RacGAP1 expression, increasing tumor malignant potential, as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer.

Rac GTPase-activating protein (RacGAP) 1 plays a key role in controlling various cellular phenomena including cytokinesis, transformation, invasive migration and metastasis. This study investigated the function and clinical significance of RacGAP1 expression in colorectal cancer (CRC). The intrinsic functions of RacGAP1 in CRC cells were analyzed using small interfering RNA (siRNA). We analyzed RacGAP1 mRNA expression in surgical specimens from 193 CRC patients (Cohort 1) by real-time PCR. Finally, we validated RacGAP1 protein expression using formalin-fixed paraffin-embedded samples from 298 CRC patients (Cohort 2) by immunohistochemistry. Reduced RacGAP1 expression by siRNA in CRC cell lines showed significantly decreased cellular proliferation, migration and invasion. In Cohort 1, RacGAP1 expression in CRC was significantly higher than in adjacent normal mucosa and increased according to tumor node metastasis stage progression. High RacGAP1 expression in tumors was significantly associated with progression and prognosis. In Cohort 2, RacGAP1 protein was overexpressed mainly in the nuclei of CRC cells; however, its expression was scarcely observed in normal colorectal mucosa. RacGAP1 protein expression was significantly higher in CRC patients with higher T stage, vessel invasion and lymph node and distant metastasis. Increased expression of RacGAP1 protein was significantly associated with poor disease-free and overall survival. Multivariate analyses revealed that high RacGAP1 expression was an independent predictive marker for lymph node metastasis, recurrence and poor prognosis in CRC. Our data provide novel evidence for the biological and clinical significance of RacGAP1 as a potential biomarker for identifying patients with lymph node metastasis and poor prognosis in CRC.

Single-port laparoscopic management of adhesive small bowel obstruction.

Laparoscopic adhesiolysis has been the focus of much recent attention; however, the role of single-port laparoscopic surgery for adhesive small bowel obstruction remains unclear. We report our experience of performing single-port laparoscopic surgery for adhesive small bowel obstruction through a retrospective review of 15 consecutive patients who underwent single-port laparoscopic surgery for single adhesive small bowel obstruction between 2010 and 2012. We analyzed data on patient demographics, operating time, conversion, and surgical morbidity. Surgery was completed successfully without conversion to laparotomy or the need for additional intraoperative ports in 14 patients, but the remaining patient had peritoneal dissemination from colon cancer. The median operative time was 49 (25-148) min, and the estimated blood loss was 19 (2-182) ml. There were no major postoperative complications. We conclude that single-port laparoscopic surgery is a technically feasible approach for selected patients with adhesive small bowel obstruction when preoperative imaging identifies a single adhesive obstruction.

Chemoradiotherapy followed by restorative proctocolectomy with partial intersphincteric resection for advanced rectal cancer associated with ulcerative colitis: report of a case.

The role of restorative proctocolectomy with ileal J-pouch anal anastomosis (IPAA) is uncertain for patients with ulcerative colitis (UC), when advanced lower rectal cancer is diagnosed. We report what to our knowledge is the first documented case of successful preoperative chemoradiotherapy followed by IPAA with partial intersphincteric resection of advanced rectal cancer associated with UC. A 59-year-old woman with a 24-year history of extensive UC was found to have advanced rectal cancer located 2 cm from the anal verge. She underwent preoperative conventional chemoradiotherapy followed by restorative proctocolectomy with total mesorectal excision. The procedure included intersphincteric resection of one quadrant and construction of an IPAA with diverting ileostomy. The postoperative course was uneventful, and the ileostomy was closed 6 months after the initial surgery. The patient was doing well with good pouch function and no evidence of recurrent disease 1 year after her initial surgery.

Prognostic significance of a systemic inflammatory response in patients undergoing multimodality therapy for advanced colorectal cancer.

