Cold-inducible RNA-binding protein (CIRP) is related to a family of stress-induced RNA-binding proteins. It is primarily found in the nucleus, where it regulates transcription. Under stress, CIRP translocates to the cytoplasm where it modulates translation; a subset is secreted as extracellular CIRP (eCIRP) which is a damage-associated molecular pattern (DAMP) molecule that stimulates the production of inflammatory mediators. Elevated blood eCIRP levels may foster immune tolerance and facilitate tumor growth. Increased CIRP levels have been noted in various malignancies including colorectal cancer (CRC). This study’s objective was to determine plasma eCIRP levels before and after minimally invasive colorectal resection (MICR) for CRC.

To assess plasma eCIRP levels prior to and following minimally invasive colorectal resection in the context of cancer pathology.

MICR patients from an IRB-approved data/tissue bank for whom plasma samples were available were eligible. Plasma specimens were obtained preoperatively (preop) and at least 3 time’s postop [between postoperative day (POD) 1-41]; late samples were grouped into 7-day blocks and were considered separate time points. eCIRP levels were assessed via enzyme-linked immunosorbent assay (pg/mL) and results presented as mean ± SD, analysis with Wilcoxon paired t-test).

A total of 83 CRC patients who underwent MICR [colon 66%, rectal 34%; laparoscopic-assisted (LA), 70%; hand-assisted laparoscopic (HAL), 30%] were studied. The mean preop eCIRP level was 896.8 ± 757.0 pg/mL. Elevations in mean plasma levels (P = < 0.001) were noted on POD1 (2549 ± 2632 pg/mL, n = 83), POD3 (1871 ± 1362 pg/mL, n = 77), POD7-13 (1788 ± 1403 pg/mL, n = 57), POD14-20 (1473 ± 738.8 pg/mL, n = 30), and POD21-27 (1681 ± 1375 pg/mL, n = 21). No significant differences were noted at POD 28-41. Higher values were noted in the HAL’s (vs LA) group, however, there were more rectal cancers in the former.

Elevated plasma eCIRP levels persist for a month post MICR for CRC (change from baseline, 77%-184%); highest values seen on POD1. The initial surge may be due to the acute inflammatory response while later elevations may be related to wound healing and remodeling. The higher levels noted in the HAL’s group (with greater IL and more rectal cases) suggest the extent of surgical trauma impacts eCIRP levels. Further investigations are needed.

• Effects of surgery
• Plasma extracellular cold-inducible RNA-binding protein levels
• Colorectal resection
• Colorectal cancer
• Angiogenesis

• minimally invasive colorectal cancer resection plasma osteopontin levels

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that inhibits urokinase-type plasminogen activator and tissue-type plasminogen activator. PAI-1 participates in angiogenesis, wound healing and tumor invasion, and additionally regulates endothelial cell proliferation, angiogenesis and tumor growth. The purpose of the present study was to measure plasma PAI-1 levels perioperatively in patients with colorectal cancer (CRC) undergoing minimally invasive colorectal resection (MICR). Patients with CRC who underwent elective MICR were eligible for the study. All patients were enrolled in an approved data/plasma bank. Patients with preoperative, postoperative day (POD) 1, POD 3, and at least one POD 7-34 plasma sample collection were studied. Plasma PAI-1 levels were determined in duplicate using ELISA, and the medians and 95% confidence intervals (CIs) were determined. The correlations between postoperative plasma PAI-1 levels and length of surgery were evaluated. PAI-1 levels were compared between patients who underwent laparoscopic-assisted vs. hand-assisted surgery. The preoperative PAI-1 levels of stage I, II, III and IV pathological stage subgroups were also compared. A total of 91 patients undergoing MICR for CRC were studied. The mean incision length was 8.0±3.9 cm, and the length of stay was 6.8±4.3 days. Compared with the median preoperative levels (17.30; 95% CI: 15.63-19.78 ng/ml), significantly elevated median levels were observed on POD 1 (28.86; 95% CI: 25.46-31.22 ng/ml; P<0.001), POD 3 (18.87; 95% CI: 17.05-21.78 ng/ml; P=0.0037), POD 7-13 (26.97; 95% CI: 22.81-28.74 ng/ml; P<0.001), POD 14-20 (25.92; 95% CI: 17.85-35.89 ng/ml; P=0.001) and POD 21-27 (22.63; 95% CI: 20.03-30.09 ng/ml; P<0.001). The PAI-1 levels in the hand-assisted group were higher compared with those in the laparoscopic-assisted group for 4 weeks after surgery; however, a significant difference was found only on POD 1. Therefore, plasma PIA-1 levels were found to be significantly elevated for 4 weeks after MICR, and the surgery-related acute inflammatory response may account for the early postoperative PIA-1 increase. Furthermore, PAI-1-associated VEGF-induced angiogenesis in the healing wounds may account for the late postoperative elevations, and increased PAI-1 levels may promote angiogenesis in residual tumor deposits.

