RESUMEN
PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline BRCA2 mutation with acquired resistance to olaparib related to biallelic BRCA2 reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline BRCA2 mutations. Within the germline BRCA2-positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.
RESUMEN
Androgen receptor (AR) has essential roles during prostate cancer progression. With genome-wide AR-binding sites mapped to high resolution, studies have recently reported AR as a transcriptional repressor. How AR inhibits gene expression and how this contributes to prostate cancer, however, are incompletely understood. Through meta-analysis of microarray data, here we nominate nephroblastoma overexpressed (NOV) as a top androgen-repressed gene. We show that NOV is directly suppressed by androgen through the AR. AR occupies the NOV enhancer and communicates with the NOV promoter through DNA looping. AR activation recruits the polycomb group protein EZH2, which subsequently catalyzes histone H3 lysine 27 tri-methylation around the NOV promoter, thus leading to repressive chromatin remodeling and epigenetic silencing. Concordantly, AR and EZH2 inhibition synergistically restored NOV expression. NOV is downregulated in human prostate cancer wherein AR and EZH2 are upregulated. Functionally, NOV inhibits prostate cancer cell growth in vitro and in vivo. NOV reconstitution reverses androgen-induced cell growth and NOV knockdown drives androgen-independent cell growth. In addition, NOV expression is restored by hormone-deprivation therapies in mice and prostate cancer patients. Therefore, using NOV as a model gene we gained further understanding of the mechanisms underlying AR-mediated transcriptional repression. Our findings establish a tumor-suppressive role of NOV in prostate cancer and suggest that one important, but previously underestimated, manner by which AR contributes to prostate cancer progression is through inhibition of key tumor-suppressor genes.
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Regulación Neoplásica de la Expresión Génica/genética , Proteína Hiperexpresada del Nefroblastoma/biosíntesis , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Hiperexpresada del Nefroblastoma/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , TranscriptomaRESUMEN
Mycosis fungoides is typified by a cutaneous infiltrate of CD4+ lymphocytes with a Th2 phenotype. As the disease advances, there is increased expression of Th2 cytokines. This results in a subsequent suppression of Th1 cytokines and impaired cell mediated cytotoxic host response to the lymphoma cells. Disarming this cell mediate cytotoxic immune response creates a relentless cycle of disease progression. A cell mediated cytotoxic immune response can be stimulated with the use of Th1 cytokines such as IL-2 and IL-12. In this report, the Authors review the rational for the use of these particular cytokines in the treatment of mycosis fungoides. Further they comment on the experience and success regarding these two agents in phase I and II trials for the treatment of mycosis fungoides. Lastly, they discuss other potential cytokine therapies which could play a role in the future treatment of mycosis fungoides.
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Antineoplásicos/uso terapéutico , Toxina Diftérica/uso terapéutico , Interleucina-12/uso terapéutico , Interleucina-2/uso terapéutico , Micosis Fungoide/tratamiento farmacológico , Antineoplásicos/efectos adversos , Linfocitos T CD4-Positivos/patología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Toxina Diftérica/efectos adversos , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Interleucina-12/efectos adversos , Interleucina-2/efectos adversos , Células Madre Neoplásicas/patología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The multikinase inhibitor sunitinib has enhanced the treatment of renal cell carcinoma and gastrointestinal stromal tumor through an improved clinical response with decreased systemic toxicities. However, sunitinib is frequently associated with dermatological adverse reactions. The physical and psychosocial impact of frequent dermatological toxicities can affect consistent antineoplastic therapy and quality of life. PATIENTS AND METHODS: Dermatological adverse reaction information was compiled from Pfizer Medical Information and from abstracts from the 2007 American Society of Clinical Oncology annual meeting, Prostate Cancer Symposium, and Gastrointestinal Cancers Symposium. Published clinical trials of sunitinib in MEDLINE, Cochrane Library, Cochrane Controlled Trials Register, and EMBASE Drugs and Pharmacology databases were also included. Information was accessed on or before June 30, 2007. RESULTS: In the pooled analysis, all-grade hand-foot skin reaction occurred in 19% of patients (5% grades 3-4), skin discoloration in 28% (0% grades 3-4), dry skin in 16% (1% grades 3-4), skin rash in 13% (1% grades 3-4), dermatitis in 8% (2% grades 3-4), hair color changes in 10% (0% grades 3-4), alopecia in 6% (0% grades 3-4), and phototoxicity in <0.1%. CONCLUSIONS: Dermatological reactions associated with sunitinib occur frequently. Evidence-based treatment recommendations are needed in order to maximize quality of life and optimize clinical outcome.
