Few days of unloading are sufficient to induce a decline of skeletal muscle mass and function; notably, contractile force is lost at a faster rate than muscle mass.r The reasons behind this disproportionate loss of muscle force are still poorly understood. r We provide strong evidence of two mechanisms only hypothesized until now for the rapid muscle force loss in only 10 days of bed rest.r Our results show that an initial neuromuscular junction instability, accompanied by alterations in the innervation status and impairment of single fibre sarcoplasmic reticulum function contribute to the loss of contractile force in front of a preserved myofibrillar function and central activation capacity.r Early onset of neuromuscular junction instability and impairment in calcium dynamics involved in excitation-contraction coupling are proposed as eligible determinants to the greater decline in muscle force than in muscle size during unloading.
This simplified FOLFOXIRI combination can be delivered easily in outpatient settings, with manageable toxic effects, and has very promising antitumor activity. While the safety profile seems to be improved in comparison with our previous FOLFOXIRI regimen, antitumor activity and efficacy appear to be maintained.
The FOLFOXIRI regimens we studied have significant antitumor activity and allow a radical surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer not selected for a neoadjuvant approach and also those with extrahepatic disease. The median survival of patients with resected disease is promising.
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