Clinical evaluation of a multitarget fecal immunochemical test-sDNA test for colorectal cancer screening in a high-risk population: a prospective, multicenter clinical study.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

Grade G2 Rectal Neuroendocrine Tumor Is Much More Invasive Compared With G1 Tumor.

BACKGROUND: To compare clinicopathologic feature of rectal neuroendocrine tumor (NET) grade G1 with G2 NET. METHODS: Six hundred-one cases of rectal G1 and G2 NETs diagnosed in our center were analyzed. RESULTS: Of 601 cases of rectal NET, 515 cases were with grade G1 and 86 cases were with grade G2. Median tumor size was 0.7 cm. Compared with G1 NET, G2 tumors were with significantly larger tumor size (0.8 vs 2.2 cm, p < 0.001), less percentages of patients with tumors confined to submucosa (92.6 vs 42.8%, p < 0.001), more frequent presence of microvascular invasion (MVI) (3.6 vs 16.9%, p < 0.001) or peri-neural invasion (PNI) (2.0 vs 24.1%, p < 0.001). Incidence of lymph node and distant metastasis was 5.2 and 2.1% in G1 NET compared with 44.2 and 31.4% in G2 tumor, respectively (p < 0.001). For tumors sized 1-2 cm and confined to submucosa, incidence of lymph node metastasis was 6.1% for G1 NET compared with 21.1% for G2 NET. Status of MVI/PNI was predictive of lymph node metastasis for G2 tumor rather than G1 NET in this subgroup. CONCLUSIONS: Rectal G2 NET was much more invasive with significantly elevated prevalence of lymph node metastasis compared with G1 tumor.

Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study.

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.

Prediction of hepatic metastasis and relapse in colorectal cancers based on concordance analyses with liver fibrosis scores.

BACKGROUND: Liver fibrosis, resulted from several liver diseases, are increasing up to 25% in population in global. It remains undetermined how much impact liver fibrosis have on the development of hepatic metastasis and relapse in colorectal cancer (CRC). Hence the aim of this study was to clarify the role of liver fibrosis on hepatic metastasis and relapse in CRC undergoing curative therapy. METHODS: We enrolled consecutive 1652 patients with radical colorectal surgery as the discovery cohort, and the validation set enrolled 432 CRC patients with hepatic metastasis. To determine liver fibrosis, the NFS, FIB4 and APRI scores were applied. The influence of liver fibrosis on hepatic metastasis and relapse was assessed by survival analyses. Nomograms with fibrosis score incorporated were established to identify the incremental value for individualized relapse estimation, which was then assessed with respect to calibration, discrimination, and clinical usefulness. RESULTS: The high liver fibrosis score patients had significantly worse outcomes than low score in 5-year hepatic metastasis (22.6 vs. 8.7%) in discovery cohort, and relapse (58.2 vs. 44.1%) in validation cohort. Multivariate analysis also revealed liver fibrosis as an independent prognostic factor. The distribution analysis also demonstrated higher liver fibrosis score a powerful prognostic factor for hepatic metastasis and relapse. The nomogram incorporated with liver fibrosis score resulted in better performance than TNM staging system and clinicopathologic nomograms. Importantly, the discriminatory capacity of the fibrosis score was superior to that of the CRS score in predicting hepatic specific disease-free survival (DFS) and relapse-free survival (RFS), as demonstrated by the C-index and AUC. The concordance study showed well agreement among NFS, FIB4 and APRI in predicting DFS and RFS. Among these three noninvasive liver fibrosis scores, NFS score performed the best in predicting hepatic specific DFS and RFS. CONCLUSION: The liver fibrosis was a powerful predictor of hepatic specific DFS and RFS in CRC. Fibrosis niche may be a favorable microenvironment for metastatic formation in the liver.

A Risk Signature With Inflammatory and T Immune Cells Infiltration in Colorectal Cancer Predicting Distant Metastases and Efficiency of Chemotherapy.

