RESUMEN
BACKGROUND: Ampullary adenocarcinoma (AA) originates from either intestinal (INT) or pancreaticobiliary (PB) epithelium. Different prognostic factors of recurrence have been identified in previous studies. METHODS: In 91 AA patients of the AGEO retrospective multicentre cohort, we evaluated the centrally reviewed morphological classification, panel markers of Ang et al. including CK7, CK20, MUC1, MUC2 and CDX2, the 50-gene panel mutational analysis, and the clinicopathological AGEO prognostic score. RESULTS: Forty-three (47%) of the 91 tumours were Ang-INT, 29 (32%) were Ang-PB, 18 (20%) were ambiguous (Ang-AMB) and one could not be classified. Among these 90 tumours, 68.7% of INT tumours were Ang-INT and 78.2% of PB tumours were Ang-PB. MUC5AC expression was detected in 32.5% of the 86 evaluable cases. Among 71 tumours, KRAS, TP53, APC and PIK3CA were the most frequently mutated genes. The KRAS mutation was significantly more frequent in the PB subtype. In multivariate analysis, only AGEO prognostic score and tumour subtype were associated with relapse-free survival. Only AGEO prognostic score was associated with overall survival. CONCLUSIONS: Mutational analysis and MUC5AC expression provide no additional value in the prognostic evaluation of AA patients. Ang et al. classification and the AGEO prognostic score were confirmed as a strong prognosticator for disease recurrence.
Asunto(s)
Adenocarcinoma/genética , Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco/genética , Neoplasias Duodenales/genética , Adenocarcinoma/clasificación , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Factor de Transcripción CDX2/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias del Conducto Colédoco/clasificación , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/patología , Neoplasias Duodenales/clasificación , Neoplasias Duodenales/metabolismo , Neoplasias Duodenales/patología , Femenino , Humanos , Inmunohistoquímica , Queratina-20/metabolismo , Queratina-7/metabolismo , Masculino , Persona de Mediana Edad , Mucina 5AC/metabolismo , Mucina-1/metabolismo , Mucina 2/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma frequently associated with celiac disease. We report a case of EATL complicating adult autoimmune enteropathy (AIE). Analysis of phenotype, rearrangements in T-cell receptor genes, and chromosome alterations by high-resolution comparative genomic hybridization identified features distinct from those described for types I and II EATL. Furthermore, EATL arose from a single T-cell clone that had been present for several years in AIE-associated, oligoclonal, intestinal T-cell infiltrate. Emerging T-cell clones should be monitored in patients with AIE who receive long-term immunosuppressive therapy.
Asunto(s)
Linfoma de Células T Asociado a Enteropatía/etiología , Genes Codificadores de los Receptores de Linfocitos T , Neoplasias Intestinales/etiología , Poliendocrinopatías Autoinmunes/complicaciones , Biopsia , Células Clonales/inmunología , Células Clonales/patología , Hibridación Genómica Comparativa , Linfoma de Células T Asociado a Enteropatía/genética , Linfoma de Células T Asociado a Enteropatía/inmunología , Linfoma de Células T Asociado a Enteropatía/patología , Femenino , Reordenamiento Génico de Linfocito T , Predisposición Genética a la Enfermedad , Humanos , Inmunosupresores/uso terapéutico , Neoplasias Intestinales/genética , Neoplasias Intestinales/inmunología , Neoplasias Intestinales/patología , Persona de Mediana Edad , Fenotipo , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Poliendocrinopatías Autoinmunes/inmunologíaRESUMEN
In the last decades a new class of therapeutic drugs have been developed that block tumor angiogenesis. These antiangiogenic molecules, which target VEGF or VEGFR, PDGFR, and c-kit, can act not only on endothelial cells but also on immune cells. Some antiangiogenic molecules inhibit the development of immunosuppressive mechanisms developed by the tumors to escape the immune system (such as regulatory T cells, myeloid-derived suppressor cells, and immunosuppressive cytokines). These immunomodulatory effects must be characterized in detail to enable a better prescription of these treatments. In this paper we will focus on the impact of anti-angiogenic drugs on immunosuppression and their potential combination with immunotherapeutic strategies. Interestingly, immune parameters or their modulation during treatment could serve as potential biomarkers of response or resistance to anti-angiogenic therapies.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Factores Inmunológicos/farmacología , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Humanos , Inmunidad/efectos de los fármacos , Inmunidad/inmunología , Factores Inmunológicos/uso terapéutico , Neoplasias/inmunología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/inmunologíaRESUMEN
Immune escape is a prerequisite for tumor development. To avoid the immune system, tumors develop different mechanisms, including T cell exhaustion, which is characterized by expression of immune inhibitory receptors, such as PD-1, CTLA-4, Tim-3, and a progressive loss of function. The recent development of therapies targeting PD-1 and CTLA-4 have raised great interest since they induced long-lasting objective responses in patients suffering from advanced metastatic tumors. However, the regulation of PD-1 expression, and thereby of exhaustion, is unclear. VEGF-A, a proangiogenic molecule produced by the tumors, plays a key role in the development of an immunosuppressive microenvironment. We report in the present work that VEGF-A produced in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved in CD8(+) T cell exhaustion, which could be reverted by anti-angiogenic agents targeting VEGF-A-VEGFR. In view of these results, association of anti-angiogenic molecules with immunomodulators of inhibitory checkpoints may be of particular interest in VEGF-A-producing tumors.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Neoplasias/genética , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Unión Proteica , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8⺠and CD45⺠lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phaseâ Iâ to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.
