Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26-bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26-bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubesin vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed.

Background: the improved survival rates achieved using new polychemotherapy regimens in patients with metastatic pancreatic cancer (mPDAC) have suggested a potential role for surgery following a favorable response to initial chemotherapy (IC). The purpose of this systematic review is to summarize the available evidence on the role of surgery following IC in mPDAC, focusing on oligometastatic disease to the liver (lmPDAC). Methods: studies reporting on patients with lmPDAC undergoing surgery after IC were included. The main outcome was overall survival (OS). Results: six observational retrospective studies were included in the qualitative analysis. Data were retrieved on 2087 patients. The most common IC regimen in patients undergoing surgery was FOLFIRINOX (N 84, 73%). Only three studies reported survival comparison among patients treated with IC+surgery vs. IC alone. Median OS varied from 23 to 56 months after conversion surgery vs. 11 to 16.4 months after IC alone. Conclusions: despite wide heterogeneity of chemotherapy regimens, different downstaging criteria and potential selection biases, patients with oligometastatic lmPDAC undergoing surgery after IC have significantly higher survival rates compared to patients treated with IC alone. Future trials are needed for definition of univocal criteria of downstaging, oligometastatic definition and indications for surgery.