DARPP-32 Promotes TRAIL Resistance Through Regulation of BCL-XL in Gastric Cancer Cells

Abstract

Background: Recently a new anus-preserving operation of intersphincteric resection (ISR) has been introduced for very low rectal cancer. Here, we have clinically analyzed the oncologic and functional outcomes of ISR to prove the validity of the new operative procedure. Patients and Methods: Since 1982, a total of 206 patients received abdominoperineal resection (APR). We have histologically evaluated the tumor spread in very low rectal cancer treated with APR to clarify the potential indication of ISR with or without external sphincter muscle resection (ESR). Then, ISR has been performed in 83 patients based on the histologic theory since 2000. Histologic results: When the lowest edge of a tumor was located above the dentate line (defined as Pa cancer), the invasion and/or metastasis was rarely beyond the internal sphincter muscle. When the lowest edge was located at or below the dentate line (defined as Pb cancer), invasion and/or metastasis tended to extend into the levator muscle (29%), intersphincteric space (43%), external sphincter muscles (20%) and into the intermuscular groove (21%). Clinical results: Preoperative chemoradiation therapy was not performed. ISR was performed in 44 (68%) of 65 patients with Pa cancer and ESR, in 32%. In 18 patients with Pb cancer, ESR was performed in 61% and ISR, 39% (p=0.0514). Morbidity developed in 24% including anastomotic leakage (4.8%), colonic necrosis (2.4%), ileus (2.4%), and others. Curative operation was accomplished in 80 patients. There were 21 patients with Stage 0-1, 29 patients with Stage 2, and 24 patients with Stage 3. Radial margin (RM) < 1 mm was found in 9 (11%). Total recurrence rate was 20%. Distant metastasis developed in 10%. Local recurrence including pelvic node metastasis developed in 12.5% with no significant difference between ISR and ESR patients. Multivariate Cox regression analysis showed that RM < 1 mm was the most powerful independent risk factor of local recurrence (HR:10.057, 95%CI:2.274-44.476, p=0.0023). Both recurrence-free and cancer-specific 5-year survivals showed no significant difference between ISR and ESR patients (72% vs 82%, p=0.3412, 86% vs 96%, p=0.2051). Anal function showed good continence (Wexner score < 6, Kirwan grade 1-2,) in 60-70% of ISR patients and in 4050% of ESR patients. Multivariate logistic regression analysis showed that the resected volume of external sphincter muscles was the most powerful independent adverse factor affecting anal function. Conclusion: Both ISR and ESRwere acceptable techniques of anus-preservation for very low rectal cancer. However, appropriate preoperative treatments including neoadjuvant chemotherapy are necessary before operation to keep RM safe and to control local recurrence. Some ideal procedures are required to improve anal function.