Search

We report a case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after total proctocolectomy followed with ileal pouch-anal anastomosis (TPC-IPAA) for ulcerative colitis (UC). The patient was a 46-year-old woman. She was diagnosed with UC of pancolitis in 2000. High grade dysplasia was detected in the transverse colon after a surveillance colonoscopy in 2021. She underwent laparoscopy-assisted TPC-IPAA. On the sixth postoperative day, she had a decreased level of consciousness that worsened on the following day. Her laboratory data showed a serum sodium level of 108 mEq/L and the plasma osmolality was 234 mOsm/kg. We did not find any other abnormalities in the laboratory examination that could cause hyponatremia. Computed tomography scan showed no central nervous system disturbances such as a pituitary tumor, antidiuretic hormone-producing tumors, or pulmonary diseases. The patient was diagnosed with Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) caused by surgical invasion. We started to administer 3% sodium chloride slowly to improve the hyponatremia. Her serum sodium level became normal and stable. Although it is rare for SIADH to be caused by abdominal surgery, if hyponatremia is observed after surgery, the possibility of postoperative SIADH should be considered.

The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.

Cripto-1 is a plasma membrane protein which is not expressed in adult tissue, but some tumors are accompanied by re-activation. We studied the clinical and biological significance of Cripto-1 in colorectal cancer. Cripto-1 was positive in 68 out of 192 cases (35%) by immunohistochemistry. Cripto-1 expression was correlated with worse prognosis and was an independent prognostic factor. Cripto-1-silenced colorectal cancer cell lines had reduced cell proliferation, migration, and activation of Akt and MAPK signaling pathways

A 70's woman complaining blood stool and lower abdominal pain visited a local doctor and was given the diagnosis of rectal cancer by colonoscopy. CT, MRI, and bone scintigraphy revealed multiple lymph node and bone metastasis and peritoneal dissemination. She had developed disseminated intravascular coagulation(DIC)during hospitalization, and the cause was considered to be disseminated carcinomatosis of the bone marrow. Thus, we emergently started chemotherapy with mFOLFOX6, in conjunction with anticoagulation therapy, and the DIC was resolved 11 days after the introduction. Partial response was achieved and the chemotherapy has been continued after 5 months from the onset of the DIC. Since the prognosis of solid tumor patients who developed DIC has been reported to be extremely poor, prompt introduction of chemotherapy should be considered.

A 56-year-old man was referred to our hospital for multidisciplinary treatment of advanced sigmoid colon carcinoma with a suspected bladder invasion. The patient received 8 courses of modified Leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6)plus panitumumab as neoadjuvant chemotherapy for reliable and safe radical resection after ileostomy construction. There was a significant reduction in the tumor size following chemotherapy; hence, low anterior resection was performed. In addition, since preoperative and intraoperative findings suggested bladder invasion, a total cystectomy with ileal conduit urinary diversion was performed. The pathological diagnosis was ypT4b, N0, M0, and ypStage Ⅱc, with all surgical margins being negative. Subsequently, the patient received adjuvant chemotherapy with 4 courses of mFOLFOX6, and his condition improved with no incidence of cancer recurrence following 8 months after the operation. Neoadjuvant chemotherapy for locally advanced colon cancer is one of the effective treatments for reliable and safe radical resection.

The splicing of microexons (very small exons) is frequently dysregulated in the brain of individuals with autism spectrum disorder. However, little is known of the patterns, regulatory mechanisms and roles of microexon splicing in cancer. We here examined the transcriptome-wide profile of microexon splicing in matched colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between CRC and normal tissue. The 21 genes harboring the differentially spliced microexons were enriched in gene ontology terms related to cell adhesion and migration. RNA interference-mediated knockdown experiments identified two splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC cells. RBFOX2 and PTBP1 were found to directly bind to microexon-containing pre-mRNAs and to control their splicing in such cells. Differential microexon splicing was shown to be due, at least in part, to altered expression of RBFOX2 and PTBP1 in CRC tissue compared to matched normal tissue. Finally, we found that changes in the pattern of microexon splicing were associated with CRC metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1 might influence CRC metastasis through the regulation of microexon splicing.

