Gyung Mo Son

Multicenter Analysis of Risk Factors for Anastomotic Leakage After Laparoscopic Rectal Cancer Excision The Korean Laparoscopic Colorectal Surgery Study Group

Objective:To assess the risk factors for clinical anastomotic leakage (AL) in patients undergoing laparoscopic surgery for rectal cancer. Background:Little data are available about risk factors for AL after laparoscopic rectal cancer resection. Methods:This was a retrospective analysis of 1609 patients with rectal cancer who had undergone laparoscopic surgery for rectal cancer with sphincter preservation. Clinical data related to AL were collected from 11 institutions. Univariate and multivariate analyses were performed to determine the risk factors for AL. Results:AL was noted in 101 (6.3%) of the patients. The leakage rate ranged from 2.0% to 10.3% for each hospital (P = 0.04). In patients without protective stomas (n = 1187), male sex [hazard ratio (HR), 3.468], advanced tumor stage (HR, 2.520), lower tumor level (HR, 2.418), preoperative chemoradiation (HR, 6.284), perioperative transfusion (HR, 10.705), and multiple firings of the linear stapler (HR, 6.181) were significantly associated with AL. Our theoretical model suggested that the HR for patients with 2 risk factors was significantly higher than that the HR for patients with no or only 1 risk factor. Conclusions:Male sex, low anastomosis, preoperative chemoradiation, advanced tumor stage, perioperative bleeding, and multiple firings of the linear stapler increased the risk of AL after laparoscopic surgery for rectal cancer. A diverting stoma might be mandatory in patients with 2 or more of the risk factors identified in this analysis.

Self-Assembled Polymeric Micelles Based on Hyaluronic Acid-g-Poly(d,l-lactide-co-glycolide) Copolymer for Tumor Targeting

Graft copolymer composed hyaluronic acid (HA) and poly(d,l-lactide-co-glycolide) (PLGA) (HAgLG) was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA) to have amine end group in the end of chain (PLGA-amine). PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX)-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC)-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting.

The clinical significance of preoperative serum levels of carbohydrate antigen 19-9 in colorectal cancer

Purpose Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) are the most frequently used tumor markers in the clinical setting of colorectal cancer (CRC). This study was designed to investigate the correlation between preoperative serum levels of CA 19-9 (pre-CA 19-9) and the clinicopathologic factors of patients with CRC. Methods A study was performed on 333 patients with histologically diagnosed colorectal adenocarcinoma between December 2008 and November 2011, based on prospective collected data. The clinical data such as age, sex, location of tumor, size of tumor, differentiation, depth of tumor (T), lymph node metastasis (N), distant metastasis (M), lymphatic invasion, venous invasion, perineural invasion, stage, and preoperative serum levels of CEA (pre-CEA) and pre-CA 19-9 were obtained. These patients were classified into two groups according to pre-CA 19-9 (CA 19-9 high: >39 U/mL, n = 61 [18.3%]; CA 19-9 normal: <39 U/mL, n = 272 [81.7%]). Results Sixty-one patients among 333 patients (18.3%) with CRC showed a high pre-CA 19-9. The elevation of pre-CA 19-9 was significantly associated with size of tumor (4.8 ± 0.1 cm vs. 6.1 ± 0.3 cm, P < 0.001), right colon cancer (P < 0.001), depth of tumor (P < 0.001), lymph node metastasis (P < 0.001), distant metastasis (P < 0.001), perineural invasion (P = 0.008), peritoneal seeding (P < 0.001), and stage (P < 0.001). On multivariate analysis, high pre-CA 19-9 was shown to be independently associated with high pre-CEA, lymph node metastasis, right colon cancer, large tumor size, and peritoneal seeding. There were twelve patients confirmed for peritoneal seeding among 333 patients (3.6%). Conclusion High pre-CA 19-9 in advanced colorectal cancer might provide important information to predict the possibility of peritoneal seeding.

Acupuncture for recovery after surgery in patients undergoing colorectal cancer resection: a systematic review and meta-analysis

Objective To assess the efficacy/effectiveness and safety of acupuncture in patients recovering from colorectal cancer resection. Methods We systematically searched four English language databases (Medline, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and AMED (Allied and Complementary Medicine Database)) and one Chinese database (CAJ, China Academic Journals). Randomised trials of acupuncture compared with usual/routine care, sham interventions or active comparators in patients undergoing colorectal cancer resection were eligible for inclusion. Postoperative symptoms and quality of life (QoL) were the primary outcomes for the review. Results Of 1225 screened hits, seven randomised trials with 540 participants were included. High or uncertain risk of bias and significant heterogeneity were observed. All outcomes were measured before discharge, and no trial explicitly reported post-discharge outcomes. The response to acupuncture in terms of postoperative symptoms was inconsistent across trials. QoL was not measured in the included studies. For certain outcomes reflecting physiological recovery, favourable effects of acupuncture were observed compared with sham acupuncture, namely time to first flatus (n=207, three studies; mean difference (MD) −7.48 h, 95% CI −14.58 to −0.39 h, I2=0%) and time to first defaecation (n=149, two studies; MD −18.04 h, 95% CI −31.90 to −4.19 h, I2=0%). Two studies reported there were no acupuncture-related adverse events, whereas the remaining studies did not consider adverse events. Conclusions We found low-to moderate-quality evidence for the efficacy and safety of acupuncture for recovery after surgery in colorectal cancer patients. Future trials with adequate allocation concealment, blinding of outcome assessors, and measurement of post-discharge outcomes including QoL or functional recovery are warranted. Trial Registration Number CRD42014015537.

