Prognostic Impact of Resection Margin Length in Patients Undergoing Resection for Mid-Common Bile Duct Cancer: A Single-Center Experience.

INTRODUCTION: The purpose of this study was to analyze survival outcomes after segmental bile duct resection (BDR) for mid-common bile duct cancer according to the length of the tumor-free BDR margins. METHOD: A total of 133 consecutive patients underwent BDR for mid-bile duct cancers between December 2007 and June 2017. The Cox proportional hazard model was used to verify the cutoff value of the R0 resection margin. The patients were divided into 3 groups according to resection margin status (group 1; R0 resection margin ≥5 mm; group 2, R0 resection margin <5 mm; and group 3, R1 resection margin). RESULTS: The median follow-up period of the study cohort was 24 months. A resection margin of 5 mm in length was verified to be suitable as a reliable cutoff value. The median disease-free and overall survival (OS) periods were 32 and 49 months in group 1, 13 and 20 months in group 2, and 23 and 30 months in group 3, respectively (p = 0.03 and p < 0.001). The length of the tumor-free resection margin (hazard ratio, 2.01; 95% confidence interval, 1.10-3.67; p = 0.022) was independent factor affecting OS. CONCLUSIONS: BDR for mid-bile duct cancer appears to be a feasible surgical option in selected patients with careful preoperative imaging assessment and intraoperative frozen-section diagnosis. Our results suggest achieving a BDR margin ≥5 mm to improve survival outcomes.

Inhibition of 15-PGDH prevents ischemic renal injury by the PGE2/EP4 signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A2A receptors.

In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE2 is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE2 signaling, as they could be blocked by pharmacological inhibition of PGE2 synthesis. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A2A receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

Prognostic significance of Human epidermal growth factor receptor-2 expression in patients with resectable gastric adenocarcinoma.

BACKGROUND: The purpose of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2) overexpression and clinicopathologic factors and overall survival rate in patients who underwent curative gastrectomy for gastric adenocarcinoma. METHODS: Among patients who underwent curative gastrectomy for gastric adenocarcinoma at Inje University Paik Hospital from January 2012 to December 2015, 782 patients underwent an immunohistochemical analysis to evaluate HER2 expression levels. Clinicopathologic records that were collected from a gastric cancer database were retrospectively reviewed to identify clinicopathologic factors and survival rates of the patients. RESULTS: HER2 overexpression was detected in 166 patients (21.2%). There was a statistically significant correlation between HER2 expression level and sex (p = 0.013), histologic differentiation (p < 0.001), Lauren classification (p < 0.001), and T pathologic stage (p = 0.022). There were no statistically significant relationships between HER2 expression level and overall 5-year survival rate (p = 0.775) and overall 5-year survival rate of gastric adenocarcinoma classified according to the TNM stage (stage I: p = 0.756, stage II: p = 0.571, stage III: p = 0.704). The HER2 expression level was not affected by the overall 5-year survival rate in the uni- and multivariate analyses. CONCLUSIONS: In this study, the HER2 overexpression rate in gastric adenocarcinoma was 21.2% and was observed in well- and moderately differentiated types according to histologic differentiation, intestinal type according to the Lauren classification, male, and low T stage. There was no correlation between HER2 expression level and overall 5-year survival rate, and HER2 expression level was not associated with independent prognostic factors.

Doxifluridine versus Tegafur/Gimeracil/Oteracil (S-1) as adjuvant chemotherapy for patients with gastric cancer after gastrectomy: A propensity score-matched analysis.