OBJECTIVES: The inflammation-based Glasgow Prognostic Score (GPS) is associated with outcome in a variety of cancers. This study investigated whether a modified GPS (mGPS) could predict survival in patients undergoing multimodality therapy for advanced colorectal cancer (CRC). METHODS: We enrolled 245 patients with advanced CRC who received chemotherapy. The mGPS was recorded prior to first-line chemotherapy and to cytoreductive therapy including secondary surgery and/or radiofrequency ablation. The prognostic significance of the mGPS was analyzed using Kaplan-Meier, univariate, and multivariate analyses. RESULTS: In patients who received chemotherapy alone (n = 163), the mGPS prior to chemotherapy was an independent prognostic indicator of survival [odds ratio (OR) 1.858; 95% confidence interval (CI) 1.213-2.846; p = 0.0044]. In patients who also underwent cytoreductive therapy (n = 82), the mGPS decreased after chemotherapy in 22 patients (27%) and increased in 5 (6%). In these patients, the mGPS prior to cytoreductive therapy was an independent prognostic indicator of survival (OR 3.412; 95% CI 1.198-9.720; p = 0.0216), but the mGPS prior to chemotherapy was not. CONCLUSIONS: The mGPS is an independent prognostic indicator of survival in patients undergoing multimodality therapy for advanced CRC, if recorded at a relevant time point.

Stromal CXCR4 and CXCL12 expression is associated with distant recurrence and poor prognosis in rectal cancer after chemoradiotherapy.

BACKGROUND: Distant recurrence remains the major cause of mortality in rectal cancer patients with preoperative chemoradiotherapy (CRT). Recently, cancer stroma has been implicated in influencing proliferation, invasion, and metastasis of cancer cells. It has been reported that expression of CXCR4 and its ligand CXCL12 are associated with migration, invasion, and proliferation of colorectal cancer. MATERIALS AND METHODS: A total of 53 patients with rectal cancer underwent preoperative CRT. Total RNAs of residual rectal cancer stromal cells after CRT were obtained from formalin-fixed paraffin-embedded (FFPE) specimens using microdissection. The expression levels of CXCR4 and CXCL12 genes were measured using real-time reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemical staining of these markers after CRT was also investigated. RESULTS: Of the 53 patients, 16 (30.1%) and 14 (26.4%) showed detectable CXCR4 and CXCL12 levels, respectively. We found a significant positive correlation between expression levels of CXCR4 and CXCL12. Patients who developed distant recurrence had twofold higher expression levels of both CXCR4 and CXCL12 compared with those without recurrence after CRT (P < 0.01). Elevated expression levels were also associated with poor probability of recurrence-free survival in both genes (P < 0.01). Additionally, positive CXCL12 expression, but not CXCR4, was significantly correlated with poorer overall survival (P < 0.01). CXCR4 and CXCL12 expression determined using immunohistochemistry was observed in not only cancer but also stromal cells. CONCLUSION: Our results suggest that evaluation of the expression of both genes may be useful for predicting distant recurrence and poor prognosis in rectal cancer patients treated with preoperative CRT followed by surgery.

Circulating form of human vascular adhesion protein-1 (VAP-1): decreased serum levels in progression of colorectal cancer and predictive marker of lymphatic and hepatic metastasis.

BACKGROUND AND OBJECTIVES: Vascular adhesion protein-1 (VAP-1) is an endothelial cell molecule that controls leukocyte tissue infiltration. Elevated serum soluble VAP-1 (sVAP-1) has been described in certain diseases with an inflammatory component. However, sVAP-1 expression or function has not been studied in colorectal cancer. The present study determined the relationships between preoperative serum sVAP-1 and clinicopathological features and prognosis in colorectal cancer. METHODS: One hundred patients with histologically proven colorectal cancer and 33 normal volunteers were included. Preoperative serum was collected, and sVAP-1 levels were assayed by enzyme-linked immunosorbent assay. RESULTS: Mean sVAP-1 level in patients was significantly higher than in controls, and decreased with disease progression. Mean sVAP-1 level was significantly correlated with venous invasion, lymph node metastasis, distant metastasis including hepatic metastasis, and advanced TNM classification. Furthermore, sVAP-1 was an independent marker for predicting lymph node or hepatic metastasis. Prognosis of patients with a lower sVAP-1 level was significantly worse than those with elevated sVAP-1. CONCLUSIONS: Preoperative low sVAP-1 level is associated with poor prognosis in colorectal cancer. Measuring serum sVAP-1 may provide valuable information in predicting patients with lymph node or hepatic metastasis.

