RESUMEN
BACKGROUND/AIM: Peripheral blood mononuclear cells (PBMCs) activated with immobilized monoclonal antibody against cluster of differentiation 3 (CD3) secrete cytokines in their culture supernatant (termed ACD3S). We examined the antitumor efficacy of ACD3S-activated NK-92 cells in vitro and in vivo. MATERIALS AND METHODS: Interleukin (IL) 2-depleted NK-92 cells were reactivated with ACD3S, analyzed for their phenotype and tested for cytotoxicity, and perforin and interferon γ (IFNγ) production. Severe combined immunodeficient (SCID) mice xenografted with human melanoma and breast cancer cells were treated with ACD3S-activated NK-92 cells and tumor growth was monitored. RESULTS: Brief activation of IL2-depleted NK-92 cells with ACD3S fully restored their in vitro cytotoxicity towards tumor cells. ACD3S-activated NK-92 cells were phenotypically similar to standard NK-92 cells, but exhibited prolonged cytotoxicity and produced higher levels of IFNγ. When adoptively transferred to tumor-bearing SCID mice, these cells retarded the growth of melanoma and breast tumors. CONCLUSION: Stimulation of NK-92 cells with ACD3S may be useful in clinical cancer therapy, as an alternative method for ex vivo natural killer cell activation.
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Neoplasias de la Mama/terapia , Citocinas/inmunología , Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/trasplante , Melanoma/terapia , Animales , Anticuerpos Inmovilizados/inmunología , Anticuerpos Monoclonales/inmunología , Neoplasias de la Mama/inmunología , Complejo CD3/inmunología , Citocinas/administración & dosificación , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Linfoma no Hodgkin/patología , Células MCF-7 , Melanoma/inmunología , Ratones , Ratones SCID , Distribución Aleatoria , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Tumour-associated lymphocytes (TALs) present in effusions of ovarian cancer patients exhibit impaired activities, due to the immunosuppressive environment of the ascites. Means to enhance their cytotoxicity against autologous tumour cells are of clinical importance. The immunomodulator prothymosin alpha (proTα) increases the specific lysis of tumour cells by activated CD8(+) T-lymphocytes and its immunoreactivity is exerted by the carboxy-terminal decapeptide, proTα(100-109). These two molecules were studied on TALs in vitro, and in SCID mice bearing human ovarian tumours. METHODS: TALs and tumour cells were isolated from 41 ovarian cancer patients and co-cultured in the presence of proTα or proTα(100-109). The cytotoxicity of peptide-stimulated TALs was tested against autologous tumour cells and K562. Ex vivo peptide-stimulated TALs from three patients were adoptively transferred intraperitoneally in SCID mice, previously inoculated with each patient's autologous tumour cells. RESULTS: ProTα and its immunoreactive peptide proTα(100-109), enhanced the cytotoxic activity of TALs against autologous tumour cells in vitro, but marginally affected the lysis of K562. The effect of proTα and proTα(100-109) was higher after 7-14 days of stimulation, whereas TAL cytotoxicity was significantly decreased after 21 days. Mice administered TALs, ex vivo activated with proTα or proTα(100-109) for 7 days, showed a relatively lower tumour increase rate and a prolongation of their survival, compared to controls. CONCLUSION: Our data demonstrate that, in the presence of tumour antigens, proTα and proTα(100-109) enhance the depressed cytotoxicity of TALs against autologous tumour cells in vitro and retard tumour growth in vivo.
