Ho-Kyung Chun

Safety and Efficacy of Methylnaltrexone in Shortening the Duration of Postoperative Ileus Following Segmental Colectomy: Results of Two Randomized, Placebo-Controlled Phase 3 Trials

PURPOSE: Postoperative ileus contributes to surgical morbidity and is associated with prolonged hospitalization and increased health care costs. The efficacy and safety of the peripherally acting &mgr;-opioid receptor antagonist methylnaltrexone in shortening the duration of postoperative ileus following segmental colectomy was evaluated. METHODS: Two identically designed, multicenter, double-blind, parallel-group, placebo-controlled studies randomly assigned patients undergoing segmental colectomy (study 1, N = 515; study 2, N = 533) to receive 12 or 24 mg of methylnaltrexone intravenously or placebo every 6 hours starting within 90 minutes of surgery completion, continuing for up to 10 days or up to 24 hours after gastrointestinal recovery. The primary efficacy end point was the time from the end of surgery to the first bowel movement. Safety was evaluated via standard assessments (ie, adverse events and related withdrawals, physical examinations, laboratory tests, vital signs, electrocardiograms) and assessment of surgical complications. RESULTS: The primary and secondary efficacy outcomes (time to discharge eligibility, time to hospital discharge, and clinically meaningful events of nausea and vomiting following segmental colectomy) did not differ significantly between patients treated with either a dose of methylnaltrexone or with placebo. Rates of adverse events and serious adverse events were comparable across all treatment groups in both studies. The most commonly observed adverse events were nausea, pyrexia, and vomiting. CONCLUSIONS: Although the efficacy of methylnaltrexone in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous methylnaltrexone at doses of 12 mg and 24 mg was safe, in general, and well tolerated in postcolectomy patients. The utility of intravenous methylnaltrexone in treating postoperative ileus remains unproven.

The role of palliative resection for asymptomatic primary tumor in patients with unresectable stage IV colorectal cancer.

BACKGROUND: The prognostic role of surgical resection of primary tumors is not well established in patients with asymptomatic unresectable stage IV colorectal cancer. OBJECTIVE: The aims of this study were to reveal the prognostic role of surgical resection of primary tumors and to define prognostic factors affecting long-term oncological outcomes in patients with asymptomatic unresectable synchronous metastases. DESIGN: This study was a retrospective analysis of prospectively collected data. PATIENTS: Between 2000 and 2008, a total of 416 patients with asymptomatic unresectable stage IV colorectal cancer were analyzed with propensity score matching. MAIN OUTCOME MEASURES: Prematching baseline characteristics were compared by bivariate analysis, and 113 pairs were selected after 1:1 matching with propensity scores estimated from logistic regression. The primary end point was overall survival. RESULTS: Among 416 patients, 218 (52.4%) underwent palliative resection of the primary tumor. Before propensity score matching, palliative resection resulted in a better survival rate than nonresection in univariate analysis (p < 0.001), but not in multivariate analysis (p = 0.08). After matching, the 5-year overall survival rate was significantly lower for patients with peritoneal metastasis and clinical M1b stage tumors in univariate analysis (p = 0.004 and p = 0.02). However, neither peritoneal metastasis nor clinical M1b stage showed any prognostic significance in multivariate analysis. The overall 5-year survival rate of the postmatching group was 4.9% and 3.5% in the palliative resection and nonresection groups. Consequently, palliative resection was not associated with a significant increase in survival compared with nonresection (p = 0.27). A subgroup analysis performed according to the site of metastasis also did not show any significant survival benefit of palliative resection after matching. LIMITATIONS: Selection bias and potential confounders were limitations of this study. CONCLUSIONS: Resection of the primary tumor in patients with asymptomatic unresectable stage IV colorectal cancer was not associated with an improvement in overall survival after propensity score matching.

A circumferential resection margin of 1 mm is a negative prognostic factor in rectal cancer patients with and without neoadjuvant chemoradiotherapy.

