Endoscopic radial incision and cutting technique for treatment-naive stricture of colorectal anastomosis: Two case reports.

BACKGROUND: Anastomotic stenosis (AS) after colorectal surgery was treated with balloon dilation, endoscopic procedure or surgery. The endoscopic procedures including dilation, electrocautery incision, or radial incision and cutting (RIC) were preferred because of lower complication rates than surgery and are less invasive. Endoscopic RIC has a greater success rate than dilation methods. Most reports showed that repeated RICs were needed to maintain patency of the anastomosis. We report that single session RIC was applied only to treatment-naive patients with AS. CASE SUMMARY: Two female patients presented with AS. One patient had advanced rectal cancer and the other had a refractory stenosis following surgery for endometriosis at sigmoid colon. The endoscopic RIC procedure was performed as follows. A single small incision was carefully made to increase the view of the proximal colon and the incision was expanded until the surgical stapling line. Finally, we made a further circumferential excision with endoscopic knife along the inner border of the surgical staple line. At the end of the procedure, the standard colonoscope was able to pass freely through the widened opening. All patients showed improved AS after a single session of RIC without immediate or delayed procedure-related complications. Follow-up colonoscopy at 7 and 8 mo after endoscopic RIC revealed intact anastomotic sites in both patients. No treatment-related adverse events or recurrence of the stenosis was demonstrated during follow-up periods of 20 and 23 mo. CONCLUSION: The endoscopic RIC may play a role as one of treatment options for treatment-naive AS with short stenotic lengths.

Penile metastasis in rectal cancer with pathologic complete response after neoadjuvant chemoradiotherapy: The first case report and literature review.

RATIONALE: Penile metastasis in rectal cancer is very rare and often originates from prostatic or bladder cancer. The prognosis of penile metastasis is poor and its treatments are more often palliative than curative due to association with disseminated metastases. Pathologic complete response (pCR) in rectal cancer with neoadjuvant chemoradiotherapy (CRT) has been shown to be surrogate marker of favorable long-term outcomes and currently has no report of penile metastasis. Here, we first report isolated penile metastasis in rectal cancer with pCR after neoadjuvant CRT. PATIENT CONCERN: The patient was a 74-year-old male with metastasis to the glans penis from rectal cancer diagnosed 9 months after abdominoperineal resection. Physical examination revealed palpable multiple nodules on the glans penis. DIAGNOSIS: Penile biopsy revealed metastatic carcinoma from the rectal cancer. INTERVENTION: Chemotherapy was started as soon as possible, because patient suffered urinary discomfort by rapid growing metastatic lesions. He is currently receiving palliative chemotherapy with modified FOLFOX-6 (mFOLFOX-6; oxaliplatin with 5-fluorouracil and folinic acid) plus bevacizumab. OUTCOME: The patient is still alive 4 months after diagnosis with markedly decreased metastatic lesions. LESSON: We propose that although penile metastasis in rectal cancer with pCR after preoperative neoadjuvant CRT is extremely rare, it might help to start early palliative chemotherapy and clinicians should be aware of this possibility.

Results of Laparotomy and Laparoscopy for Perforated Colonic Diverticulitis.

BACKGROUND AND OBJECTIVES: The applications of laparoscopic surgery are expanding, but there is still controversy about its application in patients with peritonitis resulting from diverticulitis perforation. This study aimed to investigate the factors affecting the postoperative mortality rate in patients undergoing surgery for perforated diverticulitis. Further, we compared the recovery courses of patients between open and laparoscopic surgeries. METHODS: We analyzed the medical records of adult patients with peritonitis caused by perforated diverticulitis from six hospitals of Hallym University Medical Center from January 2006 to December 2016. RESULTS: A total of 166 patients were identified. In the univariate analysis, the statistically significant factors associated with postoperative mortality were age ≥ 60 years, body mass index ≥ 23 kg/m2, American Society of Anesthesiologists score ≥ 3, hypertension, serum blood urea nitrogen ≥ 23 mg/dL, creatinine ≥ 1.2 mg/dL, albumin < 3.0 g/dL, modified Hinchey score ≥ grade III, formation of stoma, and laparoscopic surgery. In multivariate analysis, serum albumin < 3.0 g/dL was the only factor associated with mortality. After case-control matching, we compared postoperative hospital course and prognosis between open and laparoscopic surgery groups. There was no significant difference in the clinical course between the groups. No significant difference was observed in the complication rate, reoperation rate, readmission rate, and mortality. CONCLUSION: Low preoperative serum albumin level (<3.0 g/dL) affects the mortality rate of patients after surgery. The hospital course and prognosis after laparoscopic surgery and conventional open surgery are comparable in patients with peritonitis caused by diverticulitis perforation.