Elevated CD133, but not VEGF or EGFR, as a predictive marker of distant recurrence after preoperative chemoradiotherapy in rectal cancer.

CD133 has been postulated to be a colon cancer stem cell (CSCs) marker. Recent investigations suggest that CSCs might contribute to cancer recurrence and resistance to conventional therapies. This study aimed to evaluate the role of CD133 in residual cancer cells after chemoradiotherapy (CRT) for rectal cancer. Forty patients with rectal cancer underwent CRT followed by surgery. Total RNAs of rectal cancer cells before (n=30) and after (n=40) CRT were isolated. Intratumoral CD133, vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) levels were measured using real-time reverse transcription polymerase chain reaction. Immunohistochemical staining of CD133 after CRT was also investigated. CD133 in residual cancer cells was higher than in stromal cells in post-CRT specimens (p<0.0001). The levels of CD133 were found to have increased in post-CRT specimens (p=0.0184), while VEGF and EGFR levels decreased during CRT (p<0.0001 and p=0.0002, respectively). Patients who developed distant recurrence had a higher post-CRT CD133 compared with those patients without recurrence (p=0.0136). Elevated post-CRT CD133 was associated with poor disease-free survival (p=0.0168). Immunohistochemical staining of the cytoplasmic and apical/endoluminal membranous CD133 was observed in residual cancer cells after CRT. CD133 expression in residual cancer cells after CRT may indicate a treatment resistant phenotype in putative CSCs. Elevated CD133, but not VEGF or EGFR, on FFPE specimens may be a predictive marker of distant recurrence and poor survival after preoperative CRT in rectal cancer.

Ovarian autoamputation in a neonate: a case report with literature review.

A case of ovarian autoamputation in an asymptomatic neonate is presented. An abdominal cyst was detected in a 30-week-gestation fetus on an antenatal ultrasound scan (USS). Postnatal USS confirmed the presence of a cyst in the right pelvis and revealed it to be 3.2 cm in diameter. CT and MRI revealed cyst wall calcification and intracystic hemorrhage. To confirm the diagnosis and treatment, the cyst was surgically removed. During the operation, a free autoamputated right ovarian cyst was found and removed from the abdomen. Ovarian cyst autoamputation is an extremely rare complication. In this article, we review the infantile ovarian autoamputation cases reported in the literature and assess their diagnosis and therapeutic management.

Efficacy and safety of laparoscopic surgery in elderly patients with colorectal cancer.

Colorectal cancer (CRC) is predominantly a disease of the elderly. Elderly patients may also exhibit poorer outcomes due to the increased burden of comorbidities, functional dependency and limited life expectancy. The aim of this study was to evaluate the outcome of laparoscopic surgery in elderly patients with CRC. A total of 148 patients who underwent laparoscopic surgery at our institution between January, 2000 and December, 2011 were enrolled. We compared the differences between elderly patients (aged >75 years, n=48) and non-elderly patients (aged <75 years, n=100) and evaluated the demographics and disease-related operative and prognostic data. Postoperative complications occurred in 24 (16.2%) of the 148 patients. The American Society of Anesthesiologists score and comorbidity were found to be significantly correlated with complications and the multivariate analysis demonstrated that pulmonary disease, but not age, was an independent factor affecting postoperative complications (odds ratio = 3.21, 95% confidence interval: 1.02-10.14, P=0.0470). Patients with pulmonary comorbidities also exhibited similar rates of postoperative complications compared with 259 matched patients who underwent open surgery during same period (41.2 vs. 46.7%, respectively; P=0.7547). In conclusion, chronological age alone should not be considered a contraindication for laparoscopic surgery for CRC in elderly patients. In addition, selection criteria for laparoscopic CRC surgery in elderly as well as non-elderly patients should include pulmonary comorbidities.

Elevated platelet count as predictor of recurrence in rectal cancer patients undergoing preoperative chemoradiotherapy followed by surgery.

