Dong-Guk Park

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 µM and 250 µM 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 µM. 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.

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 µM 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.

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.

Upregulation of stromal cell-derived factor 1α expression is associated with the resistance to neoadjuvant chemoradiotherapy of locally advanced rectal cancer: Angiogenic markers of neoadjuvant chemoradiation

The ability to achieve pathologic downstaging after neoadjuvant chemoradiotherapy (NCRT) is correlated with improved survival in locally advanced rectal cancer (LARC). However, there is no effective predictive markers. In this study, the expression of angiogenic markers was evaluated in pre-treatment biopsies and corresponding post-treatment resection specimens, and were correlated to histopathological tumour characteristics and response. Fifty-five patients with stage II/III rectal cancer treated with 5-fluorouracil (5-FU)-based NCRT were studied. All patients were administered NCRT followed by surgical resection. Immunohistochemical staining for angiogenic markers [hypoxia-inducible factor 1α (HIF‑1α), vascular endothelial growth factor (VEGF), stromal cell‑derived factor 1α (SDF-1α) and placental growth factor (PlGF)] was performed on specimens obtained before NCRT and after surgery. Expression of VEGF, PlGF and HIF-1α protein was downregulated after NCRT in the rectal cancer tissues (P<0.001, P=0.001 and P=0.044, respectively). However, SDF-1α was upregulated after NCRT (P<0.001). Moreover, upregulated expression of SDF-1α (P=0.016) and positive PlGF staining (P=0.001) after NCRT were significantly associated with resistance to NCRT. On multivariate analysis, positive PlGF staining after NCRT was found to be independently associated with resistance to NCRT (P=0.013). Our data suggest that SDF-1α and PlGF should be evaluated as new targets for NCRT in LARC.

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

Multimodality therapy, such as a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), is associated with improved survival for selected patients with peritoneal metastasis of various cancer types. Despite this, this procedure is not widely accepted due to its high rates of morbidity and mortality. In several studies on the combined use of CRS and HIPEC to treat patients with a variety of cancer types, the rates of grade III/IV morbidity and mortality ranged from 22% to 34% and from 0.8% to 4.1%, respectively. Common major postoperative complications included neutropenia, anastomotic leakage, pneumonia, postoperative bleeding, intra-abdominal abscess, systemic sepsis, wound infection, pleural effusion, and renal insufficiency [1]. Kim et al. [2] reported 30-day rates of postoperative morbidity and mortality of 30.4% and 0%, respectively, which are comparable to the results reported in Newton et al. [1] and Jo et al. [3]. The occurrence of major complications was found to be associated with the number of organ resections (more than 3), the duration of surgery (≥630 minutes) and the amount of blood loss (≥600 mL) during surgery. However, contrary to other reports, all four patients with recurred colorectal cancer treated with cetuximab had grade III postoperative complications [2]. Recently, we reported the results of a 2-year follow-up at our center. The rate of morbidity above grade III was 22.2%. Pulmonary complications, such as pleural effusion and pneumonia, were the most common (29.6%) complications, followed by acute renal failure (14.8%), wound problems (13.0%), and prolonged ileus (11.1%). Anastomotic leakage developed in 1 patient. The rate of mortality was 7.4%. The causes of death included pulmonary complication, septic shock related to anastomotic leakage, and hypovolemic shock from gastrointestinal bleeding [3]. According to data from the National Surgical Quality Improvement Program (NSQIP), age ≥ 60 years, preoperative albumin < 3 g/dL, and poor preoperative performance status are major factors contributing to morbidity [4]. Major operative factors are the peritoneal cancer index, bowel resection, diaphragmatic involvement [5], the use of a distal pancreatectomy, and surgeon’s experience. Furthermore, hepatobiliary procedures, urologic procedures, and preoperative use of bevacizumab have weak associations with the occurrence of morbidity. In a NSQIP analysis, increased operative time, intraoperative transfusion, and the use of a gastrectomy with intraperitoneal chemotherapy were associated with increased morbidity and mortality [4]. Studies suggest that perioperative systemic chemotherapy does not appear to increase the rate of major morbidities from the use of a combined CRS and HIPEC procedure, with the possible exception of preoperative bevacizumab, which has been associated with increased operative complications. Intraperitoneal chemotherapy increases neither morbidity nor mortality greatly over surgery alone [4]. One of the major limitations of this study [2] is that the number of patients treated with the combined CRS and HIPEC procedure was small (n = 23). Some studies suggest that approximately 140– 180 procedures are needed to minimize severe morbidity [6], but in this paper, even though the number of patients was small, the rate of morbidity was comparable to the value in a report published by a large-volume center. This suggests that the combined use of CRS and HIPEC will become a somewhat popular procedure, in spite of its being a complex procedure. The combined use of CRS and HIPEC to treat patients with disseminated intra-abdominal malignancies is a complex procedure with the potential for high morbidity and mortality. However, when the combined CRS and HIPEC procedure is performed by experienced surCorrespondence to: Dong-Guk Park, M.D. Department of Surgery, Dankook University College of Medicine, 119 Dandae-ro, Dongnam-gu, Cheonan 31116, Korea Tel: +82-41-550-3931, Fax: +82-41-565-6167 E-mail: dkpark@dankook.ac.kr

