Comprehensive Evaluation of Relapse Risk (CERR) Score for Colorectal Liver Metastases: Development and Validation.

BACKGROUND: The calculation of the tumor burden score (TBS) is not perfect because the bilobar spread of colorectal liver metastasis (CRLM) is neglected. The identification of an ideal prognostic scoring system for CRLM remains controversial. MATERIALS AND METHODS: Patients who underwent curative intent liver resection for CRLM from one medical center were enrolled in cohort 1 (787 patients) and cohort 2 (162 patients). Tumor relapse-free survival (RFS) was the main outcome. A Cox regression model was used to identify independent predictors of prognosis. The time-dependent area under the curve, calibration curve, and C-index were employed to validate the predictive ability of the survival model. RESULTS: Modified TBS (mTBS) was established by a mathematical equation with parameters including CRLM size, CRLM number, and unilobar or bilobar metastasis. Five preoperative predictors of worse RFS were identified in cohort 1 and incorporated into the Comprehensive Evaluation of Relapse Risk (CERR) score: KRAS/NRAS/BRAF-mutated tumor (1 point); node-positive primary (1 point); extrahepatic disease (1 point); carcinoembryonic antigen level > 200 ng/mL or carbohydrate antigen 19-9 (CA19-9) >200 U/mL (1 point); and mTBS between 5 and 11 (1 point) or 12 and over (2 points). Patients in cohort 1 were stratified by their CERR score into risk groups: the high-risk group (CERR score 4 or more), the medium-risk group (CERR score 2-3), and the low-risk group (CERR score 0-1). Importantly, internal validation in cohort 1 and further validation in cohort 2 both showed the superior discriminatory capacity of the CERR score. CONCLUSION: mTBS should be promoted. The CERR score is a powerful prognostic tool that can help determine optimal clinical management strategies. IMPLICATIONS FOR PRACTICE: This work resulted in the successful modification of the tumor burden score and development of a comprehensive and practical prognostic scoring system-the Comprehensive Evaluation of Relapse Risk (CERR) score. The CERR score, with a better prognostic discriminatory ability, outperformed the Fong score. Perhaps more importantly, the CERR score is a powerful prognostic tool because it unified the most consistently reported prognostic factors. Therefore, the CERR score can assist doctors in determining optimal clinical management strategies.

A novel patient-derived organoids-based xenografts model for preclinical drug response testing in patients with colorectal liver metastases.

BACKGROUNDS: Cancer-related mortality in patients with colorectal cancer (CRC) is predominantly caused by development of colorectal liver metastases (CLMs). How to screen the sensitive chemotherapy and targeted therapy is the key element to improve the prognosis of CLMs patients. The study aims to develop patient-derived organoids-based xenografted liver metastases (PDOX-LM) model of CRC, to recapitulate the clinical drug response. METHODS: We transplanted human CRC primary tumor derived organoids in murine spleen to obtain xenografted liver metastases in murine liver. Immunohistochemistry (IHC) staining, whole-exome and RNA sequencing, and drug response testing were utilized to identify the homogeneity in biological and genetic characteristics, and drug response between the PDOX-LM models and donor liver metastases. RESULTS: We successfully established PDOX-LM models from patients with CLMs. IHC staining showed that positive expression of CEA, Ki67, VEGF, FGFR2 in donor liver metastases were also well preserved in matched xenografted liver metastases. Whole-exon sequencing and transcriptome analysis showed that both xenografted and donor liver metastases were highly concordant in somatic variants (≥ 0.90 frequency of concordance) and co-expression of driver genes (Pearson's correlation coefficient reach up to 0.99, P = 0.001). Furthermore, drug response testing showed that the PDOX-LM models can closely recapitulated the clinical response to mFOLFOX6 regiments. CONCLUSIONS: This PDOX-LM model provides a more convenient and informative platform for preclinical testing of individual tumors by retaining the histologic and genetic features of donor liver metastases. This technology holds great promise to predict treatment sensitivity for patients with CLMs undergoing chemotherapy.

Short-term and long-term outcomes of robotic rectal surgery-from the real word data of 1145 consecutive cases in China.

