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Background: Defecation status is an important determinant of quality of life. Previous studies showed that postoperative defecation disorders occurred after open surgery for ulcerative colitis (UC)...

Early detection of surgical site infection (SSI) allows for appropriate management after Crohn's disease (CD) surgery. The aim of this study was to evaluate the usefulness of bacterial culture of postoperative drainage fluid after CD surgery.This study included 110 patients with CD who underwent surgery with bowel resection between January 2010 and March 2020 at Osaka University Hospital. Patients with only perianal surgery or incomplete records were excluded. Risk factors for SSI were evaluated in the context of clinical findings, including bacterial culture of postoperative drainage fluid, and bacterial species related to SSI were also examined.Of 110 patients, 18 (16.4%) developed SSI. Organ/space SSI developed in six, and a positive bacterial culture of drainage fluid (D-Posi) was found in five (83.3%). Of 104 patients without organ/space SSI, 31 (29.8%) were D-Posi (This study suggests the usefulness of postoperative drainage fluid bacterial culture for early diagnosis of SSI after CD surgery.

Stoma outlet obstruction (SOO) is much more common after total proctocolectomy (TPC) and ileal-pouch anal anastomosis (IPAA) for ulcerative colitis (UC) compared to after rectal surgery for cancer. Few prior reports have evaluated anatomical risk factors for SOO. In this study we aimed to clarify the risk factors for SOO after IPAA, focusing on the anatomical perspective.This study included 68 UC patients who underwent IPAA with diverting ileostomy. These cases were analyzed based on clinicopathological factors and computed tomography (CT)-based anatomical factors.SOO was identified in 18 patients (26.5%). We compared this SOO group with the non-SOO group. The two groups significantly differed in sex distribution, and patients in the SOO group tended to have a longer postoperative hospital stay. Regarding surgery-related factors, patients who underwent two-stage surgery and experienced high-output syndrome tended to develop SOO. Analysis of anatomical risk factors revealed that SOO was more common in patients with a longer distance between the root of their superior mesenteric artery and the bottom of the external anal sphincter (rSMA-bEAS). This tendency remained significant even with adjustment for patient height. In multivariate analyses, adjusted rSMA-bEAS (191.0 mm/m) and male sex were independent risk factors associated with SOO.A long rSMA-bEAS distance suggests that the mesentery is likely to be under tension. In such cases, surgeons should endeavor to avoid tension in the mesentery as much as possible.

Epithelial–mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it “mesenchymal score.” This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.

It is highly controversial whether a lymphadenectomy for treating distant lymph nodes, such as the para-aortic lymph node, provides clinical benefit in colorectal cancer (CRC). This study aimed to investigate the benefit of a lymphadenectomy for para-aortic lymph node metastasis (PALM) in CRC, by evaluating the extent of dissection. This retrospective cohort study included 28 consecutive patients with pathologically positive PALMs in CRC that underwent lymphadenectomies from October 2001 to March 2018 at our institute. We analyzed the rates of 3-year recurrence-free survival (RFS), postoperative complications, and peri-operative death. We examined RFS in two groups with different operation types. One group received radical resections (radical group), defined as a systematic dissection of para-aortic lymph nodes, which removed the area under the renal vein and above the aortic bifurcation. The other group (targeted group) received targeted dissections, which removed specific swollen para-aortic lymph nodes. The radical group had a significantly better RFS than the targeted group. In addition, females had significantly better RFS prognoses than males. Univariate and multivariate Cox regression analyses identified two clinical factors significantly associated with RFS: sex (P = 0.0100) and surgical procedure (P = 0.0033). Postoperative complications after PALM resections occurred in 35.7% of patients. There was no postoperative mortality. Our study suggested that a radical lymphadenectomy for treating PALMs in CRC could be performed safely and could prolong the RFS. More studies are necessary to strengthen the evidence in support of this conclusion.

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E‐mutated tumors via in silico analysis using a large‐scale clinical database. We found that BRAF V600E‐mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E‐mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E‐mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild‐type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E‐mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP‐1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E‐mutated CRC and indicate the therapeutic implications of targeting this gene., There was no significant difference in the expression of ENO1 in BRAF V600E‐mutated CRC and other types of CRC, but ENO2 levels were significantly higher in BRAF V600E‐mutated CRC.

Aim Many inflammation‐nutrition scores, including the Glasgow Prognostic Score (GPS), have been reported as prognostic biomarkers in patients with colorectal cancer (CRC). We aimed to examine the predictive ability of the GPS and to improve the GPS. Methods We included a total of 438 patients with stage 0‐III CRC who underwent curative surgery from 2010 to 2013. They were divided into a training set comprising 221 patients and a validation set comprising 227 patients, according to the date of surgery. In the training set, the GPS was verified using a Cox regression model, and cut‐off values for C‐reactive protein (CRP) and albumin for relapse‐free survival (RFS) were calculated using receiver operating characteristics (ROC) curves. The improved GPS (iGPS) was developed with additional optimal cut‐off values. We also compared the iGPS with the conventional GPS in the validation set. Results The high GPS (GPS: 1‐2) was correlated with RFS and overall survival (OS) in the training set. Cut‐off values of CRP and albumin for RFS were 1.6 and 3.9, and we modified the GPS accordingly, adding the cut‐off values of 2 and 3.9 to CRP and albumin, respectively. In the validation set, a high iGPS was an independent prognostic factor for RFS (hazard ratio [HR]: 2.273; 95% confidence interval [CI]: 1.212‐4.364; P = .011), although the conventional GPS was not. Conclusion The iGPS was a more accurate prognostic predictor for patients with stage 0‐III CRC., We examined the predictive ability of the Glasgow Prognostic Score in patients with stage 0‐III colorectal cancer and sought to improve it.

