Ultralow Anterior Resection and Coloanal Anastomosis for Low-Lying Rectal Cancer: An Appraisal Based on Bowel Function.

BACKGROUNDS/AIMS: On the basis of acceptable oncologic results, ultralow anterior resection (ULAR) and colo-anal anastomosis plus hand-sewn coloanal anastomosis have been performed for treating very low-lying rectal cancer. However, many patients experience bowel dysfunction after ULAR. Studies have provided inadequate data on bowel dysfunctions and only a few functional studies have focused on low rectal cancer. Therefore, we aimed to elucidate the severity of bowel dysfunction after ULAR in a single-surgeon cohort. METHODS: In this prospective observational study, we analyzed data of 203 patients who underwent sphincter-preserving surgery for low-lying rectal cancer (tumor located within 5 cm from the anus) between January 2011 and December 2014. During routine follow-up, examinations (3-6 months interval) after ileostomy closure, patients were asked about their bowel functions based on the Wexner incontinence and LAR syndrome (LARS) scores. Patients were divided into 2 groups: LAR group (LAR with double-stapled anastomosis) and ULAR group (ULAR with coloanal anastomosis), and functional scores were compared between 6 and 36 months. Seven risk factors for major LARS were analyzed. RESULTS: At 36 months after surgery, 94.2 and 70.6% of patients in the ULAR group still had moderate to severe incontinence and major LARS respectively. Fecal incontinence improved significantly over time (ULAR group, 14.4 vs. 7.2, p = 0.045; LAR group, 13.9 vs. 5.4, p < 0.05). However, improvement in LARS over time was observed in the LAR group only (26.5 vs. 19.7, p = 0.045). In the ULAR group, the difference did not reach a statistical significance (33.6 vs. 26.0, p = 0.10). Major LARS and moderate incontinence were significantly higher in the ULAR group than in the LAR group (70.6 vs. 47.6%, p = 0.001; 82.4 vs. 32.0%, p = 0.012 respectively). Among the 7 factors evaluated in multivariable analysis, old age (> 70), male sex, ULAR per se, and chemoradiation therapy were found to be meaningful risk factors for major LARS. CONCLUSION: In patients with low rectal cancers undergoing ULAR plus coloanal anastomosis, bowel dysfunctions were severe. Bowel dysfunctions improved over time, but most patients still experienced major bowel dysfunctions even 36 months after surgery. Risk factors for bowel dysfunctions were old age, male sex, adjuvant chemoradiation therapy, and ULAR. Therefore, ULAR should be performed in carefully selected patients with low-lying rectal cancer.

Changes in anorectal physiology following injection sclerotherapy using aluminum potassium sulfate and tannic acid versus transanal repair in patients with symptomatic rectocele; a retrospective cohort study.

BACKGROUND: Following injection sclerotherapy using ALTA (aluminum potassium sulfate and tannic acid) (ALTAS) and transanal rectocele repair (TAR), changes in anorectal physiology were analyzed to compare the significance of the two treatments. METHODS: ALTAS was administered to 23 patients and 18 patients were treated using TAR. Efficacy measures included changes in defecography, anorectal manometry and constipation scoring system value. RESULTS: This was a retrospective cohort analysis conducted on prospectively collected data. Comparing anorectal physiology pre- and post- ALTAS, a statistically significant difference in push was observed with pre-ALTAS treatment (pre-A) at 104.33 ± 4.91° compared with post-ALTAS treatment (post-A) at 113.95 ± 4.74° (p < 0.001). With a pre-A value of 1.55 ± 0.18 cm and a post-A value of 2.46 ± 0.34 cm, perineal descent also showed an increase as well (p < 0.001). The rectocele size decreased post-A from a pre-A value of 7.74 ± 0.86 cm compared with a post-A value of 2.91 ± 0.52 cm (p < 0.001). The rectal sensation improved post-A compared with pre-A. Comparing anorectal physiology results of ALTAS and TAR treatments, no differences in defecography and rectal sensation were detected pre- and post-treatment. However, in terms of anorectal manometry, the mean resting pressure and maximal squeezing pressure showed statistical difference with two treatments. CONCLUSIONS: ALTAS treatment is a feasible option resulting in rapid and effortless long-term outcome, with low rates of complications. Therefore, this treatment may be an effective alternative for patients with symptomatic rectocele.