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Inhibidores de la Angiogénesis/efectos adversos , Erupciones por Medicamentos/etiología , Indoles/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirroles/efectos adversos , Erupciones por Medicamentos/epidemiología , Erupciones por Medicamentos/prevención & control , Humanos , Incidencia , Calidad de Vida , SunitinibRESUMEN
Mycosis Fungoides and Sézary Syndrome are the most common types of cutaneous T-cell lymphomas. There is no current standard of care for Mycosis Fungoides/Sézary Syndrome, with a general tendency to rely on topical interventions for early disease delaying systemic, more toxic therapy until the development of extensive symptoms. Knowledge of the biological characteristics of this disease has allowed for the development of rational interventions and a significant advance in its treatment. Retinoids are active in Mycosis Fungoides/Sézary Syndrome with the newer rexinoids being available in topical and systemic forms. Interferon alpha remains one of the most active therapeutic agents for Mycosis Fungoides/Sézary Syndrome, especially in combination with other agents such as PUVA. The monoclonal antibody alemtuzumab leads to responses in at least half of patients with advanced disease with its side effect profile consisting mainly of immunosupression and infusion reactions. The recombinant IL2-diphteria toxin denileukin diftitox (Ontak) is active in this disease and appears to have a beneficial effect in symptoms relief and quality of life. Extracorporeal photochemotherapy as an immunostimulating intervention seems to be very effective in a subset of patients, but its availability is limited to less than a hundred centers worldwide. Experimental and less studied interventions include autologous and allogeneic peripheral stem cell transplantation, Interleukin-12, the histone-deacetylator depsipeptide and the synthetic deoxynucleotide CpG7909. Cutaneous T-cell lymphoma has served as a paradigm for the development of biological agents. Further knowledge of the signaling pathways in Mycosis Fungoides/Sézary Syndrome will allow for the development of more effective treatment strategies.
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Antineoplásicos/uso terapéutico , Inmunoterapia , Linfoma Cutáneo de Células T/terapia , Neoplasias Cutáneas/terapia , Antineoplásicos/inmunología , Humanos , Linfoma Cutáneo de Células T/inmunología , Neoplasias Cutáneas/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: A prospective multi-institutional phase II trial was undertaken to define the activity and toxicity of a unique decrescendo infusion of interleukin-2 (IL-2) in combination with interferon (IFN) in patients with metastatic renal cell carcinoma. The identical regimen has shown promise in advanced melanoma. PATIENTS AND METHODS: Between February 1997 and March 1999, 47 patients with metastatic renal cell carcinoma, from five institutions, were treated with outpatient s.c. IFN (10 mU/m2/day) on days 1-5, followed by inpatient IL-2 via continuous i.v. decrescendo infusion [18 million International Units (MIU) (I mg)/m2/6 h, followed by 18 MIU/m2/12 h, then 18 MIU/m2/24 h and 4.5 MIU/m2/24 h for the following 3 days] on days 8-12, in a hospital ward without intensive care unit (ICU)-type monitoring. Treatment was repeated every 4 weeks. In contrast to high dose IL-2 protocols, patient eligibility did not require pulmonary function tests and allowed serum creatinine up to 2 mg/dl. RESULTS: Among 44 eligible patients, 57% (25) had their primary in place, 57% (25) had bone or visceral involvement, and only 4% (2) had lung as their only site of disease. The overall response rate in 43 response-evaluable patients was 16.3% [95% confidence interval (CI) 5.3 to 27.3], with three complete responses and four partial responses observed. The median survival was 13 months; nine patients remain alive at >23 months. The median duration of response is 36 months (range 11.5 to 48+ months). Toxicity was modest, consisting of typical cytokine-induced systemic symptoms and rare organ dysfunction. Severe grade 4 toxicity occurred in only 13% of the 130 cycles. CONCLUSIONS: This unique, reasonably well tolerated IL-2/IFN combination induced a modest response rate with a number of durable remissions. While the optimal IL-2-based regimen for the treatment of advanced renal cell carcinoma remains elusive, the present regimen should attract considerable interest. This is based on tumor activity very similar to high dose IL-2 in a patient population not as carefully selected for optimal organ function.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Interleucina-2/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Renales/patología , Esquema de Medicación , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Interferón-alfa/farmacología , Interleucina-2/efectos adversos , Interleucina-2/farmacología , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
