RESUMEN
BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Células Neoplásicas Circulantes/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Estudios de Seguimiento , Humanos , Mutación , Metástasis de la Neoplasia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Proteínas ras/genéticaRESUMEN
Acute compartment syndrome (ACS) is an orthopaedic emergency that requires urgent fasciotomy and decompression to avoid significant morbidity. It is most commonly caused by a fracture or crush injury. We present a case of a patient who developed ACS of the posterior compartment of the thigh secondary to a low energy fall and avulsion of sclerotic arterioles. There was no fracture and the patient was not anti-coagulated. They had fasciotomy and embolization of responsible vessels. This case demonstrates the need for high clinical suspicion needed for ACS and the morbidity associated with a delayed fasciotomy. A literature research demonstrated no case reports of a patient developing ACS with no fracture, no crush injury and no history of anti-coagulation.