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Citotoxicidad Inmunológica/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Oligopéptidos/farmacología , Neoplasias Ováricas/terapia , Precursores de Proteínas/farmacología , Timosina/análogos & derivados , Adulto , Anciano , Animales , Ascitis/inmunología , Ascitis/patología , Células Cultivadas , Técnicas de Cocultivo , Citotoxicidad Inmunológica/inmunología , Femenino , Humanos , Inmunoterapia Adoptiva/métodos , Células K562 , Estimación de Kaplan-Meier , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Ratones , Ratones SCID , Persona de Mediana Edad , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Precursores de Proteínas/química , Timosina/química , Timosina/farmacología , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
INTRODUCTION: The presence of CD3(+) tumor-infiltrating lymphocytes (TILs) has been found to correlate with improved survival in epithelial ovarian cancer, but the association of TIL subpopulations with clinical outcome remains controversial. We performed a prospective analysis of TIL subpopulations from patients with epithelial ovarian cancer and their activation status and studied their association with prognosis. METHODS: Flow cytometric analysis was performed on TIL subpopulations isolated from 45 fresh ovarian tumor specimens, obtained during surgery, after mechanical dissociation and enzymatic degradation. Vascular endothelial growth factor and tumor necrosis factor alpha levels in ascites and serum were measured by enzyme-linked immunosorbent assay. RESULTS: Significantly increased numbers of CD56(+) cells (natural killer and natural killer-like T cells; P = 0.045), activated CD4(+)HLA-DR cells (P = 0.046), and activated CD8(+)CD25(+) cells (P = 0.028) were found in serous and endometrioid carcinomas compared with mucinous and clear cell carcinomas. A high percentage of CD4(+)CD25(hi) cells (regulatory T cells) and activated CD4(+)HLA-DR cells significantly associated with improved median overall survival (not reached vs 35 months [P = 0.0241] and not reached vs 35 months [P = 0.0144], respectively) and median progression-free survival (30 months vs 14 months [P = 0.0819] and 30 months vs 13 months [P = 0.0479], respectively). Vascular endothelial growth factor ascites levels were inversely correlated with CD14(+) (rho = -0.529, P = 0.001), whereas HLA-DR8(+)CD8 lymphocytes were inversely correlated with both ascites and serum vascular endothelial growth factor levels (rho = -0.494, P = 0.006, and rho = -0.586, P = 0.037, respectively). CONCLUSIONS: The presence of regulatory T cells and activated CD4(+) cells within the tumor microenvironment is associated with improved overall and progression-free survival in patients with ovarian cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos Infiltrantes de Tumor/patología , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Linfocitos T/patología , Factor A de Crecimiento Endotelial Vascular/sangre , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/secundario , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/secundario , Adulto , Anciano , Anciano de 80 o más Años , Complejo CD3/metabolismo , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/secundario , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/secundario , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/metabolismo , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Port-a-cath systems are often essential for the administration of long-term chemotherapy in the treatment of malignancies because they improve venous access, but they are associated with complications, mainly thrombosis of central veins. In the present report, we describe a case of right subclavian and superior vena cava port-a-cath-related thrombosis causing superior vena cava syndrome (SVCS) in a patient affected by Hodgkin's disease. The patient underwent percutaneous revascularization with stent positioning, experiencing immediate relief of symptoms. Endovascular procedures for the treatment of nonmalignant SVCS seem to represent a challenging therapeutic option.
