. KIT or PDGFRA mutations were detected in 12 of 14 GIST, 9 in KIT exon 11, 2 in KIT exon 9 and 1 in PDGFRA. CONCLUSION: A statistical analysis of these 28 cases suggests a nonrandom association between GIST and DT. Further studies may be able to elucidate the underlying biology responsible for this association.
Assuntos
Fibromatose Agressiva/complicações , Fibromatose Agressiva/epidemiologia , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Data regarding the role of systemic therapy in patients with advanced well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are limited. METHODS: From 2000 to 2010, 208 patients with advanced WDLPS/DDLPS received chemotherapy in 11 participating institutions. Clinical and pathological data were collected by reviewing medical records. RESULTS: Median age was 63 years (range 32-84). Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. Using RECIST, objective response was observed in 21 patients (12%), all treated with anthracyclines. Median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI) 3.3-5.9]. On multivariate analysis, age and performance status (PS) were the sole factors significantly associated with poor PFS. Median overall survival (OS) was 15.2 months (95% CI 11.8 -18.7). On multivariate analysis, grade and PS were the sole factors significantly associated with OS. CONCLUSIONS: Chemotherapy was associated with clinical benefit in 46% of patients with advanced WDLPS/DDLPS. OS remains poor, even though visceral metastatic disease is less frequent than in other sarcomas.
Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Lipossarcoma/tratamento farmacológico , Neoplasias Retroperitoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Lipossarcoma/mortalidade , Lipossarcoma/secundário , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Retroperitoneais/mortalidade , Neoplasias Retroperitoneais/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM: Trabectedin sensitivity is increased in cells with functional nucleotide excision DNA repair, whereas efficient homologous recombination repair leads to resistance. On this basis, a retrospective study of mRNA expression of BRCA1 (breast cancer susceptibility 1 gene), XPG (Xeroderma pigmentosum group G gene) and ERCC1 (excision-repair cross complementing group 1 gene) in tumour samples from sarcoma patients treated with trabectedin was conducted, to correlate DNA repair profiles with patient outcome. MATERIALS AND METHODS: Quantification of expression in paraffin embedded tumour samples from 245 patients with advanced sarcomas was performed by qRT-PCR (quantitative real-time polymerase chain reaction). Median values were used as cut-off to define low/high mRNA expression. RESULTS: Low BRCA1 mRNA expression in tumour samples correlated with statistically significant better response to trabectedin. In contrast to other DNA interacting agents, high expression of XPG was significantly correlated with increased response to the drug and high ERCC1 or XPD (Xeroderma pigmentosum group D gene) expression did not have a detrimental impact. A composite signature including low BRCA1 and high ERCC1 and/or XPG identifies a highly sensitive population of sarcomas with significantly improved treatment outcome. DISCUSSION: This retrospective study indicates that the DNA repair profile predicts improved outcomes in advanced sarcoma patients when treated with trabectedin. This clinical utility of this signature should be evaluated in prospective enriching studies in sarcoma and other malignancies for patients sensitive to trabectedin.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Reparo do DNA , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/genética , Tetra-Hidroisoquinolinas/uso terapêutico , Proteína BRCA1/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas Nucleares/genética , RNA Mensageiro/metabolismo , Recombinação Genética , Estudos Retrospectivos , Trabectedina , Fatores de Transcrição/genética , Resultado do TratamentoRESUMO
METHODS: The effect of histamine on inositol phosphate generation and interleukin-6 (IL-6) release from the synovial sarcoma cell line SW982 was investigated. RESULTS: SW982 cells express functional H1 and H2 receptors. The H1 receptor antagonist [3H]-mepyramine binds to membranes from SW982 cells with high affinity and the binding was potently blocked by H1 antagonists. Histamine potently stimulated phosphoinositide (PI) hydrolysis and Ca2+ mobilization with EC50 of 4.0 +/- 0.8 microM and 1.3 +/- 0.6 microM respectively and these activities were blocked by the H1 selective antagonist mepyramine. Histamine (EC50 = 1.8 +/- 1.1 microM) stimulated the release of IL-6 that was attenuated by selective H1 antagonists. The PKC inhibitor, GF1090203X, blocked the histamine stimulated IL-6 release. The H2 selective antagonist, cimetidine, had no significant effect on histamine-induced PI turnover, Ca2+ mobilization and IL-6 release. CONCLUSION: We conclude that histamine stimulates IL-6 release from SW982 cells by binding to the H1 receptor and this is coupled to the PI/PKC signal transduction pathway. Development of an H1 antagonist that inhibits the release of IL-6 from synoviocytes may be beneficial for the treatment of inflammatory joint disease.