A left ventricular assist device (LVAD) is used for patients with severe heart failure. We present a case of a 35-year-old man who had undergone LVAD implantation 2 years ago for dilated phase of hypertrophic cardiomyopathy. He had right lower abdominal pain and was diagnosed with acute appendicitis. Single-incision laparoscopic surgery for appendicitis was performed. We incised approximately 3 cm of the umbilicus carefully because the driveline of LVAD was passing just caudal to the umbilicus. LVAD is only available for patients waiting for cardiac transplantation in Japan, and the number of patients with LVAD has been increasing. Adequate anticoagulant therapy is necessary because device thrombosis often causes fatal complications, but during emergency cases, the surgeons have to be cautious of bleeding and injury to the driveline of LVAD.

Objectives In the 9th edition of the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma (JCCRC), ovarian metastasis is classified as distant metastasis. We assessed the significance of resection of ovarian metastases and the validity of this 9th edition of JCCRC for ovarian metastases from colorectal cancer (CRC). Methods We retrospectively analyzed the clinicopathological factors and overall survival of 17 patients with ovarian metastases from CRC who underwent resection and 110 female CRC patients with Stage IV (M1a) disease. Results The patients with only ovarian metastases who underwent resection had a longer median survival time than patients with both ovarian and peritoneal metastases who underwent resection (45.4 months vs. 9.3 months, P = 0.029). The 5-year overall survival of the patients with only ovarian metastases who underwent R0 resection was as long as that of the female Stage IV (M1a) CRC patients after R0 resection (50% vs. 48%, P = 0.334). Conclusions We found that, after resection, patients with only ovarian metastases had significantly better prognoses than patients with ovarian and peritoneal metastases. R0 resection of ovarian metastasis indicated as good prognosis as R0 resection of metastasis to one distant organ without ovaries. So the 9th edition of JCCRC, which classifies ovarian metastasis from CRC as distant metastasis, is appropriate.

Highlights • Pain in the anus or presented with red, flat, elevated lesions in the anus needs to suspecte anal canal cancer. • To differentiate between extramammary Paget’s disease (EMPD) and Anorectal cancer with pagetoid spread (PS) is difficult. • A two-stage operation, a local excision followed by pathological diagnosis and an additional excision,can be useful in PS., Introduction Paget’s disease is an intraepithelial invasion by a malignant tumour and is characterised by erythema and inflammation. It can manifest as mammary or extramammary Paget’s disease (EMPD), with the latter often developing in the perianal area. Anorectal cancer can cause transepithelial invasion into the epidermis, resulting in an appearance similar to that of EMPD. This is called pagetoid spread (PS), which is completely different from EMPD. These two conditions are difficult to differentiate because of the nature of intricacy and requirements of histopathology. Presentation of case We present a case in which differential diagnosis between these two conditions was not possible during the preoperative examination, resulting in difficulties in treatment. The patient was a 70-year-old woman who experienced pain in the anus since the previous month and presented with red, flat and elevated lesions. Discussion Treatment for dermatitis was ineffective, and endoscopic examination did not indicate rectal or anal cancer. However, immunohistochemical examination of the biopsy specimen suggested PS. Thus, two-stage operation was planned. Transanal surgery was performed to confirm the diagnosis of PS and intersphincteric resection was allowed as a radical surgery. Conclusion Thus, when differentiation between EMPD and PS is intricacy, two-stage operation is useful in selecting an appropriate radical surgery method, leading to preservation of anal function.

Malnutrition has been considered to be associated with the prognosis of cancer. The Geriatric Nutritional Risk Index (GNRI), based on serum albumin levels, present body weight, and ideal body weight, is a simple screening tool to predict the risk of nutrition-related morbidity and mortality in elderly patients. We aimed to evaluate whether preoperative GNRI was associated with postoperative complications and prognosis in elderly patients with colorectal cancer (CRC). We retrospectively enrolled 313 CRC patients aged ≥65 years after curative surgery and classified them into an all-risk GNRI (≤98) group and a no-risk GNRI (>98) group. Kaplan-Meier analysis showed overall survival was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.009). Multivariable analyses showed low GNRI (≤98) was an independent risk factor for postoperative complications (P = 0.048) and overall survival (P = 0.001) in the patients. Among the complications, the incidence of surgical site infection, in particular, was significantly higher in the all-risk GNRI group (P = 0.008). In conclusion, low preoperative GNRI (≤98) was associated with increased postoperative complications and poor prognosis. Preoperative GNRI can be used as an identifier for potential high-risk group of morbidity and mortality in elderly CRC patients.

