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1.
Cell ; 184(15): 4032-4047.e31, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34171309

RESUMEN

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.


Asunto(s)
Neoplasias/genética , Neoplasias/inmunología , Empalme del ARN/genética , Animales , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/inmunología , Antígenos de Neoplasias/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Epítopos/inmunología , Etilenodiaminas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Hematopoyesis/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia , Inflamación/patología , Ratones Endogámicos C57BL , Péptidos/metabolismo , Isoformas de Proteínas/metabolismo , Pirroles/farmacología , Empalme del ARN/efectos de los fármacos , Sulfonamidas/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología
2.
PLoS Pathog ; 20(7): e1010785, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38976755

RESUMEN

The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αß T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αß T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion in organs and blood was higher after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection was prevented when masking γδ T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire composed of a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. This better survival potential of TCM cells was confirmed by a detailed scRNASeq analysis of the two γδ T cell memory subsets which also revealed their similarity to classically adaptive αß CD8 T cells. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches.


Asunto(s)
Infecciones por Herpesviridae , Memoria Inmunológica , Células T de Memoria , Muromegalovirus , Receptores de Antígenos de Linfocitos T gamma-delta , Animales , Ratones , Muromegalovirus/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Infecciones por Herpesviridae/inmunología , Memoria Inmunológica/inmunología , Células T de Memoria/inmunología , Reinfección/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Citomegalovirus/inmunología
3.
N Engl J Med ; 386(25): 2363-2376, 2022 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-35660797

RESUMEN

BACKGROUND: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer. METHODS: We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. RESULTS: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. CONCLUSIONS: Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).


Asunto(s)
Antineoplásicos , Neoplasias Primarias Secundarias , Neoplasias del Recto , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Reparación de la Incompatibilidad de ADN , Humanos , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/patología , Receptor de Muerte Celular Programada 1/efectos de los fármacos , Estudios Prospectivos , Neoplasias del Recto/genética , Neoplasias del Recto/terapia , Recto/patología , Resultado del Tratamiento
4.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33558238

RESUMEN

Propranolol, a nonselective ß-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.


Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Acuaporina 1/metabolismo , Hemangioma Capilar/metabolismo , Síndromes Neoplásicos Hereditarios/metabolismo , Neovascularización Patológica/metabolismo , Propranolol/farmacología , Telocitos/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Hemangioma Capilar/tratamiento farmacológico , Humanos , Ratones , Síndromes Neoplásicos Hereditarios/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Propranolol/uso terapéutico , Proteoma/genética , Proteoma/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Telocitos/efectos de los fármacos , Telocitos/fisiología
5.
Gastric Cancer ; 26(2): 234-249, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36528833

RESUMEN

BACKGROUND: Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+ cells and their clinical significance in GC patients. METHODS: Using GC cell lines and patient-derived xenografts, we evaluated CD44+ and CD44v3+ GC cells molecular signature and their tumorigenic, chemoresistance, invasive and metastatic properties, and expression in patients-derived tissues. RESULTS: CD44v3+ cells, which represented a subpopulation of CD44+ cells, were detected in advanced preneoplastic lesions and presented CSCs chemoresistance and tumorigenic properties in vitro and in vivo. Molecular and functional analyses revealed two subpopulations of gastric CSCs: CD44v3+ CSCs with an epithelial-mesenchymal transition (EMT)-like signature, and CD44+/v3- CSCs with an epithelial-like signature; both were tumorigenic but CD44v3+ cells showed higher invasive and metastatic properties in vivo. CD44v3+ cells detected in the primary tumours of GC patients were associated with a worse prognosis. CONCLUSION: CD44v3 is a marker of a subpopulation of CSCs with metastatic properties in GC. The identification of metastasis-initiating cells in GC represents a major advance for further development of anti-metastatic therapeutic strategies.


Asunto(s)
Carcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Células Madre Neoplásicas/metabolismo , Carcinoma/patología , Receptores de Hialuranos , Transición Epitelial-Mesenquimal
6.
Nucleic Acids Res ; 47(6): 2739-2756, 2019 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-30759257

RESUMEN

G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound.


Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas de la Ataxia Telangiectasia Mutada , Autofagia/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , G-Cuádruplex , Neoplasias/patología , Células A549 , Animales , Apoptosis/genética , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Autofagia/genética , Línea Celular Tumoral , Senescencia Celular/genética , Daño del ADN/efectos de los fármacos , Células HeLa , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Neoplasias/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Int J Cancer ; 147(11): 3177-3188, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32525595

RESUMEN

Fluoropyrimidine (FP) plus platinum chemotherapy has been recently established as a second-line (L2) preferred option in advanced biliary tract cancer (aBTC) (ABC-06 phase III trial). However, the overall survival (OS) benefit was limited and comparison with FP monotherapy was not available. Our aim was to assess the OS of patients treated with a FP monotherapy compared to a doublet with irinotecan or platinum in L2. We performed a retrospective analysis of two large multicenter prospective cohorts: a French cohort (28 centers) and an Italian cohort (9 centers). All consecutive patients with aBTC receiving FP-based L2 after gemcitabine plus cisplatin/gemcitabine plus oxaliplatin L1 between 2003 and 2016 were included. A subgroup analysis according to performance status (PS) and an exploratory analysis according to platinum sensitivity in L1 were planned. In the French cohort (n = 351), no significant OS difference was observed between the FP monotherapy and doublet groups (median OS: 5.6 vs 6.8 months, P = .65). Stratification on Eastern Cooperative Oncology Group (ECOG) PS showed similar results in PS 0-1 and 2. Median OS was not different between FP monotherapy, platinum- and irinotecan-based doublets (5.6 vs 7.1 vs 6.7 months, P = .68). Similar findings were observed in the Italian cohort (n = 174) and in the sensitivity analysis in pooled cohorts (n = 525). No L2 regimen seemed superior over others in the platinum resistant/refractory or sensitive subgroups. Our results suggest that FP monotherapy is as active as FP doublets in aBTC in L2, regardless of the patient PS and country, and could be a therapeutic option in this setting.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Irinotecán/administración & dosificación , Platino (Metal)/administración & dosificación , Pirimidinas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Capecitabina/uso terapéutico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Francia , Humanos , Irinotecán/uso terapéutico , Italia , Masculino , Persona de Mediana Edad , Platino (Metal)/uso terapéutico , Estudios Prospectivos , Pirimidinas/uso terapéutico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
8.
Oncologist ; 25(2): e266-e275, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32043796

RESUMEN

BACKGROUND: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting. MATERIALS AND METHODS: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR). RESULTS: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007). CONCLUSION: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF. IMPLICATIONS FOR PRACTICE: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.


Asunto(s)
Anticuerpos Monoclonales , Neoplasias Colorrectales , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo/uso terapéutico , Humanos , Masculino , Estudios Retrospectivos
9.
Int J Cancer ; 144(4): 886-896, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30155929

RESUMEN

Prognosis and oncologic treatment feasibility in solid organ transplant patients with de novo cancer remain poorly described. We investigated the impact of immunosuppressive therapy modifications after de novo cancer diagnosis on oncologic treatment feasibility, toxicities, and prognosis. Patients with de novo cancer (excluding nonmelanoma skin cancers) were selected from a monocentric cohort of 4,637 kidney and liver allograft recipients. We assessed oncologic treatment optimality according to guidelines and analyzed immunosuppressive drug modifications and oncologic treatment impacts on treatment feasibility, toxicities, and graft/patient survivals. A total of 180 patients with 205 cancers were included: mean age 60 years, median delay from transplantation to first de novo cancer 5 years. In 46% of cases, immunosuppressive therapy was modified after cancer diagnosis: 24% dose reduction and 22% mTOR inhibitor introduction. Optimal oncologic treatment was performed in 80% and 38% of patients with localized and advanced cancer respectively. Transplantation and immunosuppression hindered optimal oncologic treatment in 11% instances. Immunosuppressive therapy modifications did not affect oncologic treatment tolerance nor graft survival. In multivariate analysis, optimal oncologic treatment and mTOR inhibitor introduction improved survival of patients with de novo carcinoma. Optimal oncologic treatment is feasible in kidney and liver allograft recipients without safety concerns. Optimal oncologic treatment and mTOR inhibitor introduction seem to markedly improve survival of patients with de novo carcinoma.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Riñón/métodos , Trasplante de Hígado/métodos , Neoplasias/terapia , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Aloinjertos , Terapia Combinada , Femenino , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias/patología , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Análisis de Supervivencia , Serina-Treonina Quinasas TOR/metabolismo
10.
J Hepatol ; 70(1): 58-65, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30213589