Prognostic significance of systemic inflammatory response in stage II colorectal cancer.

BACKGROUND: It is considered that stage II colorectal cancers have heterogeneous oncological outcomes. It remains to be determined whether inflammatory markers can predict survival after curative surgery in these patients. The aim of this study was to investigate the prognostic impact of preoperative inflammatory markers after curative surgery in stage II colorectal cancers. METHODS: Two hundred sixty-one patients with stage II colorectal cancers who underwent curative surgery between January 2006 and December 2011 were reviewed. Oncologic outcomes were analyzed with neutrophil count, lymphocyte count, monocyte count, neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio. RESULTS: Univariate analysis showed that high NLR (hazard ratio (HR), 3.506; 95% confidence interval [CI], 1.415-8.688; P = 0.007) and low LMR (HR, 2.436; 95% CI, 1.010-5.880; P = 0.048) were associated with worse disease-free survival (DFS), and high NLR (HR, 2.834; 95% CI, 1.419-5.662; P = 0.003) and low LMR (HR, 2.374; 95% CI, 1.188-4.742; P = 0.014) were associated with worse overall survival (OS) in stage II colorectal cancer. Cox multivariate analysis demonstrated that high NLR was independently associated with worse DFS (HR, 3.163; 95% CI, 1.058-9.455; P = 0.004) and OS (HR, 3.018; 95% CI, 1.467-6.207; P = 0.003) in stage II colorectal cancer. CONCLUSION: Among the systemic inflammatory markers, NLR is a strong predictor of worse DFS and OS in stage II colorectal cancer.

Prognostic Significance of Lymphocyte Counts in Colon Cancer Patients Treated with FOLFOX Chemotherapy.

PURPOSE: There is increasing interest in immune function in combination with chemotherapy for cancer treatment. However, the effects of chemotherapy on the human immune system remain to be determined. The aim of this study was to investigate the prognostic impact of lymphocyte and neutrophil counts in colon cancer patients who were treated with curative surgery and adjuvant chemotherapy. METHODS: Two hundred thirty-one patients with colon cancers who underwent curative surgery and FOLFOX adjuvant chemotherapy between November 2005 and December 2011 were included. Oncologic outcomes were analyzed with neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio (NLR) before and after chemotherapy. RESULTS: The 5-year DFS rate was lower in colon cancer patients with low lymphocyte count during chemotherapy (61.9 vs. 76.7%, P = 0.026). Cox multivariate analysis demonstrated that low lymphocyte count during chemotherapy was independently associated with poor disease-free survival (HR 1.829; 95% CI 1.096-3.050; P = 0.021) in colon cancer patients who underwent FOLFOX adjuvant chemotherapy. CONCLUSION: Lymphocyte count during chemotherapy is a strong predictor of worse disease-free survival in colon cancer patients who have undergone FOLFOX adjuvant chemotherapy.

Preoperative neutrophil to lymphocyte ratio predicts survival in patients with T1-2N0 colorectal cancer.

PURPOSE: Neutrophil to lymphocyte ratio (NLR) is reported to be associated with prognosis of colorectal cancer. The aim of this study is to determine whether the NLR is a predictor of oncological outcomes in patients with stage I colorectal cancer who underwent curative surgery. METHODS: Two hundred sixty-nine patients with stage I colorectal cancer who underwent surgical resection between December 2003 and December 2011 were retrospectively reviewed. The cutoff for NLR was defined as three by maximizing log-rank test statistics. We compared patients with a low NLR and those with a high NLR in terms of survival. RESULTS: The 5-year disease-free survival (DFS) and cancer-specific survival (CSS) rates were lower in patients with a high NLR compared to those with a low NLR in stage I colorectal cancer (89.5% vs. 97.4%, P = 0.006; 94.0% vs. 98.9%, P = 0.022). Cox multivariate analysis demonstrated that preoperative NLR was independently associated with DFS (HR, 5.216; 95%CI, 1.400-19.431; P = 0.014) and CSS (HR, 6.190; 95%CI, 1.034-37.047; P = 0.046) in patients with stage I colorectal cancer. CONCLUSION: The preoperative NLR is a prognostic factor predicting DFS and CSS in patients with stage I colorectal cancer who underwent curative surgery.

