Impact of the coronavirus disease 2019 pandemic on gastric and colorectal cancer surgeries: a multicenter epidemiologic study from the Kinki region of Japan.

The coronavirus disease 2019 pandemic affected cancer surgeries and advanced cancer diagnoses; however, the trends in patient characteristics in medical institutions during this time, and the surgical approaches used are unclear. We investigated the impact of the pandemic on gastric and colorectal cancer surgeries in the Kinki region of Japan. We grouped 1688 gastric and 3493 colorectal cancer surgeries into three periods: "pre-pandemic" (April 2019-March 2020), "pandemic 1" (April 2020-March 2021), and "pandemic 2" (April 2021-September 2021), to investigate changes in the number of surgeries, patient characteristics, surgical approaches, and cancer progression after surgery. Gastric and colorectal cancer surgeries decreased from the pre-pandemic levels, by 20% and 4%, respectively, in pandemic 1, and by 31% and 19%, respectively, in pandemic 2. This decrease had not recovered to pre-pandemic levels by September, 2021. Patient characteristics, surgical approaches, and cancer progression of gastric and colorectal surgeries did not change remarkably as a result of the coronavirus disease 2019 pandemic.

Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase.

Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase-DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.

Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells.

Cancer stem cell (CSC)-specific markers may be potential therapeutic targets. We previously identified that Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal adenomas. Based on the analysis of mouse Dclk1+ tumor cells, we aimed to identify a CSC-specific cell surface marker in human colorectal cancers (hCRCs) and validate the therapeutic effect of targeting it. IL17RB was distinctively expressed by Dclk1+ mouse intestinal tumor cells. Using Il17rb-CreERT2-IRES-EGFP mice, we show that IL17RB marked intestinal TSCs in an IL13-dependent manner. Tuft cell-like cancer cells were detected in a subset of hCRCs. In these hCRCs, lineage-tracing experiments in CRISPR-Cas9-mediated IL17RB-CreERT2 knockin organoids and xenograft tumors revealed that IL17RB marks CSCs that expand independently of IL-13. We observed up-regulation of POU2F3, a master regulator of tuft cell differentiation, and autonomous tuft cell-like cancer cell differentiation in the hCRCs. Furthermore, long-term ablation of IL17RB-expressing CSCs strongly suppressed the tumor growth in vivo. These findings reveal insights into a CSC-specific marker IL17RB in a subset of hCRCs, and preclinically validate IL17RB+ CSCs as a cancer therapeutic target.

Prognostic impact of the combination of neutrophil-to-lymphocyte ratio and Glasgow prognostic score in colorectal cancer: a retrospective cohort study.

PURPOSE: Although neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte count, and Glasgow prognostic score (GPS) are well-known prognostic markers in cancer, their prognostic importance is still controversial. We evaluated the prognostic value of NLR, PLR, monocyte count, and GPS in colorectal cancer (CRC). METHOD: We retrospectively evaluated 448 CRC patients undergoing curative resection. We compared overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) between dichotomized groups by the optimal cutoff point. Univariate and multivariate analyses were applied to identify prognostic factors. RESULT: High NLR, high monocyte count, and high GPS exhibited significantly worse prognosis in OS, CSS, and DFS compared with low NLR, low monocyte count, and low GPS, respectively. In contrast, PLR was not significantly associated with OS, CSS, and DFS. The univariate and multivariate analyses indicated that poor OS was significantly associated with age ≥ 69 and high NLR; that poor CSS was significantly associated with age ≥ 69, M factor, high CA19-9, adjuvant chemotherapy, and high GPS; and that poor DFS was significantly associated with venous invasion, high NLR, and high GPS. When 448 patients were classified into three groups based on NLR and GPS, there was a significant difference in OS, CSS, and DFS between all the three groups. Patients with NLR ≥ 2.05 and GPS = 1/2 exhibited remarkably poorer prognosis, whereas those with both NLR < 2.05 and GPS = 0 exhibited remarkably better prognosis. CONCLUSION: Combination of NLR and GPS can be a novel scoring system to effectively stratify outcome in CRC.