The impact of systemic inflammatory response (SIR) on prognostic and predictive outcome in rectal cancer after neoadjuvant chemoradiotherapy (CRT) has not been fully investigated. This retrospective study enrolled 89 patients with locally advanced rectal cancer who underwent neoadjuvant CRT and for whom platelet (PLT) counts and SIR status [neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR)] were available. Both clinical values of PLT and SIR status in rectal cancer patients were investigated. Elevated PLT, NLR, PLR, and pathologic TNM stage III [ypN(+)] were associated with significantly poor overall survival (OS). Elevated PLT, NLR, and ypN(+) were shown to independently predict OS. Elevated PLT and ypN(+) significantly predicted poor disease-free survival (DFS). Elevated PLT was identified as the only independent predictor of DFS. PLT counts are a promising pre-CRT biomarker for predicting recurrence and poor prognosis in rectal cancer.

Preoperative assessment of vascular anatomy by multidetector computed tomography before laparoscopic colectomy for transverse colon cancer: report of a case.

Although the safety of laparoscopic surgery for colon cancer has been reported in many randomized controlled trials, concerns about the difficulty of surgery for transverse colon cancer has not been fully resolved, mainly because of the variation in the vascular anatomy of mesenteric vessels, which leads to difficulty in determining the optimal operative procedure and the extent of lymph node dissection. We present the case of a patient with transverse colon cancer who underwent laparoscopic surgery after preoperative assessment using a combination of endoscopic clipping and three-dimensional computed tomography angiography (3DCTA). A 68-year-old man was diagnosed with transverse colon cancer, and laparoscopic surgery has been planned. 3DCTA showed right-middle and left-middle colic arteries arising independently from the superior mesenteric artery. The relationship between the clip and vessels showed that the right-middle colic artery was the feeding artery of the tumor. Operative findings were consistent with 3DCTA findings, and transverse colectomy with lymph node dissection was successfully performed.

Puborectal sling interposition combined with seton drainage for pouch-vaginal fistula after rectal cancer surgery with colonic J pouch-anal reconstruction: report of a case.

The management of postoperative rectovaginal fistula (RVF) after rectal cancer surgery is difficult and requires reconstruction of the anastomotic site and fistula. Though various surgical procedures have been reported for the repair of RVFs, the results of surgical repair are often unsatisfactory, and failure of the initial repair leads to difficulty in the later operations. Furthermore, it has been reported that cases associated with local infection result in low success rates. We report a case of an 80-year-old woman with a recurrent colonic J pouch-vaginal fistula after anoabdominal rectal resection with partial internal sphincteric resection, who achieved a good outcome following a repair using a puborectal sling interposition combined with seton drainage. It may be a useful option for RVF management in repair of such pouch-vaginal fistula after coloanal anastomosis with intersphincteric resection.

Conversion Therapy Using mFOLFOX6 With Panitumumab for Unresectable Liver Metastases From Multiple Colorectal Cancers With Familial Adenomatous Polyposis.

A 39-year-old man received a diagnosis of unresectable multiple liver metastases from multiple colorectal cancers with familial adenomatous polyposis. After construction of an ileostomy, modified FOLFOX6 (mFOLFOX6) with panitumumab was administrated because rectal cancer and sigmoid colon cancer are KRAS wild type. The 13 courses of chemotherapy resulted in a marked reduction in the size of liver metastases and sigmoid colon cancer. Consequently, curative resection with total colectomy, ileal pouch anal anastomosis, and liver metastasis resection with radiofrequency ablation was performed. Progression of KRAS wild-type rectal cancer after chemotherapy suggested that each clone from rectal and sigmoid colon cancer might have a different sensitivity to epidermal growth factor receptor antibody. Immunohistochemical analysis revealed loss of PTEN expression in rectal cancer compared with liver metastases from sigmoid colon cancer, showing that the difference of mFOLFOX6 with panitumumab might be related to activation of the PI3K-AKT pathway.

Elevated serum angiopoietin-like protein 2 correlates with the metastatic properties of colorectal cancer: a serum biomarker for early diagnosis and recurrence.

