堀江 久永

PURPOSE: Low anterior resection syndrome (LARS) causes devastating symptoms and impairs the quality of life (QOL). This study investigated the incidence and risk factors of LARS and their association with the QOL in patients with lower rectal tumors. METHODS: Patients who underwent anus-preserving surgery for lower rectal tumors between 2014 and 2019 and who had anal defecation between 2020 and 2021 were surveyed. The LARS score measured severity, and the QOL was evaluated using the Japanese version of the Fecal Incontinence Quality-of-Life Scale (JFIQL). The primary endpoint was the incidence of Major LARS, and the secondary endpoints were risk factors and association with the JFIQL. RESULTS: Of 107 eligible patients, 82 (76.6%) completed the LARS survey. The incidence of Major LARS was 48%. Independent risk factors included neoadjuvant chemoradiotherapy (CRT) and a short interval (< 24 months after surgery; odds ratio, 4.6; 95% confidence interval: 1.1-19, both). The LARS score was moderately correlated with the JFIQL generic score (correlation coefficient: - 0.54). The JFIQL scores were significantly worse in the Minor and Major LARS groups than in the No LARS group. CONCLUSIONS: Major LARS was found in 48% of lower rectal tumors, and independent risk factors include neoadjuvant CRT and a short interval. The QOL was significantly impaired in patients with both Minor and Major LARS.

Lateral lymph node (LLN) metastasis in T1 rectal cancer has an incidence of less than 1%. However, its clinical features are largely uncharted. We report a case of LLN metastasis in T1 rectal cancer and review the relevant literature. A 56-year-old female underwent rectal resection for lower rectal cancer 2 years previously (pT1bN0M0). During follow-up, an elevated tumor marker CA19-9 was documented. Enhanced CT and MRI showed a round shape nodule 2 cm in size on the left side of pelvic wall. PET-CT showed high accumulation of FDG in the same lesion, leading to a diagnosis of isolated LLN recurrence. Because no other site of recurrence was detected, surgical resection of the LLN was performed. Microscopic findings were consistent with metastatic lymph node originating from the recent rectal cancer. Adjuvant chemotherapy for six months was given, and patient remains free of recurrent disease seven months after LLN resection. Although LLN recurrence after surgery for T1 rectal cancer is rare, post-surgical follow-up should not be omitted. When LLN metastasis is suspected on CT, MRI and/or PET-CT will be recommended. Surgical resection of LLN metastasis in patients with T1 rectal cancer may lead to favorable outcomes, when recurrence in other areas is not observed.

AIM: Low anterior resection syndrome (LARS) causes devastating symptoms and impairs quality of life (QOL). Although its incidence and risk factors have been reported, these data are scarce in Japan. This study aimed to elucidate the incidence and risk factors of LARS as well as to evaluate its association with QOL in Japanese patients. METHOD: Patients with anal defecation at the time of the survey between November 2020 and April 2021 were included, among those who underwent anus-preserving surgery for rectal tumors between 2014 and 2019 in tertiary referral university hospital. The severity of LARS and QOL were evaluated with the LARS score and the Japanese version of the fecal incontinence quality of life scale (JFIQL), respectively. Primary endpoint was the incidence of major LARS. Secondary endpoints were risk factors and association with JFIQL. RESULTS: Of 332 eligible patients, 238 (71.7%) answered the LARS survey completely. The incidence of major LARS was 22% overall, and 48% when limited to lower tumors. Independent risk factors included lower tumors (OR: 7.0, 95% CI: 2.1-23.1, p = 0.001) and surgical procedures with lower anastomoses (OR: 4.6, 95% CI: 1.2-18.5, p = 0.03). The JFIQL generic score correlated moderately with the LARS score (correlation coefficient of -0.65). The JFIQL generic score was also significantly lower in lower tumors. CONCLUSIONS: The incidence of major LARS is 22% in Japanese patients, and independent risk factors include lower tumors and surgical procedures with lower anastomoses. More severe LARS is associated with worse QOL which is significantly more impaired in patients with lower tumors.