BACKGROUND: There is ongoing debate about the appropriate criterion for defining a positive circumferential resection margin after radical surgery for rectal cancer. OBJECTIVE: The purpose of this work was to determine the importance of the extent of the circumferential resection margin with regard to outcomes in patients with rectal cancer who underwent total mesorectal excision with and without neoadjuvant chemoradiotherapy. DESIGN: This was a retrospective review of prospectively collected data. SETTINGS: The study was conducted in a tertiary care hospital. PATIENTS: We reviewed the medical charts of 780 patients with rectal cancer who underwent radical surgery from 2004 to 2009. There were 599 patients (76.8%) who did not receive neoadjuvant chemoradiotherapy and 181 patients (23.2%) who did. MAIN OUTCOME MEASURES: The relationship between the extent of the circumferential resection margin (0.5, 1.0, 2.0, and 3.0 mm) and recurrence and survival was assessed. RESULTS: Among circumferential resection margins ⩽0.5, ⩽1.0, ⩽2.0, and ⩽3.0 mm, the HR was highest and disease-free survival was longest for a circumferential resection margin ⩽1 mm in both the chemoradiotherapy and nonchemoradiotherapy groups. A circumferential resection margin ⩽1 mm, lymphatic invasion, histology, pathologic T category, pathologic N category, preoperative CEA, and adjuvant chemotherapy were independent predictors of disease-free survival in the nonchemoradiotherapy group. In the chemoradiotherapy group, a circumferential resection margin ⩽1 mm and histology were independent predictors of disease-free survival. Multivariate analysis revealed that a circumferential resection margin ⩽1 mm was an independent prognostic factor for overall survival in both of the 2 groups. LIMITATIONS: This was a single-institution, retrospective study. CONCLUSIONS: A circumferential resection margin of ⩽1 mm had a strong association with disease-free survival compared with circumferential resection margins ⩽0.5, ⩽2.0, and ⩽3 mm. A circumferential resection margin ⩽1 mm was an independent predictor of a poor outcome in both the nonchemoradiotherapy and chemoradiotherapy groups.

Loss of E-Cadherin Expression Is Associated with a Poor Prognosis in Stage III Colorectal Cancer

Purpose: The epithelial-mesenchymal transition (EMT) is known to be associated with tumor progression, invasion and metastasis in colorectal cancer (CRC). Materials and Methods: Tissue samples obtained from 409 patients with stage III CRC treated from 2006 to 2007 were examined by immunohistochemistry to reveal the expression levels of E-cadherin, fibronectin, vimentin and α-smooth muscle actin (SMA). Results: Among the 409 patients, 402 cases (98.3%) showed positive E-cadherin expression. Positive E-cadherin expression was associated with well or moderately differentiated cell types and a stable microsatellite status. In multivariate analysis, a preoperative carcinoembryonic antigen level >5 ng/ml (p = 0.021), advanced N stage (p = 0.017), positive vascular invasion (p = 0.048), positive perineural invasion (p = 0.002) and negative E-cadherin expression (p = 0.002, relative risk = 5.098, 95% CI = 1.801-14.430) were poor prognostic factors affecting disease-free survival. The declining E-cadherin expression was associated with a poor outcome in terms of overall survival in univariate (p = 0.016) but not in multivariate analyses (p = 0.303, relative risk = 1.984, 95% CI = 0.539-7.296). Fibronectin, vimentin and α-SMA were of no prognostic value in this study. Conclusion: The expression pattern of EMT markers in stage III CRC suggests that declining E-cadherin expression is a possible immunohistochemical predictor of patient prognosis.

Prognostic comparison between mucinous and nonmucinous adenocarcinoma in colorectal cancer.