Background: Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), which can be prevented with anti-inflammatory therapies. However, inflammatory biomarkers do not necessarily reflect the progression of fibrosis, and hence, an indicator that reflects the therapeutic effects of available anti-inflammatory drugs on fibrosis is needed. This study shows that tissue inhibitor of metalloproteinase-1 (TIMP-1) is a potential therapeutic indicator for ongoing intestinal fibrosis in IBD patients.Methods: TIMP-1 mRNA levels in human myofibroblasts were measured, and TIMP-1 expression in the intestine of 10 Crohn’s disease (CD) patients was examined by immunohistochemistry. Colitis was induced in C57BL/6 mice by administration of 1.5% dextran sodium sulfate for 7 days; then, the mice were treated with anti-TNF-α antibody or phosphate-buffered saline for 14 days. Intestinal fibrosis was evaluated by Masson’s trichrome staining, and TIMP-1 mRNA levels in the intestinal tissue and plasma TIMP-1 levels were measured.Results: TIMP-1 expression in human fibroblasts increased after differentiation into myofibroblasts. TIMP-1 expression in CD intestinal tissue was significantly higher in the inflammation area than in the fibrotic or normal areas. In a murine colitis mode in which TIMP-1 mRNA levels were increased, anti-TNF-α antibody administration significantly attenuated inflammation and fibrosis assessed by a reduction in TIMP-1 mRNA levels in intestinal tissue and plasma TIMP-1 levels.Conclusions: The results in this study show that TIMP-1 is a potential new biomarker that could be used to assess the effectivity of different therapeutic strategies for intestinal inflammation and fibrosis in IBD patients.

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and have been shown to promote cancer aggressiveness. In our previous study, analysis of expression profiles obtained from paired CAFs and normal fibroblasts from colorectal cancer (CRC) tissue revealed that gene sets related to the Wnt signaling pathway were highly enriched in colorectal CAFs. Furthermore, among the components of the β-catenin-independent Wnt pathway, Wnt5a was highly expressed in CAFs. Since Wnt5a is considered to be a regulator of CRC progression in CAFs, we performed immunohistochemical analysis on Wnt5a in 171 patients who underwent surgery for CRC. Positive staining for Wnt5a was often found in cancer stroma, particularly in fibromatous areas, although the immunoreactivity for Wnt5a was weak in cancer cells. Wnt5a status in CAFs was significantly associated with tumor size, depth of invasion, lymphatic and vascular invasion, lymph node metastasis, TNM stage, and recurrence. Subsequent in vitro analyses using human recombinant Wnt5a protein revealed that cancer cell proliferation and migration were significantly increased by stimulation with Wnt5a. Our findings suggest that Wnt5a-derived CAFs play a crucial role in CRC progression and have potential as a target of anti-cancer therapies.

Recent studies have shown that the tumor microenvironment plays a significant role in the progression of solid tumors. As an abundant component of the tumor microenvironment, cancer‐associated fibroblasts (CAFs) have been shown to promote tumorigenesis and cancer aggressiveness, but their molecular characteristics remain poorly understood. In the present study, paired CAFs and normal fibroblasts (NFs) were isolated from five colorectal cancer (CRC) tissues from patients who underwent surgical resection. The gene expression profiles of CAFs and NFs identified by RNA sequencing were compared to understand the complex role of CAFs in cancer progression. Gene Set Enrichment Analysis revealed that the gene sets related to the Wnt signaling pathway were highly enriched in CAFs, as well as TGFβ signaling, which is considered to be a regulator of CAFs. Among the components of this pathway, Wnt2 was specifically expressed. The observations led us to speculate that Wnt2 is extremely involved in regulating CRC progression by CAFs. Thus, we performed immunohistochemical analysis on Wnt2 in 171 patients who underwent surgery for colorectal adenocarcinoma. Positive staining for Wnt2 was mainly observed in cancer stroma, although the immunoreactivity was weak in cancer cells. Wnt2 expression in CAFs was significantly correlated with depth of tumor (P, The analysis here involved comparing gene expression between cancer associated and normal fibroblasts using RNA sequencing, which identified that components of the Wnt signaling pathway were highly expressed in cancer associated fibroblasts, and Wnt2 in particular. We then conducted immunohistochemical analysis on Wnt2 in 171 patients who had undergone colorectal adenocarcinoma surgery. We found strong correlations between Wnt2 expression and progression‐related variables such as tumor depth and lymph node metastasis.

A simplified method has been proposed as a substitute for conventional methods to evaluate the behavior of expansive concrete. In this study, an experimental program was performed to investigate the applicability of the simplified method under steam curing. Two estimation methods for measuring the expansive strains under constraint were compared based on the expansive energies. Specimens were cured with steam or at 20 °C from their first casting up to 1 day. They were then sealed or water-cured at 20 °C for 7 days to investigate the effect of later curing. The range of applicability of the simplified method was analyzed. A new concept for the simplified method of estimating the expansion by using the axial strain was then proposed. The two measurement methods showed a high correlation, which validates the use of the simplified method under steam curing.

