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Methylation of cysteine dioxygenase type 1 (CDO1) gene, a tumor suppressor gene, has been studied in various cancers; however, there is no information regarding Barrett esophagus cancer. In this study, the clinical significance of CDO1 methylation in Barrett esophagus adenocarcinoma (BEA) was clarified. CDO1 gene promoter methylation was analyzed for DNA from the patient's specimens using quantitative methylation-specific polymerase chain reaction. Thirty-eight BEA patients who underwent resection were identified between 2000 and 2014. Hypermethylation of CDO1 gene was demonstrated to be frequently recognized even at early stage in BEA by quantitative methylation-specific polymerase chain reaction. In BEA, there is a robust prognostic difference between stage I and stage II/III/IV with regard to 5-year relapse-free survival (P = 0.0016) and 5-year overall survival (P = 0.0024), and the tumor size separated by 7 cm was also a prognostic factor. There was significant difference in CDO1 gene methylation according to the tumor size (P = 0.036). BEA patients with CDO1 gene methylation were shown marginally significantly poorer prognosis (P = 0.054) than otherwise patients. In conclusion, higher CDO1 gene methylation was seen in BEA at earlier stage than in squamous cell carcinoma, and it may account for aggressive phenotype of BEA. [ABSTRACT FROM AUTHOR]

Respiratory symptoms are rarely reported as side effects of oxaliplatin, 5-fluorouracil, and Leucovorin(FOLFOX)therapy. We report a case of a patient with FOLFOX-induced unilateral interstitial pneumonia. The patient was a 68-year-old man who underwent ileocecal resection of cecum cancer. FOLFOX regimen was started as an adjuvant chemotherapy. After the administration of 11 courses, he visited our hospital with fever, dyspnea, and anorexia. We diagnosed this as FOLFOX- induced unilateral interstitial pneumonia through a blood test, chest radiograph, computed tomography, and bronchoscopy. Treatment was started with 30 mg of prednisolone, and the dosage was gradually decreased. The patient responded well to the treatment and was discharged from the hospital without any complications on the 33th day after admission.

Background: Pancreas-related complications after laparoscopic gastrectomy (LG) for gastric cancer can be fatal. We developed a gastrectomy procedure with no pancreas contact to prevent such complications and herein report the surgical outcomes., Methods: We retrospectively reviewed 182 consecutive patients with gastric cancer who underwent LG at Kitasato University Hospital from January 2017 to January 2020. These patients were divided into a pancreas-contact group (C group) and pancreas-contactless group (CL group) for comparison of postoperative complications, and inflammatory parameters such as body temperature (BT) and C-reactive protein (CRP)., Results: Postoperative complications of CDc grade ≧ IIIa were significantly fewer in the CL group than in the C group [0/76 (0%) vs. 6/106 (5.7%), P = 0.035]. The median drain amylase (drain-AMY) on postoperative day 1 (POD1) was significantly lower in the CL group than in the C group (641 vs. 1162 IU/L, P = 0.02), as was BT at POD1 (37.4 °C vs. 37.7 °C, P = 0.04), the patient group with a BT above 37.5 °C at POD3 [5/76 (6.5%) vs. 18/106 (17%), P = 0.037], and those showing a CRP above 20.0 mg/dL at POD3 [5/76 (6.5%) vs. 20/106 (19%), P = 0.018]., Conclusions: Our technique to prevent pancreas contact during supra-pancreatic lymph node dissection during LG could minimize the inflammatory response and prevent further postoperative complications. Further large-scale, prospective studies are now required., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A 31-year-old man presented to our hospital's Emergency Department with sudden epigastric pain and vomiting. He had undergone endoscopic resection via the retroperitoneal route for a retroperitoneal tumor located in the left diaphragmatic crus of the esophageal hiatus at another hospital 8 months previously. Radiography and computed tomography showed inversion of the stomach beyond the diaphragm into the thoracic cavity, with the gastroesophageal junction serving as the fulcrum point. This finding led to a diagnosis of postoperative diaphragmatic hernia accompanied by an upside-down stomach (UDS). The prolapsed stomach in the thoracic cavity was reduced to the abdominal cavity using laparoscopic surgery. The postoperative course was favorable, and the patient was discharged from the hospital on postoperative day 7. No recurrence has been observed in the past 5 years. The pathological condition of a UDS observed in esophageal hiatal hernias may be found in postoperative diaphragmatic hernias. Laparoscopic surgery for a postoperative diaphragmatic hernia with a UDS is considered a useful surgical procedure. Laparoscopic surgery can simultaneously confirm the viability of the herniated organs, reduce the organs to the abdominal cavity, and close and reinforce the diaphragm.

Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Postoperative infectious complications have a negative impact on survival outcomes in patients with gastric cancer. It is recently reported that preoperative chemotherapy may eliminate this negative impact. This study aimed to confirm whether preoperative chemotherapy can eliminate the negative impact of postoperative infectious complications (IC) on survival outcomes and elucidate the association between postoperative infectious complications and recurrence patterns., Methods: We retrospectively reviewed data of 86 patients who received preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by R0 gastrectomy at the Kitasato University between 2006 and 2016. Patients who developed grade II or higher infectious complications during hospitalization were grouped into the IC group, while others were grouped into the non-IC (NIC) group. Survival outcomes and recurrence patterns were analyzed between the two groups., Results: Infectious complications with Clavien-Dindo classification of grade II or higher were found in 12 patients (14.0%, IC group). The median observational period was 61 months. Overall survival and progression-free survival were similar in the IC and NIC groups. Recurrence occurred in 39 patients. The proportions of peritoneal and lymph node recurrences were not significantly different between the two groups. However, the proportion of distant metastasis in the IC group was significantly higher than that in NIC group (3/4 [75%] vs. 9/35 [17%], p = 0.04)., Conclusions: Pathological stage after neoadjuvant therapy plays a stronger role in recurrence than postoperative complications. Lymph node and peritoneal metastasis may be suppressed by preoperative chemotherapy.

The clinical efficacy of DNA cytology test (CY) in gastric cancer (GC) has been retrospectively proposed using cancer-specific methylation of cysteine dioxygenase type 1 (CDO1). We confirmed the clinical utility of DNA CY in a prospective cohort. Four hundred GC samples were prospectively collected for washing cytology (UMIN000026191), and detection of the DNA methylation of CDO1 was assessed by quantitative methylation-specific PCR in the sediments. Endpoint was defined as the match rate between conventional CY1 and DNA CY1 (diagnostic sensitivity), and the DNA CY0 rate (diagnostic specificity) in pStage IA. DNA CY1 was detected in 45 cases (12.5%), while CY1 was seen in 31 cases (8.6%) of 361 chemotherapy-naïve samples, where the sensitivity and specificity of the DNA CY in the peritoneal solutions were 74.2% and 96.5%, respectively. The DNA CY was positive for 3.5/0/4.9/11.4/58.8% in pStage IA/IB/II/III/IV, respectively (P < .01). In the multivariate analysis, DNA CY1 was independently correlated with pathological tumor depth (pT) (P = .0012), female gender (P = .0099), CY1 (P = .0135), P1 (P = .019), and carcinoembryonic antigen (CEA) (P = .036). The combination of DNA CY1 and P factor nearly all covered the potential peritoneal dissemination (P1 and/or CY1 and/or DNA CY1) (58/61:95.1%). DNA CY1 had a significantly poorer prognosis than DNA CY0 in GC patients (P < .0001). DNA CY1 detected by CDO1 promoter DNA methylation has a great value to detect minimal residual disease of the peritoneum in GC clinics, representing poor prognosis as a novel single DNA marker., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: CDO1 is a presumed tumor suppressor gene in human cancers, the expression of which is silenced by promoter DNA methylation. Moreover, CDO1 harbors functionally oncogenic aspects through modification of mitochondrial membrane potential. We recently proposed that this oncogenic feature allows for the prediction of the efficacy of postoperative chemotherapy in colon cancer. The present study aims to elucidate the efficacy of prediction of success of postoperative chemotherapy in advanced gastric cancer to improve the treatment strategy of patients., Materials and Methods: Forced expression of CDO1 in gastric cancer cell lines was assessed using the JC-1 assay. Promoter DNA methylation was investigated in quantitative TaqMan methylation-specific polymerase chain reaction in 321 pathological stage II/III advanced gastric cancer cases treated by curative gastrectomy with or without postoperative chemotherapy., Results: (1) Forced expression of CDO1 led to increased mitochondrial membrane potential, accompanied by augmented survival in gastric cancer cells under anaerobic conditions. These results suggest that CDO1-expressing cancer cells survive more easily in anaerobic lesions which are inaccessible to anticancer drugs. (2) Intriguingly, in cases with the highest CDO1 methylation (ranging from 15% to 40%), patients with postoperative chemotherapy showed significantly better survival than those with no postoperative chemotherapy. (3) A robust prognostic difference was observed that was explained by differential recurrences of distant metastasis (P = 0.0031), followed by lymph node (P = 0.0142) and peritoneal dissemination (P = 0.0472)., Conclusions: The oncogenic aspects of CDO1 can be of use to determine patients with gastric cancer who will likely respond to treatment of invisible systemic dissemination by postoperative adjuvant chemotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We report a case of laparoscopic partial hepatectomy after nab-paclitaxel plus ramucirumab(nab-PTX plus RAM)combination therapy for postoperative liver recurrence of gastric cancer. The patient was a 50's man who underwent laparoscopic distal gastrectomy, D2 lymph node dissection, and Billroth-I reconstruction for gastric cancer. The pathological findings were L, Gre, Post, Type 3, por>tub2, pT3N3a, M1(CY1), fStage Ⅳ. Postoperative chemotherapy with S-1 was performed. The CT examination 6 months after the operation revealed a total of 3 tumors(maximum diameter of 5×4 cm)in liver segments S6, 7, and 8. We started nab-PTX plus RAM combination therapy for liver metastases and performed laparoscopic partial hepatectomy when 12 courses of the treatment were completed. The postoperative course was uneventful, and the patient was discharged on postoperative day 7. Pathological results suggested that the tumor was exposed on the cut surface, and 6 courses of nab-PTX plus RAM combination therapy were administered postoperatively. The patient has been recurrence-free 12 months after the operation.

