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Accurate tumor stage diagnosis during laparoscopic surgery remains difficult. We clarify the impact of new diagnostic strategy using narrow-band imaging (NBI) during laparoscopic surgery for colorectal cancer compared with other strategies.We defined angiogenesis (Ag) and fibrosis (Fib) grades using NBI laparoscopy (lap-NBI), and assessed the clinicopathological features associated with these grades for 67 patients with colorectal cancer who underwent surgery. We assessed vessel density and gray scale with computer software.NBI-Ag-grade and NBI-Fib-grade of the serosal surface of cancer lesions and peritoneal nodules correlated with vessel density and gray scale of those assessed by Image J computer software. NBI-Fib-grades of liver nodules also correlated with gray scale. NBI-Ag- grade and Fib-grade of the serosal surface of cancer lesions correlated with pathological depth of invasion. These NBI grades of pathological metastatic peritoneal nodules were higher than those of pathologically benign peritoneal nodules. NBI- Fib grades of pathological metastatic liver nodules were higher than those of pathologically benign liver nodules. In multivariate analysis, lap-NBI was associated with different diagnosis for T3, T4 and non-T3, and non-T4. Moreover, lap-NBI was associated with different diagnosis for T4 and non-T4. Predictive value for T4 by lap-NBI showed high sensitivity (85%) specificity (87%), positive predictive value (74%), negative predictive value (93%), and overall accuracy (87%). Sensitivity and overall accuracy of lap-NBI was superior to that of other diagnostic modalities.We clarified the usefulness of the new diagnostic strategy using lap-NBI during laparoscopic surgery for colorectal cancer in comparison with other strategies.

Biliary peritonitis is a rare cause of acute abdomen with life threatening consequences, ant it is usually associated with the perforation of biliary tract or upper gastrointestinal tract...

Laparoscopic ventral rectopexy was performed in 84 patients with complete rectal prolapse from January 2016 to December 2019. In the initial 27 cases, three cases had recurrence, especially in cases of a long rectal prolapse measuring over 10 cm. In order to avoid recurrence, the transanal vacuum test was performed following the dissection of the rectovaginal septum towards the pelvic floor. The disappearance of rectal prolapse is confirmed by the intraoperative transanal vacuum test. When the posterior wall of the rectum showed the presence of prolapse according to the transanal vacuum test, then laparoscopic ventral rectopexy was converted to laparoscopic posterior rectopexy. In 94 cases in which laparoscopic ventral rectopexy was attempted, laparoscopic ventral rectopexy was completed in 57 cases, while the procedure was converted to laparoscopic posterior rectopexy in 37 cases. The recurrence rate following laparoscopic ventral rectopexy decreased from 11.1% (3/27) to 1.7% (1/57) after beginning to use the transanal vacuum test. Laparoscopic ventral rectopexy using the transanal vacuum test is therefore considered to be a useful technique to reduce postoperative recurrence.

Background: Our previous study using a mammary fat pad mouse model showed that P4H9, produced by the β2 integrin epitope, detected a molecule on fibroblasts in response to carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-expressing cancer cells. P4H9-detected molecule (PDM) expression appeared to be associated with myofibroblast differentiation. In this study, we investigated whether PDM is expressed on fibroblasts and cancer cells in clinical tissue samples, and whether the presence of PDM-expressing colorectal cancer cells is correlated with clinicopathological features of patients. Methods: Immunohistochemistry was conducted to detect P4H9 on clinical tissue samples from 156 patients with colorectal cancer. Risk factors for metastases and survival were calculated for clinical implication of PDM-expressing spindle-shaped fibroblasts. Results: Multivariate analysis showed that PDM-expressing spindle-shaped fibroblasts were an independent risk factor for lymph node metastasis, hematogenous metastasis, and poor survival. A Kaplan–Meier survival curve indicated that PDM-expressing spindle-shaped fibroblasts were associated with shorter survival time (P