RESUMEN

BACKGROUND & AIMS: Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver. METHODS: We aimed to determine, by pathological review, the prognostic significance of both intra-tumoral and non-tumoral TLSs in a series of 273 patients with HCC treated by surgical resection in Henri Mondor University Hospital. Findings were further validated by gene expression profiling using a public data set (LCI cohort). RESULTS: TLSs were identified in 47% of the tumors, by pathological review, with lymphoid aggregates, primary and secondary follicles in 26%, 16% and 5% of the cases, respectively. Univariate and multivariate analyses showed that intra-tumoral TLSs significantly correlated with a lower risk of early relapse (<2 years after surgery, hazard ratio 0.46, p = 0.005). Interestingly, the risk of recurrence was also related to the degree of TLS maturation (primary or secondary follicles vs. lymphoid aggregates, p = 0.01). A gene expression signature associated with the presence of intra-tumoral TLS was also independently associated with a lower risk of early relapse in the LCI cohort. No association between the density of TLSs located in the adjacent non-tumoral liver and early or late recurrence was observed. CONCLUSIONS: We have shown that intra-tumoral TLSs are associated with a lower risk of early relapse in 2 independent cohorts of patients with HCC treated by surgical resection. Thus, intra-tumoral TLSs may reflect the existence of ongoing, effective anti-tumor immunity. LAY SUMMARY: Tertiary lymphoid structures provide a critical microenvironment for generating anti-tumor immune responses, and are associated with improved clinical outcome in most cancers investigated. Their role in hepatocellular carcinoma is however debated. We show in the present study that intra-tumoral tertiary lymphoid structures are associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ, effective anti-tumor immunity.


Asunto(s)
Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/patología , Estructuras Linfoides Terciarias/patología , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biopsia , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Pronóstico , Estudios Retrospectivos , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/metabolismo , Factores de Tiempo
11.
Oncologist ; 24(12): e1331-e1340, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31152084

RESUMEN

BACKGROUND: BRAFV600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown. MATERIALS AND METHODS: We built a multicenter clinico-biological database gathering data from patients with BRAFV600E -mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model. RESULTS: We included 287 patients (median age, 67 years [28-95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97-27.04), and median progression-free survival in the first-line setting was 4.34 months (95% CI, 3.81-5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti-epidermal growth factor receptor) were not associated with overall and progression-free survival. Stage IV disease (synchronous metastases) and absence of curative-intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009). CONCLUSION: Despite that BRAFV600E -mutant mCRCs are associated with poor overall and progression-free-survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAFV600E mCRC in day-to-day practice. IMPLICATIONS FOR PRACTICE: Mismatch repair (MMR) testing and resectability discussion in patients with BRAFV600E metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with BRAFV600E -mutant mCRC.


Asunto(s)
Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia
13.
Hepatology ; 68(1): 89-102, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29152775

RESUMEN

Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70%-80% of patients. However, some important challenges remain in diagnosing high-risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of HB tumors have been described, C1 and C2, with C2 being the subgroup with the poorest prognosis, a more advanced tumor stage, and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed, but it has not been transferred into clinical routine. To address these issues, we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A, and C2B, identifiable by a concise four-gene signature: hydroxysteroid 17-beta dehydrogenase 6, integrin alpha 6, topoisomerase 2-alpha, and vimentin, with topoisomerase 2-alpha being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by quantitative RT-PCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in the Fanconi anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, a Food and Drug Administration-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway-associated double-strand DNA repair, and significantly impedes HB growth in vivo. CONCLUSION: The highly proliferating C2A subtype is characterized by topoisomerase 2-alpha gene up-regulation and FA pathway activation, and the HB therapeutic arsenal could include bortezomib for the treatment of patients with the most aggressive tumors. (Hepatology 2018;68:89-102).


Asunto(s)
ADN-Topoisomerasas de Tipo II/metabolismo , Hepatoblastoma/clasificación , Hepatoblastoma/genética , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores/metabolismo , Bortezomib/farmacología , Bortezomib/uso terapéutico , Reparación del ADN/efectos de los fármacos , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Perfilación de la Expresión Génica , Células Hep G2 , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/enzimología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/enzimología , Análisis de Secuencia de ARN
14.
Invest New Drugs ; 37(6): 1289-1291, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-30806848

RESUMEN

Introduction New therapeutic strategies combining axitinib and immune checkpoint blockers are ongoing in metastatic renal cell carcinoma (mRCC). These strategies do not consider the pharmacokinetic variability of axitinib. We aimed to describe the risk of axitinib under-exposure using routine pharmacologic therapeutic monitoring (PTM). Methods We analyzed axitinib dosage in nine patients with mRCC. Routine axitinib concentration measurements were centralized at Henri Mondor University Hospital (Créteil, France) using a validated method. The primary objective was to describe the evolution of Cmax dosages (1 to 6 h after oral intake) during routine axitinib titration. Results Nine patients with available Cmax axitinib dosages were included. Four out of the nine patients had axitinib titration and Cmax dosages were performed before and after titration. All but one corrected their plasma axitinib exposure after titration, suggesting of a titration success. The last patient was monitored in the Henri Mondor Hospital routine PTM program and a pharmacokinetic profiling was performed after controlled oral intake. Results suggested a poor axitinib absorption. This patient experienced early tumor progression as best response. Conclusion We report a patient with significant axitinib under-exposure, possibly due to a poor absorption. PTM should be evaluated and considered in drug developments evaluating combination therapies based on axitinib.


Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Axitinib/farmacocinética , Axitinib/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/metabolismo , Monitoreo de Drogas , Femenino , Humanos , Absorción Intestinal , Neoplasias Renales/metabolismo , Persona de Mediana Edad , Resultado del Tratamiento
15.
Haematologica ; 104(10): 2017-2027, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30923103

RESUMEN

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.


Asunto(s)
Benzotiazoles/farmacología , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Factor de Transcripción STAT5/metabolismo , Microambiente Tumoral , Tirosina Quinasa 3 Similar a fms/metabolismo , Hipoxia de la Célula , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Células K562 , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Factor de Transcripción STAT5/genética , Regulación hacia Arriba/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa del Receptor Axl
16.
Am J Pathol ; 187(7): 1473-1484, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28460208

RESUMEN

APRIL is a member of the tumor necrosis factor cytokine family involved in the regulation of B-cell immunity. We present a study of the infection by Helicobacter species of transgenic (Tg) C57BL6 mice, ectopically expressing the human form of APRIL. Wild-type (WT) and APRIL Tg mice were infected with Helicobacter felis and Helicobacter pylori and compared with noninfected animals. Mice were euthanized 18 months after infection, and inflammatory responses and histologic alterations were analyzed. Flow cytometry results revealed that WT-infected mice had less leukocyte infiltration than APRIL Tg-infected mice. In WT-infected mice, infiltrates in gastric tissues were predominantly composed of T cells, mainly CD4+ for H. pylori and CD8+ for H. felis. In APRIL Tg-infected mice, leukocyte infiltrates were composed of B cells with few CD4+ T cells for both species. B cells expressed B surface markers compatible with a marginal zone origin. These results were confirmed by immunohistochemistry. B cells in particular were involved in lymphoepithelial lesions, a hallmark of gastric MALT lymphoma. Monoclonality was observed in a few infiltrates in the presence of lymphoepithelial lesions. These results confirm the importance of APRIL in the development of gastric lymphoid infiltrates induced by Helicobacter species in vivo. We believe that APRIL Tg mice infected by Helicobacter species may represent a novel animal model of gastric lymphomagenesis.


Asunto(s)
Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Linfoma de Células B de la Zona Marginal/microbiología , Linfoma no Hodgkin/microbiología , Neoplasias Gástricas/microbiología , Animales , Linfocitos B/microbiología , Linfocitos B/patología , Carga Bacteriana , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/patología , Modelos Animales de Enfermedad , Femenino , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/patología , Humanos , Inmunohistoquímica , Inflamación , Tejido Linfoide/microbiología , Tejido Linfoide/patología , Linfoma de Células B de la Zona Marginal/inmunología , Linfoma de Células B de la Zona Marginal/patología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estómago/microbiología , Estómago/patología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología
17.
PLoS Pathog ; 11(3): e1004702, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25747674

RESUMEN

Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αß and/or γδ T cell-deficient mice, we here show that γδ T cells are as competent as αß T cells to protect mice from CMV-induced death. γδ T cell-mediated protection involved control of viral load and prevented organ damage. γδ T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3ε-/- mice from CMV-induced death confirming the protective antiviral role of γδ T cells. As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27- γδ T cells. NK cells were the largely preponderant producers of IFNγ and cytotoxic granules throughout the infection, suggesting that the protective role of γδ T cells did not principally rely on either of these two functions. Finally, γδ T cells were strikingly sufficient to fully protect Rag-/-γc-/- mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αß T cell compromised patients.


