YM155, specific survivin inhibitor, can enhance artesunate-induced cytotoxicity in HCT116 colon cancer cells

Purpose@#A water-soluble variant of the artemisinin called artesunate, approved as an antimalarial agent, can induce cell death on various cancer cell types. We studied the mechanism of cell death of artesunate on HCT116 colorectal cancer cells. @*Methods@#We treated HCT116 colon cancer cells with artesunate, holo-transferrin, deferoxamine mesylate, ferrostatin, necrostatin-1, and YM155. We observed the growth inhibition of artesunate on HCT116 colon cancer cells by morphologic findings. Inhibition of cell growth was assessed by MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide) assay and long-term growth inhibition by colony-forming assay. Apoptosis was investigated by flow cytometry and Western blot analysis. @*Results@#Artesunate inhibited the proliferation of HCT116 colon cancer cells effectively. Co-treatment with YM155, a specific survivin inhibitor, enhanced the artesunate-induced cell death. Co-treatment with the iron-chelating agent deferoxamine rescued artesunate induced cell death and increased long-term cell survival and proliferation. @*Conclusion@#In this study, we demonstrated that artesunate-induced cytotoxicity in HCT116 colon cancer cells by suppressing the expression of survivin and partially by ferroptosis. Our findings suggest that the co-treatment artesunate with YM155 can induce more potent cell death on HCT116 colon cancer cells and shows new insight for the treatment of colorectal cancer patients.

YM155, specific survivin inhibitor, can enhance artesunate-induced cytotoxicity in HCT116 colon cancer cells

Purpose@#A water-soluble variant of the artemisinin called artesunate, approved as an antimalarial agent, can induce cell death on various cancer cell types. We studied the mechanism of cell death of artesunate on HCT116 colorectal cancer cells. @*Methods@#We treated HCT116 colon cancer cells with artesunate, holo-transferrin, deferoxamine mesylate, ferrostatin, necrostatin-1, and YM155. We observed the growth inhibition of artesunate on HCT116 colon cancer cells by morphologic findings. Inhibition of cell growth was assessed by MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide) assay and long-term growth inhibition by colony-forming assay. Apoptosis was investigated by flow cytometry and Western blot analysis. @*Results@#Artesunate inhibited the proliferation of HCT116 colon cancer cells effectively. Co-treatment with YM155, a specific survivin inhibitor, enhanced the artesunate-induced cell death. Co-treatment with the iron-chelating agent deferoxamine rescued artesunate induced cell death and increased long-term cell survival and proliferation. @*Conclusion@#In this study, we demonstrated that artesunate-induced cytotoxicity in HCT116 colon cancer cells by suppressing the expression of survivin and partially by ferroptosis. Our findings suggest that the co-treatment artesunate with YM155 can induce more potent cell death on HCT116 colon cancer cells and shows new insight for the treatment of colorectal cancer patients.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy as Treatment Options for Peritoneal Metastasis of Advanced Gastric Cancer

PURPOSE: This study aimed to examine the outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis (PM) of advanced gastric cancer (AGC). MATERIALS AND METHODS: Between May 2015 and June 2017, 38 CRS and HIPEC procedures were performed in patients with PM of AGC at the Dankook University Hospital. We prospectively collected and analyzed data regarding PM grade, morbidity and mortality rates, and short-term follow-up results (median, 13.5 months). RESULTS: The mean peritoneal cancer index was 15 (range, 0–39). Complete cytoreduction was achieved in 21 patients (55.2%), whereas complications occurred in 16 (42.1%) and 2 (5.7%) patients died. The overall median patient survival time was 19 months. The patients who underwent complete cytoreduction had a median survival time of 26 months, which was significantly longer than the median survival time of 16 months in the patients who did not undergo complete cytoreduction (P=0.006). CONCLUSIONS: CRS with HIPEC may have a beneficial effect in patients with PM of AGC. However, the rates of complications and mortality associated with this combined therapeutic approach are high. Therefore, this treatment should be performed only in selected patients by surgeons experienced in the field of gastric cancer with PM.