Background Defaecatory function is often poor after anterior resection. Denervation of the neorectum following high ligation of the inferior mesenteric artery (IMA) is a possible cause of impaired defaecatory function. The purpose of this randomized clinical trial was to clarify whether the level of ligation of the IMA in patients with rectal cancer affects defaecatory function. Methods Between 2008 and 2011, patients who underwent anterior resection for rectal cancer were randomized to receive either high or low ligation of the IMA. The primary endpoint was to demonstrate the superiority of low ligation in terms of defaecatory function. Results One hundred patients were enrolled in the study; 51 were randomized to high ligation of the IMA and 49 to low ligation. There were no differences between the groups in terms of clinical data, except tumour stage, which was more advanced in the high-ligation group (P = 0·046). Nor were there any differences in defaecatory function, self-assessment of defaecation, Faecal Incontinence Quality of Life scale or continence score between groups at 3 months and 1 year. The number of harvested lymph nodes was similar. The rate of symptomatic anastomotic leakage was 16 per cent in the high-ligation group and 10 per cent in the low-ligation group (P = 0·415). Conclusion The level of ligation of the IMA in patients with rectal cancer did not affect defaecatory function or the incidence of postoperative complications. Registration number: NCT00701012 (http://www.clinicaltrials.gov).

Because anorectal melanoma, a rare cancer with a poor outcome, does not respond well to local radiation therapy or systemic chemotherapy, surgery is the primary treatment. Herein, we present a case of anorectal melanoma with lateral and inguinal lymph node metastases. A 61-year-old woman presented with rectal bleeding. Colonoscopy revealed a black tumor with ulceration in the anorectum. A CT scan revealed an anorectal tumor with left lateral lymph node swelling and right inguinal lymph node swelling. We performed a laparoscopic abdominoperineal resection with lateral lymph node dissection and right inguinal lymph node dissection. One year after the initial operation, pulmonary metastases were observed, and pulmonary resection was performed. After the pulmonary resection, brain metastases developed, and surgical resection was performed. Despite the recurrence of disease, the patient has survived for 52 months since the initial surgery and continues to receive systemic chemotherapy.

The effectiveness of lateral lymph node dissection for extending the survival of patients with advanced lower rectal cancer remains unclear. The purpose of this study was to clarify the survival benefit of lateral lymph node dissection according to the region of involvement and the number of lateral lymph nodes involved. We reviewed 131 consecutive patients with advanced lower rectal cancer, who had undergone curative resection with total mesorectal excision plus extended lateral lymph node dissection at Wakayama Medical University Hospital. Twenty-six (19.1 %) of these patients had lateral lymph involvement. We performed univariate and multivariate analyses for the 3-year disease-free and overall survival of these patients. Multivariate analysis revealed that the number (>1) and the region (common iliac artery region or external iliac artery region) of lateral lymph node metastasis are independent predictive factors for recurrence and survival. The Kaplan–Meier analysis demonstrated that patients with one lymph node metastasis in the internal iliac artery or obturator region had better survival. Lateral lymph node dissection resulted in survival benefit for patients with single lateral lymph node involvement in the internal iliac artery region or the obturator region.

Background: Preoperative chemoradiation therapy (pCRT) is a standard procedure for patients with advanced lower rectal cancer. It has been reported that pCRT cannot prolong the survival of patients with advanced lower rectal cancer. The aim of this study is to address the controllable and uncontrollable pathological factors of pCRT in predicting local and distant recurrences. Methods: One hundred two patients with stages 2 and 3 cancer were consecutively enrolled to the study. The first 51 patients (October 2008-August 2010) underwent curative resection without pCRT. The latter 51 patients (September 2010-May 2015) underwent curative resection after pCRT. Pathological factors of patients were evaluated to assess the association between local and distant recurrences. Results: Multivariate analyses for local and distant recurrences of patients without pCRT revealed that the independent risk factors were tumor deposit and perineural invasion respectively. pCRT was able to diminish circumferential resection margin, tumor deposit, venous invasion, and lymphatic permeation but not neural invasion and lymph node involvement. Kaplan-Meier curve of local and distant recurrence-free survival of patients with pCRT illustrated that tumor deposit is controllable, whereas perineural invasion is uncontrollable by pCRT. Conclusion: pCRT-uncontrollable perineural invasion may be a factor for distant recurrence of advanced rectal cancer patients, leading to poor survival.

