Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer.

Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate-treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.

Simple Detection and Culture of Circulating Tumor Cells from Colorectal Cancer Patients Using Poly(2-Methoxyethyl Acrylate)-Coated Plates.

Here we aimed to establish a simple detection method for detecting circulating tumor cells (CTCs) in the blood sample of colorectal cancer (CRC) patients using poly(2-methoxyethyl acrylate) (PMEA)-coated plates. Adhesion test and spike test using CRC cell lines assured efficacy of PMEA coating. A total of 41 patients with pathological stage II-IV CRC were enrolled between January 2018 and September 2022. Blood samples were concentrated by centrifugation by the OncoQuick tube, and then incubated overnight on PMEA-coated chamber slides. The next day, cell culture and immunocytochemistry with anti-EpCAM antibody were performed. Adhesion tests revealed good attachment of CRCs to PMEA-coated plates. Spike tests indicated that ~75% of CRCs from a 10-mL blood sample were recovered on the slides. By cytological examination, CTCs were identified in 18/41 CRC cases (43.9%). In cell cultures, spheroid-like structures or tumor-cell clusters were found in 18/33 tested cases (54.5%). Overall, CTCs and/or growing circulating tumor cells were found in 23/41 CRC cases (56.0%). History of chemotherapy or radiation was significantly negatively correlated with CTC detection (p = 0.02). In summary, we successfully captured CTCs from CRC patients using the unique biomaterial PMEA. Cultured tumor cells will provide important and timely information regarding the molecular basis of CTCs.

High postoperative carcinoembryonic antigen as an indicator of high-risk stage II colon cancer.

Postoperative carcinoembryonic antigen (post-CEA) has recently been reported to be a reliable prognostic factor for colon cancer. However, most clinicians decide whether or not to conduct adjuvant chemotherapy (AC) for stage II colon cancer according to major guidelines, which do not include post-CEA in their high-risk criteria. The present study aimed to assess post-CEA in stage II colon cancer for which the significance of AC is unknown. The present study analyzed 199 consecutive patients with stage II colon cancer who underwent curative surgery between January 2007 and December 2016. The CEA value was considered high when it was ≥5.0 ng/ml. The prognostic value of high post-CEA values was assessed. Overall, 19 patients exhibited high post-CEA levels. Kaplan-Meier survival curve analysis demonstrated that patients with high post-CEA levels had significantly worse relapse-free survival (RFS) and overall survival (OS) than those with normal post-CEA [RFS, 63.5 (high post-CEA) vs. 88.0% (normal post-CEA), P=0.003; OS, 76.5 (high post-CEA) vs. 96.8% (normal post-CEA), P<0.001]. Multivariate analysis demonstrated that high post-CEA remained a significant independent risk factor for worse RFS [hazard ratio (HR), 3.98; P=0.006]. The same was also demonstrated for patients without AC (HR, 5.43; P=0.008). To the best of our knowledge, the present study was the first to demonstrate that high post-CEA levels may be an indicator of high-risk stage II colon cancer, even for patients without AC. These results highlight the need for a multicenter prospective study.

Functional assessment of miR­1291 in colon cancer cells.

miR­1291 exerts an anti­tumor effect in a subset of human carcinomas, including pancreatic cancer. However, its role in colorectal cancer (CRC) is largely unknown. In the present study, the expression and effect of miR­1291 in CRC cells was investigated. It was identified that miR­1291 significantly suppressed the proliferation, invasion, cell mobility and colony formation of CRC cells. Additionally, miR­1291 induced cell apoptosis. A luciferase reporter assay revealed that miR­1291 directly bound the 3'­untranslated region sequence of doublecortin­like kinase 1 (DCLK1). miR­1291 also suppressed DCLK1 mRNA and protein expression in HCT116 cells that expressed DCLK1. Furthermore, miR­1291 suppressed cancer stem cell markers BMI1 and CD133, and inhibited sphere formation. The inhibitory effects on sphere formation, invasion and mobility in HCT116 cells were also explored and verified using DCLK1 siRNAs. Furthermore, miR­1291 induced CDK inhibitors p21WAF1/CIP1 and p27KIP1 in three CRC cell lines, and the overexpression of DCLK1 in HCT116 cells led to a decrease of p21WAF1/CIP1 and p27KIP1. Intravenous administration of miR­1291 loaded on the super carbonate apatite delivery system significantly inhibited tumor growth in the DLD­1 xenograft mouse model. Additionally, the resultant tumors exhibited significant upregulation of the p21WAF1/CIP1 and p27KIP1 protein with treatment of miR­1291. Taken together, the results indicated that miR­1291 served an anti­tumor effect by modulating multiple functions, including cancer stemness and cell cycle regulation. The current data suggested that miR­1291 may be a promising nucleic acid medicine against CRC.

