Tumor immune microenvironment of primary colorectal adenocarcinomas metastasizing to the liver or lungs.

BACKGROUND: Because of the heterogeneity of metastatic colorectal cancer (mCRC), a genome-wide analysis was performed to characterize the tumor immune microenvironment (TIME). METHODS: RNA-seq analysis of 62 primary CRCs without and 63 with systemic metastasis (SM- and SM+ groups) was conducted, and the data were used in a training set after adjustment by propensity score matching. Samples were further subdivided into those with hepatic metastasis (CHM subgroup), pulmonary metastasis (CPM subgroup), or concurrent CHM and CPM (concurrent group). Validation was done by quantitative reverse-transcription polymerase chain reaction using another 40 primary CRC samples. RESULTS: Compared with the CHM or CPM subgroups, the concurrent group showed upregulated in inflammatory or immune processes, cytokine secretion, and myeloid leukocyte migration. Nine candidate genes were selected: SM-specific IDO1, JAM3, and PDE2A; CHM- or CPM-specific BIRC7; CPM-specific HISI1H2BK, and both SM-specific and CHM- or CPM-specific EPHB6, LPL, THBD, and PPBP. In a validation set of primary CRCs, JAM3 and IDO1 (p = 0.044 and p = 0.036, respectively) were confirmed to show significant upregulation and downregulation, respectively, in the SM+ group, whereas HIST1H2BK (p = 0.017) was significantly upregulated in the CPM subgroup. CONCLUSIONS: Our findings indicate that a host-suppressive TIME is established in the primary tumor of mCRC and identify immune-related site-specific markers of mCRC.

Resection after preoperative chemotherapy versus synchronous liver resection of colorectal cancer liver metastases: A propensity score matching analysis.

This study aimed to determine the prognostic effects of preoperative chemotherapy for colorectal cancer liver metastasis (CLM).We retrospectively evaluated 2 groups of patients between January 2006 and August 2012. A total of 53 patients who had ≥3 hepatic metastases underwent resection after preoperative chemotherapy (preoperative chemotherapy group), whereas 96 patients who had ≥3 hepatic metastases underwent resection with a curative intent before chemotherapy for CLM (primary resection group). A propensity score (PS) model was used to compare the both groups.The 3-year disease-free survival (DFS) rates were 31.7% and 20.4% in the preoperative chemotherapy and primary resection groups, respectively (log-rank = 0.015). Analyzing 32 PS matched pairs, we found that the DFS rate was significantly higher in the preoperative chemotherapy group than in the primary resection group (3-year DFS rates were 34.2% and 16.8%, respectively [log-rank = 0.019]). Preoperative chemotherapy group patients had better DFSs than primary resection group patients in various multivariate analyses, including crude, multivariable, average treatment effect with inverse probability of treatment weighting model and PS matching.Responses to chemotherapy are as important as achieving complete resection in cases of multiple hepatic metastases. Preoperative chemotherapy may therefore be preferentially considered for patients who experience difficulty undergoing complete resection for multiple hepatic metastases.

Oncologic and Functional Hazards of Obesity Among Patients With Locally Advanced Rectal Cancer Following Neoadjuvant Chemoradiation Therapy.

OBJECTIVE: Obesity is a major health concern and risk factor for colorectal cancer that may also impact cancer treatment and outcomes. Rectal cancer response to chemoradiotherapy (CXRT) is associated with long-term survival and sphincter preservation. The purpose of this study was to evaluate the impact of obesity on treatment outcomes after neoadjuvant CXRT for rectal cancer. METHODS: A retrospective cohort study of patients diagnosed (1993 to 2010) with cT3-4 or cN+ (by endorectal ultrasound, computed tomography, or magnetic resonance imaging) rectal carcinoma and treated with CXRT and total mesorectal excision was performed. Patients were classified as obese (body mass index ≥30 kg/m) or nonobese (body mass index <30 kg/m), and by response to CXRT: complete (pCR) or incomplete (pIR). Associations between obesity, tumor response, and sphincter preservation were evaluated using multivariate logistic regression analysis and survival outcomes by Cox regression. RESULTS: A total of 753 patients met criteria and 28.7% (n=216) patients were obese. Obese and nonobese groups did not differ in age, sex, tumor location, grade, or number of examined lymph nodes. However, obesity was associated with a lower rate of pCR (ORmulti=0.60; 95% confidence interval, 0.38-0.94; P=0.04) and among mid to low rectal cancer patients, a lower rate of sphincter preservation (ORmulti=0.67; 95% confidence interval, 0.45-0.99). Among both obese and nonobese patients, CR was associated with more favorable recurrence-free survival than pIR. CONCLUSIONS: Considering the increasing obesity prevalence and its association with CXRT response, oncologic outcomes, and sphincter preservation, further study is needed regarding the impact of obesity on neoadjuvant treatment response. Moreover, obesity should be targeted as a modifiable risk factor for adverse outcomes following multimodality treatment for rectal cancer.