Angiosarcoma involving the gastrointestinal tract is extremely rare. We present a case of multifocal angiosarcoma involving the colon and bone. A 73-year-old male presented with anemia and pain in the left supra-iliac lesion. Colonoscopy revealed multiple hemorrhagic-appearance tumors. Computed tomography scan showed masses in the sigmoid colon and bone. A left-sided colectomy was performed to prevent bleeding from the tumor. The histopathological diagnosis was angiosarcoma of multiple sites of the colon. We chose a combination of paclitaxel and zoledronate as the chemotherapy regimen. After surgery, bone lesions were diminished by chemotherapy and showed no uptake on (18)F-fluorodeoxyglucose-positron emission tomography. The patient survived for 38 months after surgery.

This study evaluated the impact of obesity on learning to perform laparoscopic surgery for colon cancer.We compared the outcomes for 72 patients with colon cancer treated by a single surgeon between June 2005 and July 2008. The first 36 patients who underwent surgery were considered to be during the "early period," and the other 36 patients who underwent surgery as the "late period," and the patients with a body mass index (BMI) ≥25 kg/m(2) were defined as being obese.During the early period, the tumor stages of obese patients were less advanced than those of nonobese patients, whereas the length of the operation, surgical blood loss, and wound diameter of obese patients were worse than those of nonobese patients. Furthermore, the tumor stages in the obese patients during the late period were more advanced than those in obese patients during the early period, whereas the length of the operation and number of dissected lymph nodes in the obese patients during the late period were better than those in obese patients during the early period.We demonstrated that the differences of the surgical outcomes between obese and nonobese patients undergoing laparoscopic colon resection decreased as the surgeon's experience increased.

Because anorectal melanoma, a rare cancer with a poor outcome, does not respond well to local radiation therapy or systemic chemotherapy, surgery is the primary treatment. Herein, we present a case of anorectal melanoma with lateral and inguinal lymph node metastases. A 61-year-old woman presented with rectal bleeding. Colonoscopy revealed a black tumor with ulceration in the anorectum. A CT scan revealed an anorectal tumor with left lateral lymph node swelling and right inguinal lymph node swelling. We performed a laparoscopic abdominoperineal resection with lateral lymph node dissection and right inguinal lymph node dissection. One year after the initial operation, pulmonary metastases were observed, and pulmonary resection was performed. After the pulmonary resection, brain metastases developed, and surgical resection was performed. Despite the recurrence of disease, the patient has survived for 52 months since the initial surgery and continues to receive systemic chemotherapy.