A 30's extremely obese patient(body mass index: BMI 45 kg/m2)was referred to our hospital with a chief complaint of bloody urine and stool. Colonoscopy revealed a sigmoid colon tumor. Barium enema examination revealed stenosis of the sigmoid colon. CT scan showed a tumor in the sigmoid colon, with bladder invasion. The para-aortic lymph node was partially swollen. We considered surgery to be high risk because of the patient's severe obesity. Therefore, we decided to examine the possibility of radical surgery followed by chemotherapy(mFOLFOX6/cetuximab)with weight reduction. Following this, the tumor had shrunk remarkably, and the patient's BMI decreased from 45 kg/m2 to 39 kg/m2. The visceral fat area was reduced from 298 cm2 to 199 cm2 at the umbilical level. We then performed a sigmoid colectomy with partial resection of the bladder. Thus, chemotherapy combined with weight loss enabled us to perform radical surgery safely for a locally advanced sigmoid colon cancer in a patient with severe obesity.

A 50's man was referred to our hospital because of sigmoid colon cancer with multiple liver metastases and para-aortic lymph node metastases. Although blood test showed elevated D-dimer(50 μg/mL), there was no significant thrombus in contrast-enhanced CT scan. Since cancer pain and symptoms of bowel obstruction had continued after endoscopic stent placement, we resected primary lesion. Despite anemia and elevated D-dimer level had persisted after the operation, there were no obvious bleeding source nor thrombus. Continuous intravenous heparin infusion was started for hypercoagulability. Then, D-dimer and CRP levels were promptly decreased. Since schizocyte and giant platelets were observed in peripheral blood smear, he was eventually diagnosed with thrombotic microangiopathy as a paraneoplastic syndrome. However D- dimer and CRP levels were re-elevated, and it seemed to be necessary to control cancer progression. Thus, cetuximab monotherapy was started considering his performance status. After starting cetuximab, fever and CRP level were immediately improved. Cetuximab appeared to be very effective, but he died of acute subdural hematoma. Continuous intravenous heparin infusion was supposed to be effective in the treatment of thrombotic microangiopathy along with the management of cancer.

Background Antimesenteric cutback end‐to‐end isoperistaltic anastomosis (Sasaki‐Watanabe anastomosis; Sasaki‐W anastomosis), which was developed in our department, is a novel hand‐sewn anastomotic technique for Crohn's disease intended to prevent anastomotic stenosis and preserve the peripheral circulation. Aim The aim of the present study is to present the surgical technique of Sasaki‐W anastomosis and to assess the safety and the early results of the surgical anastomotic recurrence of Sasaki‐W anastomosis. Patients and Methods The present study was a single‐center retrospective cohort study. As an early‐period group, 13 patients with Crohn's disease, who were mainly selected from cases considered to be at high risk of recurrence, underwent 15 Sasaki‐W anastomoses from August 2009 to January 2012. As a late‐period group, 36 patients with Crohn's disease, who were selected regardless of risk factors, underwent 37 Sasaki‐W anastomoses from September 2016 to March 2020. The medical data including patient characteristics, surgical records, postoperative details, and surgical recurrences were assessed. Results There were no intraoperative complications. With a median follow‐up of 107 mo, surgical recurrence occurred in one patient at 106 mo after surgery in the early‐period group. The cumulative surgical recurrence‐free rate in the early‐period group was 100% at 5 y and 86% at 10 y after surgery. No patients required reoperation in the late‐period group. Conclusion Sasaki‐W anastomosis is safe and feasible. Although long‐term study is needed, this anastomotic technique can be a reasonable operative option for Crohn's disease., Antimesenteric cutback end‐to‐end isoperistaltic anastomosis (Sasaki‐Watanabe anastomosis; Sasaki‐W anastomosis) is a novel hand‐sewn anastomotic technique for Crohn’s disease intended to prevent anastomotic stenosis and preserve the peripheral circulation. Here we show the surgical technique and early results of surgical anastomotic recurrence.