ALDH1 is a prognostic factor for patients treated with neoadjuvant chemoradiotherapy and radical resection for stage III rectal cancer.

BACKGROUND AND OBJECTIVES: The factors relating to changes within a tumor after preoperative chemoradiotherapy associated with rectal cancer prognosis remain to be determined. The aim of this study was to investigate the expression of CD133 and ALDH1 and to analyze the predictive and prognostic roles in patients with rectal cancer after chemoradiotherapy. METHODS: We analyzed the expression levels of ALDH1 and CD133 in patients with middle and lower rectal cancers who underwent preoperative chemoradiotherapy between March 2005 and December 2011. RESULTS: The expression of CD133 was not associated with survival. The 5-year overall survival rates were lower in patients with high ALDH1 expression compared to low ALDH1 expression in stage III rectal cancer (61.0% vs. 89.7%, P=0.031). Cox multivariate analysis demonstrated that high ALDH1 expression (HR, 5.425; 95% CI, 1.116-26.373; P=0.036), cT (HR, 12.861; 95% CI, 2.188-75.591; P=0.005), and pN2 (HR, 28.481; 95% CI, 4.757-170.518; P<0.001) were independently associated with overall survival in 51 patients with stage III rectal cancer. CONCLUSIONS: Expression of ALDH1 indicates a more aggressive feature of stage III rectal cancer and can stratify stage III rectal cancer into different survival groups.

Pretreatment selection of regimen according to genetic analysis improves the efficacy of chemotherapy in the first line treatment of metastatic colorectal cancer.

BACKGROUND AND OBJECTIVES: Metastatic colon cancer patients are treated with the chemotherapy regimens, FOLFOX and FOLFIRI, in either order. So far, we cannot predict the response of chemotherapeutic agent, so it is necessary to find which regimen is adequate before starting chemotherapy. METHODS: Enrolled patients are randomized into either conventional treatment or planned treatment preceded by pretreatment genetic analysis. Blood samples of patients in planned treatment group (N = 53) were analyzed for the genetic polymorphism before selection of chemotherapeutic agents. Target genes were XPD-751, GSTP-1-105, XRCC1-399 for oxaliplatin, UGT1A1 for irinotecan. The response was measured by computed tomographic scan after completion of three cycles of chemotherapy. RESULTS: Overall response rate was significantly higher in planned group (67.9% vs. 46.3%, P = 0.020). In FOLFOX group, response rate was significantly improved in the planned patients(77.1% vs. 50%, P = 0.018). In FOLFIRI group, the difference didn't reach statistical significance (50% vs. 42.5%, P = 0.776). CONCLUSIONS: We found significantly improved response rates in the chemotherapy of metastatic colon cancer by pretreatment genetic analysis, especially in FOLFOX group.

Comparison of oncological outcomes between neoadjuvant and adjuvant chemotherapy combined with surgery for resectable synchronous colorectal liver metastases.