Urinary Bladder Injury During Colonoscopy Without Colon Perforation

We report a case of urinary bladder perforation during colonoscopy. A 67-year-old female, who had undergone a transabdominal hysterectomy for uterine myomas 15 years ago, visited the emergency department with complaint of abdominal pain after a screening colonoscopy. Laparoscopic examination revealed severe adhesion between the sigmoid colon and the urinary bladder. The urinary bladder wall was weakened, and several perforation sites were found. The surgery was converted to a laparotomy. After a thorough examination, we performed primary repair for the perforation sites, followed by an omentopexy.

Is Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy a Safe and Effective Procedure for Treating Patients With a Peritoneal Surface Malignancy?

No abstract available.

Cytoreductive surgery and intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal cancer: 2-year follow-up results at a single institution in Korea

PURPOSE: The purpose of this study was to examine 2-year follow-up results of cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for peritoneal carcinomatosis (PC) of colorectal cancer. METHODS: We performed 54 cases of CRS and IPC in 53 patients with PC of colorectal cancer from December 2011 to December 2013. We collected data prospectively and analyzed the grade of PC, morbidity and mortality, and short-term follow-up (median, 10 months; range, 2–47 months) results. RESULTS: Mean peritoneal cancer index (PCI) was 15 (range, 1–35), and complete cytoreduction was possible in 35 patients (64.8%). Complications occurred in 25 patients (46.3%) and mortality occurred in 4 patients (7.4%). Excluding the 4 mortalities, 17 patients out of 49 patients (31.5%) were alive at the time of the last follow-up and the overall median survival was 10.3 months. Patients with complete cytoreduction had a median survival of 22.6 months, which was significantly longer than the median survival of 3.5 months for patients without complete cytoreduction (P < 0.001). PCI grade, CCR grade, cell type, and postoperative chemotherapy were significant prognostic factors by univariate analysis. Positive independent prognostic factors by multivariate analysis included PCI grade and postoperative chemotherapy. CONCLUSION: CRS and IPC increased the survival of patients with low PCI and postoperative systemic chemotherapy was mandatory. However, this combined therapeutic approach showed high rate of complications and mortality. Therefore, this aggressive treatment should be performed in only selected patients by considering the general condition of the patient and the extent of PC.

Peritoneal Metastatic Goblet-Cell Carcinoid Tumor Treated With Cytoreductive Surgery and Intraperitoneal Chemotherapy

We report a case of a goblet-cell carcinoid tumor of the appendix which metastasized to the peritoneum and was treated by using cytoreductive surgery (CRS) with intraperitoneal chemotherapy. A 47-year-old male presented with chronic constipation and was diagnosed as having a rectal adenocarcinoma with a signet-ring-cell component under colonoscopy. Computed tomography suggested peritoneal metastases with diffuse nodular parietal peritoneal thickening of the entire abdomen and focal invasion of the upper rectum by a seeding mass. CRS with intraperitoneal chemotherapy was done under the diagnosis of a rectal adenocarcinoma with peritoneal metastases. The pathologic diagnosis was a goblet-cell carcinoid tumor of the appendix with peritoneal metastasis. The histological discrepancy between a peritoneal metastatic mass and a rectal mass was due to the mixed histological pattern of a goblet-cell carcinoid tumor. A metastatic mass may not share identical immunohistochemical characteristics from its origin. This histologic discrepancy necessitates caution in diagnosing a distant metastasis of a goblet-cell carcinoid tumor.

Clinical Trial on the Incidence of Wound Infection and Patient Satisfaction After Stoma Closure: Comparison of Two Skin Closure Techniques

