RESUMEN
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.
Asunto(s)
Sarcoma , Tropomiosina , Adulto , Fusión Génica , Humanos , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas , Receptor trkA/genética , Sarcoma/diagnóstico , Sarcoma/tratamiento farmacológico , Sarcoma/genéticaRESUMEN
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.
Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Dacarbazina/administración & dosificación , Leiomiosarcoma/tratamiento farmacológico , Liposarcoma/tratamiento farmacológico , Trabectedina/administración & dosificación , Administración Intravenosa , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/administración & dosificación , Dacarbazina/efectos adversos , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Leiomiosarcoma/mortalidad , Leiomiosarcoma/patología , Liposarcoma/mortalidad , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Factores de Tiempo , Trabectedina/efectos adversos , Adulto JovenRESUMEN
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.
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Adenina/análogos & derivados , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Piridinas/uso terapéutico , Adenina/efectos adversos , Adenina/farmacocinética , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18 , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Piridinas/efectos adversos , Piridinas/farmacocinética , Piridinas/farmacología , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Cuidados Paliativos , Estudios Retrospectivos , Sarcoma/mortalidad , Sarcoma/secundario , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/patología , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Proliferación Celular/efectos de los fármacos , Dioxoles/uso terapéutico , Sarcoma/tratamiento farmacológico , Tetrahidroisoquinolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Terapia Recuperativa , Sarcoma/metabolismo , Sarcoma/mortalidad , Sarcoma/patología , Trabectedina , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
Asunto(s)
Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Condrosarcoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Condrosarcoma/mortalidad , Condrosarcoma/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , PronósticoRESUMEN
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.
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Fibromatosis Agresiva/complicaciones , Fibromatosis Agresiva/epidemiología , Tumores del Estroma Gastrointestinal/complicaciones , Tumores del Estroma Gastrointestinal/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
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.
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Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Liposarcoma/tratamiento farmacológico , Neoplasias Retroperitoneales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Liposarcoma/mortalidad , Liposarcoma/secundario , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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.
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Neoplasias Óseas , Osteosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Humanos , Osteosarcoma/diagnóstico , Osteosarcoma/patología , Osteosarcoma/terapia , Guías de Práctica Clínica como Asunto , Sarcoma/diagnóstico , Sarcoma/patología , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells from T cell receptor transgenic mice. The administration of IL-12 at the time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti-CTLA-4 antibody are not anergized, and behave identically to T cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen, and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti-CTLA-4 antibody is sufficient to convert a normally tolerogenic stimulus to an immunogenic one.
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Antígenos de Diferenciación/inmunología , Anergia Clonal , Tolerancia Inmunológica , Inmunoconjugados , Interleucina-12/inmunología , Linfocitos T/inmunología , Células TH1/inmunología , Abatacept , Traslado Adoptivo , Animales , Anticuerpos/inmunología , Antígenos CD , Antígenos de Diferenciación/metabolismo , Enfermedades Autoinmunes/inmunología , Antígeno CTLA-4 , Diferenciación Celular , Citometría de Flujo , Inflamación/inmunología , Interferón gamma/metabolismo , Interleucina-12/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
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.
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Antineoplásicos/uso terapéutico , Tumor de Células Gigantes de las Vainas Tendinosas/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Adulto , Australia , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Europa (Continente) , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptores del Factor Estimulante de Colonias/antagonistas & inhibidores , Estudios Retrospectivos , Resultado del Tratamiento , Estados UnidosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Liposarcoma/tratamiento farmacológico , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Liposarcoma/patología , Liposarcoma/cirugía , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Mutación , Piridinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Exones/genética , Humanos , Niacinamida/análogos & derivados , Compuestos de Fenilurea , SorafenibRESUMEN
PURPOSE: To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m2 of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients. RESULTS: One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1% (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = -0.28; P = .21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables. CONCLUSION: ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.
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Antineoplásicos Alquilantes/uso terapéutico , Dioxoles/uso terapéutico , Isoquinolinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Dioxoles/efectos adversos , Dioxoles/farmacocinética , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Isoquinolinas/efectos adversos , Isoquinolinas/farmacocinética , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Tetrahidroisoquinolinas , Trabectedina , Resultado del TratamientoRESUMEN
PURPOSE: To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population. PATIENTS AND METHODS: Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 microg/m(2) every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria. RESULTS: Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean +/- standard deviation), 1.04 +/- 0.48 ng/mL and 35.6 +/- 16.2 L/h/m(2), respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion. CONCLUSION: ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.
