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1.
Ann Oncol ; 32(4): 533-541, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33482247

RESUMEN

BACKGROUND: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. PATIENTS AND METHODS: This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. RESULTS: Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. CONCLUSIONS: With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.


Asunto(s)
Antineoplásicos , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Sarcoma , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Humanos , Mesilato de Imatinib/uso terapéutico , Italia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sarcoma/tratamiento farmacológico
2.
Ann Oncol ; 32(3): 395-403, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33276076

RESUMEN

BACKGROUND: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study. PATIENTS AND METHODS: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints. RESULTS: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR. CONCLUSIONS: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico
3.
Intern Med J ; 45(2): 140-7, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25404097

RESUMEN

BACKGROUND: Anthracyclines and trastuzumab are well recognised to cause cardiac toxicity. Further to their effects on left ventricular (LV) function, anthracyclines in particular are considered to cause negative arterial remodelling. Whether these changes reverse is unknown. In addition, whether trastuzumab causes specific effects on arterial remodelling is yet undetermined. METHODS: Patients receiving these agents for treatment of breast cancer and healthy volunteers prospectively underwent clinical evaluation and cardiovascular magnetic resonance (CMR) imaging at baseline, 1, 4 and 14 months post-therapy, including functional assessment, measurement of aortic pulse wave velocity (PWV) using velocity encoded imaging and distensibility at ascending aorta (AA) and proximal descending aorta (PDA). RESULTS: Twenty-nine patients pretherapy and 12 volunteers demonstrated no differences in PWV, distensibility and LV function. Among cancer subjects, PWV increased acutely, P = 0.002 (4 months), then decreased by 14 months (P < 0.001). In addition, a decrease was observed in distensibility at the AA within 1 (P = 0.001) and 4 months (P < 0.001) of commencing therapy. At the PDA, only significant reduction was observed at 14 month distensibility when compared with baseline, P < 0.001. Patients with anthracycline exposure only had a greater reduction in aortic distensibility in the AA with time, P = 0.005 at 1 month, P < 0.001 at 4 months and P = 0.009 at 14 months. CONCLUSION: Acute changes are observed in PWV and distensibility at the AA following contemporary breast cancer chemotherapy and partially reverse a year after therapy is discontinued, with more severe effects seen with anthracyclines.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Imagen por Resonancia Cinemagnética/métodos , Rigidez Vascular/efectos de los fármacos , Adulto , Anciano , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores/análisis , Neoplasias de la Mama/patología , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/diagnóstico , Estudios de Casos y Controles , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Humanos , Persona de Mediana Edad , Variaciones Dependientes del Observador , Análisis de la Onda del Pulso , Valores de Referencia , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Tiempo , Trastuzumab , Resultado del Tratamiento
4.
Br J Cancer ; 100(8): 1245-9, 2009 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-19367282

RESUMEN

Lomeguatrib, an O(6)-methylguanine-DNA methyltransferase inactivator, was evaluated in an extended dosing regimen with temozolomide, designed according to pharmacodynamic data from previous studies. Patients with unresectable stage 3 or 4 cutaneous or unknown primary melanoma metastases were treated with lomeguatrib 40 mg, b.i.d. for 10 or 14 days and temozolomide 75-100 mg m(-2) on days 1-5. Drugs were administered orally with cycles repeated every 28 days, for up to six cycles. A total of 32 patients were recruited to the study. Lomeguatrib for 10 days with temozolomide 75 mg m(-2) was established as the optimal extended lomeguatrib dosing schedule, with haematological toxicity being dose limiting. There were two partial responses to treatment giving an overall response rate of 6.25%. Extending lomeguatrib administration beyond that of temozolomide requires a reduced dose of the latter agent. Only limited clinical activity was seen, suggesting no advantage for this regimen over conventional temozolomide administration in the treatment of melanoma.