Background Left ventricular assist devices (LVADs) currently play an important role in the treatment of patients with end-stage heart failure who require a bridge to heart transplantation or destination therapy. With the development and improvement of the LVADs, the morbidity and mortality rates are declining and life expectancies increasing, and the number of patients with LVADs requiring non-cardiac surgery is likely to increase. We present the case of a patient with implantable LVAD who underwent laparoscopic right hemicolectomy for ascending colon cancer. Case description The patient was a 66-year-old man who underwent LVAD implantation as a BTT 3 years prior. He suffered from severe anemia at follow-up, and a colonoscopy revealed ascending colon cancer. The LVAD pump was implanted in the epigastrium. The long C-shaped subfascial driveline tunnel was made, and driveline exit site was located on the left lateral abdominal wall. We assessed the positional relationship between the tumor and the driveline using X-ray and three-dimensional computed tomography (3D CT) images. 3D CT image allowed us to easily identify the location of the driveline, and we determined to perform laparoscopic right hemicolectomy. The port sites were decided upon carefully to avoid the driveline injury, and the driveline was marked on the skin before surgery. There were no adhesions in the abdominal cavity, and both the LVAD and the driveline were observable. The trocars were in nearly the same positions as in a standard laparoscopic right hemicolectomy. During the operation, the LVAD and the driveline did not interfere with the trocars. We successfully completed a standard laparoscopic right hemicolectomy despite hemorrhagic tendency. The patient was discharged without any bleeding complications during the postoperative course. Conclusion Laparoscopic surgery is feasible and safe for patients with LVADs with intensive preoperative simulation and perioperative prevention of infection.

A 65-year-old male was diagnosed with rectal cancer invading the urinary bladder, swollen para-aorticlymph nodes, and multiple liver metastases in abdominal CT. After 8 courses of mFOLFOX6 plus panitumumab, the rectal cancer, para-aortic lymph nodes metastasis, and liver metastases decreased significantly in size. Rectal cancer and liver metastases were considered resectable, hence low anterior resection of the rectum was performed. Intraoperative frozen section analysis showed negative metastaticinvolvement of the para-aorticlymph nodes and surgical margins of the urinary bladder; therefore, the urinary bladder was completely preserved. Partial resection of the liver was performed 2 months later. In conclusion, the patient showed good surgical and quality of life results. Thus, the bladder-sparing strategy with preoperative chemotherapy could be considered for appropriately selected rectal cancer patients with urinary bladder involvement.

A 45-year-old woman was referred to our hospital complaining of diarrhea. Colonoscopy showed a rectal tumor. Histological examination showed moderately differentiated adenocarcinoma. A CT scan revealed a tumor extending from the lower rectum to the anal canal with a lateral pelvic lymph node(LPLN)swelling. We administered neoadjuvant chemoradiotherapy (45 Gy/25 Fr, S-1 80mg/m / 2/day)and the tumor and LPLN shrank remarkably, with a clinically complete response by CT and PET-CT. We then performed abdominoperineal resection with D3 lymph node and bilateral LPLN dissection. Pathological examination revealed complete disappearance of the cancer cells in the primary site, while lymph node metastasis was detected in one LPLN. We report here a rare case in which LPLN metastasis remained despite the pathological complete response of the primary tumor.

A 69-year-old man was referred to our institute for the surgical resection of focal resistant peritoneal GIST during imatinib administration. He had been diagnosed with GIST of the small intestine with liver and peritoneal metastases, and imatinib treatment was initiated. Shortly after imatinib administration, the primary lesion perforated, and thus, partial resection of the small intestine was performed. Imatinib treatment was resumed after the first surgery, and he achieved partial response. However, computed tomography scans obtained 7 months after the first surgery showed focal progression, a peritoneal metastasis near the right kidney. Under the diagnosis of focally imatinib-resistant GIST, local resection of the metastatic tumor was performed. In this case, an exon 11 mutation of c-kit was noted initially. After the imatinib treatment, an additional point mutation was observed in exon 18 that caused resistance to imatinib. Therefore, imatinib treatment was reinitiated after the second surgery, and other metastases were well controlled. In case of GIST with multiple metastases, appropriate treatment should be selected based on the resistance of each lesion.

A 60s man was diagnosed with rectal cancer and underwent low anterior resection of the rectum. The pathological diagnosis was mucinous adenocarcinoma, pT3(SS), pN0, pM0, pStage Ⅱ. Two years after the primary surgery, contrast-enhanced CT showed local recurrence on the oral side of the anastomosis. As the tumor had invaded the left seminal vesicle and coccygeus muscle, neoadjuvant chemoradiotherapy(NACRT)(S-1 80mg/m / 2 plus 45 Gy/25 Fr)was performed. After NACRT, abdominoperineal resection, including the left seminal vesicle, coccygeus muscle, and coccygeal bone, was performed. Pathological examination showed a histological response of Grade 2 and that R0 resection was achieved. Although the only radical treatment of locally recurrent rectal cancer is R0 resection, we performed R0 resection with Grade 2 histological response to NACRT.

