Interleukin-1 Receptor Type 2 Acts with c-Fos to Enhance the Expression of Interleukin-6 and Vascular Endothelial Growth Factor A in Colon Cancer Cells and Induce Angiogenesis.

Interleukin-1 receptor type 2 (IL1R2) acts as a decoy receptor of exogenous IL-1; however, its intracellular activity is poorly understood. We previously demonstrated that IL1R2 intracellularly activates the expression of several proinflammatory cytokines and affects cell migration. In this study, we found that intracellular IL1R2 expression was increased in human colorectal cancer cells (CRCs) compared with normal colon cells. We also observed that the mRNA levels of IL1R2 were highly correlated with IL-6 in tumor tissues of CRC patients. By modulating its expression in CRC cells, we verified that enhanced IL1R2 expression transcriptionally activated the expression of IL-6 and VEGF-A. Conditioned medium harvested from IL1R2-overexpressing CRC cells contained higher levels of IL-6 and VEGF-A than that from vector control cells and significantly enhanced the proliferation, migration, and tube formation of cultured endothelial cells. We further demonstrated a positive association of intracellular IL1R2 levels with tumor growth and microvessel density in xenograft mouse models. These results revealed that IL1R2 activates the expression of angiogenic factors. Mechanistically, we revealed that IL1R2 complexes with c-Fos and binds to the AP-1 site at the IL-6 and VEGF-A promoters. Together, these results reveal a novel function of intracellular IL1R2 that acts with c-Fos to enhance the transcription of IL-6 and VEGF-A, which promotes angiogenesis in CRC.

Transanal Total Mesorectal Excision Versus Laparoscopic Surgery for Rectal Cancer Receiving Neoadjuvant Chemoradiation: A Matched Case-Control Study.

BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) has been indicated for locally advanced rectal cancer. While utilization of laparoscopy in rectal cancer surgery has been popular in recent years, tumors receiving nCRT is still a surgical challenge. Transanal total mesorectal excision (TaTME) has emerged as a focused area of laparoscopic surgery that is becoming an increasingly acceptable approach in the field of rectal surgery. METHODS: Between December 2013 and April 2015, a total of 50 patients (38 males) with post-nCRT middle or lower rectal cancer who then underwent TaTME at two separate institutions were prospectively documented. Overall, 100 matched control cohorts who received conventional laparoscopic rectal surgery (LapTME) were simultaneously retrieved from a prospectively registered database. Four parameters of sex, age, clinical stage, and American Society of Anesthesiologists (ASA) score were matched for surgical outcomes, and short-term oncological results, including complications and pathological outcomes, were analyzed. RESULTS: Both the TaTME and LapTME groups received 5-fluorouracil-based chemotherapy and 5 weeks of long-course radiation therapy. Mean operative time for the TaTME group was 182.1 ± 55.4 min (156.6 ± 37.8 min in two-team-approach cases) and 178.7 ± 34.8 min for the LapTME group. The TaTME group yielded longer distal margin lengths. No significant differences were observed in blood loss, intraoperative complication rate, conversion rate, anastomosis type, and free circumferential margin rate. CONCLUSION: This matched case-control study demonstrated that TaTME is safe and feasible. Compared with LapTME, TaTME not only achieves identical circumferential margin status without compromising other operative and quality parameters but also benefits patients by achieving a longer distal margin. Thus, TaTME has the potential to become an option in managing irradiated rectal cancer.

The evolving practice of hybrid natural orifice transluminal endoscopic surgery (NOTES) for rectal cancer.

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) has emerged as the area of focus in laparoscopic surgery. Hybrid NOTES (hNOTES) has some potential advantages for treating rectal cancer. METHODS: Between May 2013 and November 2013, a total of 20 patients (11 males) who received hNOTES at two institutes participating in the study were documented and reviewed. Surgical outcomes, including complications and pathological outcomes, were analyzed. RESULTS: The mean age of patients was 57.8 ± 10.1 years (range 34-78). Eleven patients received preoperative neoadjuvant chemoradiotherapy, with the mean distance between tumor and anal verge being 5.9 ± 1.7 cm (mean 2-8). The mean estimated intraoperative blood loss was 68 ± 106 ml (range 30-500), with one case converted to open procedure due to uncontrolled bleeding. Eight cases underwent simultaneous two-team approach. The mean operative time was 200.8 ± 47.7 min (range 110-285). Circular stapling was performed for 14 cases (70 %) as the anastomosis, and protective stoma performed for 17 cases (85 %). The overall postoperative complication rate was 25 %. Two cases (10 %) develop pelvic abscess due to leakage, which were controlled by medical treatments. The distal and circumferential margins were all free of tumor cells, and the mean distal margin length was 2.4 ± 0.98 cm (range 0.5-4). CONCLUSIONS: Hybrid NOTES for rectal cancer is safe and feasible. Rapid experience-building accelerates its evolution, as reflected here by the high stapling rate and the idea of a two-team approach. It has the potential to become an option of treating rectal cancers.

Robotic or transanal total mesorectal excision (TaTME) approach for rectal cancer, how about both? Feasibility and outcomes from a single institution.

