Woo Yong Lee

Surgical autonomic denervation results in altered colonic motility: an explanation for low anterior resection syndrome?

BACKGROUND We hypothesized that the bowel dysfunction known as low anterior resection syndrome is caused by denervation of the left colon. The purpose of this study is to determine how surgical denervation changes left colon motility and to identify the mechanism of this change. MATERIALS AND METHODS Strain gauge transducers were implanted on the serosal surface of the descending colon of male SD rats (250-300 g). After a 2-h baseline recording, motility was recorded for another 2 h after either simple left colon manipulation (n = 6) or surgical left colon denervation (n = 6). Various pharmacologic agents were then administered before denervation to determine the mechanism by which denervation changed left colon motility. Changes in motility were calculated by determining a % motility index (MI) (%MI = MI posttreatment/MI baseline) with significance defined as P < .05. RESULT Denervation resulted in an increased mean %MI (128.8 +/- 15.4) compared with simple manipulation of the bowel, which decreased mean %MI (87.9 +/- 25.3) (P < .05). In the second set of experiments, both guanethidine and phentolamine increased mean %MI after injection (P < .05), but no additional increase of %MI occurred after denervation (P < .05). However, propranolol produced no increase of motility after injection and it did not affect the increase in motility observed after denervation (P < .05). CONCLUSION Surgical denervation of the left colon results in a significant increase in motility. Pharmacologically, this increase seems to be the result of destruction of an inhibitory alpha-sympathetic pathway. This increased motility may contribute to low anterior resection syndrome.

Animal models of colorectal cancer with liver metastasis

Liver metastasis is a leading cause of death in patients with colorectal cancer. Investigating the mechanisms of liver metastasis and control of disease progression are important strategies for improving survival of these patients. Liver metastasis is a multi-step process and relevant models representing these steps are necessary to understand the mechanism of liver metastasis and establish appropriate treatments. Recently, the development of animal models for use in metastasis research has greatly increased; however, there is still a lack of models that sufficiently represent human cancer. Thus, in order to select an optimal model for of a given study, it is necessary to fully understand the characteristics of each animal model. In this review, we describe the mouse models currently used for colorectal cancer with liver metastasis, their characteristics, and their pros and cons. This may help us specify the mechanism of liver metastasis and provide evidence relevant to clinical applications.

Prognostic factors in sporadic colon cancer with high-level microsatellite instability

BACKGROUND The microsatellite instability-high (MSI-H) phenotype of colon cancer has a good prognosis and limited response to chemotherapy. We aimed to investigate prognostic factors and oncologic outcomes in patients with MSI-H sporadic colon cancer. METHODS A total of 329 patients with MSI-H sporadic colon cancer who underwent radical surgery from January 2004 to December 2012 at a single institution were included. We analyzed prognostic factors and oncologic outcomes according to chemotherapy in these patients compared with patients with MSI-low/microsatellite stable colon cancer. RESULTS Among the 329 patients, 174 were male and 155 were female. The median age was 59 years. The population consisted of 220 patients with stage II, 97 with stage III, and 12 with stage IV disease. Old age and advanced stage were independent poor prognostic factors of overall survival (OS; P = .014 and P = .040, respectively) and advanced stage and presence of perineural invasion were independent poor prognostic factors of disease-free survival (DFS; P = .004 and P = .001, respectively). In addition, a greater number of poor prognostic factors were associated with worse survival (P < .001). Patients with stage II disease showed no differences in OS and DFS according to receiving or not receiving chemotherapy (P = .140 and P = .694, respectively). CONCLUSION Old age, advanced stage, and presence of perineural invasion were independent and poor prognostic factors in patients with MSI-H sporadic colon cancer. Survival rates of MSI-H colon cancer patients with stage II disease were not improved by adjuvant chemotherapy.

MCT4 Expression Is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Monocarboxylate transporters (MCT) are transmembrane proteins that control the lactate metabolism and are associated with poor prognosis in solid tumors, including colorectal cancer. Here, we aimed to investigate the biological and clinical role of MCTs in colorectal cancer and to assess the potential of therapeutic application. A total of 16 human colorectal cancer cell lines, 11 patient-derived cells from malignant ascites [patient-derived cells (PDC)], and 39 matched pairs of primary colorectal cancer and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo. siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by IHC and used for survival analysis. Expression of MCTs was demonstrated in colorectal cancer cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both in vitro and in vivo. An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MCT4 was markedly increased in PDCs, and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia-inducible factor 1-α (HIF1α) was also highly expressed in PDCs, whereas HIF1α knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse-free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for colorectal cancer with peritoneal carcinomatosis and serve as a prognostic indicator. Mol Cancer Ther; 17(4); 838–48. ©2018 AACR.