PURPOSE: Angiopoietin-like protein 2 (ANGPTL2) is a mediator of chronic inflammation and inflammatory carcinogenesis. The biologic and clinical significance of ANGPTL2 remains unknown in human cancer. Therefore, we investigated the function of ANGPTL2 and evaluated its clinical significance in both primary tumors and matched sera in patients with colorectal cancer. EXPERIMENTAL DESIGN: A colorectal cancer cell line was transfected with siRNA against ANGPTL2 for the assessment of its function. We examined ANGPTL2 expression in colorectal cancer tissues (n = 195) by immunohistochemistry. Finally, we screened serum ANGPTL2 levels from 32 colorectal cancers and 23 normal controls (NC), and validated these results in serum samples obtained from 195 colorectal cancers and 45 NCs by ELISA. RESULTS: Knockdown of ANGPTL2 in vitro significantly inhibited cell proliferation, migration, and invasion, whereas it enhanced anoikis. ANGPTL2 was overexpressed in colorectal cancer tissues, and was significantly associated with advanced T stage, lymph node, and liver metastasis. Likewise, serum ANGPTL2 levels in colorectal cancers were significantly higher than NCs (P < 0.01), and allowed distinguishing of colorectal cancers from NCs with high accuracy (AUC = 0.837). The subsequent validation step confirmed that serum ANGPTL2 levels in colorectal cancers were significantly higher than in NCs (P < 0.0001), and had a high AUC value (0.885) for distinguishing colorectal cancers from NCs. High serum ANGPTL2 was significantly associated with advanced T stage, lymph node and liver metastasis, early relapse, and poor prognosis in colorectal cancers. CONCLUSION: Serum ANGPTL2 is a novel diagnostic and recurrence-predictive biomarker in patients with colorectal cancer.

C-reactive protein as predictor of recurrence in patients with rectal cancer undergoing chemoradiotherapy followed by surgery.

BACKGROUND: The clinical significance of the systemic inflammatory response (SIR) in patients with rectal cancer undergoing neoadjuvant chemoradiotherapy (CRT), to the best of our knowledge, has not been thus far investigated. PATIENTS AND METHODS: The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and C-Reactive protein (CRP) levels for 84 patients with rectal cancer undergoing CRT were available as indicators of SIR status. The impact of SIR status on the prognosis of these patients was assessed. RESULTS: Elevated NLR, CRP, carcinoembryonic antigen (CEA) and pathological TNM stage III [ypN(+)] were identified as significant prognostic factors for poor overall survival (OS), with CRP and ypN(+) being validated as independent predictors of OS. Elevated CRP and CEA levels were significant predictive factors for poor disease-free survival (DFS), and an elevated CRP level was identified as the only independent predictive factor for DFS. In addition, an elevated CRP level predicted for poorer OS and DFS in patients with pathological TNM stage I-II [ypN(-)]. CONCLUSION: CRP is a promising predictor of recurrence and prognosis in patients with rectal cancer treated by CRT.

Prognostic significance of opioid use in the active treatment of advanced colorectal cancer.

This study aimed to evaluate the oncologic significance of opioid use during active treatment for advanced colorectal cancer (CRC). The patients included in this study underwent therapeutic chemotherapy for metastatic and/or recurrent CRC. The primary outcomes measured were the characteristics of CRC patients who were administered opioid to maintain compliance with cancer treatments as well as the impact of opioid use on cancer-specific survival. Of the 245 patients, 117 (48%) were administered opioid during chemotherapy. No significant associations were detected between opioid use and clinicopathological factors, with the exception of age (<65 or ≥65 years; P= 0.0281), pathology (differentiated or undifferentiated; P= 0.0007) and response rate to chemotherapy (P= 0.0056). Patients administered opioid had significantly poorer cancer-specific survival compared to patients who did not receive opioid. The mean cancer-specific survival periods were 606±57 days (chemotherapy with opioid), <636±46 days (chemotherapy without opioid), <1140±95 days (multimodal therapy with opioid) and <1556±160 days (multimodal therapy without opioid). Additionally, oncologic emergencies due to cancer progression were significantly correlated with opioid use (P=0.0002), although no statistically significant differences were detected between the cancer-specific survival period and oncologic emergencies. The use of opioid to maintain compliance with active cancer therapy is advised in modern CRC management. However, CRC patients that were administered opioid may have potential progressive disease, thus clinicians need to be aware of the oncologic emergencies possibly arising during an active CRC therapy.

Phase I study of 5-fluorouracil, leucovorin and bevacizumab in combination with radiation therapy in patients with locally advanced rectal cancer.