Innate lymphoid cells (ILC) are responsible for mucosal tissue homeostasis and are involved in the progression and suppression of several types of cancer. However, the effects of ILCs on colorectal cancer are poorly understood. We characterized human ILCs in normal colon and colorectal cancer tissue, investigating their role in the tumor immune microenvironment. Normal mucosa and tumor tissues were obtained from patients with colorectal cancer, and the cells were isolated by enzymatic digestion. NKp44+ ILC3s with high expression of tertiary lymphoid structure (TLS) formation–related genes, including LTA, LTB, and TNF, accumulated in the normal colonic mucosa and T1/T2 tumors. However, the number of NKp44+ ILC3s was significantly reduced in T3/T4 tumors compared with normal colonic mucosa and T1/T2 tumors. NKp44+ ILC3s present in T3/T4 tumors had decreased expression of TLS formation–related genes, whereas stromal cells had decreased expression of CXCL13, CCL19, and CCL21. The decreasing number of NKp44+ ILC3s during tumor progression correlated with the TLS density in tumors. Thus, our results indicate that NKp44+ ILC3s infiltrate colorectal cancer tissue, but the number of cells decreases in T3/T4 tumors with associated decreases in TLS induction.

A 69-year-old man underwent single-incision laparoscopic colectomy for a colon tumor. He had comorbid relapsing polychondritis, an uncommon and intractable chronic inflammatory disease that shows various symptoms and systemically invades the cartilaginous tissue throughout the body. In this case, the bronchial wall was edematous and the glottis was incompetent. Steroids were also administered. Although the patient had high-risk factors for surgical complications, none occurred during the perioperative period. Once the C-reactive protein value returned to within the normal range after surgery, we reduced the steroid dose. This is the first report of single-incision laparoscopic colectomy for a patient with relapsing polychondritis.

Crohn’s disease causes chronic inflammation in the gastrointestinal tract and its pathogenesis remains unclear. In the intestine of Crohn’s disease patients, CD14+CD11+CD163low macrophages contribute to inflammation through the induction of Th17 cells and production of inflammatory cytokines; the CD14+CD11c+163high fraction is anti-inflammatory through the production of IL-10 in normal cases. In this report, the 16S rRNA gene amplicon sequencing method was used to identify bacteria that are specifically present in intestinal CD14+CD11c+ macrophages of Crohn’s disease patients. Bacteria present in intestinal CD14+CD11c+ macrophages and mucus of Crohn’s disease patients were separated into different clusters in principal coordinates analysis. There was a statistically significant increase in the relative composition of CD14+CD11c+ macrophages from mucus in two phyla (Proteobacteria [p = 0.01] and Actinobacteria [p = 0.02]) and two families (Moraxellaceae [p Pseudomonadaceae [p = 0.01]). In addition, OTU-1: Acinetobacter and OTU-8: Pseudomonadaceae tended to concentrate in the CD14+CD11c+CD163low subset, whereas OTU-10: Proteus, OTU-15: Collinsella tended to concentrate more in the CD14+CD11c+CD163high subset than the other subset and mucus.

This review outlines current topics on the surgical treatment of benign colorectal diseases, with a focus on inflammatory bowel disease (IBD) and diverticulitis. Treatment options for IBD and diverticulitis have evolved in the last few years as a result of medical advances in technology and new clinical trials. Therefore, treatment options and strategies need to be updated to provide optimal care for patients. The purpose of this review is to elucidate recent global trends and update the surgical treatment strategy for IBD and diverticulitis based on literature published in the past 2 years. Prevalence of IBD, including ulcerative colitis and Crohn's disease, has increased over the last few decades. During this period, many new medical therapies were introduced for the treatment of IBD, including biological therapy, immunomodulators, and leukocyte apheresis therapy. As a result, new surgical strategies for IBD are required. In order to improve surgical outcomes in IBD patients, the influence of preoperative treatment on postoperative complications needs to be considered. The incidence of diverticulitis is also increasing with lifestyle changes and increasing numbers of older people. For diverticulitis with perforation and generalized peritonitis, surgery is the gold standard. Elective surgery after conservative treatment of diverticulitis is also an option because of high recurrence rates. With an increase in diverticulitis, systematic strategies are essential for an appropriate approach to diverticulitis, taking into account various factors, including the patient's background.

The population is aging rapidly, and the population of patients who undergo surgeries is aging, too. Elderly patients have much risk of postoperative delirium, which increases the number of adverse events. The aim of this study was to investigate the risk factors of postoperative delirium in elderly patients with colorectal cancer.We conducted a retrospective cohort analysis of consecutive patients aged 70 years and older who underwent surgeries for colorectal cancer at our department in the period from May 2012 to October 2019. We investigated the correlation between the incidence of postoperative delirium and Comprehensive Geriatric Assessment (CGA) scores, comorbidities, and perioperative factors. Postoperative delirium was retrospectively diagnosed by checking clinical records.Postoperative delirium was diagnosed in 36 of 271 patients (13.3%) with colorectal cancer. Among many comorbidities, only renal disease was significantly associated with postoperative delirium. Among the items in the CGA, age; Mini-Mental State Exam (MMSE), Barthel Index, Instrumental Activities of Daily Living (IADL), Vitality Index, and Geriatric Depression Scale (GDS) scores; and grip strength were associated with postoperative delirium. Among perioperative factors, blood transfusion was associated with postoperative delirium. Multivariate logistic regression analysis identified older age, MMSE, GDS, and grip strength as significant independent risk factors for postoperative delirium.This single-center retrospective observational study demonstrated that grip strength is an independent predictor of postoperative delirium, along with age, MMSE, and GDS.