Large Cell Neuroendocrine Carcinoma of the Colon With Carcinomatosis Peritonei.

Colorectal large-cell neuroendocrine carcinomas (NECs) are extremely rare and have very poor prognosis compared to adenocarcinomas. A 74-year-old man presented with abdominal pain, diarrhea and hematochezia. The histopathologic report of colonoscopic biopsy performed at a local clinic was a poorly differentiated carcinoma. An abdominopelvic computed scan revealed irregularly enhanced wall thickening at the sigmoid colon with regional fat stranding and lymphnode enlargement. He underwent a laparoscopic high anterior resection with selective peritonectomy for peritoneal carcinomatosis, intraoperative peritoneal irrigation chemotherapy, and early postoperative intraperitoneal chemotherapy for 5 days. The tumor had a high proliferation rate (mitotic count > 50/10 HPFs and 90% of the Ki-67 index) and lymph-node metastases had occurred. On immunohistochemistry, the tumor cells expressed CD56 and synaptophysin. Large-cell NEC was confirmed. Systemic chemotherapy with cisplatin/etoposide was done. The patient is still alive after 3 years with no evidence of recurrence.

Factors predicting malignancy in adult intussusception: An experience in university-affiliated hospitals.

BACKGROUND: Intussusception is one of the common causes of intestinal obstruction in children but is uncommon in adults. Unlike pediatric intussusception, most adult cases have a demonstrable etiology. The purpose of this study was to review our experience of adult intussusception and to identify the predictive factors for malignancy in this disease. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed with intussusception and admitted to the six Hallym University-affiliated hospitals between January 2005 and July 2016. RESULTS: The 77 patients had a mean age of 50.5 years (range, 18-91 years). Enteric intussusception is the most common type of adult intussusception (33.7%), and 11 patients (14.2%) had no definite lesion at operation. The most common symptom was abdominal pain (90.9%), and 18 (23.3%) presented with chronic symptoms. Computed tomography was the most common diagnostic modality used, with a diagnostic accuracy of 96.9%. The leading point was identified in 62 (80.5%) patients. Malignancy was more frequently present in the colonic type than in the other two types (61.5% vs. 10%, 37.9%). In a multivariate analysis, chronic symptom >14 days (p = 0.031) and colonic intussusception (p = 0.026) were independent predictors for malignancy. CONCLUSIONS: Enteric intussusception is the most common type of adult intussusception, and the most common test is computed tomography. Because chronic symptoms and colonic-type intussusception were predictive factors for malignancy, en bloc resection should be considered in patients with chronic or colonic intussusception.

Correlation Between Bowel Preparation and the Adenoma Detection Rate in Screening Colonoscopy.