PURPOSE: Surgical site infection (SSI) is one of the most common complications that can occur after stoma closure. Reports have described differences in the incidence of wound infection depending on the skin closure technique, but there is no consensus on the ideal closure technique for a stoma wound. The aim of this study was to compare the incidence of SSI and the patient satisfaction between a circumferential purse-string approximation (CPA) and a primary linear closure (PC) of a stoma wound. METHODS: This prospective nonrandomized trial enrolled 48 patients who underwent a stoma closure from February 2010 to October 2013. Patients were divided into two groups according to the stoma closing technique: the CPA group (n = 34) and the PC group (n = 14). The incidences of SSI for the two groups were compared, and the patients' satisfaction with the stoma closure was determined by using a questionnaire. RESULTS: SSI occurred in 3 of 48 patients (6.3%) and was more frequent in the PC group than in the CPA group (3/14 [21.4%] vs. 0/34 [0%], P = 0.021). Time to complete healing after stoma closure in the CPA group was 32 days (range, 14-61 days). Patients in the CPA group were more satisfied with the resulting wound scar (P = 0.043). CONCLUSION: After stoma closure, CPA was associated with a significantly lower incidence of wound infection and greater patient satisfaction compared to PC. However, with the CPA technique, the time to heal is longer than it is with PC.

Antichemosensitizing effect of resveratrol in cotreatment with oxaliplatin in HCT116 colon cancer cell

PURPOSE: Although oxaliplatin is one of the most widely used chemotherapeutic agents for the treatment of advanced stages of colorectal cancers in clinic, cancer cells often develop oxaliplatin drug resistance. Thus, overcoming oxaliplatin drug resistance is a major issue in the successful treatment for advanced stages of colorectal malignancy. In order to maximize oxaliplatin therapy, we examined whether resveratrol, a natural phytochemical known to have chemopreventive effects on cancers, can have a chemosensitizing effect upon cotreatment with oxaliplatin. Survivin, a small inhibitor of apoptosis protein (IAP), expression is examined using HCT116 colon cancer cells. METHODS: In order to examine resveratrol chemosensitizing effect upon oxaliplatin cotreatment, survivin transcripts and protein expression, cell proliferation, and apoptotic responses were evaluated using HCT116 cells. Reverse transcription polymerase chain reaction (RT-PCR), Western blot, crystal violet staining analyses were performed. For survivin specific inhibition, YM155 molecule was used. RESULTS: Although oxaliplatin significantly suppressed survivin transcripts and protein expression level in HCT116 cells, resveratrol cotreatment induced restoration of survivin expression level of both transcripts and protein. Apoptotic induction by oxaliplatin only treatment was nullified upon resveratrol cotreatment. Induction of survivin restoration upon resveratrol cotreatment also occurred when survivin specific inhibitor, YM155, was used. In addition to survivin restoration, resveratrol cotreatment also induced restoration of Bcl-2/caspase-3 expression suppressed by oxaliplatin only treatment. CONCLUSION: Resveratrol has an antichemosensitizing effect upon cotreatment with oxaliplatin in HCT colon cancer cells. This antichemosensitizing effect of resveratrol can be cell-type specific. However, clinical use of resveratrol cotreatment with oxaliplatin should be approached cautiously.

Adult intussusceptions: preoperative predictive factors for malignant lead point

PURPOSE: Adult intussusception is uncommon, but an organic lesion is found to be the lead point in 75% to 90% of the cases. This study was designed to review our experience with adult intussusception and to determine if there are any preoperative predictive factors for a malignant lead point. METHODS: Thirty-three patients over 15 years of age were diagnosed with intussusceptions through operative finding over a period of 20 years. We reviewed the medical records of these patients retrospectively, and preoperative predictive factors of malignant lead points were analyzed. RESULTS: The preoperative diagnosis of intussusception had been made correctly in 86% of the cases, and computed tomography could find a lead point in 79%. A causative organic lesion was found in 29 patients (88%) pathologically; 16 cases (48%) were due to benign tumors, and 13 (39%) were due to malignant tumors. A malignant lead point was present in four of 21 enteric (20%) versus nine of 13 colonic intussusceptions (75%). The period from symptom appearance to hospital visit showed a more chronic nature in malignant neoplasm than in benign neoplasm (P = 0.006), and the location of causative organic lesion showed significant difference between benign and malignant groups (P = 0.003). CONCLUSION: Adult intussusceptions are commonly secondary to a pathologic lead point, and a computed tomography is an effective diagnostic tool for finding a lead point preoperatively. The chronic nature of the disease presentation and colonic location of the lead point may suggest a malignant neoplasm.