OBJECTIVES: The aim of this study was to identify the microbiota whose decrease in tumor area was associated with the metastatic process of distal colorectal cancer (CRC). METHODS: Twenty-eight consecutive patients with distal CRC undergoing surgical resection in our hospital were enrolled. Microbiota in 28 specimens from surgically resected colorectal cancers were analyzed using 16S ribosomal ribonucleic acid gene amplicon sequencing and the relative abundance (RA) of microbiota was evaluated. The densities of tumor-infiltrating lymphocytes (TIL) and tumor associated macrophages (TAM) in the colorectal cancers were immunohistochemically evaluated. RESULTS: Phocaeicola was the most abundant microbiota in normal mucosa. The RA of Phocaeicola in tumor tissues tended to be lower than that in normal mucosa although the difference was not significant (p=0.0732). The RA of Phocaeicola at tumor sites did not correlate either with depth of tumor invasion (pT-stage) or tumor size, however they were significantly reduced in patients with nodal metastases (p<0.05) and those with distant metastases (p<0.001). The RA of Phocaeicola at tumor sites showed positive correlation with the densities of CD3(+) or CD8(+) TIL. Since P. vulgatus was the most dominant species (47%) of the Phocaeicola, the RA of P. vulgatus and CRC metastasis and its association with TIL and TAM were also investigated. P. vulgatus showed a similar trend to genus Phocaeicola but was not statistically significant. CONCLUSIONS: A relative reduction of Phocaeicola attenuates the local anti-tumor immune response in distal CRC, which may facilitate metastatic spread.

BACKGROUND: Preoperative stoma site marking reduces the incidence of complications from elective surgery. However, the impact of stoma site marking in emergency patients with colorectal perforation remains unclear. This study aimed to assess the impact of stoma site marking on morbidity and mortality in patients with colorectal perforation who underwent emergency surgery. METHODS: This retrospective cohort study used the Japanese Diagnosis Procedure Combination inpatient database from April 1, 2012, to March 31, 2020. We identified patients who underwent emergency surgery for colorectal perforation. We compared outcomes between those with and without stoma site marking using propensity score matching to adjust for confounding factors. The primary outcome was the overall complication rate, and the secondary outcomes were stoma-related, surgical, and medical complications and 30-day mortality. RESULTS: We identified 21,153 patients (682 with stoma site marking and 20,471 without stoma site marking) and grouped them into 682 pairs using propensity score matching. The overall complication rates were 23.5% and 21.4% in the groups with and without stoma site marking, respectively (p = 0.40). Stoma site marking was not associated with a decrease in stoma-related, surgical, or medical complications. The 30-day mortality did not differ significantly between the groups with and without stoma site marking (7.9% vs. 8.4%, p = 0.843). CONCLUSIONS: Preoperative stoma site marking was not associated with a reduction in morbidity and mortality in patients with colorectal perforation who underwent emergency surgery.

BACKGROUND: The aim of this study was to evaluate the effect of staple height and rectal wall thickness on the development of an anastomotic leak after laparoscopic low anterior resection performed with the double stapling technique. METHODS: One hundred ninety-nine patients treated from 2013 to 2021 were enrolled. Patients were divided into two groups: those who developed an anastomotic leak (AL (+)) and those who did not (AL (-)). Clinicopathological factors were compared between the groups. RESULTS: Anastomotic leaks were observed in 8/199 patients (4%). A 1.5 mm linear stapler was used for 35/199 patients (17%), 1.8 mm for 89 (45%), and 2 mm for 75 (38%). In the AL (+) group (n = 8), lower staple height (1.5 mm or 1.8 mm) was used more frequently than in the AL (-) group (n = 191). Rectal wall thickness and the rectal wall thickness to staple height ratio was significantly (p < .05) greater in the AL (+) group. However, rectal wall thickness was significantly (p < .05) greater in patients who received neoadjuvant treatment and those with advanced T stage (T3,4) lesions. CONCLUSION: Linear stapler staple height and rectal wall thickness are significantly associated with the development of an anastomotic leak after laparoscopic low anterior resection. Larger staples should be selected in patients with a thicker rectal wall due to neoadjuvant treatment or adjacent advanced rectal tumors.