Asunto(s)
Infecciones por Herpesviridae/inmunología , Inmunidad Celular , Muromegalovirus/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Animales , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/patología , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Linfocitos T/patología
18.
Hepatology ; 64(6): 2038-2046, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27359084

RESUMEN

The prognosis of hepatocellular carcinoma (HCC) remains poor, with only one third of patients eligible for curative treatments and very limited survival benefits with the use of sorafenib, the current standard of care for advanced disease. Recently, agents targeting the programmed death ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) immune checkpoint were shown to display impressive antitumor activity in various solid or hematological malignancies, including HCC. PD-L1 immunohistochemical expression is thought to represent a biomarker predictive of drug sensitivity. Here, we investigated PD-L1 expression in a series of 217 HCCs and correlated our results with clinical and histological features and immunohistochemical markers (PD-1, cytokeratin 19, glutamine synthetase, and ß-catenin expression). PD-L1 expression by neoplastic cells was significantly associated with common markers of tumor aggressiveness (high serum alpha-fetoprotein levels, P = 0.038; satellite nodules, P < 0.001; macrovascular invasion, P < 0.001; microvascular invasion, P < 0.001; poor differentiation, P < 0.001) and with the progenitor subtype of HCC (cytokeratin 19 expression, P = 0.031). High PD-L1 expression by inflammatory cells from the tumor microenvironment also correlated with high serum alpha-fetoprotein levels (P < 0.001), macrovascular invasion (P = 0.001), poor differentiation (P = 0.001), high PD-1 expression (P < 0.001), and the so-called lymphoepithelioma-like histological subtype of HCC (P = 0.003). CONCLUSION: PD-L1 expression by either neoplastic or intratumoral inflammatory cells is related to tumor aggressiveness and suggests that the response to treatments targeting the PD-L1/PD-1 immune checkpoint could be restricted to particular HCC variants; thus, enrichment of these tumor subtypes in future clinical trials should be considered. (Hepatology 2016;64:2038-2046).


Asunto(s)
Antígeno B7-H1/biosíntesis , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/química , Femenino , Humanos , Neoplasias Hepáticas/química , Masculino , Persona de Mediana Edad
19.
Invest New Drugs ; 35(1): 79-86, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27783256

RESUMEN

Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities.


Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Enfermedades Renales/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase I como Asunto , Femenino , Humanos , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad
20.
Eur J Orthop Surg Traumatol ; 26(6): 581-6, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27394685

RESUMEN

BACKGROUND: The prevalence of combined humeral and glenoid defects varies between 79 and 84 % in case of chronic posttraumatic anterior shoulder instability. The main goal of this study was to evaluate the relationship between humeral and glenoid defects based on quantitative radiological criteria. METHODS: A retrospective study was performed between 2000 and 2011 including patients who underwent primary surgical shoulder stabilization for chronic posttraumatic anterior shoulder instability, with bone defects in both the glenoid and humerus and a healthy contralateral shoulder. The following measurements were taken: D/R ratio (Hill-Sachs lesion depth/humeral head radius) on an AP X-ray in internal rotation and the D1/D2 ratio [diameter of the involved glenoid articular surfaces (D1)/the healthy one (D2)] on a comparative Bernageau glenoid profile view. Measurements were taken by two observers. Correlations were determined by the Spearman correlation coefficients (r), Bland and Altman diagrams, and intra-class correlation coefficients (ICC). A sample size calculation was done. RESULTS: Thirty patients were included, 25 men/5 women, mean age 29.8 ± 11.2 years. The mean D/R was 23 ± 12 % for observer 1 and 23 ± 10 % for observer 2. The mean D1/D2 was 95 ± 4 % for observer 1 and 94 ± 6 % for observer 2. No significant correlation was found between humeral and glenoid bone defects by observer 1 (r = 0.23, p = 0.22) or observer 2 (r = 0.05, p = 0.78). Agreement of the observers for the D/R ratio was excellent (ICC = 0.89 ± 0.04, p < 0.00001) and good for the D1/D2 ratio (ICC = 0.54 ± 0.14, p = 0.006). CONCLUSION: Humeral and glenoid bone defects were not correlated. Inter-observer reliability was excellent for the D/R ratio and good for the D1/D2 ratio. LEVEL OF EVIDENCE: Nonconsecutive Patients, Diagnostic Study, Level III.


Asunto(s)
Artrodesis , Húmero , Escápula , Luxación del Hombro , Articulación del Hombro , Adulto , Artrodesis/efectos adversos , Artrodesis/métodos , Femenino , Francia/epidemiología , Humanos , Húmero/diagnóstico por imagen , Húmero/patología , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/etiología , Masculino , Evaluación de Procesos y Resultados en Atención de Salud , Prevalencia , Radiografía/métodos , Estudios Retrospectivos , Escápula/diagnóstico por imagen , Escápula/patología , Luxación del Hombro/diagnóstico , Luxación del Hombro/epidemiología , Luxación del Hombro/etiología , Luxación del Hombro/fisiopatología , Lesiones del Hombro , Articulación del Hombro/fisiopatología , Articulación del Hombro/cirugía , Estadística como Asunto
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