We examined the association between pathological lateral pelvic lymph node (LPLN) metastasis and the LPLN diameter in patients with locally advanced rectal cancer (LARC) who received a neoadjuvant chemotherapy (NAC) regimen based on oxaliplatin as induction chemotherapy. We aimed to determine whether or not the LPLN size predicts LPLN metastasis in NAC cases. We retrospectively examined data from 3 institutes for 60 patients with LARC who received mesorectal excision and LPLN dissection after NAC. We evaluated the LPLN size on magnetic resonance imaging (MRI) scans acquired before and after NAC. We performed multivariate analyses to analyze the relationship between the LPLN size and clinicopathological factors. For patients with visible LPLNs, the median short-axis diameter (SA) was significantly reduced from 5.1 mm (range 2.0–17.4) before NAC to 3.7 mm (range 2.1–19.0) after NAC (p = 0.0479). SA diameters were significantly larger in pathological LPLNs than in healthy LPLNs, both before (p = 0.0002) and after NAC (p

Introduction: A mesh plug is used worldwide for tension-free repair of an inguinal hernia. This procedure is relatively quick, is easy to learn, has a low recurrence rate, has few complications, and offers rapid recovery; however, complications specific to the mesh plug are infrequently reported. Case presentation: We present a rare case of a 70-year-old man admitted to our hospital with right lower abdominal pain and groin swelling 11 years after open inguinal hernia repair using a mesh plug. Abdominal computed tomography showed a subcutaneous abscess in the right inguinal region and a thickened ileum wall. We diagnosed that a mesh plug had penetrated into the ileum wall, resulting in an abscess. The emergency operation revealed the mesh plug migration into the ileum, and removal of the mesh plug and partial resection of the ileum were performed. At 9 months after operation, there has been no recurrence of the hernia. Conclusion: Although rare, migration of the mesh plug should be considered in patients who have undergone inguinal hernia repair and have symptoms of acute abdominal pain, particularly when there is no previous history of abdominal surgery.

Background Local recurrence is common after curative resections for rectal cancer. Surgical intervention is among the best treatment choices. However, achieving a negative resection margin often requires extensive pelvic organ resections; thus, the postoperative complication rate is quite high. Recent studies have reported that the inflammatory index could predict postoperative complications. This study aimed to validate the correlation between clinical factors, including inflammatory markers, and severe complications after surgery for local recurrent rectal cancer. Methods This retrospective study included 99 patients that underwent radical resections for local recurrences of rectal cancer. Postoperative complications were graded according to the Clavien-Dindo classification. Grades ≥3 were defined as severe complications. Risk factors for severe complications were identified with univariate and multivariate logistic regression models and assessed with receiver-operating characteristic curves. Results Severe postoperative complications occurred in 38 patients (38.4%). Analyses of correlations between inflammatory markers and severe postoperative complications revealed that the strongest correlation was found between the prognostic nutrition index and severe postoperative complications. The receiver-operating characteristic analysis showed that the optimal prognostic nutrition index cut-off value was 42.2 (sensitivity: 0.790, specificity: 0.508). In univariate and multivariate analyses, a prognostic nutrition index ≤44.2 (Odds ratio: 3.007, 95%CI:1.171–8.255, p = 0.02) and a blood loss ≥2850 mL (Odds ratio: 2.545, 95%CI: 1.044–6.367, p = 0.04) were associated with a significantly higher incidence of severe postoperative complications. Conclusions We found that a low preoperative prognostic nutrition index and excessive intraoperative blood loss were risk factors for severe complications after surgery for local recurrent rectal cancer.

Castleman's disease (CD) is a rare atypical lymphoproliferation disorder first reported in 1954. Clinically, CD is classified as unicentric or multicentric CD based on anatomical distribution. Unicentric CD primarily affects the mediastinum, and rarely affects the retroperitoneal location. The standard treatment for unicentric CD is complete surgical resection; however, this can be complicated by a high degree of attachment with other organs or hypervascularity. Preoperative angiography and embolization of the arteries that feed the problematic mass can reduce intraoperative bleeding in cases of CD with hypervascularity. In the present case report, a 44-year-old man who was found to have a pelvic retroperitoneal mass with calcification based on abdominal imaging results is discussed. Due to the hypervascularity of the mass, preoperative embolization was performed. The mass was completely resected without any complications. Additionally, a review of the literature on pelvic CD and preoperative embolization of CD was performed to provide an up-to-date reference on the management and outcomes of patients with CD.

Background The presence of lateral pelvic lymph node (LLN) metastasis is an essential prognostic factor in rectal cancer patients. Thus, preoperative diagnosis of LLN metastasis is clinically important to determine the therapeutic strategy. The aim of this study was to evaluate the efficacy of preoperative positron emission tomography/computed tomography (PET/CT) in the diagnosis of LLN metastasis. Methods Eighty-four patients with rectal cancer who underwent LLN dissection at Osaka University were included in this study. The maximum standardized uptake value (SUVmax) of the primary tumor and LLN were preoperatively calculated using PET/CT. Simultaneously, the short axis of the lymph node was measured using multi-detector row computed tomography (MDCT). The presence of metastases was evaluated by postoperative pathological examination. Results Of the 84 patients, LLN metastases developed in the left, right, and both LLN regions in 6, 7, and 2 patients, respectively. The diagnosis of the metastases was predicted with a sensitivity of 82%, specificity of 93%, positive predictive value of 58%, negative predictive value of 98%, false positive value of 7%, and false negative value of 18% when the cutoff value of the LLN SUVmax was set at 1.5. The cutoff value of the short axis set at 7 mm on MDCT was most useful in diagnosing LLN metastases, but SUVmax was even more useful in terms of specificity. Conclusions The cutoff value of 1.5 for lymph node SUVmax in PET is a reasonable measure to predict the risk of preoperative LLN metastases in rectal cancer patients.