Asunto(s)
Antineoplásicos/toxicidad , Dacarbazina/análogos & derivados , Melanoma/tratamiento farmacológico , Purinas/toxicidad , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Niño , Dacarbazina/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Selección de Paciente , Neoplasias Cutáneas/patología , Temozolomida , Trombocitopenia/inducido químicamente
5.
Ann Oncol ; 19(1): 92-8, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17785764

RESUMEN

BACKGROUND: A phase 3 study demonstrated that panitumumab, a human monoclonal anti-epidermal growth factor receptor antibody, significantly prolonged progression-free survival versus best supportive care (BSC) in patients with chemorefractory metastatic colorectal cancer. PATIENTS AND METHODS: This open-label extension study evaluated panitumumab monotherapy in BSC patients with radiographically documented disease progression in the phase 3 study. Patients received panitumumab 6 mg/kg every 2 weeks. The primary end point was safety; efficacy was also evaluated. RESULTS: One hundred and seventy-six patients were randomly assigned to the BSC arm of the phase 3 study received >/=1 panitumumab dose in this extension study. Panitumumab was well tolerated. The most frequent treatment-related adverse events were skin toxic effects. Three (2%) patients had a grade 4 treatment-related adverse event. There were no infusion reactions. One (0.6%) patient had a complete response; 19 (11%) patients had a partial response; and 58 (33%) patients had stable disease. Median progression-free survival time was 9.4 [95% confidence interval (CI): 8.0-13.4) weeks. Median overall survival time was 6.3 (95% CI: 5.1-6.8) months. Anti-panitumumab antibodies were detected in 3 (4.2%) of 71 patients with a post-baseline sample. CONCLUSIONS: These findings are comparable to those from the phase 3 study and support panitumumab monotherapy for chemorefractory colorectal cancer.


Asunto(s)
Adenocarcinoma/terapia , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/terapia , Receptores ErbB/antagonistas & inhibidores , Inmunoterapia , Proteínas de Neoplasias/antagonistas & inhibidores , Terapia Recuperativa , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Erupciones por Medicamentos/etiología , Resistencia a Antineoplásicos , Receptores ErbB/inmunología , Femenino , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/inmunología , Panitumumab , Terapia Recuperativa/estadística & datos numéricos , Análisis de Supervivencia
6.
Cancer Res ; 48(19): 5528-32, 1988 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-3262010

RESUMEN

A new form of therapy of experimental tumors, utilizing lymphokine-activated killer (LAK) cells and high doses of interleukin 2, has recently been applied in the treatment of human neoplasms. Severe side effects, suggestive of a diffuse vascular injury of unknown etiology, have prevented a more widespread application of this form of therapy. We have investigated the etiology of this clinical capillary leak syndrome, using an in vitro model of endothelial injury. LAK cells, but not interleukin 2 itself, are cytotoxic to cultured human endothelial cells, and this cytotoxicity is time and dose dependent. This human endothelial cell cytotoxicity can be inhibited by depletion of extracellular Ca2+, inhibition of the effector cell microtubular system, and inhibitors of serine proteases, but is not inhibited in the presence of toxic oxygen radical scavengers. LAK cell-mediated endothelial cytotoxicity is far more potent than that exhibited by maximally stimulated polymorphonucleocytes. LAK cell-mediated injury of human endothelium may possibly be responsible for the capillary leak syndrome observed in patients treated with high doses of interleukin 2 and LAK cells.


Asunto(s)
Endotelio Vascular/patología , Inmunización Pasiva/efectos adversos , Interleucina-2/farmacología , Células Asesinas Naturales/inmunología , Calcio/metabolismo , Células Cultivadas , Citotoxicidad Inmunológica , Humanos , Activación de Linfocitos/efectos de los fármacos , Microscopía Electrónica , Serina Endopeptidasas/metabolismo
7.
Cancer Res ; 53(15): 3455-8, 1993 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-8101760

RESUMEN

The presence of tumor cells in the circulation may predict disease recurrence and metastases. We have developed a sensitive technique for the detection of carcinoma cells in blood, using immunomagnetic beads to enrich for epithelial cells and the polymerase chain reaction to identify a tumor marker. The colon carcinoma cell line SW480, homozygous for a K-ras codon 12 mutation, was used to establish optimal conditions. The SW480 cells were serially diluted in normal blood and incubated with immunomagnetic beads labeled with a monoclonal antibody specific for epithelial cells. Cells bound to the beads were retrieved using a magnetic field and the presence of K-ras codon 12 mutations determined by a polymerase chain reaction based analysis. SW480 cells could be detected in dilutions up to 1 SW480 cell/10(5) leukocytes in whole blood.