DAB(389)IL-2 (denileukin diftitox, ONTAK) is a cytokine-targeted fusion protein that delivers the catalytic domain of diphtheria toxin to lymphoma cells expressing the interleukin-2 receptor (IL-2R). In phase I and phase III studies of DAB(389)IL-2 in patients with cutaneous T-cell lymphoma (CTCL), non-Hodgkin's lymphoma, and Hodgkin's disease in which premedications were limited to diphenhydramine and acetaminophen, acute infusion-related hypersensitivity reactions occurred in 70% of patients and vascular leak syndrome (VLS) in 27%, resulting in discontinuation of therapy in 29% of patients. There was no correlation between the dose or half-life of DAB(389)IL-2 and the occurrence of hypersensitivity events or VLS. To explore whether steroid premedication would improve the tolerability of DAB(389)IL-2, we treated 15 patients with CTCL with either dexamethasone or prednisone prior to each dose of DAB(389)IL-2. The incidence of acute infusion events was significantly decreased, with only three patients experiencing acute infusion events (one grade 4) and only two patients developing clinically apparent VLS. Grade 3 skin rash occurred in two patients and moderately severe asthenia in nine patients. A significantly improved response rate of 60% was noted with the use of steroid premedication compared to prior studies in which steroids were prohibited. We conclude that steroid premedication significantly improves the tolerability of DAB(389)IL-2 without compromising the clinical response.
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Toxina Diftérica/efectos adversos , Hipersensibilidad a las Drogas/prevención & control , Glucocorticoides/uso terapéutico , Inmunosupresores/efectos adversos , Inmunotoxinas/efectos adversos , Interleucina-2/efectos adversos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Proteínas Recombinantes de Fusión/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Dexametasona/uso terapéutico , Toxina Diftérica/uso terapéutico , Hipersensibilidad a las Drogas/etiología , Femenino , Humanos , Inmunosupresores/uso terapéutico , Inmunotoxinas/uso terapéutico , Interleucina-2/uso terapéutico , Linfocitos/inmunología , Linfoma Cutáneo de Células T/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/uso terapéutico , Premedicación , Proteínas Recombinantes de Fusión/uso terapéutico , Neoplasias Cutáneas/metabolismo , Síndrome , Resultado del TratamientoRESUMEN
Recent phase I and phase II trials using recombinant human interleukin-12 (rhIL-12) for cutaneous T cell lymphoma (CTCL) have been completed. Observations on 32 evaluable patients revealed an overall response rate approaching 50 percent. Biopsy of regressing lesions revealed an increase in numbers of CD8+ and/or TIA-1+ T cells. These results suggest that rhIL-12 may induce lesion regression by augmenting antitumor cytotoxic T cell responses. Future trials will be focused on strategies for further immune enhancement by the concomitant use of additional immune augmenting cytokines with rhIL-12.
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Antineoplásicos/uso terapéutico , Interleucina-12/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Antígenos de Diferenciación de Linfocitos T/análisis , Antígenos de Diferenciación de Linfocitos T/inmunología , Antineoplásicos/efectos adversos , Humanos , Inmunohistoquímica , Interleucina-12/efectos adversos , Linfocitos Infiltrantes de Tumor/inmunología , Linfoma Cutáneo de Células T/inmunología , Proteínas Recombinantes/uso terapéutico , Neoplasias Cutáneas/inmunología , Subgrupos de Linfocitos T/clasificación , Linfocitos T Citotóxicos/inmunología , Resultado del TratamientoRESUMEN
Quality of life (QOL) considerations are important in the treatment decision making process for prostate cancer patients. Although patient involvement in the treatment decision process has been encouraged, low health literacy can limit patient understanding of the complex information about treatments and their probable QOL outcomes and is a barrier to patient participation in the decision-making process. The objectives of the study were to evaluate (i) knowledge, level of satisfaction, and treatment preferences and intentions of men newly diagnosed with prostate cancer after participation in a CD-ROM shared decision making program; and (ii) the relationship between prostate cancer knowledge and health literacy. Thirty newly diagnosed prostate cancer patients from two Veteran's Administration (VA) hospitals in Chicago completed a demographic questionnaire and participated in an interactive CD-ROM shared decision making program. Subsequently, knowledge of prostate cancer, satisfaction with the information in the computer CD-ROM program, treatment preferences, and likelihood of following treatment preferences were assessed using interviewer-administered questionnaires. Health literacy was assessed using the Rapid Estimate of Adult Literacy in Medicine (REALM). The Pearson correlation test was used to assess the relationship between health literacy and prostate cancer knowledge. The chi2 test and the Fischer exact test were used to evaluate relationships between patient demographics and other variables. More than three-quarters of the patients rated the information in the CD-ROM as "very satisfactory" (highest possible rating). Two-thirds of the patients (21 of 30) selected a treatment after participation in the CD-ROM program and 