• colorectal surgery
• plasminogen activator inhibitor-1
• postoperative plasma levels

• KGF
• angiogenesis
• metastasis
• minimally invasive colorectal resection
• plasma levels

MMP-2 also known as gelatinase A and MMP-7 (matrilysin) are members of the zinc-dependent family of MMPs (Matrix metalloproteinase). MMP-2 and MMP-7 are remodeling enzymes that digest extracellular matrix; MMP-2 is extensively expressed during development and is upregulated at sites of tissue damage, inflammation, and in stromal cells of metastatic tumors. MMP-7 is expressed in the epithelial cells and in a variety of cancers including colon tumors. Plasma MMP-2 and MMP-7 levels were assessed before and after minimally invasive colorectal resection for cancer pathology.

To determine plasma MMP-2 and MMP-7 levels before and after minimally invasive colorectal resection for cancer pathology.

Patients enrolled in a plasma bank for whom plasma was available were eligible. Plasma obtained from preoperative (Preop) and postoperative blood samples was used. Only colorectal cancer (CRC) patients who underwent elective minimally invasive cancer resection with preop, post-operative day (POD) 1, 3 and at least 1 late postop sample (POD 7-34) were included. Late samples were bundled into 7 d blocks (POD 7-13, 14-20, etc.) and treated as single time points. Plasma MMP-2 and MMP-7 levels were determined via enzyme-linked immunosorbent assay in duplicate.

Total 88 minimally invasive CRC resection CRC patients were studied (right colectomy, 37%; sigmoid, 24%; and LAR/AR 18%). Cancer stages were: 1, 31%; 2, 30%; 3, 34%; and 4, 5%. Mean Preop MMP-2 plasma level (ng/mL) was 179.3 ± 40.9 (n = 88). Elevated mean levels were noted on POD1 (214.3 ± 51.2, n = 87, P < 0.001), POD3 (258.0 ± 63.9, n = 80, P < 0.001), POD7-13 (229.9 ± 62.3, n = 65, P < 0.001), POD 14-20 (234.9 ± 47.5, n = 25, P < 0.001), POD 21-27 (237.0 ± 63.5, n = 17, P < 0.001,) and POD 28-34 (255.4 ± 59.7, n = 15, P < 0.001). Mean Preop MMP-7 level was 3.9 ± 1.9 (n = 88). No significant differences were noted on POD 1 or 3, however, significantly elevated levels were noted on POD 7-13 (5.7 ± 2.5, n = 65, P < 0.001), POD 14-20 (5.9 ± 2.5, n = 25, P < 0.001), POD 21-27 (6.1 ± 3.6, n = 17, P = 0.002) and on POD 28-34 (6.8 ± 3.3, n = 15 P < 0.001,) vs preop levels.

MMP-2 levels are elevated for 5 wk and MMP-7 levels elevated for weeks 2-6. The etiology of these changes in unclear, trauma and wound healing likely play a role. These changes may promote residual tumor growth and metastasis.