Asunto(s)
Células Neoplásicas Circulantes , Reacción en Cadena de la Polimerasa , Secuencia de Bases , Neoplasias Colorrectales/diagnóstico , Humanos , Magnetismo , Microesferas , Datos de Secuencia Molecular , Polimorfismo de Longitud del Fragmento de Restricción , Células Tumorales Cultivadas
8.
J Clin Oncol ; 13(5): 1073-9, 1995 May.
Artículo en Inglés | MEDLINE | ID: mdl-7738613

RESUMEN

PURPOSE: To evaluate the significance of molecular marker-positive cells in a cohort of non-Hodgkin's lymphoma (NHL) patients undergoing high-dose chemotherapy and autologous peripheral-blood stem-cell transplantation (PBSCT). PATIENTS AND METHODS: Twenty-eight PBSC transplants have been performed in 24 patients with poor-prognosis NHL. Molecular analysis of the t(14;18) (q32;q21) translocation (bcl-2/immunoglobulin [Ig] heavy-chain joining locus [JH] fusion) or antigen receptor gene rearrangements was performed to determine the presence of lymphoma cells at presentation, in PBSC harvests, and before and after autologous PBSCT. Kaplan-Meier estimates of survival and Cox regression analyses were used to test the effect of bone marrow involvement, tumor-cell contamination of PBSCs, disease stage, and chemotherapy sensitivity at transplantation, and presence of marker-positive cells post-PBSCT on disease-free and overall survival. RESULTS: Thirteen of 24 patients (54%) are alive following PBSCT at a median follow-up time of 654 days (range, 193 to 1,908). Nine patients are in complete remission (CR) at day 216 to 1,799 (median, 805) and four are alive following relapse (day 440, 573, 1,188, and 1,908). Eleven patients (46%) have died: three of transplant-related complications at day 0, 1, and 13, and eight of recurrent disease (day 132 to 1,330; median, 451). Longitudinal marker studies post-PBSCT showed that of 16 relapse events, 13 (81%) were positive for the lymphoma marker at or before clinically documented relapse. Marker studies became negative post-PBSCT in nine of nine patients who entered and remained in CR. Disease-free survival (DFS) was significantly shortened in patients in whom marker-positive cells were detected in serial samples posttransplantation (P = .006). Cox regression analysis showed that patients in this group had a 24 times higher risk of relapse (P = .03). CONCLUSION: The results show that the reappearance or persistence of marker-positive cells after autologous PBSCT is strongly associated with relapse.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/terapia , Translocación Genética/genética , Adulto , Southern Blotting , Estudios de Cohortes , Terapia Combinada , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Marcadores Genéticos , Humanos , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Recurrencia , Análisis de Regresión , Análisis de Supervivencia , Resultado del Tratamiento
9.
J Clin Oncol ; 17(1): 82-92, 1999 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10458221

RESUMEN

PURPOSE: To determine the safety and efficacy of multiple cycles of dose-intensive, nonablative chemotherapy in women with poor-prognosis breast cancer. PATIENTS AND METHODS: Women with stage II breast cancer and 10 or more involved nodes or four or more involved nodes and estrogen receptor-negative tumors and women with stage III disease received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2, with progenitor cell and filgrastim support every 28 days (n = 79) or 21 days (n = 20). Patients were reviewed at least twice yearly thereafter. Twenty-six patients had bone marrow and apheresis collections assessed for the presence of micrometastatic tumor cells. RESULTS: Ninety-nine women (median age, 43 years; range, 24 to 60 years) were treated. Ninety-two completed all three cycles of chemotherapy. The major toxicity was severe, reversible myelosuppression that was more prolonged with successive cycles, and this did not differ between patients given treatment every 28 days and those treated every 21 days. Febrile neutropenia occurred in 176 (61%) of 287 cycles. Severe mucositis (grade 3 or 4) occurred in 23% of cycles but tended to be short-lived and was reversible. The cardiac ejection fraction fell by a median of 4% during treatment, and three patients developed evidence of cardiac failure after chemotherapy. Two patients (2%) died of acute toxicity. Three of 26 patients had evidence of circulating micrometastatic tumor cells. The actuarial distant disease-free and overall survival rates at 60-month follow-up were 64% (95% confidence interval [CI], 53% to 75%) and 67% (95% CI, 56% to 78%), respectively. CONCLUSION: Multiple cycles of dose-intensive, nonablative chemotherapy is a feasible and safe approach. Disease control and survival are similar to those in other studies of myeloablative chemotherapy in poor-prognosis breast cancer. The regimen is being evaluated in a randomized trial of the International Breast Cancer Study Group.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Filgrastim , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Células Neoplásicas Circulantes , Pronóstico , Proteínas Recombinantes , Tasa de Supervivencia
10.
Eur J Cancer ; 39(14): 2026-34, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12957457

