RESUMO
M3 muscarinic receptor (M3R) activation stimulates colon cancer cell proliferation, migration, and invasion; M3R expression is augmented in colon cancer and ablating M3R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M3R, M1R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M1R versus M3R in progressive stages of colon neoplasia and the effect of treating colon cancer cells with selective M1R agonists. We detected divergent expression of M1R and M3R in progressive colon neoplasia, from aberrant crypt foci to adenomas, primary colon cancers, and colon cancer metastases. Treating three human colon cancer cell lines with two selective M1R agonists, we found that in contrast to the effects of M3R activation, selective activation of M1R reversibly inhibited cell proliferation. Moreover, these effects were diminished by pre-incubating cells with a selective M1R inhibitor. Mechanistic insights were gained using selective chemical inhibitors of post-muscarinic receptor signaling molecules and immunoblotting to demonstrate M1R-dependent changes in the activation (phosphorylation) of key downstream kinases, EGFR, ERK1/2, and p38 MAPK. We did not detect a role for drug toxicity, cellular senescence, or apoptosis in mediating M1R agonist-induced attenuated cell proliferation. Lastly, adding M1R-selective agonists to colon cancer cells augmented the anti-proliferative effects of conventional chemotherapeutic agents. Collectively, these results suggest that selective M1R agonism for advanced colon cancer, alone or in combination with conventional chemotherapy, is a therapeutic strategy worth exploring.
RESUMO
BACKGROUND: The ideal timing of postoperative imaging after pituitary adenoma surgery has yet to be determined. We reviewed our pituitary database to determine whether timing of routine postoperative imaging has significantly changed patients' clinical course or outcomes. METHODS: Retrospective chart review of patients undergoing resection of pituitary adenoma at our university center between 2012 and 2017 was performed. Timing and indication for postoperative imaging, findings of immediate and delayed postoperative imaging, as well as re-operations and radiosurgery details were recorded. Visual functions such as acuity and visual fields were used as clinical outcome indicators. Statistical analysis was run using Microsoft Excel. RESULTS: Five hundred and nineteen patients were identified; 443 had imaging data in our system and were included in the study. Early (< 90 days) MRIs were obtained in 71 patients and late (≥ 90 days) in 372 patients. We found statistical differences in our demographic groups including larger tumors in the early MRI group (early mean 12.33 cm3, late mean 4.64 cm3, p < 0.001) and higher Knosp grade (p = 0.0006). We found a significant difference in rates of return to the OR (16.9% in the early group and 4.84% in the late group; p < 0.001). There was a significant difference in the rate of residual identified on first postoperative MRI: 52.11% in the early group and 29.57% in the late group (p < 0.001). There was no difference in visual outcomes between the patient cohorts. CONCLUSION: After surgical treatment of pituitary adenoma, MRI obtained before 3 months is associated with higher rates of return to OR but no difference in long-term clinical outcomes. Due to cost efficiency, we argue for a delayed first postoperative MRI. The timing of MRI should also be governed by other factors such as large pituitary macroadenomas or postoperative complications. We recommend a consistent institutional protocol for determining the most cost-effective follow-up of postoperative pituitary patients.