The Frey procedure is an effective surgery for chronic pancreatitis (CP) patients who have pancreatic head lesions with dilation of the main pancreatic duct. However, pancreatic tail lesions can cause relapsing pancreatitis after the procedure. Therefore, additional distal pancreatectomy (DP) might complement the therapeutic effect of the Frey procedure in controlling inflammation of the pancreatic tail. The Frey procedure with DP (Frey + DP) is indicated for inflammatory lesions in the pancreatic head and tail. In this study, we assessed the usefulness of Frey + DP using the retrospective clinical data of our cases. The clinical outcomes were compared between CP patients who underwent the Frey procedure (N = 44) and Frey + DP (N = 13) from January 2005 to April 2016. Frey + DP showed similarly good therapeutic effects to the Frey procedure with regard to the postoperative stay, morbidity, mortality, pain relief and nutrition, although the Frey + DP had a longer operative time, more bleeding and higher incidence of diabetes mellitus than the Frey procedure because of the additional DP. One patient in the Frey group received additional DP because of recurrent pain due to the tail lesion. Frey + DP can be a promising treatment for CP patients with pancreatic head and tail lesions.

Introduction: Exosomes are membrane-enclosed nanovesicles, which are increasingly being recognized as important cell communication components for their role in transmitting microRNAs (miRNAs). No previous study has addressed the exosomal miRNA profile in colorectal adenomas (CRAs) because the long-term culture of CRA is challenging. This study aimed to identify the miRNA signature in organoid exosomes derived from human CRA and colorectal cancer (CRC) samples. Methods: Organoid cultures were developed from resected colorectal tissues of patients with CRA or CRC undergoing surgery or endoscopic mucosal resection. Exosomes were prepared from the conditioned medium of the organoids. miRNAs were prepared from the exosomes and their source organoids. The miRNA expression profiles were compared using microarray analysis. The impact of alteration of miRNA expression on cell proliferation was examined using miRNA mimics or inhibitors in HT-29 human CRC cells. Results: We established 6 organoid lines from CRC and 8 organoid lines from CRA. Exosomal miRNA signatures were different between the organoids derived from CRA and CRC. Both exosomal and cellular miR-1246 expressions were upregulated in CRC-derived organoids compared to their expression in CRA-derived organoids. Alteration of miR-1246 expression by the miR-1246 mimic or inhibitor increased or decreased cell proliferation in HT-29 cells, respectively. Conclusions: We report for the first time the miRNA profiles of exosomes in CRA- and CRC-derived organoids. The upregulation of miR-1246 might play a role in increased cell proliferation in the process of CRA-carcinoma transition.

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

Pre-cast concrete products are sometimes manufactured in two cycles daily. It is ensured that they have the required strength at an early stage of demolding by increasing the steam curing temperature to reduce cost or increase productivity. However, the reduction in durability because of cracking due to thermal stress is a topic of concern. On the other hand, it has been known that fine blast-furnace-slag powder and expansive agents show high temperature dependence. Although they are used even in precast concrete products, the effect of steam curing on these materials is not known. Thus, in this study, the expression of compressive strength and expansion that are critical in improving the quality and productivity of precast concrete products was investigated, using high early-strength cement and two types of expansive agents, namely, ettringite-based and lime-based agents. Consequently, the strength expression was accelerated by the addition of expansive agent to ordinary cement and high early-strength cement. The extent of restrained expansion is greater for the lime-based expansive agent than for the ettringite-based expansive agent, and when an expansive agent is added to high early-strength cement, the extent of restrained expansion falls to a level lower than that in the case of ordinary cement.

Although N-myc downstream regulated gene 2 (NDRG2) is frequently downregulated in various cancers and is considered to be a candidate tumor suppressor gene, molecular mechanisms of the expressional suppression that lead to cancers are largely unknown. Recent studies indicated that epigenetic suppression of NDRG2 involved carcinogenesis and progression in several tumor types, and we demonstrated positive association with NDRG2 suppression and poor prognosis in pancreatic cancer. In this study, we analyzed mRNA and protein expressions of NDRG2 in 26 cancer cell lines (20 colorectal and 6 gastric cancers) and found that many cell lines showed variously reduced NDRG2 expressions. Furthermore, NDRG2 expressions were significantly reduced in primary resected cancer tissues compared to corresponding normal tissues immunohistochemically (19 of 20 colorectal and 14 of 17 gastric cancers). Treatment with 5-Aza-2' deoxycytidine predominantly upregulated NDRG2 expressions in NDRG2 low-expressing cell lines. Bisulfite sequencing analyses and methylation specific PCR revealed that methylation status at one of the two promoters (around exon 2) correlated well with the suppressed expression, and this is the major promoter in colorectal and gastric cancer cell lines. Our present results suggest that hypermethylation in promoter around exon 2 is functioning as essential factors of NDRG2 silencing in gastrointestinal cancers.