Histological examination of the lymph nodes (LNs) is crucial to determine the colorectal cancer (CRC) stage. We previously reported a new fat-dissociation method (FM) to detect LNs from surgically resected mesentery. This study aimed to examine the effectiveness of FM compared with that of conventional palpation method (PM) in CRC. This single-center, open-label, randomized controlled study was performed at Osaka International Cancer Institute in Japan in 2014. Randomization was performed using a computer-generated permuted-block sequence. Patients were stratified by surgical procedures and the LN dissection area. The primary endpoint was the time required for LN identification. The secondary endpoint was the number of LNs and 5-year cancer-specific survival. The 130 enrolled patients were randomly assigned in a 1:1 ratio to the FM and the PM groups. LN identification times were 45 (range 15–80) and 15 (range 7–30) minutes in the PM and the FM groups, respectively (P P = 0.047). The number of LN which could be examined pathologically was 16 (range 2–48) and 18 (range 4–95) in the PM and FM groups, respectively (P = 0.546). In right-sided CRC, the number of LNs was higher in the FM group than in the PM group (P = 0.031). Relapse-free survival rates and cancer-specific survival rates did not differ between the groups. In conclusion, FM reduced the time required for LN detection without reducing the number of detected LNs, making it is a useful method to detect LNs in surgical specimens.

The intestinal environment plays important roles in mucosal barrier homeostasis and intestinal inflammation, as clarified in studies using experimental animals but not in humans. We investigated whether environmental changes in the fecal stream cause phenotypic changes in the human mucosal barrier. We obtained human ileal samples after fecal stream diversions in patients with rectal cancer or Crohn’s disease. We investigated the bacterial load and diversity in the human defunctioned ileum, defined as the anal side of the ileum relative to the ileostomy. We also examined the epithelium and lamina propria cell phenotypes in the defunctioned ileum. After fecal stream diversion, bacterial loads decreased significantly in the defunctioned ileum. Based on the Chao1, Shannon, and observed species indices, the diversity of mucosa-associated microbiota was lower in the defunctioned ileum than in the functional ileum. Moreover, the healthy defunctioned ileum showed reductions in villous height, goblet cell numbers, and Ki-67+ cell numbers. Additionally, interferon-γ+, interleukin-17+, and immunoglobulin A+ cell abundance in the lamina propria decreased. After the intestinal environment was restored with an ileostomy closure, the impaired ileal homeostasis recovered. The defunctioned ileum samples from patients with Crohn’s disease also showed reductions in interferon-γ+ and interleukin-17+ cell numbers. Fecal stream diversion reduced the abundance and diversity of intestinal bacteria. It also altered the intestinal mucosal barrier, similar to the alterations observed in germ-free animals. In patients with Crohn’s disease, Th1 and Th17 cell numbers were attenuated, which suggests that the host–microbiome interaction is important in disease pathogenesis.

Recently developed molecularly targeted therapies such as EGFR inhibitors have notably improved the prognosis of patients with cancer. However, patients with KRAS and BRAF mutations do not currently benefit from these therapies. Here, we aimed to examine potential effects of crenolanib as a new molecularly targeted therapy in colorectal cancer. We used multiple colorectal cancer cell lines to investigate the growth-inhibitory effect of crenolanib and its effect in combination with other cytotoxic agents. Primary cultures of patient-derived organoids (PDO), a model that reflects the heterogeneity of clinical colorectal cancer, were used to further validate the effects of crenolanib. Unlike cetuximab, crenolanib remarkably suppressed ERK and AKT/mTOR pathways in HT29 cells with BRAF mutation and in HCT116 cells with KRAS mutation with corresponding growth-suppressing effects. Additive or synergistic effects were observed in treatments with combination of crenolanib and other cytotoxic drugs. Moreover, crenolanib suppressed the expression of stem cell markers, such as OCT4, NANOG, and SOX2. These observations were substantiated in seven PDOs with KRAS mutation and two PDOs without KRAS/BRAF mutations, with crenolanib suppressing the growth of all PDOs regardless of their KRAS mutation status. Furthermore, crenolanib abrogated PDGF- and TGFβ-induced increase of OCT4-positive cells in PDOs. Together, these findings suggest that crenolanib may have clinical utility for patients with colorectal cancer, especially patients with KRAS/BRAF mutations. Implications: These findings indicate that crenolanib can be a useful target agent for patients with colorectal cancer, especially patients with KRAS/BRAF mutations.

Chromosome instability is one of the hallmarks of cancer. Stromal antigen (STAG) 3 is a core component of the meiosis-specific cohesin complex, which regulates sister chromatid cohesion. Although aberrantly activated genes encoding the cohesin complex have been identified in cancers, little is known about the role of STAG3 in colorectal cancer (CRC). Here, we evaluated the prognostic impact and role of STAG3 in CRC. Analysis of 172 CRC surgical specimens revealed that high STAG3 expression was associated with poor prognosis. STAG3 knockdown inhibited cell migration and increased drug sensitivity to oxaliplatin, 5-fluorouracil, irinotecan hydrochloride hydrate, and BRAF inhibitor in CRC cell lines. The enhanced drug sensitivity was also confirmed in a human organoid established from a CRC specimen. Moreover, suppression of STAG3 increased γH2AX foci. Particularly, in BRAF-mutant CRC cells, STAG3 silencing suppressed the expression of snail family transcriptional repressor 1 and phosphorylation of extracellular signal-regulated kinase via upregulation of dual-specificity phosphatase 6. Our findings suggest that STAG3 is related to poor clinical outcomes and promotes metastasis and chemotherapeutic resistance in CRC. STAG3 may be a novel prognostic marker and potential therapeutic target for CRC.

