RESUMEN
Trans-arterial radioembolization (TARE) with Y-90 microspheres is an endovascular, liver-directed therapy suitable for treatment of locally advanced hepatocellular carcinoma (HCC) often as a way to reduce tumor size and bridge patients to resection or liver transplant. Opdivo®, or nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, is an immunotherapeutic drug approved in September 2017 for the treatment of HCC in patients who have received prior sorafenib. We report on a patient with hepatocellular carcinoma with right and left portal vein involvement, bony metastasis, and possible lung metastasis. The patient showed a significant response following consecutive treatment with TARE, sorafenib, and nivolumab. Our case suggests that TARE, sorafenib, and nivolumab may have a synergistic effect on the immune response to HCC.
RESUMEN
Breast cancer (BC) is a major health problem for women around the world. Although advances in the field of molecular therapy have been achieved, the successful therapeutic management of BC, particularly metastatic disease, remains a challenge for patients and clinicians. One of the areas of current investigation is the circulating tumor cells (CTCs), which have a determinant role in the development of distant metastasis. At the present, many of the available treatment strategies for metastatic disease are of limited benefit. However, the elucidation of the mechanisms of tumor progression and metastasis may help to identify key molecules/components that may function as therapeutic targets in the future. In the present study, the functional analysis of CTCs revealed their ability to grow and proliferate to form colonies. Immunofluorescence staining of the CTCs' colonies exhibits elevated expression of cell growth and survival associated proteins such as, survivin, ERK and Akt1. More importantly, the functional screening of the chemokine profile in BC patients' sera revealed an HR-independent elevation of the chemokine CXCL10 when compared to healthy controls. The analysis of chemokines CXCL9 and CXCL11 demonstrated an HR-dependent production pattern. The levels of both CXCL9 and CXCL11 were markedly high in HR+ patients' sera when compared to HR- patients and healthy controls. The functional analysis of HR+ and HR- BC derived cell lines when cultivated in media supplemented with patients' sera demonstrated the alteration of tumor progression and metastasis related proteins. We noted the induction of survivin, ß-catenin, MKP-1, pERK, CXCR4 and MMP-1 both at the protein and mRNA levels. The induction of those proteins was in keeping with patients' sera induced cell proliferation as measured by the MTT assay. In conclusion, our data emphasizes the role of chemokines, especially CXCL10, in BC progression and metastasis via the induction of signaling pathways, which mainly involve survivin, ß-catenin, MKP-1 and MMP-1.
Asunto(s)
Neoplasias de la Mama/genética , Quimiocina CXCL10/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Quimiocina CXCL11/metabolismo , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Progresión de la Enfermedad , Fosfatasa 1 de Especificidad Dual/genética , Fosfatasa 1 de Especificidad Dual/metabolismo , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Células MCF-7 , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de Señal , Survivin , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
In recent years, circulating tumor cells (CTCs) in metastatic cancer patients have been found to be a promising biomarker to predict overall survival and tumor progression in these patients. A relatively high number of CTCs has been correlated with disease progression and poorer prognosis. This study was designed to assess innate immune system function, known to be responsible for the immune defense against developing neoplasms, in metastatic cancer patients with CTCs. Our aim is to provide a link between indication of poorer prognosis, represented by the number of CTCs to the cytotoxic activity of natural killer cells, an important component of the innate immune system, and to represent a promising expanded approach to management of metastatic cancer patients with CTCs. Seventy-four patients, with metastatic breast, colorectal, or prostate cancer, were recruited for this study. Using a flow cytometric assay, we measured natural killer (NK) cell cytotoxicity against K562 target cells; and CTCs were enumerated using the CellSearch System. Toll-like receptors 2 and 4 expression was also determined by flow cytometry. We found that within each of our three metastatic cancer patient groups, NK cell cytotoxic activity was decreased in patients with a relatively high number of CTCs in peripheral blood compared to patients with a relatively low number of CTCs. In the breast and prostate cancer group, patients with CTCs greater than 5 had decreased NK cell cytotoxicity when compared to patients with less than 5 CTCs. In the colorectal cancer group, we found that 3 or more CTCs in the blood was the level at which NK cell cytotoxicity is diminished. Additionally, we found that the toll-like receptors 2 and 4 expression was decreased in intensity in all the metastatic cancer patients when compared to the healthy controls. Furthermore, within each cancer group, the expression of both toll-like receptors was decreased in the patients with relatively high number of CTCs, i.e. greater than 5 for the breast and prostate cancer group and greater than 3 for the colorectal cancer group, compared to the patients with relatively low number, i.e. less than 5 or 3, respectively. Treatment options to increase NK cell cytotoxic activity should be considered in patients with relatively high numbers of CTCs.
Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias Colorrectales/inmunología , Inmunidad Innata/inmunología , Células Neoplásicas Circulantes , Neoplasias de la Próstata/inmunología , Recuento de Células , Femenino , Citometría de Flujo , Humanos , Células K562 , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Masculino , Metástasis de la Neoplasia , Pronóstico , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
OBJECTIVE: To estimate the anti-tumor activity of pemetrexed in patients with advanced or recurrent carcinoma of the endometrium and to determine the nature and degree of toxicity. METHODS: A multicenter phase II trial was conducted by the Gynecologic Oncology Group (GOG). Patients must have had advanced or recurrent measurable carcinoma of the endometrium and failed one prior chemotherapy regimen. Pemetrexed at a dose of 900 mg/m(2) was administered as an IV infusion over 10 min every 21 days. RESULTS: From May 1, 2006 to July 31, 2007, 27 patients were entered by 10 member institutions of the GOG with two patients being deemed ineligible. A total of 101 cycles were administered with 28% of patients receiving five or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included anemia in 20%, leukopenia in 40%, neutropenia in 48%, and constitutional in 16%. No treatment-related deaths were reported. One patient (4%) had a partial response. Eleven patients (44%) had stable disease and eleven (44%) patients had increasing disease. Response could not be assessed in two patients (7%). Median progression-free survival was 2.7 months and overall survival was 9.4 months. CONCLUSION: Pemetrexed has minimal activity in the treatment of recurrent or persistent endometrial carcinoma at the dose and schedule tested.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Femenino , Glutamatos/efectos adversos , Guanina/efectos adversos , Guanina/uso terapéutico , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , PemetrexedRESUMEN
PURPOSE: To estimate antitumor activity and toxicity of weekly topotecan hydrochloride in patients with persistent or recurrent cervical carcinoma who failed prior treatment. PATIENTS AND METHODS: Women entered on study had or failed one prior chemotherapy regimen in addition to radiosensitizing chemotherapy, performance status less than 3, and adequate hematologic, renal, hepatic, and neurological function. Topotecan was infused at 3.0 mg/m(2) on days 1, 8, and 15 every 28 days. RESULTS: Twenty-seven patients were enrolled onto this study with 25 evaluable. Twenty-two patients had received radiation and chemotherapy prior to study. A median of two and mean of three courses of chemotherapy was given (range, one to eight courses). The most frequently severe adverse events were grade 3 anemia (28%) and grade 4 (4%) along with grade 3 neutropenia (8%) and grade 4 (8%). Two patients had grade 4 thrombocytopenia. There were no complete or partial responders. Ten patients (40%) had stable disease, twelve (48%) had increasing disease, and response could not be assessed in three (12%). The median progression-free survival was 2.4 months for the patients with increasing disease and 6.2 months (3.5-8.8 months) for those with stable disease. Disease location was equally divided within and outside the irradiated field. The 12 patients with increasing disease were more likely to have disease outside the pelvic radiation field. CONCLUSION: There were no complete or partial responders to weekly topotecan among the 25 patients in this study.