RESUMEN

This dose-finding, placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks (Q3W) to anaemic patients receiving chemotherapy. In part A, patients (haemoglobin 50% of patients achieving a haematopoietic response. Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy.


Asunto(s)
Anemia/tratamiento farmacológico , Antineoplásicos/efectos adversos , Eritropoyetina/análogos & derivados , Eritropoyetina/administración & dosificación , Hematínicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anemia/inducido químicamente , Darbepoetina alfa , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Eritropoyetina/efectos adversos , Eritropoyetina/farmacocinética , Femenino , Hematínicos/efectos adversos , Hematínicos/farmacocinética , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
11.
Biotechniques ; 22(1): 100-5, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8994656

RESUMEN

Detection of circulating tumor cells and micrometastases in patients with cancer should prove useful in determining prognosis and in planning and monitoring systemic therapies. We have developed immunomagnetic isolation of carcinoma cells followed by reverse transcription polymerase chain reaction (immunobead RT-PCR) as a method for identifying very small numbers of breast cancer cells in blood. The expression of cytokeratin 19 (K19) was used as the marker by which the isolated tumor cells were identified. The immunobead RT-PCR technique allowed detection of one tumor cell per 10(6) leukocytes in whole blood. Immunobead RT-PCR is a highly sensitive method of detecting cancer cells in a hematopoietic environment.


Asunto(s)
Inmunoensayo/métodos , Metástasis de la Neoplasia , Neoplasias/sangre , Reacción en Cadena de la Polimerasa/métodos , Anticuerpos Monoclonales/análisis , Biomarcadores de Tumor , Neoplasias de la Mama/sangre , Neoplasias de la Mama/inmunología , Carcinoma/sangre , Carcinoma/inmunología , Citometría de Flujo , Humanos , Sensibilidad y Especificidad , Células Tumorales Cultivadas
12.
Bone Marrow Transplant ; 11(1): 15-20, 1993 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8381694

RESUMEN

Twenty-seven patients with non-Hodgkin's lymphoma (NHL) have undergone peripheral blood stem cell (PBSC) harvesting for autologous transplantation (Tx). A molecular marker was found at presentation in 23/27 patients. Immunoglobulin heavy chain (IgH) or T cell receptor beta (TCR beta) rearrangements were detected by Southern blotting or the polymerase chain reaction (PCR) in 13 patients; PCR detected the bcl-2/JH fusion in 10 patients. Fifteen autologous PBSC transplants have been performed in 11 patients. In 5/11 patients, the marker was present in at least one PBSC collection (in four patients, every PBSC collection was positive). Survival data are available for nine patients (two early deaths); three patients relapsed and died (221 - 930 d), one is alive and in relapse (354 + d) and five are alive and in complete remission (330 - 1290 + d). These findings suggest that tumour cell contamination of PBSC harvests is not uncommon. Whether these cells are clonogenic and contribute to disease relapse remains to be elucidated. The presence of residual disease at the time of transplantation and the reappearance (or persistence) of marker positive cells post-transplantation both appear to be poor prognostic factors for disease-free survival.


Asunto(s)
Trasplante de Médula Ósea/patología , Linfoma no Hodgkin/cirugía , Adulto , Secuencia de Bases , Biomarcadores de Tumor , Células Sanguíneas/inmunología , Células Sanguíneas/patología , Purgación de la Médula Ósea , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/métodos , Clonación Molecular , ADN de Neoplasias/genética , Femenino , Reordenamiento Génico de Cadena Pesada de Linfocito B , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/patología , Humanos , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Células Neoplásicas Circulantes/inmunología , Células Neoplásicas Circulantes/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Trasplante Autólogo
13.
Bone Marrow Transplant ; 9(1): 11-7, 1992 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-1347478