In recent years, systemic chemotherapy has significantly improved the prognosis of metastatic colorectal cancer (CRC); however, different patients have different responses to chemotherapeutics. Dipeptidyl peptidase 9 (DPP9) is an enzyme in the dipeptidyl peptidase IV family that has been reported to increase drug sensitivity in acute myeloid leukemia. In this study, we examined the relationship between DPP9 expression and the prognosis of patients with CRC, as well as the role of DPP9 in anticancer drug resistance. Moreover, the effects of the DPP9 inhibitors talabostat and vildagliptin in CRC cell lines and primary cultured cells were assessed. High expression of DPP9 was associated with worse prognosis in 196 patients with CRC. Cell viability was markedly inhibited in CRC cell lines transfected with DPP9 small interfering RNA or small hairpin RNA. Talabostat suppressed proliferation in CRC cell lines and primary cultured cells, and increased their sensitivity to chemotherapy. Vildagliptin, a DPP family inhibitor currently administered for diabetes, also increased the sensitivity of CRC cells to anticancer drugs. DPP9 was a poor prognostic factor for CRC and could be a new therapeutic target, while vildagliptin could be used as a repositioned drug for CRC treatment.

Objective : Surgical treatment is an important option for inducing remission in Crohn's disease (CD); indeed, the longer the disease duration, the higher the cumulative surgical rate. Previous studies have shown that the pathogenesis of Crohn's disease was associated with sarcopenia, a condition of reduced skeletal muscle mass. Here, we investigated the effect of preoperative sarcopenia on postoperative disease activity. Methods : This retrospective study included 56 patients with CD with medical records that met our inclusion criteria. Sarcopenia was diagnosed, based on the psoas muscle mass index (PMI) derived from computed tomography (CT) images, with predetermined PMI cut-off values of Results : Of the 56 included subjects, nine (16%) had sarcopenia. The rate of preoperative treatment with biological drugs was significantly lower in the sarcopenia group than in the normal group. In addition, the operation time was significantly longer, and hemorrhage occurred more often in the sarcopenia group than in the normal group. Postoperatively, the CD activity index at six months had significantly decreased in the normal group (p = 0.01), but not in the sarcopenia group (p = 0.20). Univariate and multivariate analyses showed that a low total serum protein level was significantly associated with sarcopenia. Conclusion : Our results suggested that, to maximize the effect of surgical treatment for CD, an appropriate nutritional intervention should be performed before surgery, or surgery should be postponed until the patient recovers from sarcopenia.

In patients with Crohn's disease (CD) and intestinal failure, home parenteral nutrition (HPN) is a necessary lifesaving treatment. The aim of this study was to investigate the long-term outcomes of patients with CD after initiation of HPN.This study included patients with CD receiving HPN for intestinal failure. The patients were treated at Osaka University Hospital between January 2000 and December 2019. Patients' demographic characteristics, HPN dependence and complications, and mortality were analyzed. HPN dependence was estimated using the Kaplan-Meier method. Cox regression analysis was used for between-group comparisons.Twenty-one patients with CD received HPN. HPN dependence rates were 85%, 75%, 75%, and 64%, respectively, at 2, 5, 10, and 15 y after HPN initiation. Patients who weaned off HPN exhibited lower rates of immunomodulator therapy and additional intensive CD treatment (P0.05). Multivariate analysis revealed that not requiring additional intensive CD treatment was a significant factor in weaning off HPN. Two patients (9%) died, at a median of 14.9 y after HPN initiation, due to HPN-related liver disease and CD-associated carcinoma. Among all patients, 61% experienced catheter-related bloodstream infections (CRBSIs), with an incidence of 0.32/1000 catheter-days. Methicillin-resistant bacteria and Candida spp. each accounted for 27% of all pathogens detected in CRBSI.Patients with CD receiving HPN had a good prognosis, despite frequent CRBSIs in which methicillin-resistant bacteria and fungi were common pathogens. Some patients with CD can wean off HPN, even after a long period of HPN treatment. A stable disease condition during HPN might be an important factor for weaning off HPN.