PURPOSE: The adenoma detection rate is commonly used as a measure of the quality of colonoscopy. This study assessed both the association between the adenoma detection rate and the quality of bowel preparation and the risk factors associated with the adenoma detection rate in screening colonoscopy. METHODS: This retrospective analysis involved 1,079 individuals who underwent screening colonoscopy at the National Cancer Center between December 2012 and April 2014. Bowel preparation was classified by using the Aronchick scale. Individuals with inadequate bowel preparations (n = 47, 4.4%) were excluded because additional bowel preparation was needed. The results of 1,032 colonoscopies were included in the analysis. RESULTS: The subjects' mean age was 53.1 years, and 657 subjects (63.7%) were men. The mean cecal intubation time was 6.7 minutes, and the mean withdrawal time was 8.7 minutes. The adenoma and polyp detection rates were 28.1% and 41.8%, respectively. The polyp, adenoma, and advanced adenoma detection rates did not correlate with the quality of bowel preparation. The multivariate analysis showed age ≥ 60 years (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.02-1.97; P = 0.040), body mass index ≥ 25 kg/m2 (HR, 1.56; 95% CI, 1.17-2.08; P = 0.002) and current smoking (HR, 1.44; 95% CI, 1.01-2.06; P = 0.014) to be independent risk factors for adenoma detection. CONCLUSION: The adenoma detection rate was unrelated to the quality of bowel preparation for screening colonoscopy. Older age, obesity, and smoking were independent risk factors for adenoma detection.

Diagnostic and prognostic value of preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography for colorectal cancer: comparison with conventional computed tomography.

BACKGROUND/AIMS: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been used for preoperative staging of colorectal cancer (CRC). However, the diagnostic accuracy of FDG-PET/CT for detection of lymph node or distant metastasis and its prognostic role have not been well established. We therefore evaluated the diagnostic and prognostic value of FDG-PET/CT in comparison with conventional CT for CRC. METHODS: We investigated 220 patients who underwent preoperative FDG-PET/CT and CT, followed by curative surgery for CRC. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FDG-PET/CT and CT for detection of lymph node metastasis and distant metastasis were evaluated. In addition, we assessed the findings of FDG-PET/CT and CT according to outcomes, including cancer recurrence and cancer-related death, for evaluation of prognostic value. RESULTS: For detection of lymph node metastasis, FDG-PET/CT had a sensitivity of 44%, a specificity of 84%, and an accuracy of 67%, compared with 59%, 65%, and 62%, respectively, for CT (P=0.029, P=0.000, and P=0.022). For distant metastasis, FDG-PET/CT had a sensitivity of 79%, a specificity of 94%, and an accuracy of 93%, compared with 79%, 87%, and 86%, respectively, for CT (P=1.000, P=0.004, and P=0.037). In addition, positive findings of lymph node metastasis and distant metastasis on FDG-PET/CT were associated significantly with cancer recurrence or cancer-related death (P=0.009, P=0.001, respectively). CONCLUSIONS: Preoperative FDG-PET/CT had a higher specificity and accuracy compared to CT for detection of lymph node metastasis and distant metastasis of CRC. In addition, FDG-PET/CT could be a valuable prognostic tool for CRC.

Prolonged operative time in laparoscopic appendectomy: Predictive factors and outcomes.

INTRODUCTION: To our knowledge, this study is the first to identify the predictive factors and outcomes of prolonged operative time associated with laparoscopic appendectomy. We aimed to identify preoperative factors that influence operation time and to determine how operative time affects laparoscopic appendectomy outcomes. METHODS: The medical records of 3049 patients who had undergone laparoscopic appendectomy between January 2008 and December 2014 were retrospectively reviewed. Prolonged operative time was defined in the top 10% according to distribution (>90 min). A multivariate regression model was generated to assess potential predictive factors and outcomes of prolonged operative time. RESULTS: In laparoscopic appendectomy for non-perforated appendicitis, independent factors that predict a prolonged operative time as identified through multivariate analysis were elevated C-reactive protein levels, symptom duration of more than 3 days, and computed tomography findings indicating an appendiceal diameter of more than 10 mm. In laparoscopic appendectomy for perforated appendicitis, overweight, elevated C-reactive protein, symptom duration of more than 3 days, and computed tomography findings of abscess were independent predictive factors for prolonged operative time. Prolonged surgery increases the risk of complications, prolonged hospital stay, and readmission. CONCLUSIONS: Overweight, elevated C-reactive protein, symptom duration of more than 3 days, appendiceal diameter of more than 10 mm, and abscess were independent predictive factors of prolonged operative time. Furthermore, prolonged operative time was associated with adverse postoperative outcomes after laparoscopic appendectomy.