INTRODUCTION: Doxifluridine (DF), an oral 5-FU prodrug, has been used for various solid cancers due to its efficacy and low toxicity. We aim to evaluate the effect of DF as adjuvant monotherapy in advanced gastric cancer. METHODS: We retrospectively reviewed the clinical data of 263 patients with advanced gastric cancer who underwent curative gastrectomy between January 2010 and December 2013 at our institute. Since previous randomized control trials have confirmed the efficacy of S-1 as adjuvant chemotherapy in advanced gastric cancer, we analyzed the oncologic effect and patient compliance of the DF group compared to the S-1 group. After propensity score matching, 48 patients were included in each group. RESULTS: There was no significant difference in 5-year overall survival (OS) and 5-year disease-free survival (DFS) between DF and S-1 groups (5-year OS; 77.1% vs 75.0%; p = 0.729, 5-year DFS; 76.6% vs 73.9%; p = 0.748). The completion rates of the DF and S-1 groups were 60.4% and 72.9%, respectively (p = 0.194). The mean relative dose intensity of the DF and S-1 groups were 76.2% and 84.2%, respectively (p = 0.195). After multivariate analysis, the chemotherapy regimen was not a risk factor for OS and DFS, whereas relative dose intensity and pathologic stage were independent prognostic factors. CONCLUSION: There was no significant difference in the oncologic effect and patient compliance between DF and S-1 groups. DF could be an alternative option for adjuvant chemotherapy in advanced gastric cancer. In addition, we confirmed that relative dose intensity is an important independent prognostic factor for survival.

Prognostic Value of Serum Neutrophil to Lymphocyte Ratio and SUVmax in Stage I and II Colon Cancer.

OBJECTIVE: This study aimed to evaluate the correlation between maximal standardized uptake value (SUVmax) of primary colon cancer and serum neutrophil-to-lymphocyte ratio (NLR), and to assess the prognostic value of SUVmax and serum NLR in stage I and II colon cancer patients. METHODS: In this retrospective study a total of 128 patients with pathologically confirmed stage I and II colon cancer diagnosed between January 2014 and December 2017 were included. All patients underwent F-18 Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and differential white blood cell (WBC) counts before surgery. The correlations between SUVmax and NLR were assessed. The prognostic value of SUVmax and NLR for predicting recurrence-free survival (RFS) was investigated. RESULTS: The mean NLR was 2.2 ± 1.2, and the mean SUVmax of primary tumor was 15.2 ± 7.9. There was significant correlation between NLR and SUVmax (rho=0.2, p=0.02). Mean follow-up period was 59.8 ± 19.2 months and 12 patients experienced a recurrence. In univariable analysis, NLR (p=0.0084, HR=5.0223, 95% CI=1.5117-16.6853), C-reactive protein (CRP) (p=0.021, HR=4.1115, 95% CI=1.2380-13.6551), carbohydrate antigen 19-9 (CA19-9) (p=0.0134, HR=4.2683, 95% CI=1.3519-13.4766), and Kirsten ras sarcoma viral oncogene (KRAS) mutation (p=0.0338, HR=3.4703, 95% CI=1.0998-10.9499) were significant prognostic factors for the recurrence. In multivariable analysis, NLR (p=0.0256, HR=4.1155, 95% CI=1.1887-14.2490) and CA19-9 (p=0.0257, HR=4.139, 95% CI=1.1880-14.4200) were independent prognostic factors for the recurrence. CONCLUSIONS: Significant correlation was observed between SUVmax of primary colon cancer and serum NLR. Furthermore, in the multivariable analysis conducted on early colon cancer cases, NLR and CA19-9 were found to be independently associated with RFS. This suggested that NLR could be used as a supplementary tool for identifying patients at high risk of recurrence in early colon cancer. However, SUVmax was not associated with prognosis, suggesting that it cannot be used for predicting prognosis in early colon cancer.

Is 10 cm ileal resection sufficient in locally advanced caecal cancer surgery?

BACKGROUND: There is no consensus as to how much ileal resection is sufficient when performing a right hemicolectomy for right colon cancers. Locally advanced caecal cancer has the highest incidence of peri-ileal lymph node metastasis. Therefore, this study investigated whether the 10 cm ileum resection suggested by the Japanese Society for Cancer of the Colon and Rectum is oncologically safe in stage II and III caecal cancer. METHODS: The prospectively collected medical records of stage II and III caecal cancer patients who underwent a right hemicolectomy with at least D2 lymph node dissection were reviewed retrospectively. The patients were divided into two groups according to the length of proximal ileal resected: group 1 (≤10 cm) and group 2 (>10 cm). Factors contributing to the 5-year overall survival (OS) were analysed. RESULTS: The study enrolled 89 patients with pathological stage II or III caecal cancer. The >10 cm group tended to be younger (P = 0.0938) with higher pathological N stages (P = 0.0899) than the ≤10 cm group. The 5-year OS did not differ between the two groups. No significant difference was found between the two groups according to stage. Age (HR = 1.06, 95% CI = 1.02-1.10, P = 0.0069) and N2 stage (HR = 5.38, 95% CI = 1.90-15.28, P = 0.0016) were significantly associated with OS in both uni- and multivariate analyses. CONCLUSIONS: There was no OS benefit to resecting >10 cm of ileum in either stage II or III caecal cancer patients. Hence, we suggest that the '10 cm rule' is sufficient for stage II and III caecal cancer patients.