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Catéteres de Permanencia/efectos adversos , Stents , Síndrome de la Vena Cava Superior/complicaciones , Trombosis/terapia , Femenino , Enfermedad de Hodgkin/complicaciones , Humanos , Persona de Mediana Edad , Síndrome de la Vena Cava Superior/diagnóstico por imagen , Síndrome de la Vena Cava Superior/terapia , Trombosis/etiología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Several cytokines have been associated with immune regulation and prognosis in ovarian cancer. CD4+CD25+ Tregs and CD3+CD56+ NK-like T cells are involved in the immune response against the tumor. We have investigated the association of cytokines in the ascites from patients with ovarian cancer with these populations, the platinum resistance and the prognosis of these patients. PATIENTS AND METHODS: Ascites from 64 patients with ovarian cancer was analysed. Forty-two patients were studied at diagnosis (FIGO stage III in 40 cases) and were treated with cytoreductive surgery and platinum-based chemotherapy. Ascites from 9 patients with cirrhosis was used as control. Vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma), interleukin-10 (IL10) and interleukin-12 (IL12) in ascites and serum were measured by enzyme-linked immunosorbent assay (ELISA), while lymphocytic populations were studied with three-colour flow cytometry. RESULTS: VEGF ascites levels were inversely correlated with CD3+CD56+ cells (rho=-0.316, p=0.012), while a similar correlation was observed between TNFalpha ascites levels and CD4+CD25+(hi) cells (rho=-0.332, p=0.041). Among patients receiving first-line chemotherapy, VEGF levels <1900 pg/ml and TNFalpha levels >35 pg/ml were associated with platinum sensitivity (p=0.021 and p=0.028, respectively) and improved progression-free survival (PFS) (p=0.007 and p=0.045, respectively). Low VEGF levels were also associated with improved overall survival (p=0.026). CONCLUSION: VEGF and TNFalpha ascites levels are associated with prognosis in advanced ovarian cancer. Their prognostic significance may be due to their association with immunologically important populations, namely the NK T-like CD3+CD56+ cells and the Tregs CD4+CD25+(hi) cells.
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Citocinas/metabolismo , Células Asesinas Naturales/inmunología , Neoplasias Ováricas/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Ascitis/inmunología , Ascitis/metabolismo , Ascitis/patología , Complejo CD3/biosíntesis , Complejo CD3/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígeno CD56/biosíntesis , Antígeno CD56/inmunología , Citocinas/sangre , Citocinas/inmunología , Resistencia a Antineoplásicos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Interferón gamma/sangre , Interferón gamma/metabolismo , Interleucina-10/sangre , Interleucina-10/metabolismo , Interleucina-12/sangre , Interleucina-12/metabolismo , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Subunidad alfa del Receptor de Interleucina-2/inmunología , Persona de Mediana Edad , Compuestos Organoplatinos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Pronóstico , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Oral transmucosal fentanyl citrate (OTFC; brand name Actiq, Cephalon, UT) is a new opioid formulation that incorporates fentanyl into a lozenge and allows drug delivery through the buccal mucosa. This kind of absorption avoids first-pass metabolism, yielding a bioavailability substantially greater than oral administration. OTFC has a rapid onset of action and a short duration of effect. These characteristics, which resemble the course of a typical breakthrough pain episode, resulted in making OTFC the first opioid analgesic formulation specifically developed and approved for control of breakthrough pain in cancer patients. Apart from that, OTFC has been used in a variety of clinical situations of noncancer pain. This review article presents the synthesis; clinical pharmacology; pharmacokinetic and pharmacodynamic properties, toxicity, and clinical efficacy of this novel agent.
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Analgésicos Opioides/uso terapéutico , Fentanilo/uso terapéutico , Dolor/tratamiento farmacológico , Administración Tópica , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Ensayos Clínicos como Asunto , Fentanilo/administración & dosificación , Fentanilo/farmacocinética , Semivida , Humanos , Mucosa Bucal/metabolismo , Neoplasias/complicaciones , Dolor/etiologíaRESUMEN
In this study, we assessed the safety, tolerability, and effectiveness of two therapeutic regimens relating to the frequency of zoledronic acid (ZOL) infusion. Sixty adult patients with bone metastases were randomly assigned to two study groups. The first group (group A) received 4 mg ZOL every two weeks, and the second group (group B) received 4 mg ZOL every four weeks. Assessment measures included C-telopeptide (CTX) rate, the Greek Brief Pain Inventory (GBPI), the linear analogue scale assessment (LASA) of quality of life, and biochemical markers. Assessments were made at weeks 12, 24, 36, and 48. Clinical endpoints included effective decrease in bone resorption markers, pain relief and improvement of mobility status. The follow-up period was 48 weeks. No statistically significant differences between groups A and B were found in overall profile of biochemical markers, Eastern Cooperative Oncology Group (ECOG) performance status, and GBPI score at the end of the follow-up period. Assessment of bone metastases revealed a slight difference between the two groups, however this difference was not statistically significant. These findings indicate that administering zoledronic acid at four rather that two weeks has no significant impact on overall outcome.