BACKGROUND: Low-density granulocytes (LDGs) have been shown to be increased in the peripheral blood of patients with inflammatory and malignant diseases. This study evaluated LDGs in patients who underwent radical surgery for colorectal cancer (CRC) and their impact on survival. METHODS: Patients who underwent radical colectomy between 2017 to 2021 were screened for enrolment in the study. Peripheral blood was obtained in the operating room before and after surgery and cells were recovered from the mononuclear layer after density gradient preparations. The ratio of CD66b(+) LDG to CD45(+) leukocytes was determined with flow cytometry, and the association of the ratios with patient outcomes was examined. The main outcome of interest was recurrence-free survival (RFS). RESULTS: Out of 228 patients treated, 176 were enrolled, including 108 colonic and 68 rectal cancers. Overall, 38 patients were stage I, 30 were stage II, 72 were stage 3, and 36 were stage IV. The number of LDGs was markedly increased immediately after surgery and the proportion of LDGs correlated positively with operating time (r = 0.2806, P < 0.001) and intraoperative blood loss (r = 0.1838, P = 0.014). Purified LDGs produced high amounts of neutrophil extracellular traps after short-term culture and efficiently trapped tumour cells in vitro. The proportion of postoperative LDGs was significantly higher in 13 patients who developed recurrence (median 9 (range 1.63-47.0)) per cent versus median 2.93 ((range 0.035-59.45) per cent, P = 0.013). When cut-off values were set at 4.9 per cent, a higher proportion of LDGs was strongly and independently associated with decreased RFS (P = 0.005). In patients with stage III disease, adjuvant chemotherapy significantly improved RFS of patients with high ratios of LDGs, but not low LDGs. CONCLUSION: LDGs are recruited to circulating blood by surgical stress early in the postoperative interval after colectomy for colonic cancer and their postoperative proportion is correlated with recurrence.

AIM: The clinical efficacy of chemoradiotherapy (CRT) is largely dependent on host immune status. The aim of this study was to identify possible markers expressed on circulating mononuclear cells to predict tumour response in patients with locally advanced rectal cancer (LARC). METHODS: Peripheral blood samples were obtained from 47 patients diagnosed with LARC before and after CRT. The numbers of lymphocytes and monocyte subsets were analysed using flow cytometry. Based on clinical and pathological findings, patients were classified as high or low responders. RESULTS: Lymphocyte counts were markedly decreased after CRT. Total numbers of lymphocytes (p = 0.030) and CD4(+) T cells (p = 0.041) in post-CRT samples were significantly lower in low responders than in high responders. In contrast, monocyte counts were not reduced and the number of CD14dim (+) CD16(+) nonclassical (patrolling) monocytes were somewhat increased after CRT (p = 0.050). Moreover, the ratios of programmed cell death ligand 1 (PD-L1) (+) cells on patrolling monocytes before and after CRT were significantly higher in low responders than in high responders (p = 0.0046, p = 0.0006). The same trend was observed for classical and intermediate monocytes. The expression of PD-L1 on patrolling monocytes before CRT correlated inversely with the number of T cells and natural killer (NK) cells after CRT. PD-L1(+) ratio in patrolling monocytes was an independent predictor for response to CRT. CONCLUSION: Programmed cell death ligand 1 (PD-L1) expression on patrolling monocytes suppresses cell-mediated immunity in patients receiving CRT which could be related to tumour response, and may be a useful biomarker for decision-making in the management of patients with LARC.