• Effects of surgery
• Colorectal resection
• Colorectal cancer
• Plasma MMP-2 and MMP-7 levels
• Angiogenesis

Colorectal resection is associated with 3-5 wk long elevations in the plasma levels of at least 11 proangiogenic proteins that may stimulate tumor angiogenesis post-surgery. The increases during the first week after surgery may be related to the acute inflammatory response; the cause(s) of the week 2-5 increases is unknown. The wounds are a possible source because of the important role that angiogenesis plays in the healing process. The main hypothesis of the study is that wound fluid levels of the proteins studied will be elevated well beyond plasma levels which, in turn, are elevated from preoperative baseline levels.

To determine plasma and wound fluid levels of 8 proangiogenic proteins after colorectal resection for cancer and benign pathology.

Blood and wound fluid samples were taken simultaneously on postoperative (postop) day 1, 3, and later time points until wound drain removal in 35 colorectal cancer patients and 31 benign disease patients undergoing colorectal resection in whom closed wound drains had been placed in either the pelvis or the subcutaneous space of the abdominal incision. Postop plasma levels were compared to preop plasma and postop wound fluid levels (separate analyses for cancer and benign groups).

Sixty-six colorectal disease patients were studied (35 cancer, 31 benign pathology). Most patients underwent minimally invasive surgery (open surgery in 11% of cancer and 6% of benign patients). The majority in the cancer group had rectal resections while in the benign group sigmoid or right colectomy predominated. Plasma levels of all 8 proteins were significantly elevated from baseline (P < 0.05) at all post-operative time points in the cancer group and at 90% of time points (29/32) in the benign group. Wound levels of all 8 proteins were 3-106 times higher (P < 0.05) than plasma levels at 87-90 percent of postop time points; of note, wound levels were more than 10 times higher at 47-50% of time points.

Plasma protein levels were elevated for 3 weeks after surgery; wound fluid levels were much greater than corresponding blood levels. Healing wounds may be the source of the plasma increases.

• Effects of surgery
• Colorectal resection
• Colorectal cancer
• Plasma protein levels
• Wound protein levels
• Angiogenesis

• CXCL16
• Minimally invasive colorectal cancer resection

• Adult
• Aged
• Chemokine CXCL16/metabolism
• Colectomy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/surgery
• Female
• Humans
• Male
• Middle Aged
• Prognosis
• Prospective Studies

• minimally invasive colorectal resection
• plasma interleukin-8

• XELOX
• chemotherapy
• colorectal cancer
• early start
• surgery

• Cancer hallmarks
• Integrative medicine
• Multi-targeted
• Phytochemicals
• Targeted therapy

• Antineoplastic Agents, Phytogenic/therapeutic use
• Drug Resistance, Neoplasm/genetics
• Genetic Heterogeneity
• Humans
• Molecular Targeted Therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/prevention & control
• Neoplasms/therapy
• Precision Medicine
• Signal Transduction
• Tumor Microenvironment/genetics

