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PURPOSE: EGFR is a well-validated target for patients with non-small cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic cancer vaccine composed of human recombinant EGF conjugated to a carrier protein and Montanide ISA51 as adjuvant. The vaccine is intended to induce antibodies against self EGFs that block EGF-EGFR interaction. EXPERIMENTAL DESIGN: To evaluate overall survival, safety, immunogenicity, and EGF concentration in serum after CIMAvax-EGF, a randomized phase III trial was done in patients with advanced NSCLC. Four to 6 weeks after first-line chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomly assigned to a vaccine group, which received CIMAvax-EGF or a control group, treated with best supportive care. RESULTS: Long-term vaccination was very safe. Most frequent adverse reactions were grade 1 or 2 injection-site pain, fever, vomiting, and headache. Vaccination induced anti-EGF antibodies and decreased serum EGF concentration. In the safety population, median survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the control arm. These differences were not significant according the standard log rank (HR, 0.82; P = 0.100), but according a weighted log rank (P = 0.04) that was applied once the nonproportionality of the HR was verified. Survival benefit was significant (HR, 0.77; P = 0.036) in the per-protocol setting (patients receiving at least four vaccine doses): MST was 12.43 months for the vaccine arm versus 9.43 months for the control arm. MST was higher (14.66 months) for vaccinated patients with high EGF concentration at baseline. CONCLUSIONS: Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. Clin Cancer Res; 22(15); 3782-90. ©2016 AACR.
Assuntos
Vacinas Anticâncer/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Fator de Crescimento Epidérmico/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Adjuvantes Imunológicos , Vacinas Anticâncer/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Fator de Crescimento Epidérmico/sangue , Feminino , Humanos , Imunoterapia Ativa , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Estadiamento de Neoplasias , Prognóstico , Retratamento , Resultado do TratamentoRESUMO
NGcGM3 ganglioside is a tumor-specific antigen expressed in human breast tumors. The NGcGM3/VSSP vaccine, consisting in very small-sized proteoliposomes (VSSP) obtained by the incorporation of NGcGM3 into the outer membrane protein complex of Neisseria meningitidis, has been previously tested in a Phase II trial in patients with metastatic breast cancer (MBC) but emulsified with Montanide ISA 51. An Expanded Access study was carried out in MBC patients aiming to find if a nonemulsive formulation of NGcGM3/VSSP, without Montanide ISA 51, could be more safe and effective. A total of 104 patients were vaccinated with the nonemulsive formulation (900 µg), subcutaneously (SC), or with the emulsive formulation (200 µg), intramuscularly (IM). An intent-to-treat analysis of efficacy was performed with all patients, and 93 patients were split off according to the site of metastases (visceral/nonvisceral). Of note, SC-treated patients exhibited a superior median overall survival (OS) than IM-treated patients (23.6 vs. 8.2 months; log rank P = 0.001). Even though in the subset of patients with nonvisceral metastases SC vaccination duplicated the median OS compared to the alternative option (31.6 vs. 16.5 months), this difference did not reach statistical significance (log rank P = 0.118). Curiously, in patients with visceral metastases, the advantage of the nonemulsive formulation was more apparent (median OS 21.0 vs. 6.2 months; log rank P = 0.005). The vaccine was safe for both formulations.
RESUMO
Wildlife inhabiting human-dominated landscapes is at risk of pathogen spill-over from domestic species. With the aim of gaining knowledge in the dynamics of viral infections in Iberian wolves (Canis lupus) living in anthropized landscapes of northern Spain, we analysed between 2010 and 2013 the samples of 54 wolves by serology and polymerase chain reaction (PCR) for exposure to four pathogenic canine viruses: canine distemper virus (CDV), canine parvovirus-2 (CPV), canine adenovirus 1 and 2 (CAV-1 and CAV-2) and canine herpesvirus. Overall, 76% of the studied wolves presented evidence of exposure to CPV (96% by HI, 66% by PCR) and 75% to CAV (75% by virus neutralization (VN), 76% by PCR, of which 70% CAV-1 and 6% CAV-2). This represents the first detection of CAV-2 infection in a wild carnivore. CPV/CAV-1 co-infection occurred in 51% of the wolves. The probability of wolf exposure to CPV was positively and significantly correlated with farm density in a buffer zone around the place where the wolf was found, indicating that rural dogs might be the origin of CPV infecting wolves. CPV and CAV-1 appear to be enzootic in the Iberian wolf population, which is supported by the absence of seasonal and inter-annual variations in the proportion of positive samples detected. However, while CPV may depend on periodical introductions by dogs, CAV-1 may be maintained within the wolf population. All wolves were negative for exposure to CDV (by VN and PCR) and CHV (by PCR). The absence of acquired immunity against CDV in this population may predispose it to an elevated rate of mortality in the event of a distemper spill-over via dogs.