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Antineoplásicos/administración & dosificación , Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Resorción Ósea/tratamiento farmacológico , Difosfonatos/administración & dosificación , Imidazoles/administración & dosificación , Cuidados Paliativos/métodos , Anciano , Densidad Ósea/efectos de los fármacos , Neoplasias Óseas/complicaciones , Resorción Ósea/etiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ácido ZoledrónicoRESUMEN
Prothymosin alpha (proTalpha) is a 109 amino acid long polypeptide presenting distinct immunoenhancing activity in vitro and in vivo. Recent reports suggest that in apoptotic cells, proTalpha is cleaved by caspases at its carboxy(C)-terminus generating potentially bioactive fragments. In this study, we identified the peptide segment of proTalpha presenting maximum immunomodulatory activity. Calf thymus proTalpha was trypsinised, and the five fragments produced (spanning residues 1-14, 21-30, 31-87, 89-102 and 103-109) were tested for their ability to stimulate healthy donor- and cancer patient-derived peripheral blood mononuclear cell (PBMC) proliferation in autologous mixed lymphocyte reaction (AMLR), natural killer and lymphokine-activated killer cell activity, intracellular production of perforin, upregulation of adhesion molecules and CD25 expression. ProTalpha(89-102) and proTalpha(103-109) significantly fortified healthy donor-lymphocytes' immune responses to levels comparable to those induced by intact proTalpha. These effects were more pronounced in cancer patients, where peptides proTalpha(89-102) and proTalpha(103-109) partly, however significantly, restored the depressed AMLR and cytolytic ability of PBMC, by simulating the biological activity exerted by intact proTalpha. ProTalpha(1-14), proTalpha(21-30) and proTalpha(31-87) marginally upregulated lymphocyte activation. This is the first report showing that proTalpha's immunomodulating activity can be substituted by its C-terminal peptide(s). Whether generation and externalization of such immunoactive proTalpha fragments occurs in vivo, needs further investigation. However, if these peptides can trigger immune responses, they may eventually be used therapeutically to improve some PBMC functions of cancer patients.
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Neoplasias/inmunología , Fragmentos de Péptidos/inmunología , Precursores de Proteínas/química , Precursores de Proteínas/inmunología , Timosina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Animales , Sitios de Unión , Bovinos , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Inmunofenotipificación , Técnicas In Vitro , Leucocitos Mononucleares/inmunología , Prueba de Cultivo Mixto de Linfocitos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Fragmentos de Péptidos/genética , Precursores de Proteínas/genética , Homología de Secuencia de Aminoácido , Timosina/química , Timosina/genética , Timosina/inmunologíaRESUMEN
OBJECTIVE: To evaluate the effectiveness and improvement in quality of life (QOL) of epoetin alfa administration supplemented with oral iron as a therapeutic regimen for patients with solid malignancies and anemia of chronic disease (ACD), not receiving chemotherapy and/or radiotherapy. PATIENTS AND METHODS: A total of 100 patients with cancer-related anemia, not subjected to chemotherapy and/or radiotherapy, were randomized to receive for a maximum of 24 weeks either oral iron, equivalent to 200 mg elemental iron once daily, or epoetin alfa 40,000 IU subcutaneously once weekly plus oral iron once daily. RESULTS: Patients in the epoetin alfa group had, from baseline to study end, a mean increase in hemoglobin (Hb) levels of 2.4 g/dL, whereas in the control group the mean Hb level decreased by 0.1 g/dL, (p<0.001). Improvement in QOL as assessed by the LASA and the FACT-An questionnaire were greater in patients in the epoetin alfa group than in the control group (mean change, LASA-energy level: 30.4 mm vs. 0.4 mm, -daily activities: 31.7 mm vs. 0.4 mm, -overall well-being. 32.4 mm vs. 4.9, FACT-An: 43.3 vs. 13.4, respectively). As for ECOG score, patients in the epoetin alfa group had a mean improvement of 0.16 from baseline to study end (control group: 0.06). Improvement in QOL parameters and in ECOG scores correlated positively with increased hemoglobin levels. CONCLUSION: Our results suggest that weekly epoetin alfa therapy supplemented with daily oral iron increases Hb levels and improves QOL in patients with solid malignancies and ACD who are not receiving chemotherapy and/or radiotherapy. This regimen offers optimal therapy in this population taking into consideration physician's convenience and patient's compliance.