The effects of intraoperative ICG fluorescence angiography in laparoscopic low anterior resection: a propensity score-matched study.

BACKGROUND: It remains unclear whether indocyanine green (ICG) angiography could reduce the rate of postoperative anastomotic leakage (AL) following rectal surgery. The aim was to determine whether intraoperative ICG angiography could decrease symptomatic AL following laparoscopic low anterior resection (LAR). METHODS: This is a retrospective study of 149 patients with rectal cancer who underwent laparoscopic LAR at a single institution. Propensity score matching (PSM) was employed to compare groups with and without ICG angiography. RESULTS: Before PSM, the symptomatic AL rate was 10.4% (5/48) in patients with ICG angiography, compared with 6.9% (7/101) in cases without ICG angiography (P = 0.52). In patients with ICG angiography, poor perfusion of the proximal colon judged by ICG angiography led to additional colon resection in 27.1% (13/48). Symptomatic AL occurred in 30.8% (4/13) of the patients who had revision of the transection site, whereas it occurred in only 2.9% (1/35) of the patients who did not need revision of the transection site (P = 0.015). After PSM, the symptomatic AL rate was 8.8% (3/34) in patients with ICG angiography, compared with 14.7% (5/34) in cases without ICG angiography (P = 0.71). In univariate analysis, high BMI, preoperative chemotherapy, and lateral lymph node dissection were significantly associated with symptomatic AL. Multivariate analysis indicated that only lateral lymph node dissection remained significantly associated with AL (odds ratio, 10.05; 95% confidence interval, 1.75-58.61; P = 0.011). CONCLUSIONS: Intraoperative ICG angiography is useful for prediction of AL following laparoscopic LAR.

Optimal treatment strategy for rectal cancer based on the risk factors for recurrence patterns.

BACKGROUND: For rectal cancer, multimodality therapeutic approach is necessary to prevent local recurrence and distant metastasis. However, the efficacy of additional treatments, such as neoadjuvant chemoradiotherapy (nCRT), neoadjuvant chemotherapy (NAC), and lateral pelvic lymph node dissection (LPLND), has not been scrutinized. METHODS: Recurrence patterns were categorized into local recurrence and distant metastasis. Local recurrence was classified into two types: (1) pelvic cavity recurrence and (2) LPLN recurrence. First, we analyzed the risk factors for each recurrence pattern. Second, based on the status of clinically suspected involvement of circumferential resection margin (cCRM), the efficacy of additional treatments was investigated. RESULTS: A total of 240 patients was enrolled. nCRT was performed for 25 (10%), NAC was for 46 (19%), and LPLND was for 35 patients (15%). As the recurrence patterns, pelvic cavity recurrence occurred in 15 (6%), LPLN recurrence in 8 (3%), and distant metastasis in 42 patients (18%). Five-year overall survival and relapse-free survival were 87% and 70%, respectively. Multivariate analysis indicated that pelvic cavity recurrence was associated with cCRM status and tumor histology, that LPLN recurrence was with serum carcinoembryonic antigen level and LPLN swelling, and that distant metastasis was with clinical N category. In the cCRM-positive subgroup (n = 66), cumulative rate of pelvic cavity recurrence was lower in the nCRT group than in the NAC or non-NAC/nCRT group (P = 0.02 and 0.09, respectively). CONCLUSION: cCRM status was associated with pelvic cavity recurrence, and LPLN swelling was with LPLN recurrence. nCRT could reduce pelvic cavity recurrence in cCRM-positive subgroup.