• P01AG034906 NIA NIH HHS
• R01 CA164095 NCI NIH HHS
• Wellcome Trust
• P01 AG034906 NIA NIH HHS
• MOP114962 CIHR
• R01GM071725 NIGMS NIH HHS
• R01CA100816 NCI NIH HHS
• MC_UU_12022/6 Medical Research Council
• G1200MD007581 NIMHD NIH HHS
• U01 ES019458 NIEHS NIH HHS
• R01 AI076535 NIAID NIH HHS
• K01AT007324 NCCIH NIH HHS
• 1R01CA151304 NCI NIH HHS
• R01 CA131294 NCI NIH HHS
• P30AG028716-01 NIA NIH HHS
• R01-HL107652 NHLBI NIH HHS
• R01AG020642 NIA NIH HHS
• T32HL098062 NHLBI NIH HHS
• K01 AT007324 NCCIH NIH HHS
• F31 CA154080 NCI NIH HHS
• R03 CA171326 NCI NIH HHS
• ES019458 NIEHS NIH HHS
• R01 HL108006 NHLBI NIH HHS
• T32 CA059365 NCI NIH HHS
• T32 HL098062 NHLBI NIH HHS
• T32-CA059365-19 NCI NIH HHS
• R01 CA100816 NCI NIH HHS
• 1P01AT003961 NCCIH NIH HHS
• R01HL108006 NHLBI NIH HHS
• U54 CA143907 NCI NIH HHS
• R21 CA155686 NCI NIH HHS
• R01 CA170378 NCI NIH HHS
• R33 CA161873-02 NCI NIH HHS
• T32 HL134632 NHLBI NIH HHS
• R21CA169757 NCI NIH HHS
• R21CA184788 NCI NIH HHS
• R15 CA137499 NCI NIH HHS
• CA164095 NCI NIH HHS
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• R03DK089130 NIDDK NIH HHS
• P20RR016477 NCRR NIH HHS
• 5R01CA127258-05 NCI NIH HHS
• R33 CA161873 NCI NIH HHS
• R01 CA028704 NCI NIH HHS
• NCI NCIRO1 28704 PHS HHS
• R01CA170378 NCI NIH HHS
• R01CA166348 NCI NIH HHS
• 5P01CA073992 NCI NIH HHS
• R01 CA166348 NCI NIH HHS
• K08 NS083732 NINDS NIH HHS
• CA-10951 NCI NIH HHS
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• CA168997 NCI NIH HHS
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• F32 CA177139 NCI NIH HHS
• MOP125857 CIHR
• 1R01CA20009 NCI NIH HHS
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• K01DK077137 NIDDK NIH HHS
• P01 AT003961 NCCIH NIH HHS
• R01CA156776 NCI NIH HHS
• MC_U105663142 Medical Research Council
• R01 AI110613 NIAID NIH HHS
• P20 RR016477 NCRR NIH HHS
• K01 DK077137 NIDDK NIH HHS
• P01AG034906-01A1 NIA NIH HHS
• MSH-136647 CIHR
• P30 CA022453 NCI NIH HHS
• Intramural NIH HHS
• R01 CA109335-04A1 NCI NIH HHS
• P20GM103434 NIGMS NIH HHS
• R21 CA184788 NCI NIH HHS
• R01 HL107652 NHLBI NIH HHS
• F32CA177139 NCI NIH HHS
• P01 CA073992 NCI NIH HHS
• R01CA131294 NCI NIH HHS
• P30 AG028716 NIA NIH HHS
• U54 CA149145 NCI NIH HHS
• R01 CA109335 NCI NIH HHS
• R01 CA127258 NCI NIH HHS
• P20 GM103434 NIGMS NIH HHS
• F31CA154080 NCI NIH HHS
• G12 MD007581 NIMHD NIH HHS
• MC_UP_1101/3 Medical Research Council
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• MOP 64308 CIHR
• AI076535 NIAID NIH HHS
• R01 AR047901 NIAMS NIH HHS
• C301/A14762 Cancer Research UK
• R01 CA120009 NCI NIH HHS
• R01 CA151304 NCI NIH HHS
• U54CA143907 NCI NIH HHS
• 1R03CA1711326 NCI NIH HHS
• 5T32-CA059365 NCI NIH HHS
• R21CA188818 NCI NIH HHS
• I01 BX001517 BLRD VA
• P30 CA22453 NCI NIH HHS
• AR47901 NIAMS NIH HHS
• K08NS083732 NINDS NIH HHS
• R15 CA137499-01 NCI NIH HHS
• R01 CA010951 NCI NIH HHS

AIM: To assess blood chitinase 3-like 1 (CHi3L1) levels for 2 mo after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC).

METHODS: CRC patients in an Institutional Review Board approved data/plasma bank who underwent elective MICR for whom preoperative (PreOp), early postoperative (PostOp), and 1 or more late PostOp samples [postoperative day (POD) 7-27] available were included. Plasma CHi3L1 levels (ng/mL) were determined in duplicate by enzyme linked immunosorbent assay.