胆嚢原発平滑筋肉腫は非常に稀な疾患である.患者は78歳,女性で,心窩部圧迫感を主訴に近医受診し,肝臓・胆嚢の腫大を指摘された.腹部超音波検査,腹部CT検査にて胆嚢は最大径約8.5cmの不整な腫大を呈し,肝浸潤と十二指腸浸潤,中心壊死を有する胆嚢腫瘍であったが,所属リンパ節の腫大は認めなかった.上部消化管内視鏡検査で腫瘤の十二指腸下行脚への直接浸潤を認め,管腔の約3分の2周を占める潰瘍性病変を認め,大きな偽腔を形成していた.手術は肝,胃・十二指腸と横行結腸への浸潤も認められたため,肝S4a・S5切除,胆嚢摘出術,十二指腸部分切除術,幽門側胃切除,横行結腸部分切除術を施行し, Roux-en-Y法により再建した.免疫染色ではα-SMA, vimentinが陽性であり,病理組織学的にleiomyosarcomaと診断された.胆嚢原発平滑筋肉腫は予後不良な疾患であり,予後の改善のためには今後,有効な補助療法が必要であると考える.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) re-expressed and promoted hollow spheroid (HS) formation beyond the invasion front of colorectal cancer. The aim of the present study was to clarify whether CEACAM1 cytoplasmic domain isoform balance and HS are associated with resistance to 5-fluorouracil (5FU). Two-dimensional (D) or 3D culture systems were employed to evaluate the effects of CEACAM1 cytoplasmic isoform balance and HS formation on the chemosensitivity of colorectal cancer cells to 5FU. The risk factors for postoperative recurrence were calculated based on the presence of HS and various clinicopathological characteristics in 82 patients with Stage III colorectal cancer who had undergone curative surgery followed by 5FU-based chemotherapy. CEACAM1-4L-transfected HT29 and CEACAM1-4L and 4S expressing parental LS174T cells had significantly higher resistance to 5FU in comparison with CEACAM1-4S- or vector control-transfected cells. In 3D culture, HS formation induced by CEACAM1-4L induced chemoresistance to 5FU, whereas the solid spheres formed in response to CEACAM1-4S were destroyed by 5FU treatment. HS was identified as an independent factor for recurrence of Stage III colorectal cancer after curative resection followed by 5FU-based chemotherapy. Kaplan–Meier survival curves demonstrated that patients with HS had lower recurrence-free survival rate. CEACAM1 long cytoplasmic domain isoform dominance and HS formation are phenotypes associated with chemoresistance to 5FU.

The International Study Group of Rectal Cancer (ISREC) has proposed a new definition of anastomotic leakage (AL) which was simply classified into three grades; however, these criteria have not been assessed well. The aims of this study are to assess the new definition and to show the clinical features of AL after an anterior resection for rectal cancer. Fifty consecutive patients developed AL after an anterior resection for rectal cancer was retrospectively assessed. AL was defined by the ISREC criteria. Twenty-seven (54 %) patients with AL were diagnosed by drain contents. The postoperative day of diagnosis for AL was later in grade A versus grades B and C (p = 0.038 vs p = 0.006, respectively). Permanent stoma (PS) was significantly more frequent in patients with grade C but not grade B compared to the patients with no AL (p

PURPOSE This study evaluated the impact of the pelvic pillow on a single surgeon's learning how to perform laparoscopic low anterior resection (LAR) for rectal cancer. METHODS We compared the outcomes for 23 patients with rectal cancer including the first 11 patients who underwent laparoscopic LAR without the pelvic pillow, and the latter 12 patients with the pelvic pillow by a single surgeon. RESULTS The stage of the pelvic pillow (+) was more advanced than that of the pelvic pillow (-). The length of the operation and postoperative start of oral intake for the pelvic pillow (+) were shorter and earlier than those of the pelvic pillow (-). The pelvic surgical field in the pelvic pillow (+) was better and allowed better evaluation than the pelvic pillow (-). CONCLUSIONS Maintaining an excellent view of the pelvic surgical field with the pelvic pillow might have an impact on learning laparoscopic LAR.