AbstractMucinous adenocarcinoma (MAC) is a histological subtype of colorectal cancer. The oncologic behavior of MAC differs from nonmucinous adenocarcinoma (non-MAC). Our aim in this study was to characterize patients with colorectal MAC through evaluation of a large, institutional-based cohort with long-term follow-up.A total of 6475 patients with stages I to III colorectal cancer who underwent radical surgery were enrolled from January 2000 to December 2010. Prognostic comparison between MAC (n = 274, 4.2%) and non-MAC was performed.The median follow-up period was 48.0 months. Patients with MAC were younger than those without MAC (P = 0.012) and had larger tumor size (P < 0.001), higher preoperative carcinoembryonic antigen (P < 0.001), higher pathologic T stage (P < 0.001), more right-sided colon cancer (49.3%, P < 0.001), and more frequent high-frequency microsatellite instability (10.2%, P < 0.001). Five-year disease-free survival (DFS) was 76.5% in the MAC group and 83.2% in the non-MAC group (P = 0.008), and 5-year overall survival was 81.4% versus 87.4%, respectively (P = 0.005). Mucinous histology (MAC vs non-MAC) in the entire cohort was not an independent prognostic factor of DFS but had a statistical tendency (P = 0.071). In subgroup analysis of colon cancer without rectal cancer, mucinous histology was an independent prognostic factor (P = 0.026).MAC was found at more advanced stage, located mainly at the right side and was an independent factor of survival in colon cancer. Because of the unique biological behavior of MAC, patients with MAC require special consideration during follow-up.

Outcomes of Simultaneous Laparoscopic Colorectal and Hepatic Resection for Patients with Colorectal Cancers: A Comparative Study

BACKGROUND Although laparoscopic colorectal resection and laparoscopic liver resection have been accepted as effective alternatives to conventional open procedures, there are only a few reports on the clinical availability of simultaneous performance of these two procedures. We report our collective experience of patients with colorectal cancers treated with totally laparoscopic colorectal and liver resection, in comparison with those treated with an open approach. PATIENTS AND METHODS This study is a retrospective, case-match review of prospectively collected data. Between May 2008 and December 2012, 24 patients with primary colorectal cancer and associated hepatic lesions underwent simultaneous laparoscopic colorectal and liver resection (laparoscopic group). They were matched with patients who underwent an open procedure (open group; n=24 out of 232) based on the types of surgery. Patient demographics, operative details, tumor-related parameters, and postoperative outcomes were analyzed. RESULTS Demographic features and pathologic outcomes were similar in both groups. The median duration of operation was significantly longer in the laparoscopic group than in the open group (290 versus 244 minutes; P=.008), and the median estimated blood loss was larger (325 versus 250 mL; difference not significant, P=.35). However, the time to starting a soft blended diet (3.0 versus 4.5 days; P<.001) and postoperative stay (8.0 versus 10.5 days; P=.001) in the laparoscopic group were both significantly shorter than in the open group. The postoperative complication rate was lower in the laparoscopic group (17% versus 42%; difference not significant, P=.06). The minor complication rate was significantly lower in the laparoscopic group (4% versus 33%; P=.02). CONCLUSIONS A totally laparoscopic approach might provide short-term benefits associated with enhanced postoperative recovery despite a longer procedure time and larger blood loss. It can be a reasonable option for simultaneous colorectal and hepatic resection.

Intraoperative reasons for abandoning ileal pouch-anal anastomosis procedures

PURPOSE: Ileal pouch-anal anastomosis (IPAA) has become the operation of choice for most patients with chronic ulcerative colitis and familial adenomatous polyposis. However, because of technical or disease factors at the time of pouch construction, IPAA must sometimes be abandoned. A retrospective review was conducted to find reasons for IPAA failure or abandonment. METHODS: Since 1981, 103 patients have had to have an IPAA procedure at the George Washington University Medical Center in Washington, DC. All charts were reviewed and data retrospectively collected. RESULTS: Six of 103 patients (six percent) were unable to have IPAA constructed. Five patients ultimately received a standard end ileostomy, and one had an ileorectal anastomosis. The reasons for abandoning the IPAA procedure were an ischemic pouch, failure to reach the anus, poorly controlled presacral hemorrhage, desmoid of the mesentery, and finding incurable colon carcinoma. CONCLUSIONS: Information regarding the risk of failure or abandonment during the IPAA procedure should be discussed with the patient during preoperative counseling and must be included as an element of informed consent.

Low expression of transforming growth factor beta-1 in cancer tissue predicts a poor prognosis for patients with stage III rectal cancers.