LAMP-3 (Lysosome-Associated Membrane Protein 3) Promotes the Intracellular Proliferation of Salmonella typhimurium.

Lysosomes are cellular organelles containing diverse classes of catabolic enzymes that are implicated in diverse cellular processes including phagocytosis, autophagy, lipid transport, and aging. Lysosome-associated membrane proteins (LAMP-1 and LAMP-2) are major glycoproteins important for maintaining lysosomal integrity, pH, and catabolism. LAMP-1 and LAMP-2 are constitutively expressed in Salmonella-infected cells and are recruited to Salmonella-containing vacuoles (SCVs) as well as Salmonella-induced filaments (Sifs) that promote the survival and proliferation of the Salmonella. LAMP-3, also known as DC-LAMP/CD208, is a member of the LAMP family of proteins, but its role during Salmonella infection remains unclear. DNA microarray analysis identified LAMP-3 as one of the genes responding to LPS stimulation in THP-1 macrophage cells. Subsequent analyses reveal that LPS and Salmonella induced the expression of LAMP-3 at both the transcriptional and translational levels. Confocal Super resolution N-SIM imaging revealed that LAMP-3, like LAMP-2, shifts its localization from the cell surface to alongside Salmonella. Knockdown of LAMP-3 by specific siRNAs decreased the number of Salmonella recovered from the infected cells. Therefore, we conclude that LAMP-3 is induced by Salmonella infection and recruited to the Salmonella pathogen for intracellular proliferation.

HDAC inhibitors induce epithelial-mesenchymal transition in colon carcinoma cells.

The effects of histone deacetylase (HDAC) inhibitors on epithelial-mesenchymal transition (EMT) differ in various types of cancers. We investigated the EMT phenotype in four colon cancer cell lines when challenged with HDAC inhibitors trichostatin A (TSA) and valproic acid (VPA) with or without transforming growth factor-ß1 (TGF-ß1) treatment. Four colon cancer cell lines with different phenotypes in regards to tumorigenicity, microsatellite stability and DNA mutation were used. EMT phenotypes were assessed by the expression of E-cadherin and vimentin using western blot analysis, immunofluorescence, quantitative real-time RT-PCR following treatment with TSA (100 or 200 nM) or VPA (0.5 mM) with or without TGF-ß1 (5 ng/ml) for 24 h. Biological EMT phenotypes were also evaluated by cell morphology, migration and invasion assays. TSA or VPA induced mesenchymal features in the colon carcinoma cells by a decrease in E-cadherin and an increase in vimentin expression at the mRNA and protein levels. Confocal microscopy revealed membranous attenuation or nuclear translocation of E-cadherin and enhanced expression of vimentin. These responses occurred after 6 h and increased until 24 h. Colon cancer cells changed from a round or rectangular shape to a spindle shape with increased migration and invasion ability following TSA or VPA treatment. The susceptibility to EMT changes induced by TSA or VPA was comparable in microsatellite stable (SW480 and HT29) and microsatellite unstable cells (DLD1 and HCT116). TSA or VPA induced a mesenchymal phenotype in the colon carcinoma cells and these effects were augmented in the presence of TGF-ß1. HDAC inhibitors require careful caution before their application as new anticancer drugs for colon cancers.

CEACAM6 as detected by the AP11 antibody is a marker notable for mucin-producing adenocarcinomas.