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Adenovirus Caninos/isolamento & purificação , Vírus da Cinomose Canina/isolamento & purificação , Herpesvirus Canídeo 1/isolamento & purificação , Parvovirus Canino/isolamento & purificação , Lobos/virologia , Animais , Animais Selvagens , Coinfecção , Cães/virologia , Humanos , Reação em Cadeia da Polimerase , Fatores de Risco , Testes Sorológicos/veterinária , EspanhaRESUMO
OBJECTIVE: This study aimed to provide information about the molecular epidemiology of human papillomavirus (HPV) in a group of Cuban women. MATERIALS AND METHODS: DNA from cervical samples was analyzed using a quantitative real-time polymerase chain reaction (PCR), which detects 6 of the clinically most relevant high-risk HPV types. Furthermore, end point PCR and sequencing were performed. Three hundred twenty-two women (211 with positive and 111 with negative cytologic results) aged between 30 and 69 years were enrolled. Risk factors associated with HPV infections and premalignant lesions were also investigated. RESULTS: HPV DNA was detected in 76.1% (245/322) of the studied population, and 34 different genotypes were found. There was an association between HPV infection and low educational level, history of oral contraceptives, menopausal stage, as well as cigarette and/or alcohol consumption. Besides, in a multivariate analysis, previous positive Pap test result and positive colposcopy finding were both predictor variables for HPV infections and for premalignant lesions. Human papillomavirus infection was found in 94.3% of women (199/211) with positive cytologic result and in 41.4% (46/111) of those with negative results, being more likely that the first group was infected with any HPV (odds ratio = 23.43; 95% CI = 11.70-46.92; p = .000). The most common genotypes were HPV types 16, 18, 31, 58, 33, and 45. All the cases with HPV positive findings had at least 1 high-risk HPV genotype. CONCLUSIONS: This is the first report of the molecular epidemiology of HPV in Cuban women, based on results from a DNA sequence and quantitative PCR. Most individuals were infected with high-risk HPV types. These findings support the inclusion of HPV vaccine in Cuba.
Assuntos
Colo do Útero/virologia , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Adulto , Idoso , Coinfecção/epidemiologia , Cuba/epidemiologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Epidemiologia Molecular , Papillomaviridae/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNARESUMO
Increased levels of NeuGc-containing gangliosides have been described in human breast cancer. A controlled Phase II clinical trial was conducted in patients with metastatic breast cancer to evaluate immunogenicity, safety and to identify evidences of biological activity of a cancer vaccine composed by NeuGcGM3 in a proteoliposome of Neisseria meningitidis together with Montanide ISA 51 as adjuvant. After first line chemotherapy, 79 women were randomized 1:1 to receive the vaccine candidate or best supportive care. All patients achieved at least stable disease to the first line therapy for the metastatic condition. Treatment consisted on 5 vaccine doses every 2 weeks and then, monthly re-immunization to complete 15 doses. Vaccination with the NeuGcGM3 based vaccine was safe and the most frequent adverse events consisted on injection site reactions, fever, arthralgia and chills. The vaccine was immunogenic and a sustained increase of both IgG and IgM antibody titters against NGcGM3 was observed after the second vaccination month. Antibodies were able to recognize the NeuGcGM3(+) murine tumor cell line L1210 and the myeloma cell line P3X63. Humoral response was specific since vaccination did not result in Neu-Acetyl GM3 or GM2-antibody response. Hyperimmune sera from vaccinated patients were able to prevent the NeuGcGM3 mediated CD4 down-modulation on T lymphocytes. In the intent to treat analysis, there was a trend toward a survival advantage for the vaccine group and this effect was significant for women bearing non-visceral metastasis. Two phase III clinical studies with this vaccine candidate are ongoing.