RESUMEN

Sixty patients with malignancy were enrolled in a study of high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT). Stem cells were harvested prior to PBSCT using high-dose cyclophosphamide (CY) mobilization (4 or 7 g/m2) with collection of a median of 4.6 x 10(8)/kg mononuclear cells (range 0.2-9.5) and 21.6 x 10(4)/kg colony forming unit-granulocyte/macrophage (CFU-GM) (range 0.1-220). Forty-seven patients were mobilized once, 11 required two cycles and two required three cycles. Eight patients (13%) failed to reach the optimum CFU-GM target (greater than 15 x 10(4)/kg) following CY mobilization. A number of factors identified those patients who were likely to achieve optimum CFU-GM collections with CY mobilization. These included the use of the higher CY mobilization dose, a longer interval from last chemotherapy cycle to mobilization, and a higher premobilization bone marrow CFU-GM level. Patient's age, the degree of bone marrow infiltration, the nature of disease or the number of pre-mobilization chemotherapeutic cycles did not affect the ability to collect optimum CFU-GM numbers. Whilst the mobilization procedure was associated with moderate non-hematologic toxicity, significant hematological morbidity was observed primarily in patients mobilized using the 7 g/m2 dose. Refinements to the protocol, in particular the use of hematopoietic growth factors, are currently under investigation.


Asunto(s)
Células Sanguíneas/trasplante , Trasplante de Médula Ósea/métodos , Ciclofosfamida/administración & dosificación , Neoplasias/cirugía , Adolescente , Adulto , Anciano , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/patología , Eliminación de Componentes Sanguíneos , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Linfoma/sangre , Linfoma/tratamiento farmacológico , Linfoma/cirugía , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/cirugía , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Trasplante Autólogo
14.
Cancer Genet Cytogenet ; 56(2): 255-62, 1991 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-1756471

RESUMEN

A 21-year-old male presented with a large mediastinal mass and a white cell count of 420 x 10(9)/L. A diagnosis of acute lymphoblastic leukemia (ALL) was made, with 90% of cells in the bone marrow (BM) and 99% in the peripheral blood (PB) being lymphoblasts (FAB L1). Cytogenetic analysis of these cells revealed a rare variant of the t(4;11) translocation involving chromosome arm 11p rather than 11q, namely t(4;11)(q21;p14-15). The standard form of the (4;11) translocation has been associated with leukemias with mixed-lineage phenotypes. Three cases of ALL with t(4q;11p) have previously been reported. One of these cases showed phenotypic heterogeneity involving myeloid and lymphoid lineages. The leukemia reported here also exhibits lymphoid/myeloid features. Immunophenotyping of the blasts showed that most of the cells were positive for CD2, CD5, CD7, CD10 (CALLA), CD34, and HLA-DR. A significant proportion of the cells expressed CD33. These results suggest a biphenotypic rather than a biclonal disease. Molecular analysis showed rearrangement of both immunoglobulin heavy-chain genes (JH) and of a single allele of the T-cell receptor (TCR) gamma 1 gene, while retaining germline TCR beta genes.


Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 4 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética , Adulto , Antígenos CD/análisis , Reordenamiento Génico/genética , Reordenamiento Génico de Linfocito T , Antígenos HLA-DR/análisis , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Inmunofenotipificación , Cariotipificación , Masculino , Receptores de Antígenos de Linfocitos T/genética
15.
Cancer Chemother Pharmacol ; 16(2): 194-7, 1986.
Artículo en Inglés | MEDLINE | ID: mdl-3948305

RESUMEN

Fifteen patients receiving oral melphalan (4.2-5.3 mg/m2) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m2) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95-336) ng X h X ml-1, and when taken with food, 122 (47-227) ng X h X ml-1, the median reduction being 39% (P less than 0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38-71) was no different from its oral half-life [55 (27-104) min fasting; 55 (30-72) min with food] (P greater than 0.1). In these patients bioavailability was 85% (26-96)% when the drug was taken fasting and 58% (7-99)% when taken with food (P less than 0.025). Median clearance following IV administration was 362 ml/min/m2 (range 104-694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (rs = 0.915, P less than 0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.