Factors influencing on difficulty with laparoscopic total extraperitoneal repair according to learning period

Purpose Laparoscopic total extraperitoneal (TEP) repair of inguinal hernia is technically challenging enough to build high barrier to entry. The purpose of this study was to identify clinical factors influencing technical difficulty with laparoscopic TEP according to learning period. Methods We conducted a retrospective study of 112 adult patients who underwent laparoscopic TEP for unilateral inguinal hernia from January 2009 to September 2013. A technically difficult case was defined as the 70th percentiles or more in the distribution curve of operative time, major complication, or open conversion. Results The rate of body mass index (BMI) above 25 kg/m2 was significantly higher in the difficult group than the nondifficult group in the learning period of laparoscopic TEP (57.9% vs. 26.8%, respectively, P = 0.020). However, in the experience period, it revealed no statistical difference with technical difficulty (31.3% vs. 33.3%, respectively, P = 0.882). In multivariate analysis, BMI (≥25 kg/m2) was identified as a significant independent factor for technical difficulty with laparoscopic TEP in the learning period (odds ratio, 4.572; P = 0.015). Conclusion Patients BMI (≥25 kg/m2) can create technical difficulty with laparoscopic TEP only in the learning period, but not in the experience period. Therefore BMI could be applied as one of the guidelines for patient selection, especially for surgeons in the learning curve of laparoscopic TEP.

Redox-Responsive nanophotosensitizer composed of chlorin e6-conjugated dextran for photodynamic treatment of colon cancer cells

We synthesized dextran-chlorin e6 conjugates having disulfide linkage for specific targeting of colonic region and cancer cells. Reductive end group of dextran was treated with sodium borocyanohydride and conjugated with cystamine. Cystamine end group was conjugated with carboxylic acid of chlorin e6 (DEX6ss). DEX6ss conjugates were formed as spherical nanoparticles with small sizes less than 100 nm. Chlorin e6 (Ce6) was specifically released from DEX6ss nanoparticles in the presence of dextranase or glutathione (GSH), indicating that DEX6ss nanoparticles have responsiveness against dextranase and redox-environment. In darktoxicity test using normal cells and cancer cells, Ce6 and DEX6ss nanoparticles were practically nontoxic. Intracellular delivery of DEX6ss nanoparticles was significantly improved compared to Ce6 itself. DEX6ss nanoparticles achieved significantly higher ROS production and phototoxicity against HCT116 colon cancer cells than Ce6 itself. Furthermore, DEX6ss nanoparticles showed enhanced tumor targeting efficiency and longer retention in the tumor tissues at in vivo animal study with HCT116 tumor-bearing mice. Furthermore, DEX6ss nanoparticles have responsiveness against colonic enzyme, dextranase, indicating that they have potential of colon-specific delivery and dextranase-specific drug delivery capacity. We fabricated colon-specific and tumor-targetable nanophotosensitizer using DEX6ss conjugates. They showed improved cellular uptake ratio, phototoxicity, and colon-specificity. We suggest that DEX6ss nanoparticles can be considered as a promising candidate for PDT of colon cancer.

Acupuncture and PC6 stimulation for the prevention of postoperative nausea and vomiting in patients undergoing elective laparoscopic resection of colorectal cancer: a study protocol for a three-arm randomised pilot trial.