BACKGROUND: The role of neoadjuvant chemotherapy for resectable colorectal liver metastases is a subject of debate. We compared the oncologic outcomes between neoadjuvant chemotherapy and adjuvant chemotherapy combined with surgery for resectable synchronous colorectal liver metastases. METHODS: We analyzed 30 patients who underwent liver resection for resectable colorectal liver metastases combined with oxaliplatin-based neoadjuvant or adjuvant chemotherapy between May 2003 and August 2010. We assessed recurrence-free and overall survival in patients treated using neoadjuvant chemotherapy compared with those who received adjuvant chemotherapy. RESULTS: Of the 30 patients with colorectal liver metastases, 15 underwent neoadjuvant chemotherapy and 15 underwent adjuvant chemotherapy. Nine (60%) patients in the adjuvant group relapsed and nine (60%) patients in the neoadjuvant group relapsed. The neoadjuvant chemotherapy group had no significant difference in recurrence-free and overall 3-y survival (37.5% versus 45.0%, P = 0.938; 44.0% versus 66.7 %, P = 0.466) compared with the adjuvant chemotherapy group. CONCLUSION: Our results indicate that neoadjuvant chemotherapy is not inferior to adjuvant chemotherapy for resectable colorectal liver metastases, although the study was not randomized and included a limited number of patients.

Oncologic outcomes after adjuvant chemotherapy using FOLFOX in MSI-H sporadic stage III colon cancer.

BACKGROUND: Little is known of the oncological outcomes after adjuvant FOLFOX chemotherapy in patients with stage III colon cancer showing microsatellite instability high (MSI-H). In the present study we investigated the prognostic impact of MSI-H in patients with stage III colon cancer receiving FOLFOX chemotherapy. METHODS: We analyzed the MSI status in 127 patients with stage III colon cancer who underwent curative surgical resection followed by FOLFOX chemotherapy between January 2003 and December 2010. We assessed disease-free and overall survival (OS) in patients with MSI-H colon cancer compared with those showing microsatellite instability low or microsatellite stable (MSI-L/MSS) disease. RESULTS: Sixteen of the patients (12.6 %) were MSI-H, and 111 patients (87.4 %) were MSI-L/MSS. There was no significant difference between patients showing MSI-H and MSI-L/MSS except for age (P = 0.030), tumor location (P < 0.001), and differentiation (P = 0.031). Compared with MSI-L/MSS colon cancer, patients with MSI-H colon cancer had no significant difference in 5-year disease-free and OS (72.2 vs 68.5 %, P = 0.874; 68.1 vs 71.1 %, P = 0.437). CONCLUSIONS: Our study indicates that FOLFOX chemotherapy can be considered to treat stage III colon cancer patients with MSI-H after surgery, although the study was not randomized and included only a limited number of patients.

Prognostic impact of fascin-1 expression is more significant in advanced colorectal cancer.

BACKGROUND: Fascin-1 is not expressed in normal colorectal epithelium, but is up-regulated in colorectal cancer. However, its exact biological mechanism remains unknown. The purpose of this study was to investigate the relationship of fascin-1 expression with the clinicopathologic parameters and its prognostic impact in advanced colorectal cancer. MATERIALS AND METHODS: The immunohistochemical stainings for fascin-1, ß-catenin, and Ki-67 labeling index were performed with 126 stage III colorectal cancer specimens. RESULTS: Fascin-1 was found to be expressed in 74 (58.7%) of the 126 colorectal cancer specimens. Five-year survival rate was significantly low, whereas the distant recurrence rate was significantly high in patients with fascin-positive stage III colorectal cancer. There was no significant correlation between fascin-1 expression and clinicopathologic factors such as tumor size, nodal metastasis, pathologic stage, ß-catenin expression, and Ki-67 labeling index. However, fascin-1 expression was an independent prognostic factor in multivariate analysis. Patients with N1 showed no significant difference in 5-y DFS and OS according to the fascin-1 expression (79.0% versus 60.5%, P = 0.113; 86.5% versus 78.8%, P = 0.566). Patients with N2 showed marginal difference in 5-y DFS and significant difference in 5-y OS according to the fascin-1 expression (59.4% versus 32.4%, P = 0.088; 81.2% versus 39.5%, P = 0.002). CONCLUSIONS: This study suggests that fascin-1 expression in colorectal cancer may be clinically useful in predicting distant metastasis and poor survival, and we demonstrated that fascin-1 expression and N stage are significant independent prognostic factors for survival of colorectal cancer patients.