In order to accurately predict oncological outcomes of colorectal cancer (CRC), we established a risk signature with tumor infiltrating neutrophils and T immune cells for prognosis. A total of 276 CRC patients from FUSCC, and 434 patients from TCGA cohort were enrolled in the study. A risk signature model in combination with CEACAM8+ neutrophils, CD3+, CD8+ T lymphocytes, and FOXP3+ regulatory T cells was established, and the relationships with patient clinicopathological characteristics and prognosis were evaluated. In TCGA cohort, high CEACAM8 expression was observed as an independent factor of poor disease-free survival (DFS), as well as inversely correlated with CD8 (P = 0.0035) and FOXP3 expression (P = 0.05). In the FUSCC cohort for validation, the association between CEACAM8+ neutrophils and DFS had been confirmed in CRC tissue (P = 0.026). Furthermore, a risk stratification was derived from integration of CEACAM8+ neutrophils and T immune cells. In both OS and DFS, the high-risk group all demonstrated worse prognosis than low-risk group, with statistical significance (all P < 0.001). In addition, the high-risk group was correlated with post-operative relapses with accurate prediction. Furthermore, the high-risk group identified a subgroup of CRC patients who appeared not to benefit from adjuvant chemotherapy. At last, predictive nomograms were constructed with recognized independent prognosticators, showing this risk signature increasing the predictive accuracy and efficiency for OS and DFS. In conclusion, incorporation of neutrophil into T lymphocytes could provide more accurate prognostic information in CRC, and this risk stratification predicted for survival benefit from post-operative chemotherapy.

Clinicopathologic features and prognostic value of KRAS, NRAS and BRAF mutations and DNA mismatch repair status: A single-center retrospective study of 1,834 Chinese patients with Stage I-IV colorectal cancer.

Mutations of KRAS, NRAS, BRAF and DNA mismatch repair (MMR) status have become an important part of the assessment of patients with colorectal cancer (CRC), while respective clinicopathologic features and prognostic significance in specific stages and related detection strategies remain unclear. We retrospectively analyzed clinicopathologic features and prognosis of 1,834 patients with Stage I-IV colorectal adenocarcinoma. Mutations in KRAS, NRAS and BRAF and DNA MMR status were determined. The mutation rates of KRAS, NRAS and BRAF were 46.4, 3.2 and 3.5%, respectively, and the mismatch repair gene deletion (dMMR) rate was 5.6%. In a multivariate analysis, female, advanced age, tumor type histology, mucinous carcinoma and positive tumor deposits were associated with a high KRAS mutation rate. A high BRAF mutation rate was associated with female, poor differentiation, lymphovascular invasion and positive tumor deposits. Factors associated with high dMMR rates included low age, large tumor size, poor differentiation, Stages I-III. Tumor site was independently associated with KRAS mutation, BRAF mutation and dMMR. KRAS and BRAF mutations were independent risk factors for shorter overall survival (OS) in Stage IV tumors but not in Stage I-III tumors. NRAS mutation was an independent risk factor for shorter OS in Stage I-II tumors. dMMR was independently associated with longer OS in Stage III tumors.

Adjuvant chemotherapy for rectal cancer with complete pathological response (pCR) may not be necessary: a pooled analysis of 5491 patients.

BACKGROUND: It is recommended postoperative adjuvant chemotherapy for all rectal cancers undergoing neo-chemoradiotherapy regardless of the final yield pathology. However, the role of adjuvant chemotherapy in pathological complete response (pCR) remains controversial. We aimed to identify the necessarily of adjuvant chemotherapy in pCR. METHODS: Consecutive patients with pCR in Fudan University Shanghai Cancer Center (FUSCC) were enrolled. Meanwhile, a pooled analysis of individual patient with pCR was performed from PubMed and Embase databases for validation. RESULTS: A total of 171 patients form FUSCC were identified to achieve pCR with up to almost 10 years follow-up. Among them, those receiving adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (log-rank test = 0.17, P = 0.676). The 5y-DFS rates for patients in chemo group and no-chemo group was 87.5 and 88.8%, respectively, showing no significant difference (p = 0.854). No matter chemotherapy regimens, T stage, EMVI and CRM status varied, the results remained consistent. Meantime, the COX model did not demonstrate adjuvant chemotherapy as the independent risk factor for OS and DFS. Additionally, among 18 systemic recurrences in all, the rate of relapse surged rapidly on the 12 months and rose up to peak in the 36th months. In order to validate these results, nine controlled trials involving 5491 patients with pCR were included in this pooled-analysis. For both 5-year overall survival and disease-free survival, the pooling data did not produce a statistically significant effect in cases of adjuvant chemotherapy performed (RR = 0.79 and RR = 0.95, respectively, all p > 0.05). CONCLUSION: This study suggested that rectal cancer patients with pCR did not benefit from adjuvant chemotherapy and we recommended that achievement of pCR require more prolonged close follow care in case of distant metastasis.