RESULTS: PreOp and PostOp plasma sample were available for 80 MICR cancer patients for the study. The median PreOp CHi3L1 level was 56.8 CI: 41.9-78.6 ng/mL (n = 80). Significantly elevated (P < 0.001) median plasma levels (ng/mL) over PreOp levels were detected on POD1 (667.7 CI: 495.7, 771.7; n = 79), POD 3 (132.6 CI: 95.5, 173.7; n = 76), POD7-13 (96.4 CI: 67.7, 136.9; n = 62), POD14-20 (101.4 CI: 80.7, 287.4; n = 22), and POD 21-27 (98.1 CI: 66.8, 137.4; n = 20, P = 0.001). No significant difference in plasma levels were noted on POD27-41.

CONCLUSION: Plasma CHi3L1 levels were significantly elevated for one month after MICR. Persistently elevated plasma CHi3L1 may support the growth of residual tumor and metastasis.

• Colorectal cancer
• Recurrence
• Minimally inasive colorectal resection
• Chitinase 3-like 1
• Metastasis

AIM: To investigate plasma Monocyte Chemotactic Protein-1 levels preoperatively in colorectal cancer (CRC) and benign patients and postoperatively after CRC resection.

METHODS: A plasma bank was screened for minimally invasive colorectal cancer resection (MICR) for CRC and benign disease (BEN) patients for whom preoperative, early postoperative, and 1 or more late postoperative samples (postoperative day 7-27) were available. Monocyte chemotactic protein-1 (MCP-1) levels (pg/mL) were determined via enzyme linked immuno-absorbent assay.

RESULTS: One hundred and two CRC and 86 BEN patients were studied. The CRC patient’s median preoperative MCP-1 level (283.1, CI: 256.0, 294.3) was higher than the BEN group level (227.5, CI: 200.2, 245.2; P = 0.0004). Vs CRC preoperative levels, elevated MCP-1 plasma levels were found on postoperative day 1 (446.3, CI: 418.0, 520.1), postoperative day 3 (342.7, CI: 320.4, 377.4), postoperative day 7-13 (326.5, CI: 299.4, 354.1), postoperative day 14-20 (361.6, CI: 287.8, 407.9), and postoperative day 21-27 (318.1, CI: 287.2, 371.6; P < 0.001 for all).

CONCLUSION: Preoperative MCP-1 levels were higher in CRC patients (vs BEN). After MICR for CRC, MCP-1 levels were elevated for 1 mo and may promote angiogenesis, cancer recurrence and metastasis.

• Colorectal cancer
• Monocyte chemotactic protein-1
• Minimally invasive colorectal resection angiogenesis

• Cancer
• Metastasis
• Surgery
• Wound

Purpose. Truncated tissue factor (tTF) fusion protein targeting tumor vasculature can induce tumor vascular thrombosis and necrosis. Here, we generated (RGD)₃-tTF in which three arginine-glycine-aspartic (RGD) targeting integrin α_vβ₃ and tTF induce blood coagulation in tumor vessels. Methods. The bioactivities of (RGD)₃-tTF including coagulation activity, FX activation, and binding with integrin α_vβ₃ were performed. The fluorescent labeled (RGD)₃-tTF was intravenously injected into tumor-bearing mice and traced in vivo. The tumor growth, volume, blood vessel thrombosis, tumor necrosis, and survival time of mice treated with (RGD)₃-tTF were evaluated. Results. The clotting time and FX activation of (RGD)₃-tTF were similar to that of TF (P > 0.05) but different with that of RGD (P < 0.05). (RGD)₃-tTF presented a higher binding with α_vβ₃ than that of RGD and TF at the concentration of 0.2 μmol/L (P < 0.05). (RGD)₃-tTF could specifically assemble in tumor and be effective in reducing tumor growth by selectively inducing tumor blood vessels thrombosis and tumor necrosis which were absent in mice treated with RGD or TF. The survival time of mice treated with (RGD)₃-tTF was higher than that of mice treated with TF or RGD (P < 0.05). Conclusion. (RGD)₃-tTF may be a promising strategy for the treatment of colorectal cancer.