Does total mesorectal excision require a learning curve? Analysis from the database of a single surgeon's experience.

BACKGROUND: The procedure of total mesorectal excision (TME) is the gold standard in the treatment of rectal cancer. However, quality control of TME is still under debate. The present study was conducted to determine whether TME requires a learning curve to allow the surgeon to grasp the necessary technical expertise. METHODS: We performed a retrospective review of patients with rectal cancer who underwent TME with curative intention between August 1998 and December 2003; 195 consecutive patients were enrolled. From the first patient of the cohort, the first 50 patients were categorized into group 1, the next 50 into group 2, the next 50 into group 3, and the final 45 patients into group 4. Local recurrence rates were compared between the four groups. RESULTS: No significant difference in clinicopathological features was observed between the four groups, except for age, operative time, and grade of mesorectum. The local recurrence (LR) rate decreased from 22.3% in the inadequate TME group (G1) to 9.1% in the adequate TME group (G2-4) (p=0.035). In multivariate analysis, regional lymph node metastasis, mesorectal grade (incomplete or nearly complete), and early period of learning curve were independent predictors of local recurrence. CONCLUSIONS: Our results suggest that a learning curve is necessary for the development of technical expertise in the performance of TME for treatment of rectal cancer.

Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer.

Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8+ T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8+ T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.

Prognostic value of changes in serum carcinoembryonic antigen levels for preoperative chemoradiotherapy response in locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is a standard treatment modality for locally advanced rectal cancer. However, CRT alone cannot improve overall survival. Approximately 20% of patients with CRT-resistant tumors show disease progression. Therefore, predictive factors for treatment response are needed to identify patients who will benefit from CRT. We theorized that the prognosis may vary if patients are classified according to pre- to post-CRT changes in carcinoembryonic antigen (CEA) levels. AIM: To identify patients with locally advanced rectal cancer for preoperative chemoradiotherapy based on carcinoembryonic antigen levels. METHODS: We retrospectively included locally advanced rectal cancer patients who underwent preoperative CRT and curative resection between 2011 and 2017. Patients were assigned to groups A, B, and C based on pre- and post-CRT serum CEA levels: Both > 5; pre > 5 and post ≤ 5; and both ≤ 5 ng/mL, respectively. We compared the response to CRT based on changes in serum CEA levels. Receiver operating characteristic curve analysis was performed to determine optimal cutoff for neutrophil-lymphocyte ratio and platelet-lymphocyte ratio. Multivariate logistic regression analysis was used to evaluate the prognostic factors for pathologic complete response (pCR)/good response. RESULTS: The cohort comprised 145 patients; of them, 27, 43, and 65 belonged to groups A, B, and C, respectively, according to changes in serum CEA levels before and after CRT. Pre- (P < 0.001) and post-CRT (P < 0.001) CEA levels and the ratio of down-staging (P = 0.013) were higher in Groups B and C than in Group A. The ratio of pathologic tumor regression grade 0/1 significantly differed among the groups (P = 0.003). Group C had the highest number of patients showing pCR (P < 0.001). Most patients with pCR showed pre- and post-CRT CEA levels < 5 ng/mL (P < 0.001, P = 0.008). Pre- and post-CRT CEA levels were important risk factors for pCR (OR = 18.71; 95%CI: 4.62-129.51, P < 0.001) and good response (OR = 5.07; 95%CI: 1.92-14.83, P = 0.002), respectively. Pre-CRT neutrophil-lymphocyte ratio and post-CRT T ≥ 3 stage were also prognostic factors for pCR or good response. CONCLUSION: Pre- and post-CRT CEA levels, as well as change in CEA levels, were prognostic markers for treatment response to CRT and may facilitate treatment individualization for rectal cancer.

Contiguous invasion per se does not affect prognosis in colon cancer.