Adjuvant Chemotherapy Seemed Not to Have Survival Benefit in Rectal Cancer Patients with ypTis-2N0 After Preoperative Radiotherapy and Surgery from a Population-Based Propensity Score Analysis.

BACKGROUND: Adjuvant chemotherapy is currently offered routinely, as standard, after radical resection for patients with rectal cancer receiving neo-adjuvant chemoradiation. However, the efficacy of adjuvant chemotherapy in patients with ypTis-2N0M0 has not been documented to the same extent, and the survival benefit remained controversial. The purpose of this work was to determine the role of chemotherapy in patients with ypTis-2N0M0 classification. MATERIALS AND METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results database (n = 4,217). A propensity score model was utilized to balance baseline covariates. RESULTS: Of the 4,217 included patients, 335 with ypTis-2N0M0 did not receive adjuvant chemotherapy. There were comparable cancer-specific survivals (CSS) between those undergoing adjuvant chemotherapy or not (log-rank test = 0.136, p = .712) in the overall sample. After propensity score matching, the cancer-specific survival did not differ between the chemotherapy and observation groups (log-rank test = 0.089, p = .765). Additionally, the Cox model did not demonstrate adjuvant chemotherapy as the prognostic factor, with hazard ratio = 0.95 (95% confidence interval 0.69-1.32) for CSS. Furthermore, the 10-year cumulative CSS was 78.7% and 79.4% between the chemotherapy and observation groups, indicating no significance, and no impact of adjuvant chemotherapy on survival was observed in different subgroups stratified by T stage, histological grade, histology, lymph nodes, and tumor size. CONCLUSION: Patients with ypTis-2N0 rectal cancer did not benefit from adjuvant chemotherapy after preoperative radiology and radical surgery in this cohort study. These results provided new insight into the routine use of adjuvant chemotherapy for patients with rectal cancer with completed neo-adjuvant radiotherapy and curative surgery. IMPLICATIONS FOR PRACTICE: Inconsistent recommendations for patients with rectal cancer receiving neo-adjuvant chemoradiation are offered by clinical guidelines. Adjuvant chemotherapy had no cancer-specific survival benefit, not only in the whole cohort, but also in the propensity score-matched cohort. A Cox model also confirmed adjuvant chemotherapy was not a significant prognostic factor in ypTis-2N0 rectal cancer. No survival benefit conferred by adjuvant chemotherapy was observed, regardless of whether T stage, histological type, grade, lymph nodes and tumor size varied.

Baseline Peripheral Blood Leukocytosis Is Negatively Correlated With T-Cell Infiltration Predicting Worse Outcome in Colorectal Cancers.

We aimed to explore the prognostic value of blood leukocyte and to generate a predictive model to refine risk stratification for colorectal cancers. 6,558 patients with colorectal cancers were identified eligible respectively in Fudan University Shanghai Cancer Center (FUSCC) between May, 2008 and October, 2016. Then the entire set is divided into a training set and a testing set. The prognostic value of pretreatment white blood cell count and clinicopathologic parameters in the context of tumor-infiltrating lymphocytes (TIL) and neutrophils was investigated. Conventional leukocytosis (≥10,000/µl) was significantly associated with decreased overall survival (OS) and disease-free survival (DFS) (p < 0.05). In fact, moderately elevated leukocyte (≥7,500/µl) has also been identified as an independent prognostic factor for survivals in the training, testing, and entire sets, respectively. And leukocytosis correlated with advanced T-stage (p < 0.001), M-stage (p < 0.001), poor differentiation tumor (p = 0.023) and Glasgow prognostic score, even predicted for worse relapse postoperatively (p = 0.001) and resistance to chemotherapy. In addition, nomograms on OS and DFS were established according to leukocytosis and other significant factors, demonstrating a great prediction accuracy. Importantly, pretreatment leukocytosis had a significantly lower intra-tumor CD3+ and CD8+ TIL infiltration (p < 0.001 and p = 0.033), whereas low CD3+ and CD8+ TIL expression in tumor were associated with worse OS and DFS (p = 0.02 and p = 0.015). In conclusion, our study validates leukocytosis as an independent prognostic factor in colorectal cancers. Our data provide for the first-time vital insight on the correlation of peripheral pretreatment leukocytosis with the tumor-infiltrating cells contexture and might be relevant for future risk stratification.