A new monoclonal antibody recognizing CEACAM6, which we named AP11, was generated by immunizing BALB/c mice with phytohemagglutinin-activated human peripheral blood mononuclear cells. This study aims to evaluate whether CEACAM6 can serve as a tumor marker using AP11. We examined the expression of CEACAM6 with AP11 in 11 human carcinoma cell lines by flow cytometry and 439 human tissues including 282 tumor tissues and 157 normal tissues by immunohistochemistry. CEACAM6 epitope recognized by AP11 was well preserved in formalin-fixed and paraffin-embedded tissues. Adenocarcinomas of the stomach (86%), colorectum (95%), pancreas (100%), and lung (83%), urinary bladder (100%), and mucinous ovarian tumors (88%) had a high rate of CEACAM6 immunoreactivity. We observed a variable expression of CEACAM6 in hepatocellular carcinomas (35%), squamous cell carcinomas of the lung (60%), renal cell carcinomas (14%), urothelial carcinomas (13%), serous carcinomas of the ovary (17%), and breast carcinomas (11%). Small-cell carcinomas of the lung, prostatic adenocarcinomas, papillary thyroid carcinomas, malignant melanomas, giant cell tumors, and osteosarcomas were negative for CEACAM6. All normal tissues of various organs were negative for CEACAM6. In conclusion, CEACAM6 as detected by AP11, may serve as a marker for mucin-producing adenocarcinomas of the gastrointestinal tract and ovary as well as non-small cell lung cancer. Thus, AP11 represents a valuable diagnostic tool for detecting CEACMA6-positive cancers.

Mesh-based transperineal repair of a perineal hernia after a laparoscopic abdominoperineal resection.

A perineal hernia (PH) is formed by a protrusion of intra-abdominal viscera through a defect in the pelvic floor. This is a rare complication after a conventional abdominoperineal resection (APR). However, the risk of a PH may be increased after a laparoscopic resection because this technique can cause fewer postoperative adhesions, predisposing the small bowel to sliding down toward the pelvis. However, only a few case reports describe the transperineal approach for the repair of a PH after a laparoscopic APR. We present a case of a PH after a laparoscopic APR; the PH was repaired with synthetic mesh by using a transperineal approach. A transperineal approach using a mesh to reconstruct the pelvic floor is less invasive and more effective. We suggest that this technique should probably be the first choice for treating an uncomplicated PH that occurs after a laparoscopic APR.

Multicenter nonrandomized trial of ramosetron versus palonosetron in controlling chemotherapy-induced nausea and vomiting for colorectal cancer.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) have a negative impact on patients' quality of life and frequently pointed to as a major factor for treatment abandonment. Serotonin (5-HT3) receptor antagonist is considered as key treatment for CINV. Ramosetron and palonosetron are recently developed 5-HT3 receptor antagonists and known as more superior than other first-generation 5-HT3 receptor antagonists. The purpose of this study was to compare the efficacy of ramosetron and palonosetron and determine which drug is more effective for prevention of CINV. METHODS: Colorectal cancer patients treated with chemotherapy were enrolled consecutively. Patients were assigned to receive intravenous injection of ramosetron 0.3 mg or palonosetron 0.25 mg at 30 minutes before initiation of moderately emetogenic chemotherapy. Ramosetron group added oral administration of 0.1 mg ramosetron on the second and third days of chemotherapy. Efficacy parameter consisted of nausea and vomiting. RESULTS: Ninety-one patients received ramosetron and 89 patients received palonosetron. Presentation of vomiting and nausea symptoms was not significantly different between the two groups during acute (0-24 hours) and delayed period (after 24 hours). CONCLUSION: The incidence of CINV between the ramosetron and the palonosetron group has not shown any difference during acute, delayed, and overall period.

Impact of hyperglycemia on survival and infection-related adverse events in patients with metastatic colorectal cancer who were receiving palliative chemotherapy.