BACKGROUND: Locally advanced colon cancer can result in serious clinical conditions unless treated appropriately. The aim of this study was to examine the feasibility of en bloc resection and the significance of depth of invasion by analyzing the outcomes of the procedure in colon cancer invading adjacent organs. METHODS: Outcomes of 65 locally advanced colon cancer patients who underwent en bloc resections for contiguous invasion were compared with 285 pT3 colon cancer patients. RESULTS: En bloc combined resection was performed in 75 patients and 10 (13.3%) of them showed no true malignant infiltration into adjacent organs. In both pT3 and pT4 groups, there was no significant difference in major postoperative complications or mortality. The survival rate of pT4 group was similar to that of pT3 group (5-year rate, 64.0% vs. 72.7%; P = 0.287). In multivariate analysis, lymph node metastasis, lymphovascular infiltration, and perineural invasion were independently associated with patient survival. CONCLUSIONS: The prognosis of colon cancer, even in locally advanced cases, is mainly correlated with nodal status rather than depth of invasion. Therefore, en bloc combined resection in locally advanced colon cancer invading adjacent organs can improve survival as well as local control with acceptable morbidity and mortality.

Long-term follow-up of Starion™ versus Harmonic Scalpel™ hemorrhoidectomy for grade III and IV hemorrhoids.

BACKGROUND: This study represented an effort to design an alternative to Harmonic Scalpel™ with the same effectiveness but at a lower cost. The concomitant use of Starion™ and Harmonic Scalpel™ had been evaluated to determine the differences in terms of the effectiveness immediately after the operation and 3 years post-operatively. METHODS: 114 patients in the SH group (Starion™ hemorrhoidectomy) and 107 patients in the HSH group (Harmonic Scalpel™) were contacted for cumulative inspection 1 week, 4 weeks, and 3 years post-operatively to check for the recurrence rate. RESULTS: No significant difference in the pain score was observed at post-operative week 1, with the SH group scoring 2.08 ± 0.96 and the HSH group scoring 2.29 ± 1.00 (p = 0.112). No significant difference in patient satisfaction was observed at post-operative week 4, with the SH group scoring 8.63 ± 1.28 and the HSH group scoring 8.60 ± 1.32 (p = 0.847). No significant difference in wound healing was observed, with the SH group showing 18.24 ± 3.13 days and the HSH group showing 18.21 ± 2.96 days (p = 0.943). The post-operative recurrence rate was 3.5% (4/114) in the SH group at the 3-year follow-up compared to 4.7% (5/107) in the HSH group without any statistically significant difference (p = 0.662). CONCLUSIONS: Starion™ was a safe, rapid, and effective method for the treatment of Grade III or IV hemorrhoids.

Differences in biological behaviors between young and elderly patients with colorectal cancer.

BACKGROUND: We investigated the differences in biological behaviors of sporadic colorectal cancer (CRC) between young and elderly patients. CRC is a common cancer, with a mean age at onset of > 65 years. However, recent reports indicate increasing rates in younger populations. The biological behaviors of sporadic CRC in elderly patients could differ from those in young patients. METHODS: Between September 2007 and August 2012, we selected 723 CRC patients from our institution. The patients were divided into Group Y (n = 127, aged ≤50 years) and Group O (n = 596, aged >50 years). The clinicopathologic and oncologic outcomes in the two groups were compared. RESULTS: Group Y tumors were characterized by higher incidences of mucin production (13.4% vs. 6.7%; P = 0.017), high microsatellite instability (MSI-H) (19.8% vs. 5.2%; P < 0.001), and N2 stage (32.3% vs. 22.1%; P = 0.020) than those in Group O. The recurrence rates were similar in both groups (14.9% vs. 17.3%; P = 0.665). The 5-year overall survival and disease-free survival did not differ. Multivariate analysis indicated that cellular differentiation and pathologic stage were significant prognostic factors for 5-year overall survival. CONCLUSION: Although age was not a prognostic factor for overall survival and young patients did not show a worse prognosis, there were differences in mucin production, MSI-H, and N2 stage between the two groups. Further studies are needed to clarify the clinical and biological characteristics of CRC, improve its treatment strategies, and promote better outcomes in young patients.