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Anemia/tratamiento farmacológico , Anemia/etiología , Eritropoyetina/uso terapéutico , Hierro/administración & dosificación , Neoplasias/complicaciones , Administración Oral , Adulto , Anciano , Anemia/sangre , Enfermedad Crónica , Método Doble Ciego , Epoetina alfa , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Estudios Prospectivos , Calidad de Vida , Proteínas RecombinantesRESUMEN
Breakthrough pain is a transitory flare of pain occurring in most cancer patients against a background of otherwise controlled persistent pain. Treatment of breakthrough pain is a challenging phenomenon. Oral transmucosal fentanyl citrate (Actiq, Cephalon, Inc, West Chester, PA), a new opioid formulation with a unique delivery system, reflects the characteristics of breakthrough pain (rapid onset of action and short duration), making it an effective treatment for cancer patients who already receive opioids and experience flares of pain. This review article aims to present the role of oral transmucosal fentanyl citrate in the management of breakthrough pain in cancer patients. In particular, it is going to discuss the synthesis, clinical pharmacology, pharmacokinetic and pharmacodynamic properties, toxicity, and clinical efficacy of this novel agent.
Asunto(s)
Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Fentanilo/farmacología , Fentanilo/uso terapéutico , Neoplasias/complicaciones , Dolor Intratable/tratamiento farmacológico , Administración Oral , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Relación Dosis-Respuesta a Droga , Fentanilo/administración & dosificación , Fentanilo/efectos adversos , Humanos , Dimensión del Dolor , Dolor Intratable/etiología , Cuidados Paliativos/normas , Factores de Tiempo , Resultado del TratamientoRESUMEN
Breakthrough pain is a transitory flare of pain occurring in most cancer patients against a background of otherwise controlled persistent pain. Treatment of breakthrough pain is a challenging phenomenon. Oral transmucosal fentanyl citrate (OTFC; brand name Actiq, Chephalon Inc., West Chester, PA), a new opioid formulation with a unique delivery system, reflects the characteristics of breakthrough pain (rapid onset of action and short duration), making it an effective treatment for cancer patients who already receive opioids and experience flares of pain. This review article aims to present the role of oral transmucosal fentanyl citrate in the management of breakthrough pain in cancer patients. In particular, it is going to discuss the synthesis, clinical pharmacology, pharmacokinetic and pharmacodynamic properties, toxicity, and clinical efficacy of this novel agent.
Asunto(s)
Analgésicos Opioides , Fentanilo , Mucosa Bucal/metabolismo , Neoplasias , Dolor/tratamiento farmacológico , Administración Oral , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Ensayos Clínicos como Asunto , Fentanilo/administración & dosificación , Fentanilo/farmacocinética , Fentanilo/farmacología , Fentanilo/uso terapéutico , Humanos , Dolor/etiología , Resultado del TratamientoRESUMEN
We demonstrate the efficacy of two cytokine-rich supernatants, one from peripheral blood cell cultures stimulated with anti-CD3 and the other from monocyte-conditioned media, in enhancing the rapid (within 6 days) expansion and clonogenicity of CD34+, progenitor cells. We, thereby,increased the generation of mostly myeloid precursors able to support stem cell transplants.