BACKGROUND: Due to a limited patient sample size, substantial data on robotic rectal resection (RRR) is lacking. Here, we reported a large consecutive cases from the real word data to assess the safety and efficacy of RRR. METHODS: From September 2010 to June 2017, a total of 1145 consecutive RRR procedures were performed in patients with stage I-IV disease. We conducted an analysis based on information from a prospectively designed database to evaluate surgical outcomes, urogenital function, and long-term oncological outcomes. RESULTS: Of three types of RRR performed, 227 (24.2%) were abdominoperineal resections, 865 (75.5%) were anterior resections, and 3 (0.3%) were Hartmann. Conversion to an open procedure occurred in 5.9% of patients. The overall positive circumferential margin rate was 1.3%. Surgical complication rate and mortality were 16.2% and 0.8% within 30 days of surgery, respectively. Mean hospital stay after surgery and hospital cost were 6.3 ± 2.9 days and 10442.5 ± 3321.5 US dollars, respectively. Risk factors for surgical complications included male gender, tumor location (mid-low rectum), combined organ resection, and clinical T category (cT3-4). Urinary function and general sexual satisfaction decreased significantly 1 month after surgery for both sexes. Subsequently, both parameters increased progressively, and the values 1 year after surgery were comparable to those measured before surgery. At a median follow-up of 34.6 months, local recurrence and distant metastases occurred in 2.3% and 21.1% of patients, respectively. CONCLUSIONS: Robotic rectal resection was safe with preserved urogenital function and arrived equivalent oncological outcomes in a nonselected group of patients with rectal cancer.

Case report: Nutritionally supported perioperative chemo-immunotherapy for advanced gastric cancer with incomplete pyloric obstruction.

This case describes the benefits of perioperative chemo-immunotherapy for advanced gastric cancer and incomplete pyloric obstruction, supplemented with nutritional support. Early parenteral nutrition to stabilize nutritional status and mitigate nutrition impact symptoms, and in addition, throughout the chemo-immunotherapy perioperative period also maintained oral nutrition support and a tailored dietary plan. Above nutritional support maintained the patient's physical condition during immunotherapy. Eventually, this combination therapy plan leads to a partial response. On the other hand, a combination of therapies that focus more on immune checkpoint inhibitor may be able to mitigate the side effects of chemotherapy. Such findings may yield novel prospects for patients with advanced gastric cancer and incomplete pyloric obstruction, enabling them to achieve better outcomes.

Erratum: Zinc-α2-glycoprotein 1 promotes EMT in colorectal cancer by filamin A mediated focal adhesion pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.35380.].

Efficacy of the Short-Term versus Long-Term Administration of Antimicrobial Prophylaxis in Gastric Cancer Surgery: A Meta-Analysis of Randomized Controlled Trials.

Background: We performed a meta-analysis to confirm the efficacy of short-term compared with long-term administration of antimicrobial prophylaxis in gastric cancer surgery. Methods: Randomized controlled trials of the efficacy of short-term versus long-term administration of antimicrobial prophylaxis in gastric cancer surgery were searched using the MEDLINE, EMBASE, and the Cochrane Controlled Trials Register databases. The data were evaluated and statistically analyzed using RevMan version 5.3.0. Five studies including 2,053 participants who received short-term versus long-term administration of antimicrobial prophylaxis in gastric cancer surgery were considered. Results: There was no significant difference in the surgical site infection (SSI) rate between the short-term group and the long-term group (8.1% vs. 9.2%; odds ratio [OR], 0.87; 95% confidence interval [CI], 0.64-1.09; p = 0.39). Hierarchical analysis also showed no significant differences in incisional-site incisions, organ/space incisions, or leakage. Multivariable analysis showed no significant differences in gender, age (>65 years), body mass index (>25 kg/m2), D2, operation time (>3 hours), pathologic stage 3, blood loss, combined resection, diabetes mellitus, total gastrectomy, or blood transfusion between the two groups. Conclusions: Short-term administration of antimicrobial prophylaxis did not increase the incidence of SSIs after gastrectomy.

Risk factor analysis and construction of prediction models for short-term postoperative complications in patients undergoing gastrointestinal tract surgery.

Purpose: To identify risk factors associated with short-term postoperative complications in patients with gastrointestinal cancer and develop and validate prediction models to predict the probability of complications. Methods: A total of 335 patients enrolled in the primary cohort of this study were divided into training and validation sets in a chronological order. Using univariate and multivariate logistic regression analyses, the risk factors for postoperative complications were determined, and nomogram prediction models were constructed. The performance of the nomogram was assessed with respect to the receiver operator characteristic and calibration curves. Results: Patients with complications had a stronger postoperative stress response and a longer duration of daily fluid intake/output ratio >1 after surgery. Logistic analysis revealed that body mass index (BMI), body temperature on POD4 (T.POD4), neutrophil percentage on POD4 (N.POD4), fasting blood glucose on POD4 (FBG.POD4), and the presence of fluid intake/output ratio <1 within POD4 were risk factors for POD7 complications, and that BMI, T.POD7, N.POD7, FBG.POD4, FBG.POD7, and the duration of daily fluid intake/output ratio >1 were risk factors for POD30 complications. The areas under the curve of Nomogram-A for POD7 complications were 0.867 and 0.833 and those of Nomogram-B for POD30 complications were 0.920 and 0.918 in the primary and validation cohorts, respectively. The calibration curves showed good consistency in both cohorts. Conclusion: This study presented two nomogram models to predict short-term postoperative complications in patients with gastrointestinal cancer. The results could help clinicians identify patients at high risk of complications within POD7 or POD30.