Outcomes of ultra-low anterior resection combined with or without intersphincteric resection in lower rectal cancer patients.

PURPOSE: We evaluated the current practice of ultra-low anterior resection (uLAR) in patients with lower rectal cancer and compared uLARs using mostly transabdominal approach with or without intersphincteric resection (ISR). METHODS: A total of 624 consecutive lower rectal cancer patients undergoing curative uLAR were prospectively enrolled as ISR+ vs. ISR- groups (329 vs. 295 patients) between 2005 and 2012. The ISR+ group additionally received levator-sphincter reinforcement after distal resection. RESULTS: The circumferential resection margin (CRM) + rate (≤1 mm) was 2.1 % in the two groups. Postoperative ileus occurred more in the ISR- group than in the ISR+ group (p = 0.02). Substantial erectile dysfunction occurred 1.8 times more frequently in the ISR- group than in the ISR+ group (32 vs. 18.1 %; p = 0.01) among male patients at 2 years postoperatively. The urge to defecate volume and maximal tolerance volume, closely correlated with maximal squeezing pressure and/or mean resting pressure, did not differ between patients with and without chemoradiotherapy until 24 months postoperatively. Nevertheless, the urge to defecate volume was lesser in the ISR- group than in the ISR+ group at 24 months postoperatively (p = 0.022). For 301 patients in which >5 years had elapsed postoperatively, the mean 5-year local recurrence rate was 4.3 %, and the 5-year disease-free and overall survival rates were 78.9 and 92 %, respectively, without differences between the two groups. CONCLUSIONS: Compared with uLAR without ISR, the transabdominal ISR with levator-sphincter reinforcement provides a safe resection plane with competent CRM, concurrently reduces substantial complications, and marginally promotes recovery of neorectal function.

A comparison of the technical and oncologic validity between robot-assisted and conventional open abdominoperineal resection.

PURPOSE: This study was to ascertain whether a robot-assisted (RA) approach to APR might facilitate a cylindrical APR by enabling a deeper pelvic dissection during an abdominal approach, concurrently comparing the feasibility and short-term oncologic outcomes. METHODS: Forty-eight consecutive patients with lower rectal cancer who had undergone curative APR (21 RA vs. 27 open) were prospectively enrolled. The short-term operative outcomes and oncologic feasibility were evaluated and compared. A levator muscle excision was performed concomitantly with the abdominal procedure in the RA group and with the perineal procedure in the open group. RESULTS: No patients in the RA group experienced intraoperative perforation or required conversion to open APR. Overall, a cylindrical APR was performed in 72 % of patients, and subtotal excision of the levator muscle, i.e., either one or both sides of the puborectalis and pubococcygeus muscles, was more likely in the RA group (P = 0.019). A positive CRM was exclusively identified in four open APR patients. The mean number of retrieved lymph nodes was greater in the RA group (20 vs. 16, P = 0.035). There was no difference in perineal morbidity between the two groups (P = 0.445). CONCLUSIONS: The RA approach facilitates an efficient excision in the pelvic region than open APR during the abdominal procedure. The RA approach also demonstrated a trend toward improved oncologic outcomes with equivalent postoperative morbidities than with the open approach.

Completely abdominal intersphincteric resection for lower rectal cancer: feasibility and comparison of robot-assisted and open surgery.