90.5% of these patients stated that they were very or somewhat likely to adhere to their selection. However, prostate cancer knowledge was variable, with one-third of the patients scoring 69.9% or lower. Participants' health literacy was equivalent to a 7th-8th grade reading level (mean = 57.1+/-10.9), and more than one-third of participants (36.7%) had lower than 9th grade literacy levels. Participants' prostate cancer knowledge was correlated with health literacy (Pearson correlation rhor = 0.65, rhop = 0.0001). Patients were satisfied with the interactive shared decision making CD-ROM program, and two-thirds of patients were able to select a preferred treatment based on the information presented in the program that they intended to follow. However, prostate cancer knowledge scores varied among participants after participation in the CD-ROM program, raising doubts that patients were adequately informed to make appropriate choices regarding their treatment. Lower prostate cancer knowledge scores corresponded to lower literacy scores, indicating that low literacy may have hindered patient understanding of the shared decision making program. The development of shared decision making tools should include collaborative efforts with the target population to improve the success of shared decision making programs among patients with low health literacy.
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Toma de Decisiones , Educación del Paciente como Asunto , Relaciones Médico-Paciente , Neoplasias de la Próstata/terapia , Clase Social , Anciano , CD-ROM , Barreras de Comunicación , Escolaridad , Humanos , Conocimiento , Masculino , Persona de Mediana Edad , Calidad de Vida , Encuestas y CuestionariosRESUMEN
PURPOSE: To evaluate the role of 9-aminocamptothecin (9-AC), a synthetic camptothecin analog, in advanced cutaneous T-cell lymphoma (CTCL). METHODS: Eligible patients had stage IIB-IV CTCL. 9-AC was infused over 72 h at a dose of 1,100 microg/m2 per day (approximately 46 microg/m2/h) every 2 weeks, with granulocyte-colony stimulating factor (G-CSF) support. RESULTS: Twelve patients received a total of 30 cycles of 9-AC. Nine patients had stage IV disease, 5 patients had circulating Sezary cells, and 2 patients had evidence of tranformation to a large cell lymphoma. Most of the patients were heavily pretreated: 10 had received prior chemotherapy (83%), 5 of whom had received 2 or more prior regimens, including a patient who had received high-dose chemotherapy, and 7 had previously received total-skin electron beam therapy. The study was prematurely terminated due to substantial toxicity. Six patients (50%) developed an indwelling central venous catheter-related infection, 5 during a period of neutropenia. Three patients died due to sepsis 4-8 weeks after their last 9-AC treatment. Two of these patients had a previous history of bacterial sepsis. Four patients (33%) developed grade IV thrombocytopenia. Two partial responses were observed (response rate 17%), but the duration of response was brief, 4-8 weeks. CONCLUSION: 9-AC at this schedule and route of administration had activity but resulted in an unacceptable rate of complicated neutropenia and septic deaths in heavily pretreated patients with advanced CTCL who are susceptible to catheter-related infections.
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Antineoplásicos/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Antineoplásicos/efectos adversos , Camptotecina/efectos adversos , Progresión de la Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Infusiones Intravenosas , Linfoma Cutáneo de Células T/mortalidad , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/terapia , Neoplasias Cutáneas/mortalidad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor. OBJECTIVE: We attempted to determine the efficacy of peldesine (BCX-34) in a 1% dermal cream formulation as a treatment for cutaneous T-cell lymphoma (CTCL). METHODS: Ninety patients with patch and plaque phase CTCL, histologically confirmed by a referee dermatopathologist, were enrolled in a randomized, double-blind, placebo-controlled study. BCX-34 dermal cream 1% or the vehicle cream (as a placebo control) was applied twice daily to the entire skin surface for up to 24 weeks. Efficacy of the topical therapy was assessed in terms of complete or partial (> or = 50%) clearing of patches and plaques. RESULTS: Of the 89 patients able to be examined, 43 received BCX-34 and 46 received the placebo vehicle cream. One patient withdrew early and was not analyzed. The two groups were well balanced for potential prognostic factors. A total of 28% (12/43) of the patients treated with BCX-34 showed a response, but 24% (11/46) of patients who received vehicle also responded (P =.677). CONCLUSION: Although BCX-34 dermal cream 1% was not significantly better than the control as therapy for patch and plaque-phase CTCL, this appears to be the first published placebo-controlled trial evaluating treatment for CTCL. Whether the vehicle cream has more than a placebo therapeutic effect is unclear. The relatively high (24%) placebo response rate should be kept in mind in assessing other treatments for early-stage CTCL.