A trinity technique for prevention of low rectal anastomotic leakage in the robotic era.

BACKGROUND: Anastomotic leakage (AL) is a severe complication of low anterior resection (LAR) for rectal cancer, and effective prevention is urgently needed. In the robotic era, this study aimed to explore the role of innovative techniques in preventing AL in rectal cancer patients undergoing robotic LAR. METHODS: From May 2012 to May 2017, a total of 601 patients underwent robotic LAR, with 191 patients participated as control subjects (non-PST group) and 410 patients are subjected to a trinity technique (PST group). The AL rate, short-term and long-term outcomes are analyzed and compared. RESULTS: The overall rate of AL was 6.8% out of 601 patients, with Grade B at 5.7% and Grade C at 1.1%, using the ISREC grading system. The PST group presented lower incidence of both overall AL (5.1% vs 10.5%, P = 0.015) and major AL (0.2% vs 3.2%, P = 0.005), when compared with the non-PST group, respectively. Furthermore, the PST group had similar surgical complications (17.3% vs 20.9%, P = 0.286), while with lower re-hospitalization rate (2.7% vs 6.3%, P = 0.038) and reoperation rate (0.2% vs 4.2%, P = 0.001), compared with the non-PST group, respectively. Short-term recovery and long-term oncological outcomes were not significant in the two groups. By multivariate logistic regression models, the risk factors of AL of robotic LAR are confirmed as non-PST technique, estimated blood loss ≥100 mL, anastomosis from anal verge <5 cm, and distal resection margin from tumor <2 cm. CONCLUSIONS: The innovative PST technique may shed light on an effective method for preventing occurrence of AL in robotic LAR.

Predictive And Prognostic Value Of Hepatic Steatosis In Conversion Therapy For Colorectal Liver-limited Metastases: A Propensity Score Matching Analysis.

PURPOSE: To evaluate the role of hepatic steatosis (HS) in patients with synchronous colorectal liver-limited metastases (CLLMs) undergoing conversion therapy. PATIENTS AND METHODS: From March 2013 to March 2017, a total of 406 patients with initially unresectable CLLMs accepted conversion therapy in multidisciplinary team (MDT). Before the implementation of conversion therapy, all patients underwent CT scan to assess the presence of hepatic steatosis and divided into the HS group (n = 124) and the non-HS group (n = 282). After using propensity score matching (PSM) to eliminate the potential confounding bias of the two groups, the conversion hepatectomy rate and long-term oncological survival in two groups were compared. RESULTS: After 1:1 PSM, no significant difference was observed at baseline between patients in the HS group (n = 119) and the non-HS group (n = 119). Patients in the HS group had higher conversion hepatectomy rate from MDT evaluation (31.1% vs 18.5%, P = 0.029) and actual hepatectomy rate (30.2% vs 18.5%, P = 0.030), when compared with patients in the non-HS group, respectively. In addition, the HS group achieved better progression-free survival (PFS, P = 0.047) and overall survival (OS, P = 0.035) than that of the non-HS group. Multivariate logistic analysis confirmed that pretreatment HS was an independent predictor for conversion hepatectomy rate (OR, 2.393; 95% CI, 1.463-4.315, P = 0.001), and multivariate Cox analysis revealed that HS was an independent prognostic factor for PFS (HR, 0.493, 95% CI 0.281-0.866, P = 0.014) and OS (HR, 0.559, 95% CI 0.398-0.785, P = 0.001). CONCLUSION: For CLLM patients who underwent conversion therapy, hepatic steatosis could be an effective predictor for conversion hepatectomy rate and an independent prognostic factor for PFS and OS.

The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1-STAT3 signaling pathway.