The Role of Chemokines in Promoting Colorectal Cancer Invasion/Metastasis.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Although most of the primary CRC can be removed by surgical resection, advanced tumors sometimes show recurrences in distant organs such as the liver, lung, lymph node, bone or peritoneum even after complete resection of the primary tumors. In these advanced and metastatic CRC, it is the tumor-stroma interaction in the tumor microenvironment that often promotes cancer invasion and/or metastasis through chemokine signaling. The tumor microenvironment contains numerous host cells that may suppress or promote cancer aggressiveness. Several types of host-derived myeloid cells reside in the tumor microenvironment, and the recruitment of them is under the control of chemokine signaling. In this review, we focus on the functions of chemokine signaling that may affect tumor immunity by recruiting several types of bone marrow-derived cells (BMDC) to the tumor microenvironment of CRC.

Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis.

BACKGROUND & AIMS: Loss of the tumor suppressor SMAD4 correlates with progression of colorectal cancer (CRC). In mice, colon tumors that express CCL9 recruit CCR1(+) myeloid cells, which facilitate tumor invasion and metastasis by secreting matrix metalloproteinase 9. METHODS: We used human CRC cell lines to investigate the ability of SMAD4 to regulate expression of CCL15, a human ortholog of mouse CCL9. We used immunohistochemistry to compare levels of CCL15 and other proteins in 141 samples of human liver metastases. RESULTS: In human CRC cell lines, knockdown of SMAD4 increased CCL15 expression, and overexpression of SMAD4 decreased it. SMAD4 bound directly to the promoter region of the CCL15 gene to negatively regulate its expression; transforming growth factor-ß increased binding of SMAD4 to the CCL15 promoter and transcriptional repression. In livers of nude mice, SMAD4-deficient human CRC cells up-regulated CCL15 to recruit CCR1(+) cells and promote metastasis. In human tumor samples, there was a strong inverse correlation between levels of CCL15 and SMAD4; metastases that expressed CCL15 contained 3-fold more CCR1(+) cells than those without CCL15. Patients with CCL15-expressing metastases had significantly shorter times of disease-free survival than those with CCL15-negative metastases. CCR1(+) cells in the metastases expressed the myeloid cell markers CD11b and myeloperoxidase, and also matrix metalloproteinase 9. CONCLUSIONS: In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1(+) cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1(+) cells could prevent metastasis of CRC to liver.

Laparoscopic redo surgery for sigmoid volvulus following laparoscopic sigmoidectomy.

BACKGROUND: Sigmoid volvulus (SV) is an acute abdominal condition characterized by torsion of the sigmoid colon around the mesentery, and often results in intestinal obstruction that may progress to bowel ischemia, necrosis, or perforation. Although SV commonly occurs due to predisposing factors like anatomic variations, age-related motility disorders, chronic constipation, and neurologic diseases, its incidence following sigmoid colon cancer surgery has rarely been reported. Herein, we report a rare case of recurrent SV following laparoscopic sigmoidectomy, which was successfully treated by laparoscopic redo surgery. CASE PRESENTATION: The patient was a 77-year-old man who had previously undergone laparoscopic sigmoidectomy for sigmoid colon cancer. Sixteen months postoperatively, he developed an incisional hernia at the umbilical site, which was treated with a laparoscopic repair using an intraperitoneal onlay mesh. After the hernia surgery, the patient had no anastomotic leakage or stenosis on regular follow-ups. However, 65 months after the first surgery, he presented with abdominal pain and distension. A computed tomography revealed that the remnant sigmoid colon was distended in a twisting manner around the anastomosis, leading to the diagnosis of SV. Although endoscopic de-torsion was successful, the SV recurred 2 months later, requiring elective laparoscopic redo surgery. The procedure involved resection of the sigmoid colon including the prior anastomosis with a left pararectal incision and DST re-anastomosis using a 25-mm circular stapler. The operation lasted 165 min with minimal bleeding and no complications. The postoperative course was uneventful. Pathological analysis confirmed fibrosis without malignancy. The patient remains well without recurrence of SV and anastomotic stenosis more than 5 years after surgery. CONCLUSION: SV following sigmoid colon cancer surgery has rarely been reported. This case illustrates the potential need for prophylaxis against postoperative SV, especially in patients with long sigmoid colon undergoing laparoscopic surgery for colorectal cancer. Further, laparoscopic redo surgery following initial laparoscopic surgery for colorectal cancer can be performed with minimal invasiveness, especially if patient selection is properly managed.

