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2.
ESMO Open ; 9(4): 102996, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38613911

RESUMEN

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carbamatos , Cetuximab , Neoplasias Colorrectales , Mutación , Proteínas Proto-Oncogénicas B-raf , Sulfonamidas , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Cetuximab/uso terapéutico , Cetuximab/farmacología , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Carbamatos/uso terapéutico , Carbamatos/farmacología , Sulfonamidas/uso terapéutico , Sulfonamidas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Progresión de la Enfermedad , Supervivencia sin Progresión , Adulto , Anciano de 80 o más Años , Metástasis de la Neoplasia , Italia
3.
ESMO Open ; 7(6): 100606, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36327757

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers; ∼20% of patients have metastases at diagnosis, and 50%-60% subsequently develop metachronous metastases. Bone involvement, despite being rare, is usually associated with higher disease burden, worse prognosis, impaired quality of life, and significant health-related cost. In the last few years, following the positive results of the TRIBE and TRIBE2 trials, the association of FOLFOXIRI plus bevacizumab has become the new standard of care for metastatic CRC. Despite being highly efficacious in all subgroups, little is known about the activity of this regimen in patients with bone metastases. PATIENTS AND METHODS: We carried out a pooled analysis of TRIBE and TRIBE2 studies focusing on patients with skeletal deposits. RESULTS: Our analyses on the whole population showed that patients with baseline bone involvement reported shorter overall survival [OS; 14.0 versus 26.2 months; hazard ratio (HR) 2.04, 95% confidence interval (CI) 1.46-2.87; P < 0.001] and progression-free survival (PFS; 6.2 versus 11.1 months; HR 1.96, 95% CI 1.42-2.69; P < 0.001) compared with those without bone metastases; no significant interaction with the treatment was reported for PFS (P = 0.094) and OS (P = 0.38). Bone metastases had a negative prognostic implication in the multivariate analysis (HR 2.24, 95% CI 1.54-3.26; P < 0.001). Furthermore, patients with bone lesions at first radiological progression (including those with baseline bone metastases) had a shorter OS compared with those who progressed in other sites (10.4 versus 13.2 months; HR 1.48, 95% CI 1.15-1.91; P = 0.002). A trend toward inferior OS (7.5 versus 11 months, HR 1.50, 95% CI 0.92-2.45; P = 0.10) appeared in patients with basal skeletal deposits compared with those with bone involvement at first radiological progression. CONCLUSIONS: Our study confirmed the negative prognostic impact of bone metastases in CRC. Furthermore, we demonstrated for the first time that the survival advantage of triplet chemotherapy plus bevacizumab is maintained even in this prognostically unfavorable subgroup.


Asunto(s)
Neoplasias Óseas , Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/patología , Calidad de Vida , Camptotecina/uso terapéutico , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Pronóstico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológico
4.
Neurobiol Learn Mem ; 87(2): 174-80, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16990035

RESUMEN

This study tries to shed light on the paradoxical finding that two inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA), with differences in hippocampal function, perform similarly in the water maze (WM). Mice from both strains were trained on WM protocols permitting or preventing the use of vestibular signals. Hippocampal involvement in performance was then assessed by estimation of post-training mossy fiber (MF) synaptogenesis. We found that C57 and DBA mice performed similarly when both visual and vestibular information were available but only C57 mice exhibited new MF synapses. Disruption of vestibular inputs impaired performance in DBA mice but not in C57 mice which still exhibited a post-training increase of hippocampal MF synaptic terminals. This strain-specific dissociation indicates that DBA mice can navigate successfully by relying on vestibular signals without engaging their hippocampus. In contrast, vestibular signals are irrelevant for C57 mice since their suppression neither disrupts their behavior nor prevents the formation of new hippocampal synapses. These findings suggest some caution is required in considering performance on standard WM protocols as an index of hippocampus-based learning. Estimating the extent of post-training mossy fiber synaptogenesis would be helpful in solving this issue.


Asunto(s)
Hipocampo/citología , Fibras Musgosas del Hipocampo/fisiología , Plasticidad Neuronal/fisiología , Orientación , Percepción Espacial/fisiología , Sinapsis/fisiología , Animales , Conducta Animal , Hipocampo/fisiología , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Tiempo de Reacción/fisiología , Coloración y Etiquetado , Factores de Tiempo , Vestíbulo del Laberinto/fisiología
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