A New Size-based Platform for Circulating Tumor Cell Detection in Colorectal Cancer Patients

Background: Circulating tumor cells (CTCs) might play a significant role in cancer progression and metastasis. However, the ability to detect CTCs is limited, especially in cells undergoing epithelial‐mesenchymal transition. In this study, we evaluated a new size‐based CTC detection platform and its clinical efficacy in colorectal cancer. Patients and Methods: Blood samples were obtained from 76 patients with colorectal cancer and 20 healthy control subjects for CTC analysis. CTCs were enriched using a high‐density microporous chip filter and were detected using a 4‐color staining protocol including 4′,6‐diamidino‐2‐phenylindole (DAPI) for nucleated cells, CD45 monoclonal antibody (mAb) as a leukocyte marker, and epithelial cell adhesion molecule (EpCAM) mAb or cytokeratin (CK) mAb as an epithelial cell marker. CTC positivity was defined as DAPI‐positive (DAPI+)/CD45−/EpCAM+ or CK+ cells and clinical outcomes of patients were analyzed according to CTC counts. Results: CTCs were detected in 50 patients using this size‐based filtration platform. CTC+ patients were more frequently identified with a high level of carcinoembryonic antigen and advanced stage cancer (P = .038 and P = .017, respectively). CTC counts for patients with stage IV cancer (12.47 ± 24.00) were significantly higher than those for patients with cancers that were stage I to III (2.84 ± 5.29; P = .005) and healthy control subjects (0.25 ± 0.55; P < .001). In addition, progression‐free survival tended to be lower in CTC+ patients compared with CTC− patients (P = .092). In patients with stage I to III cancer, recurrence occurred only in CTC+ patients. Conclusion: CTC positivity was found to correlate with clinical features of colorectal cancer patients. Our results suggest that this new size‐based platform has potential for determining prognosis and therapeutic response in colorectal cancer patients. &NA; A study of 76 patients was performed to evaluate a new size‐based circulating tumor cell (CTC) detection platform and its clinical efficacy in colorectal cancer. CTC positivity was found to correlate with clinical features of colorectal cancer patients. Our results suggest that this new platform has potential for determining prognosis and therapeutic response in colorectal cancer patients.

Tumor heterogeneity predicts metastatic potential in colorectal cancer

Purpose: Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis. Experimental Design: Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole-exome sequencing. Tumor clonality was estimated from single-nucleotide and copy-number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated. Results: Tumor heterogeneity across colorectal cancer samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease-free survival. Highly heterogeneous primary colorectal cancer was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in APC, TP53, and KRAS were frequently detected in highly heterogeneous colorectal cancer. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as PIK3CA and NOTCH1 were low. The number and distribution of primary colorectal cancer subclones were preserved in metastatic tumors. Conclusions: Heterogeneity of primary colorectal cancer tumors can predict the potential for liver metastasis and thus, clinical outcome of patients. Clin Cancer Res; 23(23); 7209–16. ©2017 AACR.

Laparoscopic modified mesocolic excision with central vascular ligation in right-sided colon cancer shows better short- and long-term outcomes compared with the open approach in propensity score analysis

BackgroundThe introduction of complete mesocolic excision (CME) with central vessel ligation (CVL) for right-sided colon cancer has improved oncologic outcomes. However, there is controversy over the oncologic safety of laparoscopic CME with CVL. This study compared short-term and long-term oncologic outcomes between laparoscopic and open modified CME (mCME) with CVL in patients with right-sided colon cancer.MethodsWe enrolled 1239 patients who underwent open mCME with CVL and 1010 patients treated by a laparoscopic approach for right-side colon cancer between 2000 and 2013 and used 1:1 propensity score matching to adjust for potential baseline confounders between two groups.ResultsAfter propensity score matching, 683 patients who underwent open mCME with CVL were compared with 683 patients treated with a laparoscopic approach. There were no significant differences between these groups in age, sex, ASA score, TNM stage, tumor size, lymphovascular invasion, and perineural invasion. Comparison of open and laparoscopic mCME groups showed no significant difference in postoperative morbidity (21.4 vs. 18.3%, p = 0.175) and mortality (0.1 vs. 0%, p = 1.000). The laparoscopic mCME group showed shorter length of hospital stay. The 5-year overall survival rate was 83.7% in the open group and 94.7% in the laparoscopic group (p < 0.001). The laparoscopic group also showed a significantly better 5-year disease-free survival rate (82.7 vs. 88.7%, p = 0.009) and 5-year disease-specific survival rate (83.7 vs. 94.7%, p < 0.001).ConclusionLaparoscopic modified mesocolic excision with central vascular ligation is a safe and feasible approach with better short-term recovery profiles and potential oncologic benefits than the open approach for right-sided colon cancer.