15-Prostaglandin Dehydrogenase Inhibition Enhances Colon Cancer Metastasis by Up-regulation of Epithelial-to-Mesenchymal Transition Genes.

BACKGROUND/AIM: Most deaths from colon cancer are due to metastasis. Recently, PGE2 was found to influence colon cancer invasion and metastasis. 15-PGDH, an enzyme that metabolizes PGE2, is known as a tumor suppressor in colonic carcinogenesis. This study investigated the effect of 15-PGDH on colon cancer metastasis. MATERIALS AND METHODS: 15-PGDH expression by immunohistochemical staining, clinicopathologic features, and 5-year cancer-specific survival were investigated in colon cancer patients. Liver metastasis was examined by assaying 15-PGDH activity in an animal model. Changes in PGE2, proliferation, migration, and invasion of the colorectal cancer cell line HCT116, were examined using a 15-PGDH inhibitor (SW033291) or enhancer (CDDO-ME). The expression of genes involved in the epithelial-to-mesenchymal transition (EMT) was also studied. RESULTS: The absence of 15-PGDH expression significantly correlated with advanced-stage, lymph node metastasis, and decreased cancer-specific survival in colon cancer patients. Inhibition of 15-PGDH increased colon cancer liver metastasis in the animal model. The 15-PGDH inhibitor, SW033291, increased PGE2 and decreased 15-PGDH expression on HCT116. However, treatment with CDDO-ME, a substance that enhances 15-PGDH, showed the opposite results. Inhibition of 15-PGDH increased cell proliferation, migration, and invasion, but activation of 15-PGDH showed the opposite effect. Inhibition of 15-PGDH also affected the EMT markers, N-cadherin, Snail, and Twist2. CONCLUSION: 15-PGDH inhibition increased colon cancer metastasis by inducing changes in EMT-related genes via an increase in PGE2 expression and could be a promising biomarker for anticancer treatment.

Comparison between oxaliplatin therapy and capecitabine monotherapy for high-risk stage II - III elderly patients with colon cancer.

PURPOSE: 45% of colon cancer patients are elderly, yet they are often deviated from standard cancer management. The MOSAIC trial favored FOLFOX over FL with superior oncologic outcomes; however, which regimen is most beneficial in elderly population remains unclear. This study aimed to compare the efficacy of oxaliplatin-added chemotherapy and capecitabine monotherapy in high-risk stage II/stage III elderly colon cancer patients. METHODS: Colon cancer patients ≥70 years of age who received adjuvant chemotherapy at Inje University Busan Paik Hospital between February 2009 to April 2016 were included. Patients were separated into the oxaliplatin-added group and capecitabine monotherapy group. The primary outcomes were CSS and OS. RESULTS: Of 74 patients, 45 received oxaliplatin-added chemotherapy and 29 received capecitabine monotherapy. There was no difference between the two groups in CSS or OS (p = 0.9670 and p = 0.6801, respectively). The N stage was significantly associated with CSS in both uni/multivariate analysis (p = 0.0565 and p = 0.0347, respectively). The oxaliplatin-added group had more stage III patients, so we performed a subgroup analysis of CSS and OS based on stage, which also showed no significant difference. CONCLUSIONS: Capecitabine monotherapy is an oncologically safe regimen compared to oxaliplatin-added regimens in elderly patients with high-risk stage II/stage III colon cancer.

Low albumin level and longer interval to closure increase the early complications after ileostomy closure.