Introduction This study aims to assess the feasibility of acupuncture and a Pericardium 6 (PC6) wristband as an add-on intervention of antiemetic medication for the prevention of postoperative nausea and vomiting (PONV) in patients undergoing elective laparoscopic colorectal cancer resection. Methods and analysis A total of 60 participants who are scheduled to undergo elective laparoscopic resection of colorectal cancer will be recruited. An enhanced recovery after surgery protocol using standardised antiemetic medication will be provided for all participants. Participants will be equally randomised into acupuncture plus PC6 wristband (Acupuncture), PC6 wristband alone (Wristband), or no acupuncture or wristband (Control) groups using computer-generated random numbers concealed in opaque, sealed, sequentially numbered envelopes. For the acupuncture combined with PC6 wristband group, the embedded auricular acupuncture technique for preoperative anxiolysis and up to three sessions of acupuncture treatments with manual and electrical stimulation within 48 hours after surgery will be provided by qualified Korean medicine doctors. The PC6 wristband will be applied in the Acupuncture and Wristband groups, beginning 1 hour before surgery and lasting 48 hours postoperatively. The primary outcome will be the number of participants who experience moderate or severe nausea, defined as nausea at least 4 out of 10 on a severity numeric rating scale or vomiting at 24 hours after surgery. Secondary outcomes, including symptom severity, participant global assessments and satisfaction, quality of life, physiological recovery, use of medication and length of hospital stay, will be assessed. Adverse events and postoperative complications will be measured for 1 month after surgery. Ethics and dissemination All participants will provide written informed consent. The study has been approved by the institutional review board (IRB). This pilot trial will inform a full-scale randomised trial of acupuncture combined with PC6 stimulation for the prevention of PONV in patients undergoing elective laparoscopic colorectal cancer surgery. Trial registration number NCT02509143.

Distribution and Impact of the Visceral Fat Area in Patients With Colorectal Cancer.

Purpose The purposes of this study were to investigate the distribution of the visceral fat area (VFA) and general obesity and to compare visceral and general obesity as predictors of surgical outcomes of a colorectal cancer resection. Methods The prospectively collected data of 102 patients with preoperatively-diagnosed sigmoid colon or rectal cancer who had undergone a curative resection at Pusan National University Yangsan Hospital between April 2011 and September 2012 were reviewed retrospectively. Men with a VFA of >130 cm2 and women with a VFA of >90 cm2 were classified as obese (VFA-O, n = 22), and the remaining patients were classified as nonobese (VFA-NO, n = 80). Results No differences in morbidity, mortality, postoperative bowel recovery, and readmission rate after surgery were observed between the 2 groups. However, a significantly higher number of harvested lymph nodes was observed in the VFA-NO group compared with the VFA-O group (19.0 ± 1.0 vs. 13.5 ± 1.2, respectively, P = 0.001). Conclusion Visceral obesity has no influence on intraoperative difficulties, postoperative complications, and postoperative recovery in patients with sigmoid colon or rectal cancer.

Enhanced Photosensing and Photodynamic Treatment of Colon Cancer Cells Using Methoxy Poly(ethylene glycol)-Conjugated Chlorin e6

Nanophotosensitizer composed of methoxy poly(ethylene glycol) (MePEG) and chlorin e6 (Ce6) (abbreviated as Pe6) was synthesized for efficient delivery of Ce6 to the colon cancer cells. Pe6 nanophotosensitizer has small diameter less than 100 nm with spherical shape and core-shell structure. They were activated in aqueous solution while Ce6 was quenched due to its poor aqueous solubility. They showed no intrinsic cytotoxicity against normal cells and colon cancer cells. Pe6 nanophotosensitizers showed enhanced cellular uptake, phototoxicity, and reactive oxygen species (ROS) generation at in vitro cell culture experiment. Furthermore, they showed improved tumor tissue penetration and accumulation in vivo animal studies. We suggested Pe6 nanophotosensitizers as an ideal candidate for PDT of colon cancer.

Comparison of putative circulating cancer stem cell detection between the hepatic portal system and peripheral blood in colorectal cancer patients

Purpose The present pilot study was conducted to detect putative cancer stem cell (CSC) from the hepatic portal system and peripheral blood in the colorectal cancer patients and to compare them to healthy donor and diverticulitis patients. Methods Laboratory study was performed to identify the expression of cell surface markers, epithelial cell adhesion molecule (EpCAM), cytokeratin (CK) 18, CK20, CD44, and CD133, on several colon cancer cell lines. Clinical pilot study was conducted to detect putative circulating CSC as EpCAM+CD133+ cell in colorectal cancer (n = 10), diverticulitis (n = 5), and four healthy donors, by using flow cytometry. Blood was drawn from the hepatic portal system and peripheral vein. Results On laboratory study, EpCAM was expressed in whole colon cancer cell lines, and CD44 and CD133 were simultaneously expressed in 50% of the cell lines with stemness phenotype, but CK18 and CK20 were not expressed in most of the cell lines. On clinical study, the mean EpCAM+CD133+ cell counts of 11.6/105 in the hepatic portal system were somewhat lower than 15.4/105 in peripheral vein (P = 0.241). As for diverticulitis patients, EpCAM+CD133+ cells were also detected to have steeper dropped to near zero, after the surgery. Conclusion The numbers of putative CSC were not statistically different between the detection sites of the portal vein and peripheral vein in the colon cancer patients. Therefore, we may not have benefitted by getting the cells from the hepatic portal system. In addition, the CD133+EpCAM+ cells in the colon cancer patients might contain normal stem cells from cancer inflammation similar to diverticulitis.