Transanal Endoscopic and Transabdominal Robotic Total Mesorectal Excision for Mid-to-Low Rectal Cancer: Comparison of Short-term Postoperative and Oncologic Outcomes by Using a Case-Matched Analysis

Purpose This study aimed to compare short-term postoperative and oncologic outcomes of a transanal endoscopic total mesorectal excision (TME) to those of a transabdominal robotic TME. Methods A total of 62 patients with rectal cancer underwent transanal (n = 26) or robotic (n = 36) TME between June 2013 and December 2014. After case-matching by tumor location and TNM stage, 45 patients were included for analysis. The median follow-up period was 21.3 months. Operative, histopathologic and postoperative outcomes and recurrences were analyzed. Results Patients younger than 60 years of age were more frequently observed in the robotic TME group (75.0% vs. 47.6%, P = 0.059), but tumor location, cT and cN category, and preoperative chemoradiotherapy were not different between the 2 groups. Estimated blood loss was greater in the transanal group (283 mL vs. 155 mL, P = 0.061); however, the operation time and the rate of a diverting ileostomy and subsequent ileostomy repair were not different between the groups. The proximal resection margin was longer in the transanal TME group (20.8 cm ± 16.0 cm, P = 0.030), but the distal resection margins, involvements of the circumferential resection margin, TME quality, numbers of retrieved lymph nodes, postoperative complications, including anastomotic leak and voiding difficulty, and recurrence rates for the 2 groups were not statistically different. Conclusion Transanal endoscopic and transabdominal robotic TME showed similar histopathologic and postoperative outcomes with the exception of the estimated blood loss and the proximal resection margin for a select group of patients.

Clinical manifestations and risk factors of anastomotic leakage after low anterior resection for rectal cancer

Anastomotic leakage is a common complication that can be associated with catastrophic consequences. However, the risk factors and incidence of anastomotic leakage vary considerably among clinical studies because of the lack of a standardized definition, clinical course and appropriate treatment options. The aim of this study was to identify and classify the clinical manifestations and treatment of anastomotic leakage and analyse the possible risk factors after low anterior resection.

Clinical Significance of Mucinous Rectal Adenocarcinoma following Preoperative Chemoradiotherapy and Curative Surgery

Aims To investigate the efficacy and prognosis associated with preoperative chemoradiotherapy in patients with locally advanced mucinous rectal cancer (MRC). Methods Our analysis included 412 patients who underwent preoperative chemoradiotherapy and curative surgery for locally advanced rectal cancer. Among these patients, 30 had MRC and 382 had nonmucinous rectal cancer (NMRC). Tumor downstaging, defined as a lower pathologic stage than clinical stage, and survival were compared between MRC and NMRC. Results Increased frequency of cT4 disease was seen in MRC compared to NMRC (23.3% vs 8.9%, p = 0.021). Complete pathologic response rate and tumor downstaging rate were 0% and 23.3% in MRC and 15.4% and 52.4% in NMRC, respectively (p = 0.025 and p = 0.002). There was no significant difference in disease-free survival between the 2 groups (62.1% vs 75.0% at 5 years, p = 0.170), while there was a significantly lower overall survival in MRC vs NMRC (67.4% vs 88.0% at 5 years, respectively; p = 0.012). When analyzed by stage, the overall survival difference between MRC and NMRC was significant in the cT3 group (71.1% vs 89.1% at 5 years, p = 0.047) and marginally significant in the cT4 group (51.4% vs 74.5% at 5 years, p = 0.053), but not significant in subgroups with the same pathologic stage. Conclusions Mucinous rectal cancer is related to a lower response rate to chemoradiotherapy and poorer prognosis compared to NMRC, even when corrected for clinical stage. The poor prognosis in MRC might be associated with poor responsiveness to preoperative chemoradiotherapy.