The two isoforms of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), 1 with a long cytoplasmic domain (CEACAM1-L) and 1 with a short (CEACAM1-S), are involved in different signaling pathways. β2-spectrin (β2SP) is an adaptor protein that plays critical roles in the proper control of Smad access to activate receptors involved in regulation of TGF-β signaling. In this study, we examined the association between CEACAM1 isoform balance and hepatocellular carcinoma (HCC) malignant potential and investigated the possibility of a molecular interaction between CEACAM1 and β2SP.Immunohistochemical analysis was carried out with CEACAM1-L or CEACAM1-S antibodies on 154 HCC tissues to correlate with the factors of malignancy. Invasion assay was performed for the effect of CEACAM1 expression on HCC cell lines. Moreover, immunohistochemical analysis and immunoprecipitation analysis were performed to investigate the association between CEACAM1 isoform balance and β2SP.In immunohistochemical analysis, CEACAM1-L expression dominance was a risk factor for HCC recurrence (p = 0.04) and was significantly associated with a shorter survival compared with CEACAM1-S expression dominance. Invasion assay indicated that CEACAM1-4L-transfected HLF and PLC/PRF/5 cells showed significantly increased invasion (p0.0001) and CEACAM1-4S-transfected HLF cells showed significantly decreased invasion. Immunohistochemical analysis of β2SP suggested that the HCCs with CEACAM1-L-dominant expression were more strongly stained with β2SP than the HCCs with CEACAM1-S-dominant expression (p = 0.013), and coprecipitation assays indicated that CEACAM1-L could bind to β2SP.CEACAM1-L may enhance the HCC invasiveness through an interaction with β2SP and subsequent effects on TGF-β signaling.

This study demonstrated the usefulness of the post/preoperative serum carcinoembryonic antigen (CEA) ratio as a predictor of survival after surgery for stage III rectal cancer patients. One hundred and four patients with stage III rectal cancer who underwent surgery between 1991 and 2000 were enrolled. The ratio of the postoperative serum CEA value divided by the preoperative serum CEA value was defined as post/preoperative serum CEA ratio, and the patients were separated into two groups: post/preoperative serum CEA ratio ≤1 (n = 86) and >1 (n = 18). The multivariate analyses demonstrated that the intraoperative blood loss, lack of a sphincter-saving procedure and a post/preoperative serum CEA ratio >1 were independent factors predicting a poor prognosis for the overall and disease-free survival. The overall and disease-free survival rates among patients with a high preoperative serum CEA level (>5 ng/ml) or patients with a high postoperative serum CEA (>5 ng/ml) were longer in patients with a post/preoperative serum CEA ratio ≤1, in comparison to those with a post/preoperative serum CEA ratio >1. Liver metastasis was observed more frequently in patients with a post/preoperative serum CEA ratio >1. The post/preoperative serum CEA ratio may be a predictor of the prognosis after surgery for stage III rectal cancer patients.

Background The identification of molecular markers that are useful for predicting lymph node metastasis is urgently needed to determine treatment strategies for T1 colorectal cancer (CRC). We previously showed that 10 candidate genes are correlated with de-differentiation at the invasion front of CRC using a gene expression analysis. These 10 genes are potential markers that may predict lymph node metastasis by CRC. Materials and methods Samples were obtained from 161 patients with CRC. Quantitative real-time reverse transcription-polymerase chain reaction assays were performed using 66 T3 samples in order to extract genes correlated with lymph node metastasis. Immunohistochemical studies of the extracted genes were performed on 66 T3 and 95 T1 samples. A univariate analysis followed by a multivariate logistic regression model was used to examine independent risk factors for lymph node metastasis. Results The CITED1 messenger RNA expression was found to be an independent risk factor for lymph node metastasis in T3 CRC patients ( P = 0.040). A high CITED1 protein expression, as detected with immunohistochemistry, was also an independent risk factor in T3 CRC patients ( P = 0.035). In T1 colorectal cancer patients, a high CITED1 protein expression was found to be an independent risk factor for lymph node metastasis ( P = 0.010). The positive predictive and negative predictive values in the T1 colorectal cancer patients were 27.5% and 95.5%, respectively. Conclusions The CITED1 expression is correlated with lymph node metastasis in patients with CRC. In T1 colorectal cancer patients, CITED1 has the potential ability to predict the presence of lymph node metastasis.

e15075Background: Chemosensitivity is modulated by cancer cell cluster. We have shown that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promoted hollow spheroid (HS) formatio...