PURPOSE: Non-metastatic colorectal cancer patients with diabetes have poor overall survival than those without diabetes. However, the effect of hyperglycemia on survival after diagnosis of metastatic colorectal cancer (CRC) has not been assessed. Therefore, we assessed the impact of hyperglycemia on the survival and infection-related adverse events (AEs) in patients with metastatic CRC. MATERIALS AND METHODS: We reviewed the records of 206 patients with newly diagnosed metastatic CRC who were treated with palliative chemotherapy from March 2000 to December 2012 at Chungbuk National University Hospital. The mean glucose level of each patient was calculated using all available glucose results. RESULTS: The mean glucose levels ranged between 76.8 and 303.5 mg/dL, and patients were categorized into quartiles in accordance to their mean glucose level: group 1 (< 106.7 mg/dL), group 2 (106.7-117.2 mg/dL), group 3 (117.3-142.6 mg/dL), and group 4 (> 142.6 mg/dL). The median overall survival for patients in groups 1, 2, 3, and 4 were 22.6, 20.1, 18.9, and 17.9 months, respectively; however, this difference was not statistically significant (p=0.643). Compared with patients in group 1, those in groups 2, 3, and 4 were at a higher risk of infection-related AEs, according to a multivariate analysis (p=0.002). CONCLUSION: Hyperglycemia was not associated with shorter survival; however, it was associated with infection-related AEs in patients with newly diagnosed metastatic CRC receiving palliative chemotherapy.

Transanal single-port microsurgery for rectal tumors: minimal invasive surgery under spinal anesthesia.

BACKGROUND: Transanal minimally invasive surgery (TAMIS) for rectal tumors has been introduced as an alternative approach to transanal endoscopic microsurgery (TEM). TEM has some limitations, such as the need for special equipment, expensive cost, and steep learning curve. In this study, we address the technical feasibility of TAMIS under spinal anesthesia and its short-term postoperative outcomes. METHODS: From July 2011 to September 2012, 25 consecutive patients with middle or upper third rectal masses underwent TAMIS. Tumors were located 6-17 cm from the anal verge. After spinal anesthesia, a single-incision laparoscopic surgery port was inserted into the anal canal. With this access, conventional laparoscopic instruments, including a grasper and monopolar electrocautery and suction device, were used to perform the transanal excision. A hook-type monopolar electrocautery or harmonic scalpel was used for dissection. The defect of the rectum was closed by interrupted sutures. Data concerning demographics, details of operative procedure, postoperative pain, and pathologic results were collected prospectively. To evaluate anal sphincter injury, an endoanal ultrasonography and fecal incontinence severity index survey were performed at 3-6 months after the operation. RESULTS: Of the 25 patients, nine had adenocarcinomas, nine had neuroendocrine tumors, three had tubular adenomas with high-grade dysplasia, three had tubular adenomas, one had a tubulovillous adenoma, and one had a gastrointestinal stromal tumor. The median distance from the tumor mass to the anal verge was 9.0 (range 6-17) cm. The median operative time was 45.0 (range 20-120) min. All patients received TAMIS without conversion to laparoscopic resection. There were no intraoperative complications or postoperative morbidity. The median postoperative hospital stay was 3.0 (range 2-7) days. No sphincter injury was detected by endoanal ultrasonography. CONCLUSIONS: TAMIS under spinal anesthesia is a safe and feasible technique for resection of middle and upper rectal masses. Spinal anesthesia is adequate for this procedure.

Prospective multicenter phase II clinical trial of FOLFIRI chemotherapy as a neoadjuvant treatment for colorectal cancer with multiple liver metastases.

PURPOSE: This study evaluated the efficacy of neoadjuvant chemotherapy combining 5-flurouracil/folinic acid with irinotecan (FOLFIRI) in colorectal multiple liver metastases regardless of resectability. METHODS: Forty-four patients with multiple (at least two) colorectal liver metastases were enrolled at seven tertiary referral hospitals between May 2007 and September 2010. All patients received the FOLFIRI chemotherapeutic regimen. Response to chemotherapy was assessed after three cycles (6 weeks) and once more after six cycles (12 weeks) of treatment. RESULTS: Objective response was noted in 27 patients (61.4%) and 4 patients (9.1%) had progressive disease. Of 44 patients, 10 patients (22.7%) underwent curative surgery (R0 resection) and 34 patients did not receive R0 resection. Grades 3 to 4 hematological toxicity was noted in 12 patients (27.3%) and grades 3 to 4 nonhematologic toxicity was identified in 5 patients (11.4%). CONCLUSION: FOLFIRI chemotherapy as a neoadjuvant chemotherapy for multiple colorectal liver metastases regardless of resectability demonstrated the possibility of R0 resection, high rate of objective response, and tolerable toxicities in this study.