Identification of complications requiring interventions after gastrointestinal cancer surgery from real-world data: An external validation study.

Background: Recently, real-world data have been recognized to have a significant role for research and quality improvement worldwide. The decision on the existence or nonexistence of postoperative complications is complex in clinical practice. This multicenter validation study aimed to evaluate the accuracy of identification of patients who underwent gastrointestinal (GI) cancer surgery and extraction of postoperative complications from Japanese administrative claims data. Methods: We compared data extracted from both the Diagnosis Procedure Combination (DPC) and chart review of patients who underwent GI cancer surgery from April 2016 to March 2019. Using data of 658 patients at Kyoto University Hospital, we developed algorithms for the extraction of patients and postoperative complications requiring interventions, which included an invasive procedure, reoperation, mechanical ventilation, hemodialysis, intensive care unit management, and in-hospital mortality. The accuracy of the algorithms was externally validated using the data of 1708 patients at two other hospitals. Results: In the overall validation set, 1694 of 1708 eligible patients were correctly extracted by DPC (sensitivity 0.992 and positive predictive value 0.992). All postoperative complications requiring interventions had a sensitivity of >0.798 and a specificity of almost 1.000. The overall sensitivity and specificity of Clavien-Dindo ≥grade IIIb complications was 1.000 and 0.995, respectively. Conclusion: Patients undergoing GI cancer surgery and postoperative complications requiring interventions can be accurately identified using the real-world data. This multicenter external validation study may contribute to future research on hospital quality improvement or to a large-scale comparison study among nationwide hospitals using real-world data.

Downregulation of osteoprotegerin in colorectal cancer cells promotes liver metastasis via activating tumor-associated macrophage.

Osteoprotegerin (OPG) is a secreted cytokine that functions as a decoy receptor for receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL). Anti-RANKL treatment for bone metastasis has been widely accepted for solid tumors. However, the mechanism of OPG-RANKL-RANK signaling in systemic colorectal cancer (CRC) metastasis remains unclear. In this study, we investigated the relevance and function of OPG expression in CRC liver metastasis. First, we performed in silico analysis using The Cancer Genome Atlas public database and found that lower OPG expression in CRC was associated with poor overall survival. Immunohistochemistry analyses using resected specimen from patients with CRC in our institute confirmed the result. Patient-matched primary CRC and liver metastases showed a significant downregulation of OPG expression in metastatic lesions. In CRC cell lines, OPG expression did not suppress cell proliferation and migration. However, OPG expression inhibited macrophage migration by suppressing the RANKL-RANK pathway. Moreover, in vivo mouse liver metastasis models showed that OPG expression in CRC cells suppressed liver metastases. In addition, treatment with an anti-RANKL neutralizing antibody also suppressed liver metastases. These results showed that downregulation of OPG expression in CRC cells promotes liver metastasis by activating tumor-associated macrophage, which can become a candidate for targeted therapy with anti-RANKL neutralizing antibody for CRC liver metastasis.

[A case of multiple liver metastases of gastric cancer successfully treated by combination chemotherapy of S-1 and paclitaxel].

A 54-year-old man underwent distal gastrectomy for early gastric cancer in September 2002. CT performed 6 months after the operation revealed liver metastases, and they were resected. Hepatic arterial infusion therapy of 5-FU was performed; however, multiple liver metastases appeared in October 2003. We added arterial infusion of CDDP to 5-FU, but liver metastases increased. We then applied a combination chemotherapy of S-1 and paclitaxel from February 2004. Subsequently, stable disease continued, and after 67 courses of S-1 plus paclitaxel, we changed the administration to S-1 alone from August 2009. After that, liver metastases did not increase, so we discontinued chemotherapy on August 2010, followed by observation. Progression of liver metastases has not been to date.

Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain.

DNMT3 proteins are de novo DNA methyltransferases that are responsible for the establishment of DNA methylation patterns in mammalian genomes. Here, we have determined the crystal structures of the ATRX-DNMT3-DNMT3L (ADD) domain of DNMT3A in an unliganded form and in a complex with the amino-terminal tail of histone H3. Combined with the results of biochemical analysis, the complex structure indicates that DNMT3A recognizes the unmethylated state of lysine 4 in histone H3. This finding indicates that the recruitment of DNMT3A onto chromatin, and thereby de novo DNA methylation, is mediated by recognition of the histone modification state by its ADD domain. Furthermore, our biochemical and nuclear magnetic resonance data show mutually exclusive binding of the ADD domain of DNMT3A and the chromodomain of heterochromatin protein 1alpha to the H3 tail. These results indicate that de novo DNA methylation by DNMT3A requires the alteration of chromatin structure.

Effect of herbal medicine daikenchuto on gastrointestinal symptoms following laparoscopic colectomy in patients with colon cancer: A prospective randomized study.

We conducted a prospective randomized study to investigate the effect of daikenchuto (DKT) on abdominal symptoms following laparoscopic colectomy in patients with left-sided colon cancer. Patients who suffered from abdominal pain or distention on postoperative day 1 were randomized to either the DKT group or non-DKT group. The primary endpoints were the evaluation of abdominal pain, abdominal distention, and quality of life. The metabolome and gut microbiome analyses were conducted as secondary endpoints. A total of 17 patients were enrolled: 8 patients in the DKT group and 9 patients in the non-DKT group. There were no significant differences in the primary endpoints and postoperative adverse events between the two groups. The metabolome and gut microbiome analyses showed that the levels of plasma lipid mediators associated with the arachidonic acid cascade were lower in the DKT group than in the non-DKT group, and that the relative abundance of genera Serratia and Bilophila were lower in the DKT group than in the non-DKT group. DKT administration did not improve the abdominal symptoms following laparoscopic colectomy. The effects of DKT on metabolites and gut microbiome have to be further investigated.

Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5.

Mesenchymal stem cells (MSCs) are recruited from BM to the stroma of developing tumors, where they serve as critical components of the tumor microenvironment by secreting growth factors, cytokines, and chemokines. The role of MSCs in colorectal cancer (CRC) progression was controversial. In this study, we found that C-C chemokine receptor type 5 (CCR5) ligands (i.e., C-C motif chemokine ligand 3 (CCL3), CCL4, and CCL5) were highly produced from MSCs using a chemokine array screening with conditioned media from the cultured human MSCs. A relatively strong CCR5 expression could be detected within the cytoplasm of several CRC cell lines. Regarding the effect of MSC, we found that the xenografts in which CCR5-overexpressing HCT116 cells were inoculated into immunocompromised mice were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor, maraviroc, significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens (n = 89), 20 cases (29%) were high for CCR5, whereas 69 cases (71%) were low. Statistical analyses indicated that CCR5 expression in primary CRC was associated with CRC patients' prognosis. Especially, stage III/IV patients with CCR5-high CRCs exhibited a significantly poorer prognosis than those with CCR5-low CRCs. Furthermore, we investigated the effects of preoperative serum CCR5 ligands on patients' prognosis (n = 114), and found that CRC patients with high serum levels of CCL3 and CCL4 exhibited a poorer prognosis compared to those with low levels of CCL3 and CCL4, while there was no association between CCL5 and prognosis. These results suggest that the inhibition of MSC-CRC interaction by a CCR5 inhibitor could provide the possibility of a novel therapeutic strategy for CRC, and that serum levels of CCL3 and CCL4 could be predictive biomarkers for the prognosis of CRC patients.

Simultaneous robotic surgery with low anterior resection and prostatectomy/hysterectomy.