ITGAE Defines CD8+ Tumor-Infiltrating Lymphocytes Predicting a better Prognostic Survival in Colorectal Cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TIL) in colorectal tumor tissue are significantly correlated with a favorable prognosis, such as CD8+ lymphocytes, which are also called tumor-reactive lymphocytes. However, not all tumor-infiltrating T cells confer benefit to patients. Therefore, it is of substantial benefit to identify a biomarker to demarcate these tumor-reactive lymphocytes. METHODS: We investigated whether ITGAE could be used to discriminate reactive CD8+ lymphocytes in colorectal cancer (CRC). TCGA colorectal cancer data sets (n1 = 492, n2 = 386) and FUSCC set (n3 = 276) were used in this study. Further phenotyping of ITGAE+ cells and the mechanistic basis were investigated. FINDINGS: In the training and testing sets from TCGA, ITGAE expression, which is strongly correlated with cytotoxic T cell markers (CD8/CD3/PD1), independently predicted longer disease-free survival (DFS) and overall survival (OS). In line with this, the association between ITGAE+ lymphocytes and survival has been confirmed in the FUSCC cohort for validation (P = .026). ITGAE + cells in the series always co-stained with CD8 were preferentially located in the tumor. Interestingly, ITGAE+ lymphocytes tended to associate with the epithelial-mesenchymal transition (EMT) with decreased Snail and increased E-cadherin expression accompanied. Finally, gene set enrichment analysis showed that immune activation was significantly enriched in the high ITGAE+ TIL group, accompanied by enriched EMT-related pathways. INTERPRETATION: Because of the specified expression of tumor-reactive CD8+ T-cells, ITGAE may be a promising biomarker for the rapid identification of immune infiltration in CRC.

Osteoglycin-induced VEGF Inhibition Enhances T Lymphocytes Infiltrating in Colorectal Cancer.

BACKGROUND: OGN could modify tissue inflammation and immune response via local and circulating innate immune cells, which was suggestive of a reciprocal relationship between OGN and T cell infiltration in cancer. Hence, we aim to measure the OGN expression patterns and immune cells response in colorectal cancer(CRC). METHODS: This study enrolled three independent sets of patients from TCGA and the Fudan University Shanghai Cancer Center(FUSCC). The effect of OGN on T cell infiltration and the mechanism were examined in vitro and in vivo. FINDINGS: Tumor OGN expression levels were positively associated with CD3, CD8, and PTPRC expressions in the training and testing sets from TCGA, respectively. In validation set from FUSCC, OGN expression level also paralleled positively with CD8+ cell density in colorectal cancer tissue (p < .001). For a unit decrease in outcome quartile categories, multivariable OR in the lowest (vs highest) OGN expression was 0.17 (95% CI 0.08-0.33). Consistently, immunofluorescence validated that OGN was preferentially expressed with CD8+ cells in both normal epithelium and cancer tissue. Xenograft tumors arising from MC38 cells with OGN-over-expression displayed a significant increase in CD8+ cells recruitment. Hence, high expression of OGN was associated with a profound longer survival (P = .009). In mechanism, elevated OGN expression inhibited the activation of the transcriptional genes HIF-1α in CRC cells, then significantly impeded the expression of VEGF. As a result of this, T cell tumor infiltration was reduced. INTERPRETATION: OGN expression is positively associated with CD8+ cell density in colorectal cancer tissue, suggesting a possible influence of OGN expression on tumor reactive T cells in the tumor niche. FUND: No.

Osteoglycin (OGN) reverses epithelial to mesenchymal transition and invasiveness in colorectal cancer via EGFR/Akt pathway.