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Inhibidores Enzimáticos/farmacología , Guanina/análogos & derivados , Guanina/farmacología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Administración Cutánea , Adulto , Anciano , Método Doble Ciego , Inhibidores Enzimáticos/administración & dosificación , Femenino , Guanina/administración & dosificación , Humanos , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Placebos , Resultado del TratamientoRESUMEN
OBJECTIVES: To examine the reliability and validity of spousal assessments by evaluating the collateral quality-of-life (QOL) ratings of patients of lower socioeconomic status with metastatic prostate cancer because collateral ratings provide supplemental information when advanced cancer limits patient self-report. METHODS: Patients with Stage D2 prostate cancer (n = 36) of lower socioeconomic status completed validated QOL instruments (Functional Assessment of Cancer Therapy-General [FACT-G], European Organization for Research and Treatment of Cancer-Quality of Life-30, and Quality of Life Index). Spouses completed a modified FACT-G, and physicians rated performance status using Karnofsky's scale. RESULTS: The internal consistency reliability was moderate to high for patient ratings on all FACT-G subscales and for spousal ratings on the modified FACT-G physical, functional, and emotional subscales. The spouses' ratings of the patients on the social and doctor relationship subscales were below the accepted criterion for a measure's use in group comparisons. The comparisons of the mean values of the FACT-G revealed agreement between patients and spouses, except that the spouses rated the patients as having poorer emotional function than did the patients. The intraclass correlations were moderate to high for the functional and emotional subscales and were low, but significant, for the physical and social subscales. The patient and spouse FACT-G ratings correlated with the patient ratings and physician ratings across the instruments for the functional and physical domains (r = 0.48 to 0.77, for patients; r = 0.31 to 0.70, for spouses), with less consistent relationships for the social and emotional domains. CONCLUSIONS: The collateral QOL assessments from spouses are potentially useful in assessing the functional status in patients of lower socioeconomic status with metastatic prostate cancer. For subjective domains, such as the social domain, direct patient assessments are needed.
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Neoplasias de la Próstata/patología , Neoplasias de la Próstata/psicología , Calidad de Vida , Factores Socioeconómicos , Esposos , Estudios Transversales , Estudios de Factibilidad , Femenino , Humanos , Entrevistas como Asunto , Masculino , Metástasis de la Neoplasia , Psicometría , Reproducibilidad de los Resultados , Encuestas y CuestionariosAsunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , Portador Sano/epidemiología , Ensayos Clínicos como Asunto , Europa (Continente)/epidemiología , Femenino , Humanos , Japón/epidemiología , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/terapia , Masculino , Pronóstico , Estados Unidos/epidemiología , Indias Occidentales/epidemiologíaRESUMEN
PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.
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Antineoplásicos/uso terapéutico , Toxina Diftérica , Interleucina-2 , Linfoma Cutáneo de Células T/tratamiento farmacológico , Proteínas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Esquema de Medicación , Femenino , Humanos , Inmunohistoquímica , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas/administración & dosificación , Proteínas/farmacocinética , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes de Fusión , Inducción de RemisiónRESUMEN
Human T-cell lymphotropic virus-I (HTLV-I)-related adult T-cell leukemia/lymphoma (ATL) is a model disease for proof of viral oncogenesis. HTLV-I infection is endemic in southern Japan and the Caribbean basin, and occurs sporadically in Africa, Central and South America, the Middle East, and the southeastern United States. ATL occurs in only 2% to 4% of HTLV-I-infected people [1-3]. When it does occur, it is usually aggressive and difficult to treat; most people survive for less than 1 year [1-3]. Combination chemotherapy with cytotoxic agents has yielded complete response rates of 20% to 45%, but responses usually last only a few months [3]. Recently, novel treatments, such as monoclonal antibodies directed at the interleukin-2 receptor and the combination of interferon alfa and zidovudine, have been shown to be active in the treatment of patients with ATL. A small percentage of patients achieve long-lasting remissions [2,3].