Laparoscopic surgery for colorectal disease has become widespread as a minimally invasive treatment. This is important because the increasing availability of new devices allows us to perform procedures with a reduced length of surgery and decreased blood loss. We herein report the results of a literature review of energy sources for laparoscopic colorectal surgery, focused especially on 6 studies comparing ultrasonic coagulating shears (UCS) and other instruments. We also describe our laparoscopic dissection techniques using UCS for colorectal cancer. The short-term outcomes of surgeries using UCS and Ligasure for laparoscopic colorectal surgery were superior to conventional electrosurgery. Some authors have reported that the length of surgery or blood loss when Ligasure was used for laparoscopic colorectal surgery is less than when UCS was used. On the other hand, a recent study demonstrated that there were no significant differences between the short-term outcomes of UCS and Ligasure for laparoscopic colorectal surgery. It is therefore suggested that the choice of technique used should be made according to the surgeon’s preference. We also describe our laparoscopic dissection techniques using UCS (Harmonic ACE) for colorectal cancer with regard to the retroperitoneum dissection, dissection technique, dissection technique around the feeding artery, and various other dissection techniques. We therefore review the outcomes of using various energy sources for laparoscopic colorectal surgery and describe our laparoscopic dissection techniques with UCS (Harmonic ACE) for colorectal cancer.

Background The differences between the metastatic property of moderately (Mod) and well (Wel) differentiated colorectal adenocarcinoma remain unclear. Since Mod is unable to form complete acini, therefore an epithelial-mesenchymal transition (EMT) can occur in that structure. Herein, we hypothesized that Mod metastasizes more easily than the Wel counterparts. Methods The medical records of 283 consecutive patients with Mod (n = 71) or Wel (n = 212) who underwent surgery were reviewed between January 1, 2001, and December 31, 2003, for actual 5-year overall survival. We examined the differences between the clinicopathological characteristics of the Mod and the Wel groups. Results The lymph node involvement (p < 0.0001), lymphatic permeation, venous permeation, depth of invasion, liver metastasis, and carcinomatous peritonitis were significantly higher in the Mod group in comparison to the Wel group. The independent risk factors by a logistic regression analysis for lymph node involvement were as follows: lymphatic permeation, liver metastasis, and Mod (p = 0.0291, Relative Risk of 1.991: 95% Confidence Interval: 1.073-3.697). A Kaplan-Meier survival curve showed that Mod had a trend towards a poor survival (p = 0.0517). Conclusion Mod metastasizes to the lymph nodes more easily in comparison to Wel. Therefore, patients with Mod may be considered the existence of lymph node involvement.

539 Background: Cancer cells and fibroblasts are coordinated for cancer progression. Our previous study has shown that P4H9, produced by epitope for b2 integrin, detected a molecule on fibroblasts in mammary fat pad mouse model in response to Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressing cancer cells. P4H9 detecting molecule (PDM) expression appeared to be associated with myofibroblast differentiation. The aim of the present study is to investigate whether PDM express on fibroblast and cancer cells in clinical tissue samples, and whether PDM expressing cells in colorectal cancer tissue are correlated with clinicopathological features of patients with colorectal cancer. Methods: Immunohistochemistry were conducted with P4H9 on clinical tissue samples from 156 patients with colorectal cancer. The risk factors for metastases and survival were calculated for clinical implication of PDM expressing spindle shaped fibroblasts. Immunofluorescence with P4H9 were performed on CCD-18Co fibroblasts and colorectal cancer cell lines, HT29 and HCT116. Results: Multivariate analysis showed that PDM expressing spindle shaped fibroblasts was an independent risk factor for lymph node metastasis, hematogenous metastasis, and short survival. Kaplan-Meier survival curve presented that PDM expressing spindle shaped fibroblasts was associated with shorter survival time (p< 0.0001). PDM expressing spindle shaped fibroblasts is associated with metastasis and shorter survival of the patients with colorectal cancer. Immunofluorescence showed that PDM expressed on CCD-18Co fibroblasts and colorectal cancer cell lines, HCT116 with fibroblast like morphology. Conclusions: PDM expressing spindle shaped fibroblasts may play a role to bring out malignant phenotype of colorectal cancer. PDM may be a new biomarker and a novel therapeutic target for patients with colorectal cancer.