BACKGROUND: Most previous studies of intersphincteric resection (ISR) adopted a two-stage procedure involving abdominal and transanal approaches. We performed completely abdominal ISR via open and a robot-assisted (RA) approaches as treatments for lower rectal cancer (LRC). The RA approach might enable deep dissection and facilitate ISR in patients with restrictive pelvic anatomy. METHODS: A consecutive cohort of 222 LRC patients who underwent completely abdominal ISR (RA ISR, n = 108; open ISR, n = 114) was enrolled prospectively, and their short-term outcomes were evaluated. RESULTS: In a multivariate analysis, ISR was performed more frequently in the RA than in the open group (82.6 vs. 67.9 %, p = 0.008). The number of harvested lymph nodes was >12 in both groups. A positive distal resection margin was not observed in either group, and a positive circumferential resection margin was found in one patient in the RA group. Overall morbidity did not differ between the groups. Moderate to severe sexual dysfunction occurred 2.7-fold more frequently in the open group (p = 0.023) among male patients ≤65 years. Mean Wexner's fecal incontinence scores at postoperative months 6 and 12 were greater in the open group than in the RA group (p < 0.05). CONCLUSIONS: Completely abdominal ISR may be feasible in the treatment of LRC, based on a short-term study. Furthermore, RA ISR had equivalent oncological outcomes and slightly improved functional recovery relative to open ISR.

Quantified pathologic response assessed as residual tumor burden is a predictor of recurrence-free survival in patients with rectal cancer who undergo resection after neoadjuvant chemoradiotherapy.

BACKGROUND: The current study was conducted to determine whether quantified pathologic response assessed as a percentage of residual tumor cells is predictive of recurrence-free survival (RFS) in patients with rectal cancer. METHODS: The authors studied 251 patients with rectal adenocarcinoma who were treated with neoadjuvant chemoradiation and radical resection. Quantified pathologic response was defined as an estimated percentage of residual cancer cells in relation to the tumor bed: complete, no residual cancer cells; near-complete, ≤ 5% residual cancer cells; major, > 5%, and < 50% residual cancer cells; and minor, ≥ 50% residual cancer cells. The reproducibility of quantified pathologic response between 2 pathologists was assessed using tumors from 55 randomly selected patients who did not demonstrate a complete response. RESULTS: Pathologic response was complete in 21% of patients, near-complete in 20% of patients, major in 37% of patients, and minor in 22% of patients. Nineteen percent of patients had ypT0N0 disease, 27% had ypT1-2N0 disease, 21% had ypT3-4N0 disease, and 33% had N+ disease. The 5-year RFS rates by category of quantified pathologic response were as follows: complete, 95%; near-complete, 88%; major, 69%; and minor, 61% (P < .001). Major and minor response, high histologic grade, and perineural invasion were found to be significant predictors of decreased RFS on multivariate analysis. The 5-year RFS rates for patients with ypT3-4 or N+ disease were better for those with a near-complete response (94%) compared with those with a major (64%) or minor (61%) response (P < .02). Moderate to substantial agreement was observed between the 2 pathologists (κ = 0.72). CONCLUSIONS: Quantified pathologic response is a predictor of RFS in patients with rectal adenocarcinoma and stratifies patients with high pathologic stage disease.

Ovarian metastases from colorectal cancer: a clinicopathological analysis of 103 patients.

OBJECTIVE: To improve management of ovarian metastasis through assessment of clinicopathological features and treatment outcomes associated with ovarian metastasis from colorectal cancer. METHOD: We recruited 103 subjects who were diagnosed with ovarian metastasis and subjected to surgery between June 1989 and December 2005. Clinical and pathological variables were evaluated. Survival and its associated factors were analysed with a median follow-up of 31 months after ovarian surgery (range 1-129 months). RESULTS: The mean age at diagnosis was 46 years (range 14-72 years), synchronous ovarian metastasis occurred in 74 patients and metachronous in 29 patients. The primary tumour was more commonly associated with the colon rather than the rectum (84/1608, 5.2%vs 19/1534, 1.2%, P < 0.001). Combined metastases occurred in 69 patients (67%). Complete resection was achieved in 34 (33%) patients without other metastases. The estimated 5-year disease free survival and overall survival rate were 40.1% and 26.6%, respectively. From univariate analysis, lymphovascular invasion (35.6%vs 12.8%, P = 0.034), combined metastasis (50.9%vs 15.6%, P = 0.0035) and bilaterale ovarian metastasis (36.4%vs 10.6%, P = 0.015) were identified as significant poor prognosis factors, and from multivariate analysis combined metastasis and bilaterale ovarian metastasis were significant (P = 0.034 and P = 0.015, respectively). CONCLUSION: This study suggests a role for regular follow-up computed tomography scans within 6 months postoperatively and tumour marker assays for the early detection of ovarian metastasis in premenopausal women after primary surgery, especially in colonic patients with poor prognostic factors.

