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.

Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level.

Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+ ) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+ /NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two-photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT-mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.

Mechanotechnical faults and particular issues of anastomotic complications following robot-assisted anterior resection in 968 rectal cancer patients.

BACKGROUND: As most risk factors for anastomotic complications (AC) in rectal cancer patients appear to be noncorrectable, it is needed to find the correctable causes. Additionally, the outcomes of indocyanine-green fluorescence imaging (IFI) and robot-stapled anastomosis have yet been undetermined. METHODS: This study retrospectively analyzed 968 consecutive patients with rectal cancer, who underwent curative robot-assisted anterior resections between 2010 and 2018. IFI parameters and stapling features in the surgical records were reviewed, and reconfirmed. RESULTS: AC occurred in 54 patients (5.6%), 34 (3.5%) with anastomotic leakage (AL) and 24 (2.5%) with anastomotic stenosis (AS). Mechanotechnical faults including defective stapling configurations, including angles lesser than or equal to 150° and outer deviation (more than half from the center of the circle) of linear staples, between the two linear staples were independently associated with AL (P < .001 each). IFI significantly reduced AL rate (2.5% vs 5.3%, P = .029) and AS rate (2% vs 18.8%, P = .006), respectively. Robot linear stapling enabled to maintain the obtuse angle during consecutive staplings and reduced console time. AL and AS were independent risk factors for disease-free survival (P = .02) and local recurrence (P = .03), respectively. CONCLUSIONS: AC were associated with some correctable causes, namely, mechanotechnical errors and lack of use of IFI.

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.

Utility of indocyanine-green fluorescent imaging during robot-assisted sphincter-saving surgery on rectal cancer patients.

BACKGROUND: There have been few studies describing the use of indocyanine green (ICG) fluorescent imaging during robot-assisted (RA) sphincter-saving operations (SSOs) and assessing its potential role in reducing anastomotic leak (AL). METHODS: A consecutive cohort of 436 rectal cancer patients who underwent curative RA SSOs were prospectively enrolled during 2010-2014, including 123 patients with ICG imaging (ICG+ group) and 313 patients without ICG imaging (ICG- group). RESULTS: ICG imaging appeared to be helpful in identifying competent perfusion of the bowel adjacent to the anastomosis in 13 patients (10.6%) who might be susceptible to bowel ischaemia, including restrictive mesocolon. AL was remarkably greater in the ICG- group compared with the ICG+ group (5.4% vs 0.8%; p = 0.031). CONCLUSIONS: ICG imaging during RA SSO provides accurate real-time knowledge of the perfusion status at or near the anastomosis, specifically reducing AL in patients who may incur bowel ischaemia. Copyright © 2015 John Wiley & Sons, Ltd.