In inflammatory bowel disease, chronic inflammation results in the development of colon cancer known as colitis-associated cancer. This disease is associated with tumor necrosis factor-α (TNF-α) signaling. In addition, intestinal fibrosis is a common clinical complication that is promoted by transforming growth factor β1 (TGF-β1). In our previous study, MA-35 attenuated renal fibrosis by inhibiting both TNF-α and TGF-β1 signaling. This study aimed to identify the possible antitumor effects and antifibrotic effects of MA-35 using an AOM/DSS mouse model. MA-35 was orally administered every day for 70 days in the AOM/DSS mouse model. There was no difference in weight loss between the AOM/DSS group and the AOMDSS + MA-35 group, but the disease activity index score and the survival rate were improved by MA-35. MA-35 blocked the anemia and shortening of the colon induced by AOM/DSS. MA-35 reduced the macroscopic formation of tumors in the colon. In the microscopic evaluation, MA-35 reduced inflammation and fibrosis in areas with dysplasia. Furthermore, the TNF-α mRNA level in the colon tended to be reduced, and the interleukin 6, TGF-β1 and fibronectin 1 mRNA levels in the colon were significantly reduced by MA-35. These results suggested that MA-35 inhibited AOM/DSS-induced carcinogenesis by reducing inflammation and fibrosis.

A55 -year-old man was diagnosed with rectal cancer invading the urinary bladder and swollen para-aortic lymph nodes. Since distant metastasis was indicated and total pelvic exenteration was required, 6 courses of chemotherapy with mFOLFOX6 plus panitumumab were performed. After the chemotherapy, the rectal cancer and para-aortic lymph nodes significantly decreased in size, and novel distant metastasis was not observed in CT scans. Therefore, the tumor was considered resectable, and operation was performed. Intraoperative frozen section analysis showed that the para-aortic lymph nodes and surgical margin of the urinary bladder were negative. Thus, low anterior resection of the rectum and partial resection of the urinary bladder were performed. R0 resection was pathologically achieved, and adjuvant chemotherapy with S-1 was administered for 6 months. The patient is alive without recurrence for 10 months. Upfront chemotherapy can be a strategy for advanced rectal cancer with urinary bladder invasion to avoid total pelvic exenteration.

Case 1: A female patient in her 60s underwent laparoscopic intersphincteric resection for rectal cancer. After 42 months, the serum level of carcinoembryonic antigen(CEA)was elevated, and PET-CT showed a locally recurrent rectal cancer that increased FDG-uptake. Carbon ion radiotherapy(CIRT)(73.6 GyE/16 Fr)was performed. Serum CEA level and FDG-uptake were normalized. No regrowth of tumor has been found for 12 months. Case 2: A female patient in her 60s underwent abdominoperineal resection for rectal cancer. After 42 months, the serum level of CEA was elevated, and CT revealed a local recurrence of rectal cancer. Subsequently, the tumor was resected; however, resection margin was microscopically positive. Therefore, chemoradiotherapy(S-1, 60 Gy)was performed. At 31 months after local resection, a re-recurrent tumor was noted in her left ischium. Therefore, CIRT(70.4 GyE/16 Fr)was performed. Serum CEA level and FDG-uptake were normalized. No regrowth of tumor has been found for 24 months. CIRT is an effective therapy for locally recurrent rectal cancer.

A woman in her 40s who presented to a local hospital with bloody stool was referred to our hospital. Colonoscopy showed a rectal tumor, and histological examination showed moderately differentiated adenocarcinoma. CT and MRI revealed that the tumor was 65mm in diameter with no distant metastasis. After the construction of ileostomy, neoadjuvant chemoradiothera- py(NACRT: 45 Gy/25 Fr, S-1 80mg/m2)was performed. The tumor shrank remarkably, and then we performed laparoscopy- assisted low anterior resection. Pathological examination revealed complete disappearance of the cancer cells in the primary site and no appearance of cancer cells in all dissected lymph nodes. NACRT has been recently reported to provide pathological complete response, and these patients are supposed to have a good prognosis. In our case, NACRT enhanced the performance of laparoscopic curative resection while preserving anal function. NACRT should contribute to the curative resection while preserving anal function in patients with locally advanced rectal cancer.