Bezoar-induced Small Bowel Obstruction

PURPOSE: The aim of this study was to observe the clinical features of a bezoar-induced small bowel obstruction and to investigate the role of abdominal computed tomography (CT) in establishing the diagnosis. METHODS: We retrospectively reviewed 20 cases of bezoar-induced small bowel obstruction in our hospital from 1996 to 2010. RESULTS: Thirteen patients (65%) had a history of abdominal surgery. Nine patients (45%) were diagnosed with a bezoar before surgery, seven patients were diagnosed by using abdominal CT, and two patients were diagnosed with a small bowel series. Abdominal CT was performed in 15 patients, and the diagnostic accuracy was 47% (7/15). Surgery revealed ten bezoars in the jejunum and 11 in the ileum. Two patients had bezoars found concurrently in the stomach. Spontaneous removal took place in two patients. An enterotomy and bezoar extraction was performed in 15 patients. Fragmentation and milking, a small bowel resection, and a Meckel's diverticulectomy were performed in one patient each. Early operative treatment was possible (P = 0.036) once the bezoar had been diagnosed by using abdominal CT. There tended to be fewer postoperative complications in patients who were diagnosed with a bezoar by using abdominal CT, but the result was not statistically significant (P = 0.712). CONCLUSION: A preoperative diagnosis of bezoar-induced small bowel obstruction by using clinical features was difficult. Increased use of abdominal CT led to a more accurate diagnosis and to earlier surgery for bezoar-induced small bowel obstructions, thereby reducing the rate of complications.

Oncologic manifestations of neurofibromatosis type 1 in Korea / 대한외과학회지

PURPOSE: The aim of this study was to investigate the incidence and spectrum of malignant tumors in Korean neurofibromatosis type 1 (NF1) patients. METHODS: We retrospectively reviewed 125 patients who were diagnosed with NF1 at a single institution from 1995 to 2010. The incidence, location, histologic type, and radiologic findings of malignant tumors as well as development of multiple primary tumors were analyzed. RESULTS: Eighteen malignant tumors occurred in 16 patients (12.8%) among 125 Korean NF1 patients; 9 carcinomas, 8 sarcomas and 1 central nervous system (CNS) tumor. Five tumors were of nervous system origin and 13 were non-nervous system tumors. The locations of the tumors were as follow: 1 CNS, 2 lung, 3 breast, 3 stomach, 3 small bowel, 1 colon, 1 liver, 1 uterus, 1 neck, and 2 in extremities. Three malignant peripheral nerve sheath tumors (MPNSTs) occurred at the neck and extremity, and one in the liver. All three gastrointestinal stromal tumors (GISTs) had multiple tumors in the jejunum, and one MPNST and one pheochromocytoma were accompanied in two GISTs. Multiple primary tumors, benign or malignant were reported in 4 patients (25.0%), synchronously or metachronously. CONCLUSION: Korean NF1 patients had a high risk of developing malignant tumors. The common malignant tumors in Koreans such as breast, lung and stomach cancers developed frequently in addition to the NF1-related tumors such as MPNST or GIST.

Are Mutations of the EGFR Gene Promising Predictive Markers for Anti-EGFR mAbs in Colorectal Carcinomas?

No abstract available.

Change in Expression of Survivin Caused by Using Oxaliplatin in HCT116 Colon Cancer Cells