Backgrounds: Although radiation therapy is effective for many cancers, tumor regrowth and recurrence can occur after irradiation. Various mechanisms have been reported regarding the resistance, including the involvement of cancer stem cells and radioresistance genes. However, acquisition of resistance and recurrence are still crucial problems in clinical field. Tumor heterogeneity is thought to play an important role and greatly involve in the acquisition of therapeutic resistance. It is difficult to examine heterogeneous population using cancer cell lines consisted of homogenous cells. Therefore, we have developed primary cultured cells, named 2D organoid (2DO) which maintained clinical tumor heterogeneity. The purpose of this study is to reveal a novel mechanism of radiation resistance by focusing on changes in various populations and persister cells after irradiation using 2DO. Materials and Methods: Colorectal cancer cell lines and 2DOs established from surgery resected specimens were irradiated with various doses (2-10Gy once, 1-4Gy for 5 days consecutive, etc.). Cancer stem cell markers were evaluated before and after irradiation using flow cytometry. Results: In the cell lines, CD44+ cells remained after irradiation, and no significant change was observed in stem cell population before and after irradiation. In the 2DOs, CD44+ cells remained after irradiation, and in addition CD44− cells also newly emerged. The CD44− cells were sorted by cell sorter and cultured. The CD44− cells reproduced CD44+ cells and reconstructed the heterogenous population similar to the parent 2DOs. However, CD44− cells sorted from the parent cells not irradiated did not reconstructed the heterogenous population. Furthermore, the cells reproduced from the survived CD44− cells had more resistance to anti-tumor drugs than cells from the survived CD44+ cells. Other stem cell markers such as CD24 and CD133 were also examined, but no significant changes were observed before and after irradiation. Conclusions: In addition to CD44+ cells, CD44− cells also survived after irradiation. The survived CD44− cells after irradiation had more resistance to anti-tumor drugs compared with the survived CD44+ cells. These newly emerged CD44− cells may be important persister cells in tumor regrowth and recurrence. We report on the functional analysis of these cells. Citation Format: Masaru Sasaki, Norikatsu Miyoshi, Shiki Fujino, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Hirofumi Yamamoto, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki. Newly emerging CD44 negative cells after irradiation reproduce CD44 positive cells and promote radioresistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6170.

Purpose. Cancer tissues contain a substantial amount of stromal tissues, and transcriptome derived from bulk samples originates from a mixture of the cancer epithelium and stroma. Gene signature of epithelial-mesenchymal transition (EMT) cells is similar to that of stromal cells; therefore, gene signature that we considered to be related EMT might be only contamination of stroma. Here, we identify novel EMT inducers by analysis of independent gene expression profiles in the colorectal cancer epithelium and stroma. Materials and Methods. Gene expression data of pure epithelial tissue was obtained using laser microdissection technique from 13 colorectal cancer tissues. Next, the ratio of each gene expression in the stroma to in the epithelium and correlation of each gene expression with a target gene derived from The Cancer Genome Atlas (TCGA) is plotted in two dimensions, and correlation coefficients are calculated. We regard genes with high correlation coefficients but highly expressed in the epithelium as candidates of EMT inducers. We manipulate the expression of some candidate genes in colorectal cancer cell lines to investigate the alterations of EMT markers and migration ability in vitro. Results. We extract 91 new putative EMT-related genes in silico. They are highly expressed in similar cell lines to known EMT markers in a public database. Furthermore, some candidates have reported having a relation to EMT, and that indicates the validity of this procedure. The knockdown of three candidate genes upregulates epithelial gene expression and downregulates mesenchymal gene expression. The knockdown of one of the three genes reduces cell migration. In contrast, overexpression of the gene downregulates epithelial gene expression and leads to cell migration. Conclusion. We identify novel EMT inducers successfully using purified gene expression data. They could be new prognostic markers and therapeutic targets of colorectal cancer. Citation Format: Satoshi Ishikawa, Naohiro Nishida, Shiki Fujino, Takayuki Ogino, Hidekazu Takahashi, Norikatsu Miyoshi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizusima, Hirofumi Yamamoto, Koshi Mimori, Masaki Mori, Yuichiro Doki, Hidedoshi Eguchi. Identification of novel epithelial-mesenchymal transition inducers and their clinical significance in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1535.

Background Intraductal papillary-mucinous neoplasms (IPMNs) are potentially malignant intraductal epithelial neoplasms that sometimes penetrate into other organs. To the best of our knowledge, no report has yet described a case with penetration into the spleen. We recently encountered a case of IPMN with penetration of the stomach and spleen that was successfully treated by total pancreatectomy. Case presentation A 70-year-old female visited our hospital with a complaint of fever and abdominal pain. Contrast-enhanced computed tomography (CT) revealed dilatation of the main pancreatic duct in the entire pancreas and penetration into the stomach and spleen. Upper gastrointestinal endoscopy revealed mucin extruding from four openings of the fistula in the stomach. No malignancy was detected based on cytology of the mucin. Inflammation markers and tumor markers (CEA, CA19–9) were elevated in the blood. The pre-operative diagnosis was IPMN of main pancreatic duct type penetrating into the stomach and spleen. A total pancreatectomy and splenectomy were performed, combined with distal gastrectomy including resection of the fistulas between the pancreas and stomach. No postoperative complications were noted. Histopathological examination of the resected specimen revealed atrophy of the pancreatic parenchyma, and the main duct of the pancreas was filled with mucin. Mucin-producing malignant tumor cells were detected in the epithelium of the main pancreatic duct with no signs of invasion. No malignancy was found at the fistulas between the pancreas and stomach or spleen. The patient was finally diagnosed with non-invasive intraductal papillary-mucinous carcinoma (IPMC) of main pancreatic duct type. Mechanical penetration was suspected as a mechanism of the penetration. The patient remained disease-free without evidence of recurrence more than 15 months after the operation. Conclusion Though IPMNs sometimes penetrate into other adjacent organs, penetration into two organs, including the spleen, is rare. The rare case of IPMC penetrating into the stomach and spleen presented here was treated successfully by total pancreatectomy.