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Antineoplásicos Alquilantes/uso terapéutico , Dioxoles/uso terapéutico , Isoquinolinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Antineoplásicos Alquilantes/farmacocinética , Dioxoles/efectos adversos , Dioxoles/farmacocinética , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Isoquinolinas/efectos adversos , Isoquinolinas/farmacocinética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Tasa de Supervivencia , Tetrahidroisoquinolinas , TrabectedinaRESUMEN
Chemically induced tumors of inbred mice elicit immunity in animals in which the tumors are induced and in other animals of the same inbred stock. The immunity is specific for each tumor: even two tumors induced in one animal with the same carcinogen are not cross-reactive. Immunity to cancer has since been observed in the case of sarcomas and carcinomas induced by a number of chemical and physical carcinogens and in several species, including mice, rats, and guinea pigs. The nature of molecules which mediate immunity to tumors is a central question in cancer immunology. A small number of such molecules have been biochemically defined. Of these, some are viral antigens expressed in tumor cells, while the relationship of some others to viral antigens is unclear. A surprising majority of nonviral tumor antigens have turned out to bear homology with stress-induced proteins. Four families of such molecules are discussed: the gp96 (hsp100) and p84/86 (hsp90) antigens of chemically induced mouse sarcomas, hsp70 antigens of tumors obtained by transfection of normal rat fetal fibroblasts with an H-ras oncogene, and the albuminoid antigens of murine melanomas and a rat histiocytoma. (Albumin-like antigens are included among the stress-induced proteins because albumin, though constitutively expressed in adult tissues, is heat shock inducible in fetal liver.) Each of these antigens is a moderately abundant protein, present not only in tumors but also in normal tissues. Administration of each of these antigen preparations from the tumor, but not from normal tissue, renders the animal immune to challenge with live cells of the tumor from which the antigens are prepared. And yet, no structural differences in the antigens have been observed between normal tissues and tumors. It is suggested that these stress-induced proteins may not be tumor antigens per se, but may be carriers of immunogenic moieties such as short peptides. The stress-induced proteins may therefore serve either as antigen-presenting molecules like the MHC-encoded molecules or as accessory molecules in the presentation of antigens by MHC molecules. The ability of stress-induced proteins to bind to a variety of molecules, including peptides, is consistent with this possibility.
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Proteínas de Choque Térmico/inmunología , Neoplasias/inmunología , Animales , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Proteínas Portadoras/fisiología , Membrana Celular/inmunología , Membrana Celular/metabolismo , Epítopos , Proteínas de Choque Térmico/genética , Humanos , Ratones , Ratas , Homología de Secuencia de Ácido Nucleico , Albúmina Sérica/inmunologíaRESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Tumores del Estroma Gastrointestinal/terapia , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Quimioterapia Adyuvante , Terapia Combinada , Estudios de Seguimiento , Tumores del Estroma Gastrointestinal/diagnóstico , Humanos , Mesilato de Imatinib , Imagen por Resonancia Magnética , Recurrencia Local de Neoplasia/diagnóstico , Guías de Práctica Clínica como Asunto , Tomografía Computarizada por Rayos X/métodosRESUMEN
Lymphocyte activation is known to be associated with the induction of genes implicated in cytokine signaling and cellular proliferation. High-density microarrays offer the means to monitor global cellular expression profiles, temporal relationships between classes of transcripts, and alterations associated with human disease or immunosuppression. We sought to determine whether microarray analysis would accurately reflect the normal pattern of gene expression following human T cell activation, and whether the complex expression patterns identified could be analyzed to produce a functional profile of lymphocyte activation. We examined a time course of sequential expression profiles for 6,800 cellular transcripts in human lymphocytes activated with concanavalin A. Expression patterns were grouped using clustering analysis and validated using Northern blotting. Genes known to be induced following T cell activation were accurately identified, and the qualitative patterns of gene expression were well correlated between Northern and microarray analyses. Quantitative differences in gene expression levels were less well correlated between these two techniques. Expression profile analysis revealed the sequential induction of groups of functionally similar genes, whose temporal coregulation underscores known cellular events during T cell activation. This functional "fingerprint" of lymphocyte activation may prove useful for comparisons of lymphocyte responses under experimental conditions and in disease states.
Asunto(s)
Activación de Linfocitos/genética , Linfocitos T/fisiología , Activación Transcripcional/inmunología , Análisis por Conglomerados , Expresión Génica/inmunología , Humanos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Further structure-activity relationships (SAR) for a novel dipeptide series inhibitors are reported. These inhibitors retain the Phe8-His9 portion of angiotensinogen and employ a unique Leu10-Val11 replacement [(LVR), ref 2]. SAR at the Leu10 side chain revealed that the LVR derived from cyclohexylalanine provided a nearly 10-fold boost in potency for the final inhibitor. In addition SAR work was carried out to delineate the relationships between binding potency and (1) the size, shape, and charge of the side chain at the His9 position; (2) the size and topology of the side chain at the Phe8 site; and (3) the size of the Phe8 N-protecting group. One of the more potent inhibitors, 12, was shown to provide a substantial antihypertensive effect in a sodium depleted monkey model when administered intravenously. Metabolism work, in Sprague-Dawley rats, provided insights into the susceptibility of 12 to significant hepatic clearance and provided encouraging evidence for intestinal absorption.