PURPOSE: Oxaliplatin is a third-generation platinum compound, and it has no nephrotoxicity and has reduced bone marrow toxicity. Cancer cells that are resistant to cisplatin are sensitive to oxaliplatin. Oxaliplatin is used widely for the treatment of colon cancers. Recently, oxaliplatin was reported to inhibit the expression of survivin, which protects cell apoptosis. However, there are no reports on the expressions of survivin variants and the changes in intracellular localization of survivin in cancer cells. We studied the expression of survivin caused by oxaliplatin in HCT116 colon cancer cells, and we observed the localization of survivin in the mitotic phase. METHODS: We treated the HCT116 colon cancer cells with 2.0 micrometer of oxaliplatin, and we studied the expressions of survivin protein, and survivin mRNA variants, as well as the changes in intracellular localization, by using the Western blot method, RT-PCR, immunocytochemistry, and flowcytometry. RESULTS: Oxaliplatin inhibits the expression of the survivin protein and survivin mRNA in HCT116 colon cancer cells. The expression of the survivin-2B variants, which have no antiapoptotic activity but control cell mitosis by localization on a microtubule, is reduced continuously 2 days after treatment with oxaliplatin. In immunocytochemistry, expression of survivin in the cytoplasm is reduced and especially is not expressed in microtubules and contractile rings. CONCLUSION: One of the mechanisms of oxaliplatin is to inhibit the expression of and to change the localization of survivin. Based on these results, we suggest that changes in the expression of survivin variants and in their localization are two effects of oxaliplatin.

Effects of DCA on Cell Cycle Proteins in Colonocytes

PURPOSE: Evidence that indicates bile acid is a promoter of colon cancer exists. Deoxycholic acid (DCA) modifies apoptosis or proliferation by affecting intracellular signaling and gene expression. However, because previous studies have been based on studies on colon cancer cell lines, the effect of DCA on normal colonocytes is unknown. METHODS: Normal colonocytes and Caco-2 and HCT116 cells were treated with 20 micrometer and 250 micrometer of DCA, and the effect of different concentrations of DCA was measured based on the expression of cell-cycle-related proteins by using Western blots. RESULTS: The expressions of CDK2 and cyclin D1 for different concentrations of DCA in normal colonocytes and colon cancer cells were similar, but the expressions of cyclin E and A were significantly different. In HCT116 colon cancer cells, the expression of cyclin E increased regardless of the DCA concentration, but in normal colonocytes and Caco-2 cells, the expression of cyclin E was not changed or decreased. In HCT116 colon cancer cells, the expression of cyclin A was not changed or decreased regardless of the DCA concentration, but in normal colonocytes and Caco-2 cells, the expression of cyclin A was increased at a DCA concentration of 20 micrometer. CONCLUSION: The effect of DCA on stimulating cell proliferation suggests that DNA synthesis is stimulated by an increased expression of cyclin E in colon cancer cells. Our results suggest that a low dose of DCA induces cellular proliferation through increased expression of cyclin A and that a high dose of DCA induces decreased expression of cyclin E and CDK2 in normal colonocytes.

ERRATUM: Expression of LDH-5 in Colorectal Carcinomas: Correlation with Prognosis and Tumor Angiogenesis

No abstract available.

Expression of LDH-5 in Colorectal Carcinomas: Correlation with Prognosis and Tumor Angiogenesis

PURPOSE: Lactate dehydrogenase-5 (LDH-5) is one of five isoenzymes and is the most important for anaerobic glycolysis. LDH-5 is transcriptionally regulated by hypoxia-inducible factor (HIF). HIF plays a role in the response to hypoxia by activating genes involved in vascular remodeling, cell proliferation, and erythropoiesis. In this study, we investigated the clinicopathologic significance and angiogenesis of LDH-5 expression in colorectal cancer. METHODS: We retrospectively reviewed the medical records of 83 patients with colorectal cancer who underwent a surgical resection at Soonchunhyang Cheonan Hospital from January 2001 to December 2003. LDH-5 and HIF-1alpha protein expressions were evaluated in 83 human colorectal cancer specimens. These factors were related to TNM stage, lymph node metastasis, vascular, neural, and lymphatic invasion, and prognosis. RESULTS: LDH-5 was positive in 66% (55 patients) of the tumors, and HIF-1alpha was positive in 66% (55 patients) of the tumors. LDH-5 expression was significantly associated with HIF-1alpha protein expression (P<0.001). Also, LDH-5 expression was significantly associated with TNM stage and lymph node metastasis (P<0.001) while HIF-1alpha expression was significantly associated with TNM stage (P<0.001), lymph node metastasis (P<0.001), vascular invasion (P=0.011), and lymphatic invasion (P=0.005). The survival of the patients with high LDH-5 expression was worse than that of patients with low LDH-5 expression (P=0.032). CONCLUSION: Our study shows a high expression of LDH-5 in colorectal cancer. The up-regulation of LDH-5 parallels an increase in HIF-1alpha expression. The immunohistochemical assessment of tissue LDH-5 and HIF-1alpha provides important prognostic information for colorectal carcinomas.