BACKGROUND: Loop ileostomy has an important role in mitigating the serious effects of anastomotic leakage in colorectal surgery. However, the morbidity and mortality associated with ileostomy reversal cannot be overlooked. We investigated the possible risk factors for complications following ileostomy reversal. METHODS: All patients who underwent loop ileostomy closure between 2008 and 2017 at Inje University Busan Paik Hospital were identified. Medical records on patient characteristics, preoperative management, surgical techniques, postoperative management, chemotherapy/radiotherapy, and complications were retrospectively analyzed in a prospectively collected database. RESULTS: A total of 354 patients underwent loop ileostomy closure. The overall complication rate was 23.7%, with Clavien-Dindo grade I as the most common (15.8%), 5.6% in grade II, 2.2% in grade III-V, and three patients died. The two most common complications were wound infection (11.6%) and small bowel obstruction (4.8%). In univariable and multivariable analyses, closure technique or chemotherapy did not affect the outcome, but low serum albumin <3.5 g/dL (OR 7.248, CI 2.416-22.838, p < 0.001) and longer interval to ileostomy closure (OR 1.977, CI 1.167-3.350, p = 0.0113) were independent contributing factors for morbidities of ileostomy closure. CONCLUSIONS: Closure technique or chemotherapy did not affect the complication of ileostomy closure. However, serum albumin <3.5 g/dL and a longer interval to ileostomy closure were identified as risk factors for morbidity of ileostomy closure. These two factors should be corrected and planned before ileostomy closure.

Comparing short-term outcomes after totally laparoscopic distal gastrectomy and laparoscopy-assisted distal gastrectomy with Billroth I anastomosis: early experience of a single institution.

Purpose: To determine the safety and feasibility of totally laparoscopic distal gastrectomy (TLDG) with modified delta-shaped anastomosis, we compared the short-term outcomes of TLDG to those of laparoscopy-assisted distal gastrectomy (LADG) with Billroth I anastomosis. Methods: We analyzed the characteristics of 85 patients with gastric cancer who underwent laparoscopic distal gastrectomy with Billroth I anastomosis between January 2013 and December 2018. After propensity score matching, each group had 35 patients. Results: Of these 85 patients, 44 underwent TLDG and 41 underwent LADG. Propensity score matching was performed with three covariates (age, underlying disease, and hypertension), and 35 patients from each group were matched 11. After matching, the TLDG group was older than the LADG group (64.5 ± 10.6 years vs. 56.3 ± 11.2 years, p = 0.003) and had more patients with hypertension (57.1% vs. 22.9%, p = 0.003). Tumors were larger in the TLDG group than in the LADG group (23.4 ± 16.2 mm vs. 16.0 ± 7.9 mm, p = 0.018). A greater proportion of patients had fever in the TLDG group than the LADG group (42.9% vs. 20.0%, p = 0.039), and C-reactive protein from postoperative days 3 to 6 was greater in the TLDG group (11.4 ± 5.7 mg/dL vs. 7.0 ± 5.0 mg/dL, p = 0.001). Conclusion: Although our data represent only our early experience performing TLDG with modified delta-shaped anastomosis, this procedure is relatively safe and feasible. Nevertheless, compared to LADG, which is the conventional method, the operative time for TLDG was longer. Surgeons must also watch out for anastomotic complications.

Complete response of MSI-high metastatic colon cancer following treatment with regorafenib: A case report.

Regorafenib has been demonstrated to prolong survival in patients with metastatic colorectal cancer refractory to standard chemotherapy. However, overall survival is limited to 2.5 months. The present report describes a unique case of metastatic colon cancer, which showed a complete response to regorafenib. A 54-year-old woman was diagnosed with right colon cancer obstruction with peritoneal seeding. The patient underwent laparoscopic right hemicolectomy, and the pathology was T4aN2bM1, moderately differentiated adenocarcinoma with high microsatellite instability (MSI-H) and wild-type KRAS/NRAS. The first-line chemotherapy was fluorouracil, leucovorin and irinotecan with cetuximab. After 12 cycles, recurrence at the anastomotic site was identified. The patient underwent palliative colectomy, and superior mesenteric artery (SMA) lymph node metastases were evident. The patient received second-line chemotherapy of fluorouracil, leucovorin and oxaliplatin with bevacizumab. Progression of metastasis to the right common iliac lymph nodes was detected after only four cycles of therapy. Thereafter, the patient received regorafenib as third-line therapy, starting with 160 mg for two cycles and reducing the dose thereafter, for a total of 17 cycles. The previously confirmed SMA lymph node metastasis had disappeared after the seventh cycle, and the right common iliac lymph node metastasis was not visible on CT after the 16th cycle. The patient decided to terminate regorafenib and has not experienced recurrence 2 years since treatment cessation. This is the first report of refractory metastatic colon cancer with MSI-H showing a complete response to regorafenib. Further studies are required to investigate the efficacy of regorafenib in refractory metastatic colon cancer with MSI-H and to elucidate the mechanism of remission.