According to the treatment guideline for rectal neuroendocrine tumor(NET), tumor with a diameter ofC10mm should be resected endoscopically, while tumor with a diameter of10mm should be resected surgically with lymph node dissection. We experienced a case of a rectal NET with a diameter of 5mm with lymph node metastasis. A 69-year-old man underwent colonoscopy for positive fecal occult blood test. The colonoscopy revealed a submucosal tumor(SMT)with a diameter of 5 mm in the lower rectum. An endoscopic mucosal resection(EMR)was performed after SMT was diagnosed as NET by biopsy. Histopathological findings were NET-G1, 4.5×2.5 mm, v(+), ly(+). Then, laparoscopically assisted rectal resection with D2 lymph node dissection was performed. In histopathological examination, no tumor residue was observed in the specimu; however, a regional lymph node metastasis was detected. Risk factors of lymph node metastasis with rectal NET are a diameter of10 mm, recessed or ulcerated surface, and lymphovascular invasion. However, we have to keep in mind that lymph node metastasis may occur even in small rectal NET with a diameter of ≤10mm.

We here report a case of endoscopy-assisted partial duodenal resection for duodenal adenoma in a patient with familial adenomatous polyposis(FAP). A male underwent total proctocolectomy with ileal pouch anal anastomosis in 1997. Since 2004, duodenal adenomas occurred and the atypical grade of adenoma was gradually aggravated. Therefore, he underwent endoscopy-assisted partial duodenal resection in 2013. The pathological finding of the specimen showed well-differentiated tubular adenocarcinoma(pM, ly0, v0). No recurrence has been observed at 4 years after the operation. Endoscopy-assisted partial duodenal resection was minimum invasive surgery and considered to be useful for the patients with duodenal adenoma.

A52 -year-old woman was diagnosed with ascending colon cancer with ovarian metastasis and peritoneal dissemination. Since the patient did not have symptoms with intestinal obstruction, mFOLFOX6 plus bevacizumab(Bmab)was performed for 12 cycles. After chemotherapy, the tumors of ascending colon and ovary were significantly shrunken and novel distant metastasis was not observed by CT scans. Therefore, the tumors were considered to be resectable and curative resection was performed. In the surgical findings, the peritoneal disseminations were localized, and right colectomy, bilateral oophorectomy and extirpation of the peritoneal disseminations were performed. R0 resection was pathologically achieved and adjuvant chemotherapy with UFT/UZEL was administrated for 6 months. The patient is alive without recurrence for 1 year. Since right sided colon cancer is less likely to have obstruction, upfront chemotherapy can be a strategy for locally advanced right sided colon cancer with distant metastasis.

Background Recent studies have shown that the tumor microenvironment plays a significant role in the progression of solid tumors. As an abundant component of the tumor microenvironment, cancer associated fibroblasts (CAFs) have been shown to promote tumorigenesis and cancer aggressiveness, but their molecular characteristics remain poorly understood. Methods CAFs and normal fibroblasts (NFs) were isolated from freshly resected specimens from patients with colorectal cancer (CRC). RNA sequence was performed to obtain gene expression profiles of CAFs and NFs. We analyzed the profiles and compared gene expression differences between CAFs and NFs. Moreover, immunohistochemistry, proliferation assay and migration assay were performed for evaluating function of the isolated genes. Results RNA sequencing analysis revealed that the gene sets related to the Wnt signaling pathway were highly expressed in CAFs, as well as TGFβ signaling, which is considered to be a regulator of CAFs. Among the components of this pathway, Wnt2 was specifically expressed. Thus, we performed immunohistochemical analysis on Wnt2 in 171 patients who underwent surgery for colorectal adenocarcinoma. Positive staining for Wnt2 was often observed in cancer stroma, although the immunoreactivity was negative or weak in cancer cells. Wnt2 expression in CAFs was significantly correlated with depth of tumor (P Conclusions The present study showed that Wnt2 expression in CAFs was significantly related to factors leading to tumor progression, such as depth of tumor invasion and lymph node metastasis, as revealed by immunochemical examination. We also demonstrated that Wnt2 protein derived from CAFs induced cancer cell migration and invasion in CRC. These findings suggest that Wnt2 secreted by CAFs is a key role as a critical mediator in CRC progression and is a potential therapeutic target for CRC. Legal entity responsible for the study The authors. Funding Japan Society for the Promotion of Science. Disclosure All authors have declared no conflicts of interest.