The Changes of Expression of Survivin by Butyrate in HCT116 Colon Cancer Cells

PURPOSE: The causes of colon cancer can be divided into genetic and environmental components. A high-fiber diet is known to reduce the risk of colon cancer. Dietary fiber is converted to short chain fatty acid, butyrate, in the colon by bacteria. Butyrate is used as an energy source for the colonic epithelial cells, and is known to induce apoptosis in colon cancer cell lines. Survivin, a recently discovered member of the IAP (inhibitor of apoptosis) family, is known to suppress apoptosis. Not only does it suppress cell apoptosis, but it also has a protective effect from disabling G2/M phase of the cell cycle by attaching to the microtubule of the mitotic spindle. The purpose of this study is to evaluate the effect of butyrate on the expression of survivin, in HCT116 colon cancer cell lines. METHODS: Cytotoxicity of butyrate was measured by MTS method. Cell cycle phase and apoptosis was analyzed by flowcytometry. Protein expression of survivin was evaluated by Western blot analysis, and the mRNA expression by RT-PCR. RESULTS: Butyrate can induce apoptosis in HCT116 colon cancer cell line at a concentration of 6 mM. Butyrate suppressed the expression of survivin mRNA and also the expression of cytosolic and nuclear survivin. In flowcytometric analysis, the apoptotic portion was increased and the proportions of S and M phase were decreased when cultured with butyrate. CONCLUSION: We concluded that butyrate could induce cellular apoptosis partially by suppressing the expression of survivin in HCT116 colon cancer cells.

Expression of Hypoxia-inducible Factor-1alpha and Vascular Endothelial Growth Factor in Colon Cancer: Relationship to the Prognosis and Tumor Markers

PURPOSE: Angiogenesis is one of the key steps in solid tumor growth and metastasis. We investigated the prognostic significance of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) expressions as markers of angiogenesis in colon cancer. METHODS: We retrospectively reviewed the medical records of 78 patients with colon or rectal cancer who underwent a surgical resection at Soonchunhyang University Hospital from January 2000 to December 2001, and we evaluated the expression of VEGF and HIF-1alpha in archival tumor tissues by using immunohistochemistry. We recorded the clinical and the pathological characteristics of the patients and analyzed their survival outcomes. RESULTS: Thirty-four (34) patients were male, and the mean age of all the patients was 66.7 years. HIF-1alpha and VEGF were positive in 56% (44 patients) and 53% (42 patients) of the tumors, respectively. HIF-1alpha expression was significantly associated with several pathological parameters, such as TNM stage (P=0.001), lymph node metastasis (P=0.001). HIF-1alpha expression was also associated with VEGF expression (P=0.032). The survival of patients with HIF-1alpha expression was worse than that of patients with no HIF-1alpha expression (P=0.036). However, VEGF expression was not associated with other pathological characteristics. CONCLUSIONS: We suggest that, in cases of colorectal cancer, HIF-1alpha expression may be associated with expression of VEGF, progression of tumors, and poor prognosis.

Obstructive Colitis Associated with Upper Rectal Cancer

Obstructive colitis refers to ulceroinflammatory lesions that occur in the colon proximal to an obstructing lesion. The pathogenesis is unclear, but raised intraluminal pressure, distension, and bacterial stasis are thought to play a role in the development of ischemia. The normal appearance at surgery may lead to involved segments of colon being used for anastomoses with consequent complications, so an awareness of the clinical, radiological, and endoscopic features of obstructive colitis is mandatory to prevent anastomotic complications. We experienced a case of obstructive colitis associated with a partially obstructing upper rectal cancer in a 67-year-old male. Obstructive colitis was diagnosed by using colonoscopy preoperatively, and an extended resection involving both the tumor and the colitis segment was performed without complications.