Objective: Transforming growth factor beta (TGF-β) plays an important role in tumorigenesis and metastasis. It works as a tumor suppressor in the normal colon, but acts as a cancer promoter during the late stages of colorectal carcinogenesis. High expression of TGF-β is known to be associated with advanced stages, tumor recurrence and decreased survival of patients. We investigated the expression of TGF-β and its signaling axis molecules and evaluated their prognostic significance in patients with stage III rectal cancers. Methods: Tissues from 201 cases of stage III rectal cancer were subjected to immunohistochemistry for TGF-β1, type II TGF-β receptor, Smad3, Smad4 and Smad7 proteins. The immunoactivities of these molecules were evaluated and the results were compared with clinicopathological variables including patient survival. Results: Low expression of TGF-β1 protein was correlated with a decreased disease-free survival in univariate Kaplan-Meier (p = 0.003) and multivariate Cox regression (HR 9.188 and 95% CI 1.256-67.198, p = 0.029) analyses. The loss of Smad4 protein expression was associated with a reduction in disease-free survival in the univariate analysis, but this finding was not significant after the multivariate analysis. Conclusion: Low expression of TGF-β1 protein is associated with a poor prognosis for patients with stage III rectal cancers.

Local recurrence after curative resection for rectal carcinoma: The role of surgical resection.

AbstractLocal recurrence of rectal cancer is difficult to treat, may cause severe and disabling symptoms, and usually has a fatal outcome. The aim of this study was to document the clinical nature of locally recurrent rectal cancer and to determine the effect of surgical resection on long-term survival.A retrospective review was conducted of the prospectively collected medical records of 2485 patients with primary rectal adenocarcinoma who underwent radical resection between September 1994 and December 2008.In total, 147 (5.9%) patients exhibited local recurrence. The most common type of local recurrence was lateral recurrence, whereas anastomotic recurrence was the most common type in patients without preoperative concurrent chemoradiotherapy (CCRT). Tumor location with respect to the anal verge significantly affected the local recurrence rate (P < 0.001), whereas preoperative CCRT did not affect the local recurrence rate (P = 0.433). Predictive factors for surgical resection of recurrent rectal cancer included less advanced tumor stage (P = 0.017, RR = 3.840, 95% CI = 1.271–11.597), axial recurrence (P < 0.001, RR = 5.772, 95% CI = 2.281–14.609), and isolated local recurrence (P = 0.006, RR = 8.679, 95% CI = 1.846–40.815). Overall survival after diagnosis of local recurrence was negatively influenced by advanced pathologic tumor stage (P = 0.040, RR = 1.867, 95% CI = 1.028–3.389), positive CRM (P = 0.001, RR = 12.939, 95% CI = 2.906–57.604), combined distant metastases (P = 0.001, RR = 2.086, 95% CI = 1.352–3.218), and nonsurgical resection of recurrent tumor (P < 0.001, RR = 4.865, 95% CI = 2.586–9.153).In conclusion, the clinical outcomes of local recurrence after curative resection of rectal cancer are diverse. Surgical resection of locally recurrent rectal cancer should be considered as an initial treatment, especially in patients with less advanced tumors and axial recurrence.

Repeat hepatic resection in patients with colorectal liver metastases

AIM To investigate the survival outcomes of secondary hepatectomy for recurrent colorectal liver metastases (CRLM). METHODS From October 1994 to December 2009, patients with CRLM who underwent surgical treatment with curative intent were investigated. Patients were divided into two groups: patients who underwent primary hepatectomy (Group 1) and those who underwent secondary hepatectomy for recurrent CRLM (Group 2). RESULTS Survival and prognostic factors were analyzed. A total of 461 patients were included: 406 patients in Group 1 and 55 patients in Group 2. After a median 39-mo (range, 3-195 mo) follow-up, there was a significant difference between Groups 1 and 2 in terms of disease-free survival (P=0.029) although there was no significant difference in overall survival (P=0.206). Secondary hepatectomy was less effective in patients with multiple recurrent CRLM than primary hepatectomy for initial CRLM (P=0.008). Multiple CRLM and radiofrequency ablation therapy were poor prognostic factors of secondary hepatectomy in multivariate Cox regression analysis (P=0.006, P=0.004, respectively). CONCLUSION Secondary hepatectomy for single recurrent CRLM is as effective as primary surgical treatment for single recurrent CRLM. However, secondary hepatectomy for multiple recurrent CRLM is less effective than that for single recurrent CRLM.