Prognostic value of positron emission tomography/computed tomography for adjuvant chemotherapy of colon cancer.

BACKGROUND: To assess the prognostic value of preoperative 18 F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with high-risk stage II or stage III colon cancer who underwent FOLFOX chemotherapy. METHODS: The study included 166 patients with high-risk stage II or stage III colon cancer who received FOLFOX4 chemotherapy. Retrospective patient data were analysed including pathological stage, histology, disease-free survival (DFS) and the maximum standardized uptake value (SUVmax ) of the primary tumour on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. The primary end point was DFS. RESULTS: There were recurrences in 29 of the 166 patients (17.4%). Measuring the area under the receiver operating characteristic curve, the cut-off value of SUVmax with maximum sensitivity and specificity was 10.95. Using the Kaplan-Meier method, the DFS of the patients categorized by SUVmax tended to differ (P = 0.055). In univariate analyses, the risk factors for DFS were age over 70 years, higher N stage and neural invasion. SUVmax ≤ 10.95 showed a tendency, but was not significant (P = 0.0604). In multivariate analyses, the risk factors for DFS were age over 70 and neural invasion. CONCLUSIONS: The results of this study suggest that high fluorodeoxyglucose uptake of the primary mass in high-risk stage II and stage III colon cancer does not significantly correlate with DFS.

Oncological outcomes of complete versus conventional mesocolic excision in laparoscopic right hemicolectomy.

BACKGROUND: Complete mesocolic excision (CME) has been proposed for colon cancer to improve oncological outcomes. The risks and benefits of laparoscopic CME have not been examined fully. We compared short- and long-term outcomes of CME with a conventional mesocolic excision (non-CME) in laparoscopic right hemicolectomy (RHC) for right-sided colon cancer. METHODS: In total, 115 patients who underwent laparoscopic RHC with stage I-III right-sided colon cancer at Busan Paik Hospital from August 2007 to October 2011 were enrolled in this case-control study. Three trained colorectal surgeons reviewed videos of the surgeries; patients were divided into two groups: those who underwent a CME (CME group, n = 34) and those who underwent a conventional mesocolic excision (non-CME group, n = 81). RESULTS: There was no significant difference between the CME and non-CME groups in operative time, post-operative complications, or hospital stay. However, the CME group had more lymph nodes harvested (P < 0.001) and lower blood loss (P = 0.016) versus the non-CME group. There was no difference in 5-year disease-free survival rate between the groups, but 5-year overall survival rate was 100% in the CME group and 89.49% in the non-CME group (P < 0.05). CONCLUSIONS: Laparoscopic RHC with CME is safe and associated with better 5-year overall survival rate than non-CME for patients with stage I-III right-sided colon cancer. Implementation of CME surgery might improve oncological outcomes for patients with right-sided colon cancer.

Cholangiocarcinoma in choledochal cyst after cystoenterostomy: how a mistreated choledochal cyst can progress to malignancy.

This case report presents an unusual case of cholangiocarcinoma arising nearly 35 years after cystoduodenostomy for choledochal cyst. The patient visited our hospital with dyspepsia and studies revealed bezoar within the choledochal cyst caused by bile and food reflux. The patient underwent pancreaticoduodenectomy and a biopsy revealed adenocarcinoma, stage IIB. After 19 months, the patient has no recurrence to date and has recovered well. This case shows that proper surgical management and meticulous, long-term follow-up is imperative for patients with congenital choledochal cyst.