Asunto(s)
Linfocitos T CD8-positivos/citología , Neoplasias Colorrectales/inmunología , Antígenos Comunes de Leucocito/metabolismo , Antineoplásicos/uso terapéutico , Antígeno CTLA-4/metabolismo , Antígenos HLA/metabolismo , Humanos , Inmunidad Innata , Inmunoterapia/métodos , Células Asesinas Naturales/citología , Linfocitos/citología , Macrófagos/citología , Repeticiones de Microsatélite , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , VacunaciónRESUMEN
The progressive conversion of normal cells into cancer cells is characterized by the acquisition of eight hallmarks. Among these criteria, the capability of the cancer cell to avoid the immune destruction has been noted. Thus, tumors develop mechanisms to become invisible to the immune system, such as the induction of immunosuppressive cells, which are able to inhibit the development of an efficient immune response. Molecules produced in the tumor microenvironment are involved in the occurrence of an immunosuppressive microenvironment. Recently, it has been shown that vascular endothelial growth factor A (VEGF-A) exhibits immunosuppressive properties in addition to its pro-angiogenic activities. VEGF-A can induce the accumulation of immature dendritic cells, myeloid-derived suppressor cells, regulatory T cells, and inhibit the migration of T lymphocytes to the tumor. Other pro-angiogenic factors such as placental growth factor (PlGF) could also participate in tumor-induced immunosuppression, but only few works have been performed on this point. Here, we review the impact of pro-angiogenic factors (especially VEGF-A) on immune cells. Anti-angiogenic molecules, which target VEGF-A/VEGFR axis, have been developed in the last decades and are commonly used to treat cancer patients. These drugs have anti-angiogenic properties but can also counteract the tumor-induced immunosuppression. Based on these immunomodulatory properties, anti-angiogenic molecules could be efficiently associated with immunotherapeutic strategies in preclinical models. These combinations are currently under investigation in cancer patients.
RESUMEN
INTRODUCTION: Folfirinox has shown a benefit in terms of survival and quality of life in first line treatment of metastatic pancreatic cancer. However, efficacy of second line chemotherapy after folfirinox is still limited. Gemcitabine plus Nab-paclitaxel have been recently validated as first line treatment with an increased overall survival compared to gemcitabine. This combination has never been studied as second-line after folfirinox. CASE REPORT: A metastatic pancreatic cancer was diagnosed in a 60-year-old patient with a performance status of 0. After 10 cycles of folfirinox, and an initial objective response, we objectively noted progressive disease according to the RECIST 1.1 criteria together with an increased carbohydrate antigen 19-9. The multidisciplinary team decided to use gemcitabine plus Nab-paclitaxel as second line palliative chemotherapy. After 2 months, we obtained an objective response. After 6 months, this response was maintained with an acceptable tolerability. CONCLUSION: Gemcitabine plus Nab-paclitaxel, as second line palliative chemotherapy, after failure of folfirinox, could be a good strategy for patients with a performance status of 0 and 1. Obviously, this data has to be confirmed in larger patients series and in future comparative clinical studies.
Asunto(s)
Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Antígeno CA-19-9/sangre , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Carcinoma Ductal Pancreático/patología , Desoxicitidina/administración & dosificación , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Irinotecán , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Cuidados Paliativos , Neoplasias Pancreáticas/patología , Insuficiencia del Tratamiento , GemcitabinaRESUMEN
Multitarget antiangiogenic tyrosine kinase inhibitors (TKI) have been shown to reduce regulatory T cells (Treg) in tumor-bearing animals and patients with metastatic renal carcinomas. However, a direct role of the VEGF-A/VEGFR pathway inhibition in this phenomenon is a matter of debate and molecular mechanisms leading to Treg modulation in this setting have not been explored to date. Treg proportion, number, and proliferation were analyzed by flow cytometry in peripheral blood of patients with metastatic colorectal cancer (mCRC) treated with bevacizumab, a monoclonal antibody targeting specifically VEGF-A, and in colon cancer-bearing mice (CT26) treated with drugs targeting the VEGF/VEGFR axis. The direct impact of VEGF-A on Treg induction was assessed together with specific blockade of different isoforms of VEGFRs that may be involved. In CT26-bearing mice, anti-VEGF antibody and sunitinib treatments reduced Treg but masitinib, a TKI not targeting VEGFR, did not. Targeting VEGF-A/VEGFR axis seems sufficient to affect Treg percentages, without any changes in their function. Similarly, bevacizumab inhibited Treg accumulation in peripheral blood of patients with mCRCs. In vitro, Treg expressing VEGFR from tumor-bearing mice directly proliferated in response to VEGF-A. Anti-VEGF-A treatment decreased Treg proliferation in mice as well as in patients with mCRCs. VEGFR-2- but not VEGFR-1-specific blockade led to the same results. We identified a novel mechanism of tumor escape by which VEGF-A directly triggers Treg proliferation. This proliferation is inhibited by VEGF-A/VEGFR-2 blockade. Anti-VEGF-A therapies also have immunologic effects that may be used with a therapeutic goal in the future.
Asunto(s)
Neoplasias Colorrectales/inmunología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Escape del Tumor , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab , Recuento de Células , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Indoles/farmacología , Ratones , Ratones Endogámicos BALB C , Pirroles/farmacología , Sunitinib , Linfocitos T Reguladores/metabolismoRESUMEN
Gastrointestinal symptoms occurring in patients with Crohn's disease (CD) can be related to disease activity or to intercurrent infection. Absence of appropriate stool work-up can lead to misdiagnosis and wrong treatment. We report here two cases of acute cryptosporidiosis in patients with CD. This microorganism can trigger IBD flare or cause severe infections in immunocompromised host. Adding specific search for oocysts of Cryptosporidium parvum using the Ziehl-Neelsen technique to the microbiologic work-up from stools in patients with Crohn's disease seeking medical intervention for sudden exacerbation of digestive symptoms seems to be recommended.