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OBJETIVOS: Analizar la relación entre los resultados citológicos, colposcópicos e histológicos en pacientes conizadas con asa diatérmica por Lesiones de Alto Grado (LAG) de cuello uterino; clasificar la población con lesiones de alto grado en cuello uterino según edad, paridad, antecedentes familiares e inicio de relaciones sexuales; determinar relación entre citología con lesiones de alto grado y la videocolposcopia; identificar proporción de pacientes con diferentes resultados anatomopatológicos en las citologías de LAG; evaluar la utilidad del uso del asa diatérmica en lo referente a los bordes de sección en los conos realizados, así como el resultado de la prueba citológica poscono.MÉTODOS: Se estudiaron 107 pacientes de la consulta de patología de cuello del hospital "Ramón González Coro" en el año 2006, cuyos resultados iniciales de la prueba citológica fue LAG, a dichas pacientes se les realizó conización por asa diatérmica como proceder diagnóstico y terapéutico previa realización de la videocolposcopia.RESULTADOS: Se detectó que el 67 % (72 casos) de las pacientes con resultados citológicos de LAG,presentaron algún hallazgo colposcópico anormal. De las pacientes conizadas el 84,2 % tenían bordes libres de lesión. Detectamos 3 cánceres cérvicouterinos y en el 31,7 % de los casos se demostró la presencia de lesiones de bajo grado (LBG) de cuello uterino. La citología con cepillado de canal a los 6 meses posteriores al proceder quirúrgico, resultó anormal solo en seis de dichas pacientes. Comprobamos relación citohistológica en el 50 % de los casos estudiados.CONCLUSIÓN: La conización con asa diatérmica, según nuestros resultados, es un proceder seguro, eficaz y con mínimas complicaciones, que evita el ingreso hospitalario, así como, los riesgos anestésicos y quirúrgicos de la cirugía convencional
OBJECTIVES: To analyze the relationship among the cytologic, colposcopic and histologic results in patients underwent conization with diathermic loop from high grade lesions (HGL) of cervix; to classify the populations with above mentioned high grade lesions according to age, parity, family backgrounds and the onset of sexual intercourses; to determine the relation between cytology with high grade lesions and the video-colposcopy; to identify the patient's ratio presenting with different anatomical-pathological results in HGL cytologies; to assess the profit of diathermic loop use concerning to section edges in the conization carried out, as well as the result of the post-conization first results. METHODS: A total of 107 patients were studied in the cervix pathology consultation of the "Ram¾n Gonzßlez Coro" Gynecology and Obstetrics Hospital in 2006 whose first results of cytology test were HGLs, they underwent conization with diathermic loop as diagnostic and therapeutical procedure before videocolposcopy. RESULTS: The 67 percent (72 cases) of patients with cytologic results of HGLs had some abnormal colposcopic finding. From the conization patients the 84.2 percent had lesion-free edges. There were three cervicouterine cancers and in the 31.7 percent it was demonstrated the presence of cervix low-grade lesions (LGL). The cytology with channel brushing at 6 months after surgical procedure, it was abnormal in six of such patients. Also, there was a cytohistological relationship in the 50 percent of study cases. CONCLUSION: The conization with diathermic loop according to our results is a safe, effective and with minimal complications procedure avoiding the hospital admission, as well as the anesthetic and surgical risks of conventional surgery
Assuntos
Humanos , Feminino , Cirurgia Vídeoassistida/métodos , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/diagnóstico , Epidemiologia Descritiva , Estudos RetrospectivosRESUMO