The tumor-derived factors involved in the expansion and accumulation of myeloid-derived suppressor cells (MDSCs) in metastatic dissemination of colorectal cancer (CRC) to the liver has not been studied. Immunohistochemistry was used to detect sphingosine-1-phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) in human colorectal tumors. IL-6 and interferon-γ were detected by enzyme-linked immunosorbent assay (ELISA). Tumor growth, invasion, and migration were evaluated by MTT, transwell, and wound healing assays, respectively. Subcutaneous tumor-bearing and CRC liver metastasis (CRLM) nude mouse models were constructed. The percentage of MDSCs was measured using multicolor flow cytometry. Western blot assay was used to evaluate S1PR1 and p-STAT3 expression in MDSCs after separation from the liver and tumor by magnetic antibody. T-cell suppression assay was detected by carboxyfluorescein succinimidyl ester (CFSE). Aberrant co-expressed S1PR1 and p-STAT3 was correlated with metachronous liver metastasis and poor prognosis in CRC. A mutual activation loop between S1PR1 and STAT3 can enhance CRC cell proliferation, migration, and invasion in vitro and in vivo. The expression of p-STAT3 and its downstream proteins can be regulated by S1PR1. p-STAT3 was the dependent signaling pathway of S1PR1 in the promotion of cell growth and liver metastasis in CRC. The level of IL-6 and the associated MDSCs stimulated by the S1PR1-STAT3 correlated with the number of liver metastatic nodes in the CRLM mouse models and patients. Increased CD14+HLA-DR-/low MDSCs from CRLM patients inhibited autologous T-cell proliferation and predict poor prognosis. The S1PR1-STAT3-IL-6-MDSCs axis operates in both tumor cells and MDSCs involved in the promotion of growth and liver metastasis in CRC. MDSCs induced by S1PR1-STAT3 in CRC cells formed the premetastatic niche in the liver can promote organ-specific metastasis.

Zinc-α2-glycoprotein 1 promotes EMT in colorectal cancer by filamin A mediated focal adhesion pathway.

Liver metastasis is the main reason for the poor prognosis of colorectal cancer, and identifying molecules involved in liver metastases of colorectal cancer may provide effective therapeutic targets. Zinc-α2-glycoprotein 1(AZGP1) is a candidate biomarker for diagnosis and prognosis in cancer. However, its function and molecular mechanism in metastatic colorectal cancer remains largely unknown. We previously found that up-regulated AZGP1 promotes proliferation, migration and invasion in colorectal cancer cell line, here we elucidated the mechanism of AZGP1 in regulating metastasis. In this article, we found that AZGP1 was also highly expressed in colorectal cancer tissues with liver metastasis relative to those without metastasis, and abundant expression of AZGP1 was associated with poor prognosis, also, AZGP1 down regulation prevented cell metastasis in vivo and in vitro. We further demonstrated that AZGP1 promotes metastasis by regulating the epithelial-mesenchymal transition (EMT) and associating with molecules involved in the focal adhesion pathway, including the adhesion molecule FLNA, which acts as an important protein interactor. More importantly, AZGP1 down regulation inhibited the phosphorylation of FLNA mediated by the restrain of PAK2 kinase, thereby inducing its proteolysis and subsequently affecting its subcellular localization, where it regulates the EMT and promotes metastasis. Collectively, these results highlight AZGP1 as a new and promising therapeutic molecule for liver metastatic colorectal cancer.

Prognostic impact of KRAS and BRAF mutations in patients who underwent simultaneous resection for initially resectable colorectal liver metastases.

This study aimed to explore the prognostic impact of KRAS and BRAF mutations in patients who underwent simultaneous resection for synchronous colorectal liver metastases (SCRLMs) that were initially resectable. Clinicopathological and outcome data of 139 consecutive patients with SCRLMs who underwent resection between July 2003 and July 2013 was collected from our prospectively established SCRLM database. The KRAS and BRAF genotypes were evaluated in the primary cancer tissues by pyrosequencing. The prognostic value of KRAS and BRAF status was assessed by Kaplan-Meier and Cox regression analyses. KRAS and BRAF mutated in 28.8% and 7.2% of the patients with SCRLMs, respectively, but the genotypes did not significantly associate with any clinicopathologic characteristics. By Kaplan-Meier survival analysis, we found KRAS mutation was not significantly associated with short overall survival (OS) (P = 0.213), but was significantly correlated with short disease-free survival (DFS) (P = 0.041); BRAF mutation was significantly associated with both short OS and DFS (P = 0.001, P<0.001, respectively). Multivariate survival analysis showed KRAS mutation was an independent negative prognostic factor for DFS (P = 0.005) and BRAF mutation was an independent negative prognostic factor for OS and DFS (P = 0.001, P<0.001, respectively). KRAS and BRAF mutation similarly contributed to an adverse prognostic effect in patients who underwent simultaneous resection for SCRLMs that were initially resectable. These findings should suggest the use of KRAS and BRAF status in current practice as an important determinant for precision surgery for initially resectable SCRLMs.