Background Generally, cancer cell lines are established from the patients of which cancer cells are dissected, cultured and maintained in vitro. These cell lines have been traditionally used in cancer research; however, they have changed better to survive in culture condition in vitro, and not restored the original characters when they grew in vivo, meaning the lack of tumor heterogeneity. Primary culture of cancer cells derived from patients’ tumors can provide crucial information as each “individual tumor”. The primary culture method of clinical cancer and the evaluation for the treatment have not been clearly optimized in gastrointestinal cancers. Methods We have developed a simple 2D/3D-culture method for primary cancer. We obtained 40 clinical samples from surgically resected colorectal cancers (CRCs). They were mechanically and enzymatically digested and are filtered by customized preparation tools, followed by in vitro culture system. The gene expression profiles and the sensitivity for the drugs were analyzed. Results Culture cells were analyzed These cultured cancer cells were named “isolated-tumor derived Cancer Cells (iCCs).” All iCCs grew and about 90 % of iCCs were successfully passaged. These iCCs were transplanted into the subcutaneous tissue of nonobese diabetic (NOD) - severely compromised immune deficient (SCID) mice, and the tumor growth and pathological examination were evaluated. The morphology was similar to each parental clinical tumor. Microarray analyses showed that RNA expression of iCCs was similar to each parental tumor. Surface markers regarding cancer stem cells expressed in iCCs. Furthermore, multi-drug sensitivity assay by our bespoke plates including commonly used as anti-cancer/molecular target drugs was performed. Conclusions The iCCs are very similar to each parental tumor, leading to the personalized medicine, and the analyses of the tumor characteristics seem to reflect the clinical presentation. Legal entity responsible for the study The authors. Funding Japanese Agency for Medical Research and Development. Disclosure All authors have declared no conflicts of interest.

症例は40歳代の男性で，25歳頃より腸閉塞の診断で入退院を繰り返し，保存的療法で改善していた．2008年6月にS状結腸過長症と診断され，他院で腹腔鏡下S状結腸切除術を施行された．しかし同年7月に再び腸閉塞症状のため当院に入院した．入院3日目に腹膜炎症状が出現し，緊急手術を施行した．上行結腸が捻転しており同部位より口側結腸が拡張していたため，結腸右半切除術を施行した．術後も腸閉塞状態が改善せず，腹部膨満症状を改善するため，回腸人工肛門造設を施行した．その後，慢性偽性大腸閉塞症を考え，同年12月に結腸全摘術を施行した．症状の改善は認めたが，術後も腹部単純X線検査で小腸は著明に拡張した状態であったため，慢性偽性小腸閉塞症と最終診断した．術後1年経過した現在，蠕動促進薬を内服して日常生活を送っている状態である．

症例1は44歳の男性で, 肛門縁より7cmにわたる4型腫瘍で生検の結果がsignet-ring cell carcinomaであり, 術前CRT後に腹会陰式直腸切断術, 側方郭清を施行. 術後20日目に右下肢の浮腫, 疼痛が出現しCTにて骨盤内リンパ嚢腫および右外腸骨静脈～大腿静脈に血栓を認めた. 抗凝固療法およびリンパ嚢腫のドレナージを施行後, 症状は改善した. 症例2は54歳の女性で, 術前CTで側方リンパ節転移を認め, CRT後に腹会陰式直腸切断術, 側方郭清, 膣後壁合併切除を施行. 術後42日目より労作時呼吸困難が出現し, CT, USにて肺塞栓, 両側外腸骨静脈の血栓および骨盤内リンパ嚢腫を認めた. 永久型下大静脈フィルターを留置し, 抗凝固療法, 血栓溶解療法およびリンパ嚢腫のドレナージを施行後, 症状は改善した. 2症例とも骨盤内リンパ嚢腫による外腸骨静脈圧排像を認めており, リンパ嚢腫と静脈血栓塞栓症との関連が示唆された.

Although simultaneous resection of primary colorectal cancer and synchronous liver metastases is reported to be safe and effective, the feasibility of a laparoscopic approach remains controversial. This study evaluated the safety, feasibility, and short-term outcomes of simultaneous laparoscopic surgery for primary colorectal cancer with synchronous liver metastases. From September 2008 to December 2013, 10 patients underwent simultaneous laparoscopic resection of primary colorectal cancer and synchronous liver metastases with curative intent at our institute. The median operative time was 452 minutes, and the median estimated blood loss was 245 mL. Median times to discharge from the hospital and adjuvant chemotherapy were 13.5 and 44 postoperative days, respectively. Negative resection margins were achieved in all cases, with no postoperative mortality or major morbidity. Simultaneous laparoscopic colectomy and hepatectomy for primary colorectal cancer with synchronous liver metastases appears feasible with low morbidity and favorable outcomes.

The spacer placement is a prevalent procedure to separate the surrounding normal tissues from locally recurrent rectal tumor before the application of radiotherapy. However, complications could occur due to the foreign nature of the spacer. This report describes a case of 60-year-old man who had undergone radiotherapy two years earlier for a recurrent rectal tumor and presented with small bowel obstruction. A spacer was used before radiotherapy. Radiological assessment and laparotomy revealed the presence of the spacer inside the small bowel lumen. It is possible that the spacer established contact with the intestine, elicited local inflammatory reaction that facilitated the complete penetration of the intestinal wall without causing any clinical symptoms.