OBJETIVO: estudiar los principales factores de riesgo en la aparición del cáncer cérvico uterino en las mujeres menores de 30 años, tratadas en el Instituto de Oncología y Radiobiología (INOR) durante un período de 11 años, así como evaluar los beneficios recibidos por estas con el o los tratamientos utilizados para su etapa clínica. MÉTODOS: se realizó un estudio retrospectivo y descriptivo de 342 expedientes clínicos, correspondiente a mujeres jóvenes menores de 30 años diagnosticadas con cáncer cérvico uterino (CCU) y atendidas en el INOR durante un período de 11 años. Se utilizó una hoja de Microsoft Excel para la recolección de la información y se aplicó el paquete estadístico SPSS 11.1RESULTADOS: se encontró que 4/5 pacientes del total de mujeres menores de 30 años se diagnosticaron entre los 25 y los 30 años, mientras 1/5 pacientes fue menor de 25 años. El carcinoma epidermoide de cérvix fue el tumor más frecuente (80 %). Las pacientes recibieron como tratamiento: la cirugía (47,4 %), la radioterapia (42,1 %) y cirugía más radioterapia o viceversa. Los factores de riesgo que mostraron una mayor asociación con el CCU fueron la precocidad sexual y la presencia de HPV en el 27,5 %. El 34,5 % de las mujeres menores de 30 años afortunadamente eran portadoras de carcinoma in situ. Sin embargo, el 47 % de las pacientes incluidas en este análisis se detectaron con tumores localmente avanzadas (IIa, IIb y IIIb).CONCLUSIÓN: el carcinoma epidermoide de cérvix fue el tumor más frecuente en las mujeres menores de 30 años diagnosticada con CCU
OBJECTIVE: To study the main risk factors in the appearance of the cervicouterine cancer in women aged < 30, seen in the National Institute Oncology and Radiobiology (NIOR) during eleven years, as well as to assess the benefits of treatment(s) applied for its clinical stage. METHODS: A descriptive and retrospective study was conducted on 342 clinical files corresponding to young women < 30 years diagnosed with cervicouterine cancer (CUC) seen in National Institute of Oncology and Radiobiology (NIOR) during 11 years. For information collection a Microsoft Excel form applying the SPSS 11.1 statistic package. RESULTS: We founded that 4/5 patients from total of women < 30 years were diagnosed between 25 and 30 years old, whereas 1/5 of patients were < 25 years old. Cervical epidermoid carcinoma was he more frequent tumor (80 percent). Treatment includes: surgery (47,4 percent), radiotherapy (42,1 percent) and surgery plus radiotherapy or vice versa. Risk factors with a great association with CUC were sexual precocity and presence of HPV(?) in the 27,5 percent. The 34,5 percent of women < 30 years old fortunately were carriers of in situ carcinoma. However, the 47 percent of patients included in present analysis had locally advanced tumors (IIa, IIb and IIIb). CONCLUSION: The cervical epidermoid carcinoma was the more frequent tumor present in women < 30 years old diagnosed with CUC
Assuntos
Humanos , Feminino , Carcinoma de Células Escamosas/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Fatores de Risco , Epidemiologia Descritiva , Estudos RetrospectivosRESUMO
PURPOSE: We show the result of a randomized phase II clinical trial with an epidermal growth factor (EGF)-based cancer vaccine in advanced non-small-cell lung cancer (NSCLC) patients, evaluating immunogenicity, safety, and effect on survival. PATIENTS AND METHODS: Eighty patients with stage IIIB/IV NSCLC after finishing first-line chemotherapy were randomly assigned to receive best supportive care or EGF vaccinations. RESULTS: Vaccination was safe. Adverse events were observed in less than 25% of cases and were grade 1 or 2 according to National Cancer Institute Common Toxicity Criteria. Good anti-EGF antibody response (GAR) was obtained in 51.3% of vaccinated patients and in none of the control group. Serum EGF concentration showed a major decrease in 64.3% of vaccinated patients. GAR patients survived significantly more than those with poor antibody response (PAR). Also, patients whose serum EGF dropped below 168 pg/mL survived significantly more than the rest. There was a trend to an increased survival for vaccinated patients compared with controls. The survival advantage for vaccinated patients compared with controls was statistically significant in the subgroup of patients with age younger than 60 years. CONCLUSION: Vaccination with EGF was safe and provoked an increase in anti-EGF antibody titers and a decrease in serum EGF. There was a direct correlation between antibody response and survival. There was a direct correlation between decrease in serum EGF and survival. In patients younger than 60 years, vaccination was associated with increased survival.
Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Fator de Crescimento Epidérmico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Adulto , Idoso , Vacinas Anticâncer/efeitos adversos , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Fator de Crescimento Epidérmico/efeitos adversos , Fator de Crescimento Epidérmico/imunologia , Receptores ErbB/metabolismo , Feminino , Humanos , Imunoterapia Ativa/métodos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Epidermal growth factor (EGF) might be a suitable immunotherapeutic target in non-small-cell lung cancer (NSCLC). Our approach consists of active immunotherapy with EGF. The aim of the study is to characterize the humoral response and its effects on signal transduction in relation with the clinical outcome. EXPERIMENTAL DESIGN: Eighty NSCLC patients treated with first-line chemotherapy were randomized to receive the EGF vaccine or supportive care. EGF concentration in sera, anti-EGF antibodies and their capacity to inhibit the binding between EGF/EGF receptor (EGFR), and the EGFR phosphorylation were measured. RESULTS: Seventy-three percent of vaccinated patients developed a good antibody response, whereas none of the controls did. In good antibody-responder patients, self EGF in sera was significantly reduced. In 58% of vaccinated patients, the post-immune sera inhibited EGF/EGFR binding; in the control group, no inhibition occurred. Post-immune sera inhibited the EGFR phosphorylation whereas sera from control patients did not have this capacity. Good antibody-responder patients younger than 60 years had a significantly better survival. A high correlation between anti-EGF antibody titers, EGFR phosphorylation inhibition, and EGF/EGFR binding inhibition was found. There was a significantly better survival for vaccinated patients that showed the higher capacity to inhibit EGF/EGFR binding and for those who showed an immunodominance by the central region of EGF molecule. CONCLUSIONS: Immunization with the EGF vaccine induced neutralizing anti-EGF antibodies capable of inhibiting EGFR phosphorylation. There was a significant positive correlation between antibody titers, EGF/EGFR binding inhibition, immunodominance of anti-EGF antibodies, and survival in advanced NSCLC patients.
Assuntos
Anticorpos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Fator de Crescimento Epidérmico/antagonistas & inibidores , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Fator de Crescimento Epidérmico/imunologia , Receptores ErbB/imunologia , Humanos , Neoplasias Pulmonares/mortalidade , Seleção de Pacientes , Fosforilação , Proteínas Recombinantes/imunologia , Análise de SobrevidaRESUMO
Conventional treatment of non-small cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of the patients. For that reason the search for new therapeutic strategies in this type of tumor is justified. 1E10 is an anti-idiotype murine monoclonal antibody (Ab2 MAb) specific to P3 Ab1 MAb, which reacts with NeuGc-containing gangliosides, sulfatides and with antigens expressed in some tumors, including those from the lung. We report the treatment with aluminum hydroxide-precipitated 1E10 MAb of 34 stage IIIb and 37 stage IV NSCLC patients. These patients were treated with the anti-idiotype vaccine, after received standard chemotherapy and radiotherapy, in a compassionate-use basis study. Patients received five bi-weekly injections of 1 mg of 1E10/Alum, other 10 doses at 28-day intervals and later the patients who maintained a good performance status continued to be immunized at this same time interval. No evidence of unexpected or serious adverse effects was reported. The median survival time of the 56 patients who entered the study with partial response or disease stabilization and with a PS 1 after the first line of chemo/radiotherapy, was 11.50 months from starting vaccination. In contrast, the median survival time calculated for patients who started vaccination with progressive disease and/or a PS2 was 6.50 months.
Assuntos
Anticorpos Anti-Idiotípicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Adjuvantes Imunológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Alúmen , Animais , Anticorpos Anti-Idiotípicos/imunologia , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Feminino , Gangliosídeos/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de SobrevidaRESUMO
Se realizó un estudio descriptivo, retrospectivo en el hospital "Ramón González Coro" durante los primeros 8 meses del año 2005, a las pacientes sometidas a conización con asa diatérmica en la consulta de patología de cuello. Con respecto a los 78 casos realizados en el año 2004, se produjo un incremento a 135 mujeres. Se analizó la relación citocolpohistológicas, así como la presencia y significación de algunos de los factores de riesgo para la aparición de neoplasia intraepitelial cervical. Se registró que la paridad no repercutió en los resultados histológicos (p=0,1986) sin embargo se comprobó que el inicio precoz de las relaciones sexuales están asociadas con las lesiones de alto grado de cuello uterino (p=0,038). Se estudiaron los bordes de sección quirúrgico, comprobándose que en más del 85 % de las pacientes se logró resecar completamente la lesión.
A descriptive and retrospective study was conducted at "Ramón Gonzalez Coro" Hospital during the first 8 months of 2005 among the patients undergoing cone biopsy with diathermic loop in the cervix uteri pathology department. As regards the 78 cases performed in 2004, there was an increase of 135 women (57 additional cases). The cytocolpohistological relation, as well as the presence and significance of some of the risk factors for the appearance of cervical intraepithelial neoplasia were analyzed. It was observed that parity did not influence on the histological results (p=0,1986); however, it was proved that the early beginning of sexual relations is associated with high degree cervix uteri lesions (p=0,038). The edges of the surgical section were studied and it was demonstrated that in more than 85 % of the patients it was possible to resect the lesion completely.