BACKGROUND: Many types of cancers are devoid of the small leucine-rich proteoglycans: osteoglycin (OGN), but its role in tumorigenesis is poorly studied especially in colorectal cancers (CRC). Here we aim to evaluate the relationship between OGN expression patterns and the clinical course of CRC, and the role of OGN in cancer progression. METHODS: The tissue microarray staining was performed and the relevance between OGN expression and oncologic outcomes was performed using Cox regression analysis. The effect of OGN on cell proliferation and tumorigenesis was examined in vitro and in vivo. Immunoprecipitation assay, immunofluorescence analysis and internalization assay were used for mechanistic study. RESULTS: Patients with high expression of OGN were associated with a profound longer survival in CRC and the high serum OGN level was also indicative of fewer recurrences consistently. In colon cancer cells, OGN increased dimerization of EGFR, then triggered EGFR endocytosis and induced the recruitment of downstream components of the EGFR internalization machinery (Eps15 and epsin1). Above all, OGN reduced Zeb-1 expression via EGFR/Akt leading to inhibition of epithelial-mesenchymal transition. As results, in vitro and in vivo, the OGN expression was demonstrated to reduce cell proliferation, inhibit invasion of colon cancer cells then impede cancer progression. CONCLUSIONS: There is a positive association between OGN level and prolonged survival in CRC. OGN plays a restrictive role in colorectal cancer progression by reduced activation of EGFR/AKT/Zeb-1.

Radiotherapy for stage IIA rectal cancer may not benefit all.

This study sought to determine whether additional radiotherapy is necessary in patients after optimal surgery for stage IIA rectal cancer and how the different covariates influence the efficacy of radiotherapy. The first primary rectal cancer was identified from the 1988-December 2013 Surveillance, Epidemiology and End Results database. We identified 13647 patients with IIA rectal cancer, in which 39.6% received neo-adjuvant radiotherapy and in another 14.96% patients the adjuvant radiotherapy were performed. Neo-adjuvant or adjuvant radiotherapy group had better survival with 10-Year cancer-specific survival estimates as 75.1% and 73.8% compared to 68.4% of no radiotherapy group (P < 0.01). Adjusted hazard ratio (HR) demonstrated neo-adjuvant and adjuvant radiotherapy (HR: 0.814 and 0.848) were all associated with significantly decreased risk for cancer death. However, radiotherapy did not seem to yield the same survival benefit in selected population. Adjusted stratified analysis demonstrated patients with increasing age, relative large tumor size, and more retrieved regional lymph nodes had no additional benefit for cancer specific survival based on radiation use. In conclusions, unselected patients with stage IIA rectal cancer receiving radiotherapy experienced better survival in comparison to patients without radiation. However, additional radiotherapy is not beneficial for all.

Fecal Clostridium symbiosum for Noninvasive Detection of Early and Advanced Colorectal Cancer: Test and Validation Studies.

OBJECTIVE: Current non-invasive early detection of colorectal cancer (CRC) requires improvement. We aimed to identified a fecal Clostridium symbiosum-based biomarker for early and advanced colorectal cancer detection. DESIGN: In the test stage, the relative abundance of Clostridium symbiosum (C. symbiosum) was measured by qPCR in 781 cases including 242 controls, 212 colorectal adenoma (CRA) patients, 109 early CRC (tumor restricted to the submucosa) patients, 218 advanced CRC patients. The prediction accuracy was compared to Fusobacterium nucleatum (F. nucleatum), fecal immunochemical test (FIT) and CEA (carcinoembryonic antigen) and validated in an independent cohort of 256 subjects. Current status of the trial:ongoing/still enrolling. Primary endpoint:June, 2017 (Clinicaltrials.gov Identifier NCT02845973). RESULTS: Significant stepwise increase of C. symbiosum abundance was found in CRA, early CRC and advanced CRC (P<0.01). C. symbiosum outperformed all the other markers in early CRC prediction performance. The combination of C. symbiosum and FIT achieved better performance (0.803 for test cohort and 0.707 for validation cohort). For overall discrimination of CRCs, the combination of all above markers achieved the performance of 0.876. CONCLUSIONS: Fecal C. symbiosum is a promising biomarker for early and noninvasive detection of colorectal cancer, being more effective than F. nucleatum, FIT and CEA. Combining C. symbiosum and FIT or CEA may improve the diagnosis power.