Laparoscopic surgery for rectal cancer is technically challenging. Robotic and transanal TME (TaTME) are both novel approaches developed to provide better visualization and dissection. We aim to combine both approaches in a hybrid procedure and evaluate the feasibility as well as patient and oncological outcomes in this study. A review of a prospectively maintained database of patients who underwent a hybrid abdominal robotic approach with TaTME for rectal cancer between January 2016 and October 2018 was undertaken. Patient demographics, tumor characteristics and surgical outcomes were recorded and analyzed. A total of 69 patients (43 males, 26 females) received this hybrid approach. Their median age was 58 years (range 35-87) with a mean BMI of 24.3 kg/m2 (range 16.4-44.2). Median distance from anal verge was 5 cm (range 2-9). The patients had a median hospital length of stay of 7 days (range 5-28). Complication rate was 17.4% (12 patients) with 3 patients (4.3%) requiring a reoperation. TME quality was optimal with all of them either complete (81.2%) or almost complete (18.8%). 65 patients (94.2%) had an R0 resection with 4 patients (5.8%) with involved circumferential resection margins (≤ 1 mm). The median number of lymph nodes harvested was 20 (range 6-37). After a median follow-up of 27.7 months (range 7-42), local recurrence was identified in 2 patients (4%). Three patients (5.2%) had distant recurrence at the 3-year mark. Hybrid robotic abdominal dissection with transanal TME for rectal cancer appears to be feasible with comparable surgical outcomes to other traditional approaches.

Robotic transanal total mesorectal excision assisted by laparoscopic transabdominal approach: A preliminary twenty-case series report.

BACKGROUND: Laparoscopy-assisted robotic transanal total mesorectal excision is a novel surgical technique for rectal cancer resection. Compared to prior DaVinci Si system case series, this case series is the first to report robotic taTME assisted by laparoscopy (r-taTME) in which the "transanal team" operates via the DaVinci Xi system. As a result, we aim to delineate and discuss preliminary findings from our robotic taTME experiences. METHODS: A total of twenty patients (twelve males) who underwent robotic taTME assisted by laparoscopy (r-taTME) between January 2016 and November 2016 at a single institution were documented. Surgical outcomes, including complications, pathological outcomes, and short-term results, were then retrospectively analyzed. RESULTS: All patients underwent r-taTME via a two-team approach. The "abdominal team" operated via a single port method (ileostomy site), while the "transanal team" operated via the DaVinci Xi system. The mean patient age was 56.7 ± 14.3 years (range 31-79), and the mean distance from tumor to anal verge was 6.0 ± 2.7 cm (range 2-10). The mean estimated intraoperative blood loss was 88 ± 107 ml (range 30-500), and circular stapling was utilized to restore continuity in 80% of study patients. The overall postoperative complication rate was 35%, and the mean distal margin length was 3.1 ± 1.3 cm. There were three patients who had a circumferential margin (CRM) involved by cancer cells (≤1 mm). CONCLUSION: Our preliminary series report demonstrates that utilization of r-taTME assisted by laparoscopy is safe and feasible. Development of a novel transanal approach that allows single-port access alongside a multi-arm robotic system may increase the convenience and efficiency of future operation.

Transanal total mesorectal excision for rectal cancer: hype or new hope?

Rectal cancer has always posed surgical challenges to the colorectal surgeon. The quality of the total mesorectal excision (TME) performed is key in determining local disease control. Unlike the great success in adoption of laparoscopic surgery in colon cancer treatment, studies comparing laparoscopy to open rectal surgery all revealed noninferiority was not achieved. Transanal TME (taTME) is the latest advanced technique pioneered to tackle difficult pelvic dissections. The evolution of taTME surgery in recent years was explored in this review. The outcomes to date on the latest literatures are reviewed, included complications, functional outcomes, oncological results and future clinical researches. taTME, while definitely still in its early stages of development, has steadily accumulated safety and feasibility data. It not only provides a better solution to an old problem that colorectal surgeons have been attempting to tackle for quite some time, but also appears to be quite promising in terms of outcomes on numerous fronts. With structured training models, and proctored clinical application, alongside design and implementation of international-scale large multicenter randomized clinical trials, one can only hope that taTME and its innovations will not only open a new era for colorectal surgery, but also for even more surgical disease pathologies.

Prognostic Values of EPDR1 Hypermethylation and Its Inhibitory Function on Tumor Invasion in Colorectal Cancer.

Aberrant DNA methylation is a potential mechanism underlying the development of colorectal cancer (CRC). Thus, identification of prognostic DNA methylation markers and understanding the related molecular functions may offer a new perspective on CRC pathogenesis. To that end, we explored DNA methylation profile changes in CRC subtypes based on the microsatellite instability (MSI) status through genome-wide DNA methylation profiling analysis. Of 34 altered genes, three hypermethylated (epidermal growth factor, EGF; carbohydrate sulfotransferase 10, CHST10; ependymin related 1, EPDR1) and two hypomethylated (bone marrow stromal antigen 2, BST2; Rac family small GTPase 3, RAC3) candidates were further validated in CRC patients. Based on quantitative methylation-specific polymerase chain reaction (Q-MSP), EGF, CHST10 and EPDR1 showed higher hypermethylated levels in CRC tissues than those in adjacent normal tissues, whereas BST2 showed hypomethylation in CRC tissues relative to adjacent normal tissues. Additionally, among 75 CRC patients, hypermethylation of CHST10 and EPDR1 was significantly correlated with the MSI status and a better prognosis. Moreover, EPDR1 hypermethylation was significantly correlated with node negativity and a lower tumor stage as well as with mutations in B-Raf proto-oncogene serine/threonine kinase (BRAF) and human transforming growth factor beta receptor 2 (TGFßR2). Conversely, a negative correlation between the mRNA expression and methylation levels of EPDR1 in CRC tissues and cell lines was observed, revealing that DNA methylation has a crucial function in modulating EPDR1 expression in CRC cells. EPDR1 knockdown by a transient small interfering RNA significantly suppressed invasion by CRC cells, suggesting that decreased EPDR1 levels may attenuate CRC cell invasion. These results suggest that DNA methylation-mediated EPDR1 epigenetic silencing may play an important role in preventing CRC progression.