Podoplanin, α-smooth muscle actin or S100A4 expressing cancer-associated fibroblasts are associated with different prognosis in colorectal cancers.

The interactions between the tumor microenvironment and tumor cells determine the behavior of the primary tumors. Whether cancer-associated fibroblasts (CAF) have a tumor progressive or a protective role likely depends on the type of tumor cells and the CAF subpopulation. In the present study, we analyzed the prognostic significance of CAF subpopulations in colorectal cancer (CRC). CAF phenotypes were analyzed in 302 CRC patients by using antibodies against podoplanin (PDPN), α-smooth muscle actin (α-SMA), and S100A4. The relationship between the CAF phenotypes and 11 clinicopathological parameters were evaluated and their prognostic significance was analyzed from the disease-free and overall survival times. We observed that at the tumor invasive front, PDPN CAFs were present in 40% of the cases, and S100A4 or α-SMA CAFs were detected in all the cases. PDPN/S100A4 and α-SMA/S100A4 dual-stained CAFs were observed in 10% and 40% of the cases, respectively. The PDPN(+) CAFs were associated with 6 favorable clinicopathological parameters and prolonged disease-free survival time. The PDPN(-)/α-SMA(high) CAFs were associated with 6 aggressive clinicopathological parameters and tended to exhibit shorter disease-free survival time. On the other hand, the PDPN(-)/S100A4(high) CAFs were associated with 2 tumor progression parameters, but not with disease prognosis. The PDPN(+) CAF phenotype is distinct from the α-SMA or S100A4 CAFs in that it is associated with less aggressive tumors and a favorable prognosis, whereas the PDPN(-)/α-SMA(high) or PDPN(-)/S100A4(high) CAFs are associated with tumor progression in CRC. These findings suggest that CAFs can be a useful prognostic biomarker or potential targets of anti-cancer therapy in CRC.

Combined aberrant expression of E-cadherin and S100A4, but not ß-catenin is associated with disease-free survival and overall survival in colorectal cancer patients.

BACKGROUND/AIMS: Epithelial-to-mesenchymal transition (EMT) in cancers is related to metastasis, recurrence, and poor prognosis. We evaluated whether EMT-related proteins can act as prognostic biomarkers in colorectal cancer (CRC) patients. METHODS: We evaluated the expression of E-cadherin, ß-catenin, and S100A4 by immunohistochemistry (IHC) in 333 CRC tissues from the tumor center and invasive margin. Tumor budding, cell grade, tumor stage, type of tumor growth, peritumoral lymphocyte infiltration (TLI), and perineural- or lymphovascular invasion were evaluated as pathological parameters. mRNA levels of E-cadherin, N-cadherin, ß-catenin, and S100A4 from 68 specimens from the same set were analyzed by real time quantitative RT-PCR. RESULTS: Loss of E-cadherin, nuclear ß-catenin, and gain of S100A4 were higher in the invasive margin than in the tumor center. Loss of E-cadherin was associated with cell grade, macroscopic type, perineural invasion, and tumor budding, ß-catenin with microsatellite instability and tumor site, and S100A4 with growth type, macroscopic type, AJCC stage, lymphovascular invasion, and perineural invasion. The aberrant expression of E-cadherin and S100A4 not ß-catenin in the invasive margin was a significant and independent risk factor for disease-free and overall-survival by multivariate analysis, along with AJCC stage and perineural invasion. mRNA levels of ß-catenin and S100A4 were correlated with the IHC findings at the tumor invasive margin. E-cadherin and N-cadherin showed a weak inverse correlation. CONCLUSIONS: The combination of loss of E-cadherin and gain of S100A4 in the tumor invasive margin can be used to stratify patients with the same AJCC stage into different survival groups.