Very Early Colorectal Anastomotic Leakage within 5 Post-operative Days: a More Severe Subtype Needs Relaparatomy.

Early anastomotic leakage (AL), usually defined as leakage within 30 post-operative days, represents a severe entity. However, mounting evidence has indicated that majorities of leakage occur within one week after surgery, making late AL rarity. Here we analyzed 101 consecutive colorectal AL, all of which occurred within 30 post-operative days, during Jan 2013 and Dec 2015 in cancer hospital of Fudan University. AL occurring within 5 post-operative days was defined as very early AL (vE-AL). We evaluated risk factors of vE-AL compared with non-vEAL and correlated with post-leakage peritonitis and need of relaparatomy. We found that AL occurred at median time of 7 days after surgery. 23 cases were vE-AL. Reconstruction of post-peritoneum for mid-low rectal carcinoma significantly reduced incidence of vE-AL compared with non-vE-AL (p = 0.042). Patients with vE-AL was associated with presence of peritonitis (p = 0.031), the latter significantly correlated with increased re-operation rate (p = 6.8E-13). Besides, patients with vE-AL trended to correlate with increased re-operation rate after leakage (p = 0.088). In concludsion, vE-AL occurring within 5 post-operative days represents a severe subtype associated with general peritonitis and need of relaparatomy.

Smaller tumor size is associated with poor survival in T4b colon cancer.

AIM: To hypothesize that in patients with colon cancer showing heavy intestinal wall invasion without distant metastasis (T4bN0-2M0), small tumor size would correlate with more aggressive tumor behaviors and therefore poorer cancer-specific survival (CSS). METHODS: We analyzed T4bN0-2M0 colon cancer patients in the Surveillance, Epidemiology and End Results (SEER) database. A preliminary analysis of T4bN0-2M0 colon cancer patients at the Fudan University Shanghai Cancer Center is also presented. RESULTS: A total of 1734 T4bN0-2M0 colon cancer patients from the SEER database were included. Kaplan-Meier analysis revealed decreasing CSS with decreasing tumor size (P < 0.001). Subgroup analysis showed a significant association between poorer CSS with smaller tumor size in T4bN0 patients (P = 0.024), and a trend of association in T4bN1 (P = 0.182) and T4bN2 patients (P = 0.191). Multivariate analysis identified tumor size as an independent prognostic factor for CSS in T4bN0-2M0 patients (P = 0.024). Preliminary analysis of Fudan University Shanghai Cancer Center samples suggested the 5-year CSS was 50.0%, 72.9% and 77.1% in patients with tumors ≤ 4.0 cm, 4.0-7.0 cm and ≥ 7.0 cm. CONCLUSION: Smaller tumor size is associated with poorer CSS in the T4bN0-2M0 subset of colon cancer, particularly in the T4bN0M0 subgroup.

Laparoscopic vs open abdominoperineal resection in the multimodality management of low rectal cancers.