Cooperation with multiple departments is essential for the treatment of patients with rectal cancer and other pelvic cancers. In our department, we experienced two cases of rectal cancer that underwent robotic low anterior resection (LAR) and simultaneous resection of other pelvic organs (case 1 with prostatectomy and case 2 with hysterectomy) using the da Vinci Xi system. Here, we show the precise procedures of these two robotic surgeries. Under general anesthesia and lithotomy position, five da Vinci ports were symmetrically placed along the umbilical horizontal line with a 7 cm interval, and a 5 mm AirSeal Access Port was added in the right or left upper quadrant. Patients were placed with 22-degree Trendelenburg and 8-degree tilt to the right. The operators used the center port on the umbilicus as a camera port and chose the docking arms with either two-left-one-right or one-left-two-right setting depending on their preference. This port setting was quite useful for the operators from multiple departments to change the docking arms, even if their preference may be different. Moreover, assistants could use the remaining two ports to provide a well-expanded and safer surgical field. "With a familiar view" and "with a wide view" are our two concepts to safely perform extended pelvic surgeries. We have employed this symmetrical horizontal port site position as a general setting for usual rectal surgeries.

Robot-assisted low anterior resection after aluminum potassium sulfate and tannic acid sclerosing therapy for internal hemorrhoids.

BACKGROUND: Internal hemorrhoids are the most common anal diseases. Aluminum potassium sulfate and tannic acid (ALTA) injection is a new sclerosing therapy for the treatment of internal hemorrhoids. Although ALTA injection has been widely used, there are no previous reports of rectal cancer patients who underwent robot-assisted low anterior resection (Rob-LAR) after ALTA injection to treat internal hemorrhoids. CASE PRESENTATION: A 70-year-old man with rectal cancer was presented to our hospital. He had an ALTA injection 2 months before presentation at a clinic due to hematochezia with internal hemorrhoids. The rectal tumor was located 7 cm above the anal verge, and Rob-LAR with the da Vinci Xi system was performed. The patient had sclerosis on the stump of the anal side, which made it difficult to transect the rectum with linear staplers. This required multiple repeats of compression through the SmartClamp feedback. After anastomosis with the double-stapling technique, we constructed a diverting ileostomy. CONCLUSION: Although ALTA injection is a promising strategy for internal hemorrhoids, rectal cancer should be excluded before the sclerosing therapy.

Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8-CXCR2 Axis.

PURPOSE: SMAD4 is a key transcriptional factor of TGFß signaling and acts as a tumor suppressor in colorectal cancer. In the present study, we explored the immunologic effect of SMAD4 on the tumor microenvironment. EXPERIMENTAL DESIGN: Using 99 clinical specimens and human colorectal cancer cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2, and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 patients with colorectal cancer. RESULTS: SMAD4 knockdown from human colorectal cancer cells upregulated the expression of CXCL1 and CXCL8, which recruited neutrophils to colorectal cancer tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative colorectal cancer cells, they produced a large amount of CXCL1 and CXCL8 by themselves in vitro. In human clinical specimens, we found that neutrophil infiltration into the peritumoral stroma was more marked in SMAD4-negative colorectal cancer compared with that in SMAD4-positive colorectal cancer, and that both CXCL1 and CXCL8 were abundantly expressed in the tumor-infiltrating neutrophils. Neutrophils isolated from primary colorectal cancer expressed significantly higher levels of CXCL1 and CXCL8 than did those isolated from peripheral blood. Furthermore, tumor-infiltrating neutrophils expressed MMP2 and MMP9 in addition to ARG1 and IDO. Serum CXCL8 level was significantly higher in colorectal cancer patients, especially those at stage II/III, and statistical analysis indicated a high CXCL8 level was associated with a shorter overall survival and relapse-free survival. CONCLUSIONS: Blockade of the CXCL1/8-CXCR2 axis could be a novel therapeutic approach against SMAD4-negative colorectal cancer.