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Background: The aim of this study is to assess the impact of frailty on short-term outcomes after hepatectomy for colorectal liver metastasis (CRLM)., Methods: Patients were identified using the National Surgical Quality Improvement Program (NSQIP). Patients were divided into 3 categories using the 5-item Modified Frailty Index (mFI)., Results: There were 5230 patients included. 52%, 35%, and 13% had mFI scores of 0, 1, and ≥ 2 respectively. Patients with a ≥ 2 mFI score were more likely to experience minor complication (OR 1.34, 95% CI 1.06-1.69), major complication (OR 1.56, 95% CI 1.15-2.12), readmission (OR 1.55, 95% CI 1.12-2.14), unfavorable discharge (OR 2.48, 95% CI 1.62-3.80), 30-day mortality (OR 3.02, 95% CI 1.02-8.95), prolonged length of stay (OR 1.47, 95% CI 1.18-1.83), and bile leak (OR 1.51, 95% CI 1.02-2.24)., Conclusion: Frailty is associated with increased post-operative complications. The 5-item mFI can guide risk stratification, optimization, and counseling., (© 2021. The Society for Surgery of the Alimentary Tract.)

Recent reports have indicated that KRAS and TP53 mutations predict response to therapy in colorectal cancer. However, little is known about the relationship between these two common genetic alterations. Micro-RNAs (miRNAs), a class of noncoding RNA implicated in cellular processes, have been increasingly linked to KRAS and TP53. We hypothesized that lethal-7a (let-7a) miRNA regulates KRAS through TP53. To investigate the relationship between KRAS, TP53, and let-7a, we used HCT116 KRAS(mut) human colorectal cancer cells with four different genotypic modifications in TP53 (TP53(-/-), TP53(+/-), TP53(mut/+), and TP53(mut/-) ). Using these cells we observed that K-Ras activity was higher in cells with mutant or knocked out TP53 alleles, suggesting that wild-type TP53 may suppress K-Ras activity. Let-7a was present in HCT116 KRAS(mut) cells, though there was no correlation between let-7a level and TP53 genotype status. To explore how let-7a may regulate K-Ras in the different TP53 genotype cells we used let-7a inhibitor and demonstrated increased K-Ras activity across all TP53, thus corroborating prior reports that let-7a regulates K-Ras. To assess potential clinical implications of this regulatory network, we examined the influence of TP53 genotype and let-7a inhibition on colon cancer cell survival following chemoradiation therapy (CRT). We observed that cells with complete loss of wild-type TP53 alleles ((-/-) or (-/mut)) were resistant to CRT following treatment with 5-fluorouracil and radiation. Further increase in K-Ras activity with let-7a inhibition did not impact survival in these cells. In contrast, cells with single or double wild-type TP53 alleles were moderately responsive to CRT and exhibited resistance when let-7a was inhibited. In summary, our results show a complex regulatory system involving TP53, KRAS, and let-7a. Our results may provide clues to understand and target these interactions in colorectal cancer.

The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%-25% of all cancers. In particular, approximately 30%-40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.