AIM: To evaluate the safety and feasibility of laparoscopic abdominoperineal resection compared with the open procedure in multimodality management of rectal cancer. METHODS: A total of 106 rectal cancer patients who underwent open abdominoperineal resection (OAPR) were matched with 106 patients who underwent laparoscopic abdominoperineal resection (LAPR) in a 1 to 1 fashion, between 2009 and 2013 at Fudan University Shanghai Cancer Center. Propensity score matching was carried out based on age, gender, pathological staging of the disease and administration of neoadjuvant chemoradiation. Data regarding preoperative staging, surgical technique, pathological results, postoperative recovery and complications were reviewed and compared between the LAPR and OAPR groups. Perineal closure around the stoma and pelvic floor reconstruction were performed only in OAPR, not in LAPR. Therefore, abdominoperineal resection procedure-specific surgical complications including parastomal hernia and perineal wound complications were compared between the open and laparoscopic procedure. Regular surveillance of the two cohorts was carried out to gather prognostic data. Disease-free survival was analyzed using Kaplan-Meier estimate and log-rank test. Subgroup analysis was performed in patients with locally advanced disease treated with preoperative chemoradiation followed by surgical resection. RESULTS: No significant difference was found between the LAPR group and the OAPR group in terms of clinicopathological features. The operation time (180.8 ± 47.8 min vs 172.1 ± 49.2 min, P = 0.190), operative blood loss (93.9 ± 60.0 mL vs 88.4 ± 55.2 mL, P = 0.494), total number of retrieved lymph nodes (12.9 ± 6.9 vs 12.9 ± 5.4, P = 0.974), surgical complications (12.3% vs 15.1%, P = 0.549) and pathological characteristics were comparable between the LAPR and OAPR group, respectively. Compared with OAPR patients, LAPR patients showed significantly shorter postoperative analgesia (2.4 ± 0.7 d vs 2.7 ± 0.6 d, P < 0.001), earlier first flatus (57.3 ± 7.9 h vs 63.5 ± 9.2 h, P < 0.001), shorter urinary drainage time (6.5 ± 3.4 d vs 7.8 ± 1.3 d, P < 0.001), and shorter postoperative admission (11.2 ± 4.7 d vs 12.6 ± 4.0 d, P = 0.014). With regard to APR-specific complications (perineal wound complications and parastomal hernia), there were no significant differences between the two groups. Similar results were found in the 26 pairs of patients administered neoadjuvant chemoradiation in subgroup analysis. During the follow-up period, no port site recurrences were observed. CONCLUSION: Laparoscopic abdominoperineal resection for multidisciplinary management of rectal cancer is safe, and is associated with earlier recovery and shorter admission time in combination with neoadjuvant chemoradiation.

Standard chemotherapy with cetuximab for treatment of colorectal cancer.

AIM: To review and assess the evidence related to cetuximab treatment in metastatic colorectal cancer (mCRC) with regard to KRAS status. METHODS: PubMed, EMBASE, Cochrane database and American Society of Clinical Oncology meeting abstracts were searched for randomized controlled trials (RCTs) reporting the effect of KRAS status on efficacy of chemotherapy regimen with or without cetuximab in mCRC. Baseline information such as sex and age was summarized from the included studies. Hazard ratios of progression-free survival (PFS) and overall survival (OS) as well as objective response based on KRAS status were extracted for analysis. RESULTS: A total of 8 RCTs with 6780 patients were included. The combined analysis showed that cetuximab failed to improve the OS and PFS in patients with mCRC. However, in subgroup analysis, the pooled data showed that addition of cetuximab to irinotecan containing chemotherapy regimen was sufficient to improve OS and PFS in wild-type KRAS mCRC patients, but not in patients with mutant-type KRAS. The addition of cetuximab increased the incidence of adverse events such as diarrhea, rash, skin toxicity/rash, and nausea and vomiting. There was no significant publication bias existing in the included studies. CONCLUSION: The clinical benefit of cetuximab was only confirmed in patients with wild-type KRAS. KRAS status could be considered a biomarker of efficacy of cetuximab.

Direct-S: a directed mass spectrometry method for biomarker verification in native serum.

Serum has been the logical choice and most-used bio-specimen for monitoring biomarkers. However, direct analysis of low-abundance biomarkers in serum is still a problem. Here, we have established a directed mass spectrometry (inclusion list driven MS) method, Direct-S, for direct quantification of protein biomarkers in native serum samples without high-abundance protein depletion or pre-fractionation. In Direct-S, an (18)O-labeling technique was used to produce internal standards of the targeted peptides, and only targeted peptides were selected for tandem mass spectrometry (MS/MS) fragmentation to increase sensitivity and efficiency. The (16)O/(18)O ion pairs of target peptides and the elution time/fragmental pattern of the internal standards were used to facilitate the identification of the low-abundance peptides. Using Direct-S, three candidate biomarkers, α1-antitrypsin (A1AT), galectin-3 binding protein (LG3BP) and cathepsin D (CTSD), which represent different abundance levels, were quantified in serum samples of colorectal cancer (CRC) patients and healthy candidates. Direct-S exhibited good linearity of response from 20 fmol to 0.5 nmol (r > 0.9845). Reliable quantification across five orders of magnitude and as low as 71 pg µL(-1) was achieved in serum samples. In conclusion, Direct-S is a low cost, convenient and accurate method for verifying serum biomarkers.