Correlation between hMLH1/hMSH2 and p53 protein expression in sporadic colorectal cancer.

BACKGROUND/AIMS: The aim of this study was to analyze expression of hMLH1 and hMSH2 mismatch repair proteins in terms of p53 protein expression and clinicopathological parameters in sporadic colorectal cancer. METHODOLOGY: Four hundred and two cases of curative colorectal surgery for primary colorectal cancer were included in this study (patients with a familial history of colorectal cancer and familial adenomatous polyposis were not included). Clinicopathological parameters were reviewed retrospectively. HMLH1, hMSH2 and p53 protein expression in tumor tissue sections was determined using immunohistochemical staining with specific monoclonal antibodies. RESULTS: Of the 402 cases, immunohistochemical analysis showed 35 (8.7%) had loss of expression of hMLH1, 19 (4.7%) had loss of expression of hMSH2, and three cases (0.7%) had loss of expression of both proteins. Multivariate analysis showed that early age of onset (p=0.023), right side dominance (p<0.001) and poorly differentiated or mucinous cell type (p<0.001) were associated with loss of expression of hMLH1 or hMSH2. Loss of expression of hMLH1 or hMSH2 correlated with low p53 expression (p<0.001). In terms of clinicopathological parameters, p53 expression was associated only with hMLH1 or hMSH2 expression. CONCLUSIONS: Colorectal cancers not expressing hMLH1 or hMSH2 may have distinct features from those expressing these mismatch repair proteins. p53 expression appears to be implicated in a compensatory pathway with mismatch repair proteins.

[Prognostic factors of stage II rectal cancer].

BACKGROUND/AIMS: We aimed to verify the prognostic factors of stage II rectal cancer and the effect of radiation therapy on the survival and local recurrence rate. METHODS: This study was undertaken in 202 patients who underwent curative resection of rectal cancer and confirmed to be stage II between July 1989 and December 1996. Univariate and multivariate (Cox's model) analyses of survival were employed to identify prognostic factors. Statistical significance was assigned by p value of <0.05. RESULTS: Overall recurrence occurred in 32 patients. Four patterns of recurrence were observed: hematogenous recurrence in 17 patients, local recurrence in 11, peritoneal seeding in two and simultaneous hematogenous and local recurrence in two cases. Overall 5-year survival rate was 85.6% and 5 year disease free survival rate was 82.8%. There was no significant difference in local recurrence rate and survival according to radiation therapy or location of cancer. In multivariate analysis, the number of harvested lymph node was only a prognostic factor. CONCLUSIONS: The number of harvested lymph nodes has prognostic value in stage II rectal cancer. Postoperative radiation therapy should be considered for stage II rectal cancer with poor prognostic factors although radiation did not decrease local recurrence rate in present study.

[Clinical features and prognostic factors in primary adenocarcinoma of the appendix].

BACKGROUND/AIMS: Primary appendiceal adenocarcinoma is a rare neoplasm that constitutes less than 0.5% of all gastrointestinal neoplasm. The aim of this study was to figure out its clinicopathologic characteristics that are not well understood. METHODS: We reviewed the medical records of nineteen patients (9 males and 10 females) with histologically proven appendiceal adenocarcinoma. They had been treated at Asan Medical Center between June 1989 and December 2002. Their median follow-up duration was 72.5 months. RESULTS: Their median age was 56.5 (range, 33-80) years. Thirteen patients had mucinous variants and the other five had adenocarcinoma. Seven patients (36.8%) were diagnosed as acute appendicitis. In fact, none of the patients was diagnosed correctly before surgery. The operative procedure, included right hemicolectomy in 9 patients, appendectomy alone in 2 patients, and debulking of their tumors or a biopsy in 8 patients. The 5-year survival rate was 20.5%. The patients with mucinous type had better prognosis than those with the non-mucinous type (p<0.01). In the patients with mucinous type, the survival rate after debulking operation was similar to that after right hemicolectomy. CONCLUSIONS: The most important prognostic factor of primary appendiceal adenocarcinoma was histology. The outcome of debulking operation is being watched compared with that of right hemicolectomy in mucinous variant.