Validation of an endoscopic anastomotic grading score as an intraoperative method for assessing stapled rectal anastomoses.

PURPOSE: Anastomotic leak is a dreaded complication of colorectal surgery. An endoscopic grading score of the perianastomotic mucosa has been previously developed at our institution (UCI) to assess colorectal anastomotic integrity. The objective of this study is to validate the UCI anastomotic score and determine its impact in anastomotic failure. METHODS: As a follow-up study of the UCI grading score implementation during 2011 to 2014, patients undergoing stapled colorectal anastomoses after sigmoidectomy or proctectomy at a single institution from 2015 to 2018 were retrospectively reviewed. Patients were grouped into three tiers based on endoscopic appearance (grade 1, circumferentially normal mucosa; grade 2, ischemia/congestion < 30% of circumference; grade 3, ischemia/congestion > 30% of circumference). RESULTS: On the basis of endoscopic mucosal evaluation, grade 1 anastomosis was observed in 299 patients (94%), grade 2 anastomosis in 14 patients (4.4%), and grade 3 anastomosis in 5 patients (1.6%). All grade 3 classifications were immediately and successfully revised intraoperatively with reclassification as a grade 1 anastomosis. The anastomotic leak rate of the follow-up study period from 2015 to 2018 was 6.4% which was lower compared to the anastomotic leak rate of 12.2% in the original study period from 2011 to 2014 (p = 0.07). Anastomotic leak rate for the entire patient series was 8.5%. A grade 2 anastomosis was associated with higher anastomotic leak rate compared to a grade 1 anastomosis (35.7% vs. 7.4%, p < 0.05). None of the five grade 3 anastomoses resulted in an anastomotic leak upon revision. CONCLUSION: This study further validates the anastomotic grading score and suggests that its systematic implementation can result in a reduction in anastomotic leaks.

Analysis of delay in adjuvant chemotherapy in locally advanced rectal cancer.

BACKGROUND: Adjuvant chemotherapy (AC) after neoadjuvant chemoradiation and surgical resection has been the standard of care for locally advanced rectal cancer. However, there are no evidence-based guidelines regarding the optimal timing of AC for rectal cancer. The objective of this study was to evaluate the effect of AC timing on overall survival for rectal cancer. METHODS: The National Cancer Database (NCDB) from 2004 to 2016 was queried for primary clinical stage II or III rectal cancer patients who had undergone neoadjuvant chemoradiation followed by surgery and AC. Patients were grouped based on AC initiation: early ≤ 4 weeks, intermediate 4-8 weeks, and delayed ≥ 8 weeks. The primary outcome was overall survival. RESULTS: We identified 8722 patients, of which 905 (10.4%) received early AC, 4621 (53.0%) intermediate AC, and 3196 (36.6%) delayed AC. Pathological lymph-node metastasis (ypN +) was positive in 73% of early AC, 74% intermediate AC, and 63% delayed AC (p < 0.05). The 5-year survival probability was 71.1% (95% CI 68-74%) for early AC, 73.2% (95% CI 72-75%) intermediate AC, and 65.8% (95% CI 64-68%) delayed AC (p < 0.001). Using Cox proportional hazard modeling, patients undergoing delayed AC had an associated decreased survival compared to patients receiving early AC (HR 1.18; 95% CI 1.028-1.353, p = 0.018) or intermediate AC (HR 1.28; 95% CI 1.179-1.395, p < 0.01). CONCLUSIONS: Delay in AC administration may be associated with decreased 5-year survival. Compared to early or intermediate AC, patients in the delayed AC group were observed to have increased risk of death, despite having lower proportions with ypN + disease. Patients with higher socioeconomic and education status were more likely to receive early chemotherapy.

The Nogo-B receptor promotes Ras plasma membrane localization and activation.

The localization of prenylated Ras at the plasma membrane promotes activation of Ras by receptor tyrosine kinases and stimulates oncogenic signaling by mutant Ras. The Nogo-B receptor (NgBR) is a transmembrane receptor that contains a conserved hydrophobic pocket. Here, we demonstrate that the NgBR promotes the membrane accumulation of Ras by directly binding prenylated Ras at the plasma membrane. We show that NgBR knockdown diminishes the membrane localization of Ras in multiple cell types. NgBR overexpression in NIH-3T3 fibroblasts increases membrane-associated Ras, induces the transformed phenotype in vitro, and promotes the formation of fibrosarcoma in nude mice. NgBR knockdown in human breast cancer cells reduces Ras membrane localization, inhibits epidermal growth factor (EGF)-stimulated Ras signaling and diminishes tumorigenesis of xenografts in nude mice. Our data demonstrate that NgBR is a unique receptor that promotes accumulation of prenylated Ras at the plasma membrane and promotes EGF pathways.