A stem cell marker KLF5 regulates CCAT1 via three-dimensional genome structure in colorectal cancer cells.

BACKGROUND: KLF5 plays a crucial role in stem cells of colorectum in cooperation with Lgr5 gene. In this study, we aimed to explicate a regulatory mechanism of the KLF5 gene product from a view of three-dimensional genome structure in colorectal cancer (CRC). METHODS: In vitro engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP)-seq method was used to identify the regions that bind to the KLF5 promoter. RESULTS: We revealed that the KLF5 promoter region interacted with the KLF5 enhancer region as well as the transcription start site (TSS) region of the Colon Cancer Associated Transcript 1 (CCAT1) gene. Notably, the heterodeletion mutants of KLF5 enhancer impaired the cancer stem-like properties of CRC cells. The KLF5 protein participated in the core-regulatory circuitry together with co-factors (BRD4, MED1, and RAD21), which constructs the three-dimensional genome structures consisting of KLF5 promoter, enhancer and CCAT1 TSS region. In vitro analysis indicated that KLF5 regulated CCAT1 expression and we found that CCAT1 expression was highly correlated with KLF5 expression in CRC clinical samples. CONCLUSIONS: Our data propose the mechanistic insight that the KLF5 protein constructs the core-regulatory circuitry with co-factors in the three-dimensional genome structure and coordinately regulates KLF5 and CCAT1 expression in CRC.

Preoperative imatinib and laparoscopic intersphincteric resection for large rectal gastrointestinal stromal tumor: A case report.

INTRODUCTION: Anus-preserving surgery for a large rectal gastrointestinal stromal tumor (GIST) may be difficult because of the location of the tumor in the pelvis. Therefore, rectal GIST might require extensive surgery, such as abdominoperineal resection. In recent years, preoperative imatinib therapy has been used to reduce tumor size and preserve the anus in some cases. However, there have been few reports of laparoscopic anal-preserving surgery for giant rectal GIST. PRESENTATION OF A CASE: We present the case of a 55-year-old man who was referred to our hospital for examination of a 10-cm pelvic mass in the lower rectum. Endoscopic ultrasound with fine needle aspiration was performed, and the pathological findings resulted in a diagnosis of GIST. The mass had spread to the prostate and left levator ani muscles, and as a result, surgery was deemed difficult to perform without damaging the pseudo-capsule. Therefore, preoperative chemotherapy with imatinib mesylate (IM) was performed for 8 months. The mass was reduced to 7.8 cm, and laparoscopic intersphincteric resection (ISR) was performed. DISCUSSION: We also review prior cases of rectal GIST where patients had undergone anal-preserving surgery following preoperative chemotherapy with IM. Our case represented the largest tumor size in a review of cases of patients who had successful anal-preserving laparoscopic surgery following preoperative chemotherapy with IM. CONCLUSION: Preoperative chemotherapy with imatinib mesylate was effective for reducing the rectal GIST, and laparoscopic ISR was useful for anal preservation, even when a tumor is large.

[Clinical Significance of Palliative Esophageal Stent Placement for Esophageal Cancer].

BACKGROUND: Since the introduction of the guideline for the diagnosis and treatment of esophageal carcinoma in 2007, the indication for placing an esophageal stent has changed, especially with respect to the treatment of esophageal stricture after chemoradiotherapy(CRT). For CRT cases, irradiation after stent placement and stent placement after CRT are not recommended due to the risk of perforation. METHODS: Thirty-eight patients who underwent esophageal stenting in our department between January 2007 and December 2018 and who were diagnosed with thoracic esophageal cancer were included in this study. We retrospectively examined the safety and treatment effect of esophageal stent placement. RESULTS: Prior cancer therapy was observed in 16 cases(8 cases of chemotherapy and 8 cases of CRT). In the no prior therapy group, 13 cases were treated with BSC and 9 cases with chemotherapy. Esophageal stent placement after CRT was performed in 8 cases. Esophageal stent was placed 9(6-14)months after CRT. The stent patency period was 5(1-11)months, and the survival period after stent placement was 6(1-12)months. There was no difference in the frequency of complications and treatment outcomes of the CRT group compared with the non-CRT group. CONCLUSION: Cases undergoing esophageal stent placement after CRT can expect therapeutic effects similar to those of other cases. However, complications such as perforation can be fatal; thus, careful consideration should be given to each individual case for esophageal stent placement after CRT.

Prognostic factors for cytology-positive gastric cancer.