Differences in clinical characteristics and mutational pattern between synchronous and metachronous colorectal liver metastases.

PURPOSE: To investigate differences in clinical characteristics and mutational patterns between synchronous and metachronous colorectal liver metastases (CLMs). PATIENTS AND METHODS: From June 2008 to December 2014, patients with RAS wild-type CLMs treated at Zhongshan Hospital, Fudan University were included. DNA extracted from formalin-fixed paraffin-embedded tissue of primary tumors was sequenced with next-generation sequencing for single-nucleotide polymorphism of 96 genes according to custom panel. Mutations were compared between synchronous and metachronous liver metastases and correlated with clinical characteristics. RESULTS: A total of 161 patients were included: 93 patients with synchronous CLM and 68 patients with metachronous CLM. Patients with metachronous CLM were obviously elder. For pathology of primary tumors, synchronous CLMs were larger in size, poorly differentiated, and more frequently local advanced and lymph node positive. For evaluation of liver metastases, synchronous CLM had more and larger metastatic lesions. The median number of mutations in synchronous CLMs was significantly higher than in metachronous group (22 vs. 18, p<0.001). EGFR rs2227983 is the most prevalent mutation in both groups and only a part of prevalent mutations is shared in both groups. Prevalent mutations were correlated with many clinical characteristics. EGFR rs2227983, RBMXL3 rs12399211, and PTCH1 rs357564 were prognostic for latency of metachronous CLM. CONCLUSION: Clinically, synchronous CLMs, compared with metachronous CLMs, were younger and showed heavier tumor burden for both primaries and liver metastases. Genetically, we identified different mutational patterns between synchronous and metachronous CLMs and several correlations between mutations and clinical characteristics. Further researches were needed to confirm these potential key mutations of CLMs.

Patients with RAS wild-type right-sided unresectable liver-confined mCRC also benefit from cetuximab plus chemotherapy in first-line treatment.

Growing evidence indicates that primary tumor location of metastatic colorectal cancer (mCRC) can affect response to specific therapy. This study aimed to assess the impact of primary tumor location on efficacy of cetuximab in Chinese patients with mCRC. We included patients with RAS wild-type liver-limited mCRC treated with first-line cetuximab plus chemotherapy or chemotherapy alone between June 2008 and December 2016. All patients were categorized as having left-sided tumors or right-sided tumors. Progression free survival (PFS), overall survival (OS), objective response rate (ORR) and conversion rate of surgery for liver metastases was analyzed according to tumor location and treatment. Right-sided tumors were characterized with larger primary tumor, poorer differentiation, more lymph node metastases and larger and more liver metastases. For patients with left-sided tumors (N=233), addition of cetuximab to chemotherapy significantly improved ORR (68.9% vs. 30.6%, OR=5.01, P < 0.001), conversion rate of liver surgery (33.5% vs. 10.8%, OR=4.18, P < 0.001), PFS (12.1 months vs. 6.1 months, HR=0.42, P < 0.001), and OS (not evaluable vs. 23.1 months, HR=0.31, P < 0.001). Among patients with right-sided tumors (N=85), cetuximab plus chemotherapy, compared with chemotherapy alone, also significantly improved ORR (56.8% vs. 29.3%, OR=3.18, P=0.010), PFS (9.3 months vs. 5.1 months, OR=0.57, P=0.012) and OS (25.3 months vs. 16.8 months, HR=0.56, P=0.032) but conversion rate of liver surgery (20.5% vs. 9.8%, HR=2.38, P=0.171). Our results demonstrated differential effect of cetuximab on efficacy outcomes based on tumor sidedness. Also, we found that patients with right-sided tumors also benefit from cetuximab plus chemotherapy but not as great as left-sided tumors and in general, did worse. In conclusion, findings of previous studies about differential effect of anti-EGFR therapy based on tumor sidedness are applicable to an Asian population.

Additional Biomarkers beyond RAS That Impact the Efficacy of Cetuximab plus Chemotherapy in mCRC: A Retrospective Biomarker Analysis.

PURPOSE: We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. RESULTS: Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. CONCLUSIONS: In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.