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Leucemia-Linfoma de Células T del Adulto , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , Niño , Preescolar , Infecciones por Deltaretrovirus/epidemiología , Infecciones por Deltaretrovirus/transmisión , Resistencia a Antineoplásicos , Métodos Epidemiológicos , Femenino , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/fisiología , Humanos , Lactante , Recién Nacido , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/epidemiología , Leucemia-Linfoma de Células T del Adulto/terapia , Masculino , Persona de Mediana Edad , Embarazo , Complicaciones Infecciosas del Embarazo , Prevalencia , Pronóstico , Radioterapia Adyuvante , Reacción a la TransfusiónRESUMEN
PURPOSE: Primary cutaneous T-cell lymphomas (CTCLs) encompass a wide variety of lymphomas that are characterized by the localization of the malignant lymphocytes to the skin at presentation. Advances in molecular biologic techniques, including immunophenotyping and gene rearrangement studies to determine clonality, have led to more frequent diagnosis of CTCL as well as more consistent subclassification of these entities. However, there continues to be confusion in the classification, prognosis, and management of patients with CTCL. The purpose of this review is to present a summary of the diagnosis, prognosis, and treatment of CTCL, with specific emphasis on mycosis fungoides (MF) and Sézary syndrome (SS). We also present a detailed discussion of the entities that make up the differential diagnosis of CTCL. DESIGN: We reviewed the medical literature on CTCL and other diseases that make up the differential diagnosis of CTCL. RESULTS AND CONCLUSION: MF and SS are the most common forms of CTCL. The etiology of this disease is still unknown. Patients may go for months to years with skin abnormalities before being diagnosed. MF/SS is an indolent disease and patients with T1 disease have a normal life expectancy. Patients who undergo transformation to large-cell lymphoma (8% to 23% of patients) have a poor prognosis, with mean survival ranging from 2 to 19 months. Treatment for MF/SS continues to be palliative. There are many new therapies that are currently being investigated in clinical trials, and the DAB(389)IL-2 fusion protein was recently approved for the treatment of refractory MF/SS.
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Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Diagnóstico Diferencial , Humanos , Esperanza de Vida , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Cuidados Paliativos , Pronóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
PURPOSE: Primary cutaneous B-cell lymphoma (PCBCL) has only recently been recognized as a distinct clinical entity. With the advent of improved immunophenotyping and immunogenotyping, increasing numbers of PCBCL cases are being diagnosed. However, there is much confusion regarding the classification, treatment, and prognosis of these patients. The purpose of this article is to review and analyze the available data to provide the clinician with a concise summary of the diagnosis, prognosis, and treatment of PCBCL. DESIGN: We conducted a thorough review of the medical literature on PCBCL, with a focus on classification, prognosis, and treatment trials. RESULTS AND CONCLUSION: PCBCL is defined as a B-cell lymphoma originating in the skin. There is no evidence of extracutaneous disease at presentation and for 6 months after diagnosis, as assessed by adequate staging procedures. Currently, the European Organization for Research and Treatment of Cancer classification is the most concise disease classification scheme, dividing the subtypes of PCBCL by clinical behavior and histopathologic findings. Based on this classification, the most common subtype of PCBCL is follicular center cell lymphoma. PCBCL is generally an indolent form of lymphoma with a good prognosis. Although local cutaneous recurrences are observed in 25% to 68% of patients, dissemination to internal organs is rare. Five-year survival rates typically range from 89% to 96%. A specific subtype, large B-cell lymphoma of the leg, is noted to have a poorer prognosis, with a 5-year survival rate of 58%. Overly aggressive treatment of PCBCL has not been shown to improve survival or prevent relapse. The treatment of choice usually varies depending on the type of PCBCL, the body surface area, and the location of the involvement, as well as the age and general health condition of the patient. The majority of studies indicate that PCBCL is highly responsive to radiation therapy. Polychemotherapy should be reserved for involvement of noncontiguous anatomic sites or those with extracutaneous spread.