PURPOSE: Positive peritoneal lavage cytology for gastric carcinoma cells (CY1) is considered distant metastasis and is classified as Stage IV. However, patients with CY1 comprise a heterogeneous population, and their prognosis varies greatly. The prognostic factors for gastric cancer patients with CY1 were retrospectively reviewed. METHODS: The participants were 80 gastric cancer patients with CY1 in our institution encountered between 2005 and 2017. Prognostic factors were analyzed using univariate and multivariate analyses. RESULTS: The operative procedure was distal gastrectomy for 30 patients, total gastrectomy for 27 patients, staging laparoscopy for 10 patients, gastrojejunostomy for 8 patients, and probe laparotomy for 5 patients. Other distant metastases were recognized in 36 patients. A multivariate analysis revealed that other distant metastases were the strongest independent risk factor for the overall survival (p < 0.0001). When the cohort was limited to CY1 patients without other distant metastases, cN2-3 (p = 0.01), the prognostic nutritional index (PNI) < 40 (p = 0.02) and Type 4 (p = 0.03) were independent risk factors according to a multivariate analysis. The survivals of patients with cN2-3 or PNI < 40 after gastrectomy were equivalent to those with other distant metastases, as assessed by log-rank analyses. CONCLUSIONS: The prognoses of CY1 gastric cancer patients with cN2-3 or PNI < 40 were poor, even after gastrectomy.

A case of completely isolated advanced enteric duplication cyst cancer performed partial pancreatectomy.

INTRODUCTION: Enteric duplication cysts are rare and, in addition, isolated enteric duplication cysts are lower morbidity prevalence rate. These cysts lack a connection to the gastrointestinal tract or the adjacent mesenteric vasculature and have only been reported in 10 case reports. In these reports, only two reports were cases with malignant transformation. Our case was a report for the advanced cancer of the isolated enteric duplication cyst. CASE PRESENTATION: The patient was a 43 year-old woman with slightly abdominal pain and mass formation. The abdominal contrast-enhanced computed tomography showed 130 × 100 × 90 mm huge cystic mass existed in right upper peritoneal cavity. The cystic mass had thickened wall and many enhanced nodules. As these imaging findings suggested a tumor originated from pancreas and the preoperative diagnose was suspect of mucinous cystic neoplasm. In operative findings, the tumor originated from pancreatic head and did not attach to gastrointestinal tract. Final pathology indicated the cyst was an isolated advanced enteric duplication cyst cancer and not originated from pancreas. CONCLUSION: We experienced an extremely rare case of completely isolated advanced enteric duplication cyst cancer. Unique to this case, the preoperative diagnosis was suspect of mucinous cystic neoplasm arising from pancreas head and partial pancreatectomy was performed. However, in the pathological findings, this cyst diagnosed advanced enteric duplication cyst cancer.

[Clinical Outcome of Eight Patients with Perforated Colorectal Cancer].

We studied the clinicopathological findings of 8 patients with perforated colorectal cancer. Four patients were male. In 7 patients, the primary cancer site was left side colon. Chief complaints were abdominal pain in 7 patients and diarrhea in 1 patient. The emergent operation was performed in all cases. The final stages of 8 patients were as follows: 5 patients with Stage II, 2 patients with Stage III, 1 patient with Stage IV. All patients were discharged from our hospital. Postoperative chemotherapy was performed for 5 patients. Of these 8 patients, 1 patient had peritoneal dissemination and 1 patient had local recurrence. Two patients were died of cancer and 6 patients were alive. In conclusion, patient with perforated colorectal cancer were high risk cases for recurrence.

[An Analysis of Perforated Gastric Cancer with Acute Peritonitis in Our Hospital].

Perforated gastric cancer is relatively rare and the incidence is reported about 1% of all the cases of gastric cancer. We retrospectively analyzed the clinical data of the consecutive 12 patients with perforated gastric cancer who underwent operation in our hospital between January 2005 and December 2016. There were 5 men and 7 women, with an average age of 65.8 years old(34-87). Perforated gastric cancer occurred in the region U(1 cases), M(6 cases), L(5 cases). There were 11 cases with distant metastasis. We could successfully diagnosed as perforated gastric cancer in 8 cases before emergency operation. Gastrectomy was performed in 5 cases. However, the curative resection was performed only 1 case. Prognosis of perforated gastric cancer is poor. We considered as an appropriate two-step surgical strategy that the first step of surgery is an acute peritonitis treatment followed by radical gastrectomy with lymphadenectomy.

[A Case of Anal Canal Adenocarcinoma Locally Controlled by Rectal Amputation after Chemoradiotherapy].