TrkC promotes colorectal cancer growth and metastasis.

The current work reveals that TrkC receptor is crucial to many aspects of tumorigenicity and metastasis of cancer. However, with only a few exceptions, such as colorectal cancer (CRC), where suppressing tumorigenic and metastatic ability via expression of TrkC as tumor suppressor have been proposed. These diverse lines of evidence led us to investigate whether TrkC is involved in CRC progression. By using mouse models and molecular biology analyses, we demonstrate that TrkC acts as an activator in tumorigenicity and metastasis of colorectal cancer. In this study, TrkC was frequently overexpressed in CRC cells, patients' tumor samples and an azoxymethane/dextran sulphate sodium-induced mouse model of colitis-associated CRCs. TrkC expression was associated with a high-grade CRC phenotype, leading to significantly poorer survival. Also, TrkC expression promoted the acquisition of motility and invasiveness in CRC. Moreover, TrkC increased the ability to form tumor spheroids, a property associated with cancer stem cells. Importantly, knockdown of TrkC in malignant mouse or human CRC cells inhibited tumor growth and metastasis in a mouse xenograft model. Furthermore, TrkC enhanced metastatic potential and induced proliferation by aberrant gain of AKT activation and suppression of transforming growth factor (TGF)-ß signalling. Interestingly, TrkC not only modulated the actions of TGF-ß type II receptor, but also attenuated expression of this receptor. These findings reveal an unexpected physiological role of TrkC in the pathogenesis of CRC. Therefore, TrkC is a potential target for designing effective therapeutic strategies for CRC development.

Accuracy of Preoperative Local Staging of Primary Colorectal Cancer by Using Computed Tomography: Reappraisal Based on Data Collected at a Highly Organized Cancer Center.

PURPOSE: In patients with colorectal cancer, preoperative staging using various imaging technologies is important for establishing the treatment plan and predicting the prognosis. Although computed tomography (CT) has been used most widely, the versatility of CT accuracy was primarily because of the lack of specialization. In this study, we aimed to identify whether any advancement in abdominal CT accuracy in the prediction of local staging has occurred. METHODS: Between December 2014 and November 2015, patients with colorectal cancer were retrospectively enrolled. All CT findings were retrospectively reported. A total of 285 patients were included, and their retrospectively collected data were retrospectively reviewed, focusing on a comparison between preoperative and postoperative staging. RESULTS: The overall prediction accuracy of the T stage was 55.1%, with overstaging occurring in 63 (22.1%) and understaging in 65 patients (22.8%). The sensitivity and specificity were 90.0% and 68.4%, respectively. The overall prediction accuracy of the N stage was 54.7%, with overstaging occurring in 89 (31.2%) and understaging in 40 patients (14.1%). The sensitivity and specificity were 71.9% and 63.2%, respectively. The CT accuracies by pathologic stage were 0%, 62.2%, 25.3%, and 81.2% for stages 0 (Tis N0), I, II, and III, respectively. CONCLUSION: CT has good sensitivity for detecting colon cancers with tumor invasion beyond the bowel wall. However, detection of nodal involvement using CT is unreliable. In our opinion, abdominal CT alone has limitations in predicting the local staging of colorectal cancer, and additional technologies, such as CT plus positron emission tomography and/or colonography, will improve its accuracy.

Corrigendum: Correction of the IRB Approval Number. Accuracy of Preoperative Local Staging of Primary Colorectal Cancer by Using Computed Tomography: Reappraisal Based on Data Collected at a Highly Organized Cancer Center.

[This corrects the article on p. 192 in vol. 33, PMID: 29159167.].

Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study.

BACKGROUND: In patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC), outcomes with first-line chemotherapies are improved by adding weekly cetuximab. The APEC study investigated first-line once-every-2-weeks cetuximab plus chemotherapy for patients with KRAS wt mCRC; additional biomarker subgroups were also analyzed. PATIENTS AND METHODS: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated. RESULTS: In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations. CONCLUSION: The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.