418 Background: Hollow spheroid (HS) is a morophogenesis after budding at invasion front of colorectal cancer (CRC) tissue. HS formation of CRC cells has been shown to be induced by Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1) long cytoplasmic isoform dominance condition in three-dimensional (3D) in vitro culture. The aim of the current study is to address the existence and the clinical implication of HS in colorectal cancer. Methods: Immunohistochemical analyses were conducted with CEACAM1, CEACAM1-L, to address the existence of CEACAM1 expressing HS beyond the invasion front of CRC. The risk factors for metastases and survival were calculated using univariate and multivariate analyses on clinical samples from 164 patients with CRC. To investigate the role of HS for chemoresistance to 5-fluorouracil (5-FU), the risk factors for recurrence after adjuvant chemotherapy were calculated using univariate and multivariate analyses on clinical samples from 82 patients with Stage III CRC. Results: Immunohistochemical analyses showed that CEACAM1 expressing HS existed at the invasion front of colorectal cancer tissues. A multivariate analysis showed that the HS is an independent risk factor for lymph node metastasis (p = 0.004) and distant metastasis (p = 0.002). HS was also identified to be an independent prognostic factor by a Cox proportional hazards model (p = 0.020). The Kaplan-Meier evaluation for the overall survival analysis showed that HS was significantly associated with a shorter survival (p < 0.0001). Moreover, a multivariate analysis for recurrence after adjuvant chemotherapy showed that the HS is an independent risk factor (p = 0.0079). These results suggested that HS indicates malignant and chemoresistant phenotype. Conclusions: HS was significantly correlated with CRC metastasis, poor survival and chemoresistance to 5-FU. HS beyond the invasion front of CRC can be useful for diagnosis of malignant potential, and may be novel therapeutic target.

BACKGROUND: Spheroid with hollow (SWH) induced by Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1) and inner cells apoptosis is observed in three-dimensional (3D) in vitro culture and in an in vivo mouse model. However, it is unclear whether SWH exists in clinical cancer tissue. The aim of the current study is to address which cytoplasmic domain of CEACAM1 is responsible for SWH formation, and to elucidate the existence and the implication of SWH in colorectal cancer. METHODS: To address which cytoplasmic domain of CEACAM1 is responsible for SWH formation, 3D culture was conducted to investigate lumen formation of colorectal cancer cells (LS174T and HT29) transfected with CEACAM1-4L (long cytoplasmic isoform), -4S (short cytoplasmic isoform), or shRNA for CEACAM1. Immunohistochemical analyses were conducted with CEACAM1, CEACAM1-L (long cytoplasmic isoform) and M30 (cleaved cytokeratin 18 fragment) as an apoptosis marker on clinical samples from 164 patients with colorectal cancer. The risk factors for metastases and survival were calculated using univariate and multivariate analyses. RESULTS: In 3D culture experiment, CEACAM1-L is responsible for lumen formation of colorectal cancer cells. Knock down of CEACAM1 or over-expression of CEACAM1-4S inhibited lumen formation, indicating that modulation of CEACAM1 can control SWH structure. Immunohistochemical analyses showed that CEACAM1 expressing spheroid with hollow accompanying with central cells apoptosis shown by M30 staining existed at the invasion front of colorectal cancer tissues. All of SWH was stained by CEACAM1 and CEACAM1-L. It means that SWH at the invasion front has already acquired tumor initiating property. A multivariate analysis showed that the SWH is an independent risk factor for lymph node metastasis (p=0.004) and distant metastasis (p=0.002). The SWH was also identified to be an independent prognostic factor by a Cox proportional hazards model (p=0.020). The Kaplan-Meier evaluation for the overall survival analysis showed that SWH was significantly associated with a shorter survival (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5234. doi:10.1158/1538-7445.AM2011-5234