A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of the standard treatment of 5-fluorouracil/l-leucovorin (5-FU/LV) with bevacizumab, in combination with radiation therapy in patients with locally advanced rectal cancer. Eligible patients had previously untreated stage T3 or T4 locally advanced rectal cancer. Patients received radiotherapy to the pelvis, at a total dose of 45 Gy in 25 fractions. During radiotherapy, patients received three courses of a simplified LV and 5-FU regimen (sLV5FU2), in combination with bevacizumab. Bevacizumab was infused at a fixed dose of 5 mg/kg on Days 1, 15 and 29. The sLV5FU2 regimen consisted of 200 mg/m2 of LV administered by continuous intravenous (i.v.) infusion over 2 h, followed by 400 mg/m2 of 5-FU administered by i.v. bolus injection, delivered at an initial loading dose of 2,000 mg/m2 over 46 h. The dose was gradually increased to determine the MTD and RD of this regimen. Of the patients enrolled in the study, two developed Grade 3 diarrhea and one developed Grade 3 neutropenia. Since dose-limiting toxicity (DLT) occurred in two out of the six patients, 5-FU at a dose of 2,000 mg/m2 over 46 h was determined as the MTD and designated as the RD, taking into consideration the toxicities in matched patients who received standard preoperative chemoradiotherapy with sLV5FU2 during the same period. The combination of 5-FU, LV, bevacizumab and radiotherapy in patients with locally advanced rectal cancer was found to be tolerable, with encouraging response rates. Further investigation is required in a phase II setting.

Loss of the metastasis suppressor gene KiSS1 is associated with lymph node metastasis and poor prognosis in human colorectal cancer.

Cancer research is currently focused on blocking the metastatic process at its early steps. Some particularly attractive targets are metastasis suppressor genes, which control cancer cell dissemination. The aim of this study was to clarify the relationship between the expression of KiSS1, a metastasis suppressor gene, and disease progression in colorectal cancer patients. One-hundred and seventy-five patients who underwent surgery for colorectal cancer were enrolled in this study. We analyzed KiSS1 mRNA expression by real-time reverse transcription PCR in colorectal cancer tissue and paired adjacent normal mucosa. KiSS1 protein expression in early- and advanced-stage colorectal cancer samples was determined by immunohistochemical analysis. Decreased KiSS1 expression was significantly associated with lymph node metastasis and was an independent prognostic factor. Logistic regression analysis revealed that decreased KiSS1 expression was an independent risk factor for lymph node metastasis. Immunohistochemical analysis indicated that KiSS1 was highly expressed in the cell cytoplasm of early-stage colorectal cancer cells. The loss of KiSS1 appears to correlate with the progression of lymph node metastasis. An assessment of KiSS1 expression may assist in the accurate colorectal cancer diagnosis and may contribute to predict clinical outcomes.

Cytoreductive strategy for multiple intra-abdominal and abdominal wall desmoid tumors in familial adenomatous polyposis: report of three cases.

Desmoid tumors (DTs) are benign myofibroblastic neoplasms originating from the fascia or muscle aponeurosis, which occur in one-third of patients with familial adenomatous polyposis (FAP). Most FAP-associated DTs occur in the intra-abdominal or abdominal wall region, thus, their infiltrative or expansive growth causes life-threatening organ damage, such as intestinal obstruction, urethral obstruction, and mesenteric infiltration with the involvement of mesenteric vessels. Treatments including surgical resection, cytotoxic chemotherapy, nonsteroidal anti-inflammatory drugs and anti-estrogen therapy have all been tried with variable success. Here, we report on three patients with FAP who developed multiple intra-abdominal and abdominal wall DTs after total proctocolectomy and ileal pouch-anal anastomosis. Two cases underwent surgical resection of uncontrolled abdominal wall DTs after successful control of intra-abdominal DTs by systemic chemotherapy. The remaining case underwent repeated surgical resections of multiple intra-abdominal and abdominal wall DTs, and consequently had recurrent intra-abdominal DTs, with involvement of the small bowel and ureter. Surgical intervention as tumor volume reduction (cytoreduction) may be useful for cases with medical treatment-refractory or symptomatic FAP-associated abdominal DTs.