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

See Article on Page 127-132 Expression of epidermal growth factor receptor (EGFR) was found in 60-75% of colorectal carcinomas. Based on this, many studies have demonstrated the efficiency of monoclonal Abs (mAbs) in targeting the EGFR, such as cetuximab and panitumumab, in metastatic colorectal cancer (mCRC) patients. Addition of cetuximab to irinotecan-based chemotherapy significantly improved the response rate and the progression-free survival (PFS) when compared with Cetuximab mAb alone (22.9% vs. 10.8% and 4.1 vs. 1.5 months, respectively) [1]. Van Cutsem et al. [2, 3] reported that in chemonaive mCRC patients, the addition of anti-EGFR to irinotecan-based chemotherapy led to an 8.2% increase in the objective response (46.8% vs. 38.4%), a 0.9-month increase in the progression free survival (PFS) (8.9 vs. 8 months) and a 1.3-month increase in the overall survival (19.9 vs. 18.6 months). Initially, the use of anti-EGFR mAbs was restricted to mCRC patients with expression of EGFR that was detectable using immunohistochemistry. However, due to the lack of immunohistochemistry predictive value and the variable clinical response, more reliable predictive markers of the response to anti-EGFR mAbs are needed [4]. Two types of molecular predictive markers have been investigated. The first is somatic mutations in EGFR pathway effectors, such as RAS-RAF-MAPK and PI3K-Akt-PTEN. Amplification of EGFR and overexpression of EGFR ligands are associated with sensitivity to anti-EGFR mAbs, but the mutations of BRAF and PIK3A and the loss of PTEN expression are associated with resistance to anti-EGFR mAbs [2, 5]. The second is germline polymorphisms of genes involved in the EGFR pathway [6]. Nonetheless, at the present time, mutation of KRAS is the only negative molecular marker to anti-EGFR mAbs treatment [2, 5]. Recently, a somatic mutation of the EGFR kinase domain was initially reported in lung cancer and later in colorectal carcinomas. In lung cancer, mutations in the EGFR gene are associated with a high response rate to EGFR tyrosine kinase inhibitors and are prognostic for a favorable outcome. In this paper, the authors reported the incidence of the EGFR mutation in colorectal carcinomas as 22.41%. The incidence was higher than reports in Western countries, and the EGFR mutation was increased in earlier stages and in the absence of lymph node metastasis. Also exon 20 was the only mutation site, which is different from reports in Japan (mutations in exon 19 and 20). The EGFR mutation state may be an important determinant in the resistance to anti-EGFR mAbs treatment. To address this, larger studies are needed, and hopefully it will be another predictive marker for anti-EGFR mAbs therapy in mCRC [7].