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Linfoma de Células B , Neoplasias Cutáneas , Humanos , Linfoma de Células B/clasificación , Linfoma de Células B/diagnóstico , Linfoma de Células B/etiología , Linfoma de Células B/terapia , Pronóstico , Neoplasias Cutáneas/clasificación , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/terapiaRESUMEN
PURPOSE: To assess the activity and toxicity of the combination of gemcitabine and cisplatin in the treatment of chemotherapy-naive patients with metastatic urothelial cancer. PATIENTS AND METHODS: Forty-six patients with measurable stage IV carcinoma of the urothelium were enrolled onto this trial. Gemcitabine 1,000 mg/m(2) was administered intravenously for 30 to 60 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin was administered after gemcitabine on day 1 of each cycle. The first 11 patients received an initial cisplatin dose of 100 mg/m(2). Due to the hematologic toxicity observed in several of these patients, the dose was reduced to 75 mg/m(2) in the remaining 35 patients. Patients were treated with six cycles, unless disease progression or severe toxicity necessitated earlier discontinuation. RESULTS: Ten of the 46 patients achieved a complete response and nine showed a partial response. The overall response rate was 41%. The median time to treatment failure was 5.5 months. The median survival was 14.3 months, and the 1-year survival probability was 54%. Most of the toxicities were hematologic and, in general, easily manageable. CONCLUSION: Gemcitabine plus cisplatin is active in the treatment of metastatic urothelial cancer in chemotherapy-naive patients and has an acceptable clinical safety profile. Studies are under way to further define the place of gemcitabine in combination with other chemotherapeutic agents in the treatment of metastatic urothelial cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/patología , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Análisis de Supervivencia , Resultado del Tratamiento , Neoplasias Urológicas/patología , GemcitabinaRESUMEN
BACKGROUND: The aim of this study was to determine the response rates and toxicity of two regimens containing granulocyte-macrophage-colony stimulating factor (GM-CSF) in combination with interleukin-2 (IL-2) in the treatment of patients with metastatic renal cell carcinoma. METHODS: Therapy given in the first trial (Trial 1) consisted of irradiation to the primary tumor or metastatic site, followed by GM-CSF 100 microg/day administered subcutaneously (sc) for 2 weeks and IL-2 11x10(6) IU sc 4 days per week for 4 weeks. In the second trial (Trial 2), the therapy consisted of GM-CSF 125 microg/day sc for 2 weeks, followed by IL-2 11x10(6) IU sc 4 days per week and interferon-alpha 10x10(6) IU sc 2 days per week for 4 weeks, plus oral 13-cis-retinoic acid 1 mg/kg daily for 4 weeks. RESULTS: There were no responses among 20 patients in Trial 1, but 3 patients had stable disease. There was 1 partial responder (5%) of 20 evaluable patients in Trial 2 who achieved a complete response with surgical resection. An additional 3 patients maintained stable disease, 2 of whom were rendered disease free by resection of the renal primary and a single metastatic site. The 1-year survival rate was 75% (95% confidence interval [CI], 50-89) in Trial 1 and 48% (95% CI, 20-71) in Trial 2. In Trial 1, Grade 3 toxicities included fever, fatigue, anorexia, nausea/vomiting, hyperbilirubinemia, and mental status change. Toxicity was more frequent in Trial 2 and included Grade 3 fever, fatigue, anorexia, mucositis, and dermatitis. One on-study death may have been therapy-related. CONCLUSIONS: GM-CSF does not enhance the low response rate of IL-2-based immunotherapy for patients with metastatic renal cell carcinoma. New active agents are needed to treat patients with this disease.
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Carcinoma de Células Renales/secundario , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Inmunoterapia , Neoplasias Renales/terapia , Administración Oral , Adulto , Anciano , Anorexia/etiología , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/terapia , Intervalos de Confianza , Fatiga/etiología , Femenino , Fiebre/etiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Humanos , Inyecciones Subcutáneas , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Interleucina-2/uso terapéutico , Isotretinoína/administración & dosificación , Isotretinoína/efectos adversos , Isotretinoína/uso terapéutico , Masculino , Persona de Mediana Edad , Radioterapia Adyuvante , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
Allogeneic hematopoietic stem cell transplantation should be considered as a therapeutic option for patients with generalized erythoderma or tumor stage MF. Indeed, the only curative option for MF may be an allogeneic transplant. Bone Marrow Transplantation (2000) 25, 111-113.