A 73-year-old man was admitted to our hospital with anal pain. The 10 cm tumor was observed externally at the 3 o' clock side of his anus. He was unable to maintain the sitting position because of pain and had fecal incontinence and erosive skin inflammation. We identified this anal stenosis as anal canal adenocarcinoma(moderately differentiated). Thereby, no distant metastasis was found; we decided to treat the patient with conventional therapy. We made a double-hole colostomy in the sigmoid colon, and then the patient received preoperative chemoradiotherapy(CRT). Radiation therapy(RT)was adminis- tered at 40 Gy/20 Fr and oral capecitabine of 825mg/m / 2/time was administered twice a day on the RT days. The tumor shrinkage was good, and then we performed a laparoscopy-assisted abdominoperineal resection of the rectum. Pathologically therapeutic effect was Grade 1b. His activity of daily living was dramatically improved, and he can now main tan the sitting position. Twelve months postoperatively, he has no sign of recurrence. In this case, we experienced an anal canal adenocarcinoma that was possibly locally controlled by preoperative CRT and rectal amputation.

[A Case of Transverse Colon Cancer in Which Long-Term Chemotherapy Was Performed after Palliative Colonic Stent Placement].

We report a case involving a 76-year-old woman with transverse colon cancer undergoing long-term chemotherapy following palliative colonic stent placement. She visited our hospital with a diagnosis of colonic obstruction. Her abdomen was evidently distended and tender. CT revealed the apple core sign in the transverse colon-hepatic flexure area, and then bowel obstruction. The disseminated lesion occluded the superior mesenteric vein. Multiple masses were found on both lungs; a single tumor was detected in liver S6. Hence, we diagnosed her with unresectable obstructive transverse colon cancer. A colonic stent was inserted to remove the obstruction. Because primary tumor resection was rendered impossible, mFOLFOX6 was initiated with the colonic stent intact. After 5 courses, CT revealed that the liver metastasis disappeared, and lung metastases exhibited SD of a therapeutic effect. She further received 5 courses of mFOLFOX6 and 20 courses of maintenance therapy using FU. However, single liver metastasis recurred, exhibiting PD of a therapeutic effect. Histological diagnosis of liver metastasis was a consistent finding due to metastatic colorectal cancer; RAS mutation was not detected. Currently, 2 years after the diagnosis, FOLFIRI and panitumumab are being administered as the second-line treatment, with no colonic stentrelated complications.

[A Case of Sister Mary Joseph's Nodule from Multiple Colon Cancers].

A 94-year-old woman, who had been treated for multiple colon cancers 4 years ago, complained of umbilicus induration and had been followed up in a previous hospital with a diagnosis of periumbilical inflammation. Four years and 3 months postoperatively, the umbilical induration was enlarged, and umbilical metastasis of adenocarcinoma was diagnosed on biopsy. Umbilical resection was performed, and multiple peritoneal metastases were revealed. Umbilical metastases may worsen the patient's quality of life; thus, local resection was recommended positively.

[Cell-Free and Concentrated Ascites Reinfusion Therapy for Malignant Intractable Ascites from Colorectal Cancer].

Malignant intractable ascites worsens not only patient symptoms but also their daily activities. It often leads to a patient discontinuing or postponing chemotherapy. In the present study, we introduced cell-free and concentrated ascites reinfusion therapy(CART)for malignant intractable ascites from colorectal cancer. Six patients underwent 12 CART treatments using AHF-WMO as the ascites filterand AHF-UP as the concentrator(Asahi Kasei Medical Co., Ltd.)from January 2014 to January 2017. The patients included 2 men and 4 women aged 67-89 years. Primary locations were 3 rectums, 1 transverse colon, 1 descending colon, and 1 cecum. Five patients had peritoneal dissemination, and 1 patient had liver metastasis. All the patients were administrated diuretics, but they were all refractory to the treatment. The median punctured ascites volume was 3,850 mL, and the ascites reinfusion after CART was 485 mL, the median concentration was 7.5. Only one patient had a fever. Performance status(PS)improved significantly after the treatment, and appetite score also improved. One patient was fit to undergo chemotherapy after the treatment. In summary, we found that CART is a safe and acceptable procedure for malignant intractable ascites in colorectal cancer patients.

[Case of Central Venous Catheter Laceration of the Pectoralis Minor Muscle].

A 50's underwent gastrectomy for gastric cancer 4 years before. He had received chemotherapy for para-aortic lymph node metastases. A central venous catheter with a subcutaneous port was implanted via the right subclavian vein, under ultrasonographic guidance, 1 year 3 months earlier. The patient complained of swelling in his right chest during intravenous injection of ramucirumab and paclitaxel via the port. A chest radiograph revealed that a catheter fracture. A CT scan showed that the fractured catheter had lacerated the pectoralis minor muscle and the tip was in the right inferior pulmonary artery. The catheter fragment was removed using a pigtail catheter and a snare catheter via a percutaneous transfemoral approach, without any complication. The catheter was cut at 15.5 cm from the tip. This fracture was thought to be caused by a kink in the pectoralis muscle.