The aim of this study was to assess the bowel function and quality of life (QOL) in patients with ulcerative colitis (UC) after total proctocolectomy with ileal pouch anal anastomosis (IPAA). Two questionnaires [“Questionnaire sheet on the bowel function” and “Inflammatory bowel disease questionnaire (Japanese IBDQ)”] were sent to 121 patients with UC who underwent IPAA at Tohoku University Hospital. Seventy-nine patients (65%) participated in the study. The median number of daily bowel movements was 6.5, which significantly decreased with postoperative time (≤ 1, 1–5, 5–15 years) and increased with age (

We report a case of a huge gastric gastrointestinal stromal tumor(GIST)that was safely resected followingpreoperative imatinib therapy. A 72-year-old woman was hospitalized with severe abdominal distension. Computed tomography revealed a 27×17 cm tumor in the left upper abdominal cavity. The patient was diagnosed with high risk GIST by EUS-FNA. We initiated preoperative adjuvant chemotherapy with imatinib to achieve a reduction of operative risks and functional preservation. After 6 months of chemotherapy, CT showed a reduction in the tumor size and the patient underwent partial gastrectomy and partial resection of the diaphragm. Histologically, most of the tumor cells were replaced by hyalinized collagen and viable cells were scattered only around the blood vessels. Neoadjuvant chemotherapy with imatinib has the potential to become an important therapeutic option for the treatment of huge GISTs.

A70-year-old man was diagnosed with lower rectal cancer with right inguinal lymph node metastasis. Surgical resection was not suitable for this patient. Chemotherapy(IRIS plus bevacizumab followed by XELOX plus bevacizumab)was administered for 16 months. After the chemotherapy, the rectal tumor and lymph node swelling were significantly reduced and distant metastasis was not observed on CT scans. Therefore, the tumor was considered to be resectable and abdominoperineal resection of the rectum with lymph node dissection was performed. On histopathological examination, cancer cells partially remained in the rectal tumor and lateral lymph nodes, although there were no cancer cells in the inguinal lymph nodes. The patient is alive without recurrence a year later. In cases with a good response to chemotherapy, conversion therapy may become an important therapeutic option.

We report a case of a 72-year-old woman who was initially diagnosed with ovarian cancer with peritoneal carcinomatosis. Systemic chemotherapy consisting of paclitaxel and carboplatin(TC)was administered. Although a partial response(PR)was achieved after the 4 courses of TC, this regimen was discontinued due to severe adverse events. Ten months after discontinuation of TC, because abdominal CT and colonoscopy showed an intra-tumoral abscess caused by invasion of the tumor to the sigmoid colon, abdominal total hysterectomy, bilateral salpingo-oophorectomy, and a Hartmann's operation were performed to control the disease symptoms. Pathological examination revealed that the tumor was an undifferentiated carcinoma of the sigmoid colon. This case report suggests that the TC regimen may be effective for treating undifferentiated carcinoma of the colon.

Background Little is known about the roles of Notch signaling in cholangiocarcinoma (CC). The expression of hairy and enhancer of split 1 (Hes-1) has not been investigated yet in resected specimens of CC. Notch signaling has been reported to be related to cancer stem cell (CSC) like properties in some malignancies. Our aim is to investigate the participation of Notch signaling in resected specimens of extrahepatic CC (EHCC) and to evaluate the efficacy of CC cells with CSC-like properties by Notch signaling blockade. Methods First, the expression of Notch1, 2, 3, 4 and Hes-1 was examined by immunohistochemistry in 132 resected EHCC specimens. The clinicopathological characteristics in the expression of Notch receptors and Hes-1 were investigated. Second, GSI IX, which is a γ-secretase-inhibitor, was used for Notch signaling blockade in the following experiment. Alterations of the subpopulation of CD24+CD44+ cells, which are surface markers of CSCs in EHCC, after exposure with GSI IX, gemcitabine (GEM), and the combination of GSI IX plus GEM were assessed by flow cytometry using the human CC cell lines, RBE, HuCCT1 and TFK-1. Also, anchorage-independent growth and mice tumorigenicity in the cells recovered by regular culture media after GSI IX exposure were assessed. Results Notch1, 2, 3, 4 and Hes-1 in the resected EHCC specimens were expressed in 50.0, 56.1, 42.4, 6.1, and 81.8 % of the total cohort, respectively. Notch1 and 3 expressions were associated with poorer histological differentiation (P = 0.008 and 0.053). The patients with the expression of at least any one of Notch1-3 receptors, who were in 80.3 % of the total, exhibited poorer survival (P = 0.050). Similarly, the expression of Hes-1 tended to show poor survival (P = 0.093). In all of the examined CC cell lines, GSI IX treatment significantly diminished the subpopulation of CD24+CD44+ cells. Although GEM monotherapy relatively increased the subpopulation of CD24+CD44+ cells in all lines, GSI IX plus GEM attenuated it. Anchorage-independent growth and mice tumorigenicity were inhibited in GSI IX-pretreated cells in RBE and TFK-1 (P