Kil Yeon Lee

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.

NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis

BACKGROUND & AIMS HuR is a RNA-binding factor whose expression is commonly upregulated in some human tumor types. We explored the molecular mechanism underlying HuR elevation and its role in gastric cancer tumorigenesis. METHODS HuR expression and subcellular localization were determined by polymerase chain reaction, immunoblot, and immunohistochemical analyses. Its effect on tumor growth was characterized using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and soft agar analyses. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure transcriptional activation by nuclear factor kappaB (NF-kappaB) signaling. RESULTS Compared with normal gastric tissues, HuR was expressed at higher levels in gastric tumors, particularly in advanced versus early tumors; this increase was associated with enhanced cytoplasmic translocation of HuR. HuR overexpression increased proliferation of tumor cells, activating the G(1) to S transition of the cell cycle, DNA synthesis, and anchorage-independent growth. Small interfering RNA-mediated knockdown of HuR expression reduced tumor cell proliferation and response to apoptotic stimuli. No genetic or epigenetic alterations of HuR were observed in gastric tumor cell lines or primary tumors; overexpression depended on phosphatidylinositol 3-kinase/AKT signaling and NF-kappaB activity. AKT activation increased p65/RelA binding to a putative NF-kappaB binding site in the HuR promoter, the stability of HuR target transcripts, and the cytoplasmic import of HuR. CONCLUSIONS HuR is a direct transcription target of NF-kappaB; its activation in gastric cancer cell lines depends on phosphatidylinositol 3-kinase/AKT signaling. HuR activation by this pathway has proliferative and antiapoptotic effects on gastric cancer cells.

Robotic versus conventional laparoscopic surgery for rectal cancer: systematic review and meta-analysis

Purpose Robotic surgery (RS) overcomes the limitations of previous conventional laparoscopic surgery (CLS). Although meta-analyses have been published recently, our study evaluated the latest comparative surgical, urologic, and sexual results for rectal cancer and compares RS with CLS in patients with rectal cancer only. Methods We searched three foreign databases (Ovid-MEDLINE, Ovid-Embase, and Cochrane Library) and five Korean databases (KoreaMed, KMbase, KISS, RISS, and KisTi) during July 2013. The Cochrane Risk of Bias and the Methodological Index for Non-Randomized were utilized to evaluate quality of study. Dichotomous variables were pooled using the risk ratio (RR), and continuous variables were pooled using the mean difference (MD). All meta-analyses were conducted with Review Manager, V. 5.3. Results Seventeen studies involving 2,224 patients were included. RS was associated with a lower rate of intraoperative conversion than that of CLS (RR, 0.28; 95% confidence interval [CI], 0.15-0.54). Time to first flatus was short (MD, -0.13; 95% CI, -0.25 to -0.01). Operating time was longer for RS than that for CLS (MD, 49.97; 95% CI, 20.43-79.52, I2 = 97%). International Prostate Symptom Score scores at 3 months better RS than CLS (MD, -2.90; 95% CI, -5.31 to -0.48, I2 = 0%). International Index of Erectile Function scores showed better improvement at 3 months (MD, -2.82; 95% CI, -4.78 to -0.87, I2 = 37%) and 6 months (MD, -2.15; 95% CI, -4.08 to -0.22, I2 = 0%). Conclusion RS appears to be an effective alternative to CLS with a lower conversion rate to open surgery, a shorter time to first flatus and better recovery in voiding and sexual function. RS could enhance postoperative recovery in patients with rectal cancer.

Anal resting pressures at manometry correlate with the fecal incontinence severity index and with presence of sphincter defects on ultrasound

IntroductionWe describe the relationship between anorectal manometry, fecal incontinence severity, and findings at endoanal ultrasound.MethodsA total of 351 women completed the Fecal Incontinence Severity Index, underwent anorectal manometry, and endoanal ultrasound. Severity index and manometry pressures in 203 women with intact sphincters on ultrasound were compared with pressures in 148 women with sphincter defects. Relationships between resting and squeeze pressures, severity index, and size of sphincter defects were evaluated.ResultsMean severity index in patients with and without sphincter defect was 35.7 vs. 36.7 (not significant). Worsening index correlated with worsening mean and maximum resting pressure (P < 0.0001). Differences were observed in mean and maximum resting pressure between the patients with and without sphincter defects (26.6 vs. 37.2, P < 0.0001; 39.4 vs. 51.7, P < 0.001). Resting pressures correlated with the sizes of defect (P < 0.0001).ConclusionsPatients with and without sphincter defects had similar severity scores, but patients with defects had a significant decrease in resting pressures. Patients with larger sphincter defects had lower severity scores and resting pressures. Until a manometry cutoff can be set to discriminate between absence and presence of defects, both manometry and ultrasound should be offered to patients with history of anal trauma.

Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis

Purpose: PRKCDBP is a putative tumor suppressor in which alteration has been observed in several human cancers. We investigated expression and function of PRKCDBP in colorectal cells and tissues to explore its candidacy as a suppressor in colorectal tumorigenesis. Experimental Design: Expression and methylation status of PRKCDBP and its effect on tumor growth were evaluated. Transcriptional regulation by NF-κB signaling was defined by luciferase reporter and chromatin immunoprecipitation assays. Results: PRKCDBP expression was hardly detectable in 29 of 80 (36%) primary tumors and 11 of 19 (58%) cell lines, and its alteration correlated with tumor stage and grade. Promoter hypermethylation was commonly found in cancers. PRKCDBP expression induced the G1 cell-cycle arrest and increased cellular sensitivity to various apoptotic stresses. PRKCDBP was induced by TNFα, and its level correlated with tumor cell sensitivity to TNFα-induced apoptosis. PRKCDBP induction by TNFα was disrupted by blocking NF-κB signaling while it was enhanced by RelA transfection. The PRKCDBP promoter activity was increased in response to TNFα, and this response was abolished by disruption of a κB site in the promoter. PRKCDBP delayed the formation and growth of xenograft tumors and improved tumor response to TNFα-induced apoptosis. Conclusions: PRKCDBP is a proapoptotic tumor suppressor which is commonly altered in colorectal cancer by promoter hypermethylation, and its gene transcription is directly activated by NF-κB in response to TNFα. This suggests that PRKCDBP inactivation may contribute to tumor progression by reducing cellular sensitivity to TNFα and other stresses, particularly under chronic inflammatory microenvironment. Clin Cancer Res; 17(24); 7551–62. ©2011 AACR.

Frequent epigenetic inactivation of hSRBC in gastric cancer and its implication in attenuated p53 response to stresses.

hSRBC is a putative tumor suppressor located at 11p15.4, at which frequent genomic loss has been observed in several human malignancies. To explore the candidacy of hSRBC as a suppressor of gastric tumorigenesis, we analyzed the expression and mutation status of hSRBC in gastric tissues and cell lines. hSRBC transcript was expressed in all normal and benign tumor tissues examined, but undetectable or very low in 73% (11/15) cancer cell lines and 41% (46/111) primary tumors. Loss or reduction of hSRBC expression was tumor‐specific and correlated with stage and grade of tumors. While allelic loss or somatic mutations of the gene were infrequent, its expression was restored in tumor cells by 5‐aza‐2′‐deoxycytidine treatment and aberrant hypermethylation of 23 CpG sites in the promoter region showed a tight association with altered expression. Transient or stable expression of hSRBC led to a G1 cell cycle arrest and apoptosis of tumor cells, and strongly suppresses colony forming ability and xenograft tumor growth. In addition, hSRBC elevated apoptotic sensitivity of tumor cells to genotoxic agents, such as 5‐FU, etoposide and ultraviolet. Interestingly, hSRBC increased the protein stability of p53 and expression of p53 target genes, such as p21Waf1, PUMA and NOXA, while hSRBC‐mediated cell cycle arrest and apoptosis were abolished by blockade of p53 function. Our findings suggest that hSRBC is a novel tumor suppressor whose epigenetic inactivation contributes to the malignant progression of gastric tumors, in part, through attenuated p53 response to stresses.

Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors

BackgroundNORE1 (RASSF5) is a newly described member of the RASSF family with Ras effector function. NORE1 expression is frequently inactivated by aberrant promoter hypermethylation in many human cancers, suggesting that NORE1 might be a putative tumor suppressor. However, expression and mutation status of NORE1 and its implication in colorectal tumorigenesis has not been evaluated.MethodsExpression, mutation, and methylation status of NORE1A and NORE1B in 10 cancer cell lines and 80 primary tumors were characterized by quantitative PCR, SSCP, and bisulfite DNA sequencing analyses. Effect of NORE1A and NORE1B expression on tumor cell growth was evaluated using cell number counting, flow cytometry, and colony formation assays.ResultsExpression of NORE1A and NORE1B transcript was easily detectable in all normal colonic epithelial tissues, but substantially decreased in 7 (70%) and 4 (40%) of 10 cancer cell lines and 31 (38.8%) and 25 (31.3%) of 80 primary carcinoma tissues, respectively. Moreover, 46 (57.6%) and 38 (47.5%) of 80 matched tissue sets exhibited tumor-specific reduction of NORE1A and NORE1B, respectively. Abnormal reduction of NORE1 was more commonly observed in advanced stage and high grade tumors compared to early and low grade tumors. While somatic mutations of the gene were not identified, its expression was re-activated in all low expressor cells after treatment with the demethylating agent 5-aza-dC. Bisulfite DNA sequencing analysis of 31 CpG sites within the promoter region demonstrated that abnormal reduction of NORE1A is tightly associated with promoter CpG sites hypermethylation. Moreover, transient expression and siRNA-mediated knockdown assays revealed that both NORE1A and NORE1B decrease cellular growth and colony forming ability of tumor cells and enhance tumor cell response to apoptotic stress.ConclusionOur data indicate that epigenetic inactivation of NORE1 due to aberrant promoter hypermethylation is a frequent event in colorectal tumorigenesis and might be implicated in the malignant progression of colorectal tumors.

Allogeneic adipose-derived stem cells for the treatment of perianal fistula in Crohn's disease: a pilot clinical trial

Many perianal fistulae in Crohns disease do not respond to conventional surgical and medical management and recurrence rates are high. The study evaluated the safety and feasibility of allogeneic adipose‐derived stem cells for the treatment of perianal fistula in Crohns disease.

Filiform polyposis associated with sigmoid diverticulitis in a patient without inflammatory bowel disease.

Filiform polyposis (FP) of the colon is an uncommon entity that is occasionally encountered in patients with inflammatory bowel disease (IBD). FP is morphologically characterized by multiple slender worm-like projections consisting of submucosal cores lined with normal mucosa. To date, only two cases of FP have been reported in patients with inflammatory conditions of the gastrointestinal tract other than ulcerative colitis or Crohns disease. We report an additional case of FP occurring in an 83-year-old man with no history of IBD. The patient underwent anterior resection of the sigmoid colon for perforated diverticulitis. Around the diverticular orifice, localized FP involving a 13-cm colonic segment was observed. The filiform polyps consisted of submucosal fibrovascular cores lined with normal mucosa without epithelial dysplasia. To our knowledge, this is the first reported case of FP associated with colonic diverticulitis in a patient without IBD.

Mechanical Bowel Preparation and Prophylactic Antibiotic Administration in Colorectal Surgery: A Survey of the Current Status in Korea

Purpose The usefulness of mechanical bowel preparation (MBP) in colon surgery was recently challenged by many multicenter clinical trials and meta-analyses. The objectives of this study were to investigate current national opinions about MBP and prophylactic antibiotics (PA) and to provide preliminary data for developing future Korean guidelines for MBP and PA administration in colorectal surgery. Methods A questionnaire was mailed to 129 colorectal specialists. The questionnaires addressed the characteristics of the hospital, the MBP methods, and the uses of oral and intravenous antibiotics. Results A total of 73 questionnaires (56.6%) were returned. First, in regard to MBP methods, most surgeons (97.3%) used MBP for a mean of 1.36 days. Most surgeons (98.6%) implemented whole bowel irrigation and used polyethylene glycol (83.3%). Oral antibiotic use was indicated in over half (52.1%) of the responses, the average number of preoperative doses was three, and the mean time of administration was 24.2 hours prior to the operation. Finally, the majority of responders stated that they used intravenous antibiotics (95.9%). The responses demonstrated that second-generation cephalosporin-based regimens were most commonly prescribed, and 75% of the surgeons administered these regimens until three days after the operation. Conclusion The results indicate that most surgeons used MBP and intravenous antibiotics and that half of them administered oral PA in colorectal surgery preparations. The study recommends that the current Korean guidelines should be adapted to adequately reflect the medical status in Korea, to consider the medical environment of the various hospitals, and to establish more accurate and relevant guidelines.