Abstract Although preoperative chemoradiation therapy can down-stage locally advanced rectal cancer (LARC), it has little effect on distant metastases. Metformin exerts an anti-cancer effect partly through the activation of host immunity. LuM1, a highly lung metastatic subclone of colon 26, was injected subcutaneously (sc) in BALB/c mice and treated with metformin and/or local radiation (RT). Lung metastases and the primary tumors were evaluated and the phenotypes of immune cells in the spleen and lung metastases were examined with flow cytometry and immunohistochemistry. Local RT, but not metformin, partially delayed the growth of sc tumor which was augmented with metformin. Lung metastases were unchanged in metformin or RT alone, but significantly reduced in the combined therapy. The ratios of splenic T cells tended to be low in the RT group, which were increased by the addition of metformin. IFN-γ production of the splenic CD4(+) and CD8(+) T cells was enhanced and CD49b (+) CD335(+) activated NK cells was increased after combined treatment group. Density of NK cells infiltrating in lung metastases was increased after combination treatment. Metformin effectively enhances local and abscopal effects of RT though the activation of cell-mediated immunity and might be clinically useful for LARC.

Ras genes are frequently mutated in many cancer types; however, there are currently no conclusively effective anticancer drugs against Ras-induced cancer. Therefore, the downstream effectors of Ras signaling need to be identified for the development of promising novel therapeutic approaches. We previously reported that oncogenic Ras induced the expression of NF-HEV/IL-33, a member of the interleukin-1 family, and showed that intracellular IL-33 was required for oncogenic Ras-induced cellular transformation. In the present study, we demonstrated that the c-Mer proto-oncogene tyrosine kinase (MerTK), a receptor tyrosine kinase, played essential roles in oncogenic Ras/IL-33 signaling. The expression of MerTK was enhanced in transformed NIH-3T3 cells by the expression of oncogenic Ras, H-Ras (G12V), in an IL-33-dependent manner. In human colorectal cancer tissues, MerTK expression also correlated with IL-33 expression. The knockdown of IL-33 or MerTK effectively attenuated the migration of NIH-3T3 cells transformed by H-Ras (G12V) and A549, LoVo, and HCT116 cells harboring an oncogenic K-Ras mutation. Furthermore, the suppression of Ras-induced cell migration by the knockdown of IL-33 was rescued by the enforced expression of MerTK. The present results also revealed that MerTK was effectively phosphorylated in NIH-3T3 cells transformed by Ras (G12V). Ras signaling was essential for the tyrosine phosphorylation of MerTK, and the kinase activity of MerTK was indispensable for accelerating cell migration. Collectively, the present results reveal a novel role for MerTK in cancer malignancy, which may be utilized to develop novel therapeutic strategies that target Ras-transformed cells.

BACKGROUND/AIMS: Recent studies have demonstrated that the populations of several microbes are significantly increased in fecal samples from patients with colorectal cancer (CRC), suggesting their involvement in the development of CRC. The aim of this study was to identify microbes which are increased in distal CRCs and to identify the specific location of microbes increased in mucosal tissue around the tumor. METHODS: Tissue specimens were collected from surgical resections of 28 distal CRCs. Five samples were collected from each specimen (location A: tumor, B: adjacent normal mucosa, C: normal mucosa 1 cm proximal to the tumor, D: normal mucosa 3 cm proximally, and E: normal mucosa 6 cm proximally). The microbiota in the sample were analyzed using 16S rRNA gene amplicon sequencing and the relative abundance (RA) of microbiota compared among the 5 locations. RESULTS: At the genus level, the RA of Fusobacterium and Streptococcus at location A was the highest among the 5 locations, significantly different from that in location E. The dominant species of each genus was Fusobacterium nucleatum and Streptococcus anginosus. The RAs of these species gradually decreased from locations B to E with a statistically significant difference in F. nucleatum. The genus Peptostreptococcus also showed a similar trend, and the RA of Peptostreptococcus stomatis in location A was significantly associated with depth of tumor invasion and tumor size. CONCLUSION: Although the clinical relevance is not clear yet, these results suggest that F. nucleatum, S. anginosus, and P. stomatis can spread to the adjacent normal tissues and may change the surrounding microenvironment to support the progression of CRC.