Asunto(s)
Alimentos , Melfalán/metabolismo , Absorción , Administración Oral , Anciano , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Ayuno , Femenino , Humanos , Inyecciones Intravenosas , Cinética , Masculino , Melfalán/administración & dosificación , Melfalán/sangre , Melfalán/uso terapéutico , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico
16.
Cancer Chemother Pharmacol ; 22(4): 348-52, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-3168148

RESUMEN

The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m2 over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m2. Total melphalan clearance after the 5 mg/m2 dose ranged from 66.0 to 272 ml/min per m2; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m2; the fraction unbound in plasma, from 0.0598 to 0.460; and t1/2 beta, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m2 and 15 to 961 ml/min per m2 respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose excreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.


Asunto(s)
Riñón/metabolismo , Melfalán/farmacocinética , Adulto , Anciano , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Unión Proteica
17.
Cancer Chemother Pharmacol ; 20(3): 256-8, 1987.
Artículo en Inglés | MEDLINE | ID: mdl-3315285

RESUMEN

Melphalan uptake in the intestine has recently been shown to be an energy-dependent process which is affected by metabolic inhibitors. It is therefore theoretically possible that amino acids in food could reduce melphalan absorption by competing for uptake at the sites of absorption in the intestine. Since L-leucine has been shown to be the most potent inhibitor of melphalan transport into cells in vitro, this amino acid was chosen for the present study in patients. Oral melphalan (4.5 +/- 0.5 mg/m2) was given to ten fasting patients with and without a 2-g oral dose of L-leucine on separate randomized occasions at least 1 week apart. Melphalan plasma levels were measured by high-performance liquid chromatography (HPLC) for 5-h after dosing. L-Leucine plasma levels were measured by HPLC before and at 1 h after dosing. The area under the curve for melphalan was lower in seven of the patients after L-leucine. Plasma L-leucine levels 1 h after melphalan administration were 15.4 +/- 3.7 micrograms/ml fasting and 35.4 +/- 5.2 micrograms/ml after L-leucine. The results indicate that L-leucine can reduce plasma melphalan levels in some patients, probably through a reduction in absorption of the drug from the gastrointestinal tract. However, the effect, like that of food, is highly variable.


Asunto(s)
Leucina/farmacología , Melfalán/farmacocinética , Administración Oral , Anciano , Cromatografía Líquida de Alta Presión , Ensayos Clínicos como Asunto , Ayuno , Femenino , Humanos , Absorción Intestinal , Leucina/administración & dosificación , Leucina/sangre , Masculino , Melfalán/administración & dosificación , Melfalán/sangre , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Distribución Aleatoria , Factores de Tiempo
20.
Br J Cancer ; 97(4): 464-71, 2007 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-17653074

RESUMEN

The aim of this phase II study was to assess the feasibility and efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-fluorouracil (CI 5FU) sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. Patients with inoperable cancer in the pancreatic head or body without metastases were given gemcitabine at 1000 mg m(-2) weekly for 3 weeks followed by a 1-week rest and a 6-week period of radiotherapy and concurrent CI 5FU (200 mg m(-2) day(-1)). The defined target volume was treated to 54 Gy in 30 daily fractions of 1.8 Gy. After 4 weeks' rest, gemcitabine treatment was re-initiated for three cycles (days 1, 8, 15, q28). Forty-one patients were enrolled. At the end of radiotherapy, one patient (2.4%) had a complete response and four patients (9.6%) had a partial response; at the end of treatment, three patients (7.3%) had a complete response and two patients (4.9%) had a partial response. Median survival time was 11.7 months, median time to progression was 7.1 months, and median time to failure of local control was 11.9 months. The 1- and 2-year survival rates were 46.3 and 9.8%, respectively. Treatment-related grade 3 and 4 toxicities were reported by 16 (39.0%) and four (9.8%) patients, respectively. Sixteen out of 41 patients did not complete the planned treatment and nine due to disease progression. This approach to treatment of locally advanced pancreatic cancer is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomised trial.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Desoxicitidina/análogos & derivados , Fluorouracilo/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Radioterapia Conformacional , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Quimioterapia Adyuvante/efectos adversos , Terapia Combinada/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Fluorouracilo/efectos adversos , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Radioterapia Asistida por Computador/efectos adversos , Radioterapia Conformacional/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Gemcitabina
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