Purpose: With the widespread use of definitive chemoradiotherapy (dCRT) for esophageal squamous cell carcinoma (ESCC), salvage surgery for recurrence/residual patients became prevalent. However, survival impact of salvage surgery remains obscure at present., Methods: The updated clinical outcomes of salvage surgery were investigated to know its survival impact. Of the 155 ESCC patients who underwent dCRT between 2009 and 2016, we included 85 patients with recurrence or residual disease. The median follow-up was 65 months., Results: Of the 85 patients with progression disease, there were 42 and 43 patients of recurrence and residual disease, respectively. Salvage surgery was performed in 27 patients after dCRT, including 15 patients who underwent salvage esophagectomy. The 5-year overall survival (OS) of salvage surgery and otherwise patients was 66.1% and 14.5%, and the patients with salvage surgery had a significantly better prognosis (p < 0.0001). In the 15 patients who underwent salvage esophagectomy, residual disease, lymph node metastasis-positive (ycN+) after dCRT, and pathological lymph node metastasis-positive (ypN+) were significantly associated with poor prognosis (p = 0.0492, p = 0.0006, p = 0.0276), and the 5-year OS rates for the ycN/ypN combinations were 90%, 33.3%, and 0% in ycN-/ypN-, ycN+/ypN-, and ycN+/ypN+ patients, respectively (p = 0.0026). In a multivariate analysis, ycN+ was an independent poor prognostic factor (HR 13.6, 95% CI 1.65-286.8, p = 0.0154)., Conclusions: Survival impact of salvage surgery after dCRT is robust, and lymph node metastasis after dCRT may help determine the indication for salvage esophagectomy.

Purpose: The purpose of this study is to evaluate the long-term survival outcomes of KDOG1001 trial after a minimum follow-up of 3 years., Methods: Patients with bulky N2 lymph nodes, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) received up to four 28-day cycles of DCS neoadjuvant chemotherapy (docetaxel at 40 mg/m 2 , cisplatin at 60 mg/m 2 on day 1, and S-1 at 40 mg/m 2 twice daily for 2 weeks) followed by gastrectomy with D2 lymphadenectomy plus adjuvant S-1 therapy for 1 year. The final preplanned analysis of long-term outcomes including overall survival and relapse-free survival was conducted after minimum follow-up of 3 years. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN 000003642, and has been completed., Results: From May 2010 through January 2017, 40 patients were enrolled. All included patients underwent neoadjuvant chemotherapy with DCS followed by gastrectomy with D2 lymphadenectomy, and 32 (80%) completed adjuvant S-1 therapy for 1 year. After a median follow-up for surviving patients of 68 months at the last follow-up in January 2020, 3-year overall survival rate was 77.5% (95% confidence interval 62.1-87.9%), while 3-year relapse-free survival rate was 62.5% (95% confidence interval 46.8-76.0%)., Conclusion: Neoadjuvant chemotherapy with 4 cycles of DCS followed by D2 gastrectomy plus adjuvant S-1 was associated with relatively good long-term oncologic outcomes for patients with the high-risk gastric cancer.

Introduction: The aim of this study is to evaluate the efficacy of delta-shaped anastomosis compared to circular stapler anastomosis in laparoscopic distal gastrectomy with Billroth I reconstruction., Methods: This is a single-center randomized controlled study. Eligibility criteria included histologically proven gastric adenocarcinoma in the lower third of the stomach, clinical stage I tumor. Patients were preoperatively randomized to circular stapler anastomosis or delta-shaped anastomosis. The primary endpoint is the number of analgesics used during three days after surgery. We compared the surgical outcomes of the two groups. Postoperative quality of life was evaluated using the Postgastrectomy Syndrome Assessment Scale-45. This trial was registered at the UMIN Clinical Trials Registry as UMIN000025160., Results: Between December 2016 and September 2018, 39 patients (delta-shaped anastomosis 18, circular stapler anastomosis 21) were enrolled. There was no difference in the number of analgesics used during three days after surgery (median nine: delta-shaped anastomosis vs nine: circular stapler anastomosis, P = .91). There was no difference in the overall proportion with in-hospital grade II-IIIB surgical complications (11%: delta-shaped anastomosis, 14%: circular stapler anastomosis). There was no operation-related death in either arm. Regarding postoperative quality of life evaluated one month after surgery, diarrhea subscale was significantly worse in delta-shaped anastomosis than in circular stapler anastomosis., Conclusion: We did not demonstrate the advantage of delta-shaped anastomosis in terms of postoperative pain. Since delta-shaped anastomosis tended to cause postoperative abdominal symptoms related to diarrhea, we should carefully apply the delta-shaped anastomosis to laparoscopic distal gastrectomy with Billroth I reconstruction., (© 2019 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Background: The optimal dose of each drug used in the docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy remains to be clarified for the Japanese population. The purpose of this study was to determine a recommended dose for a combination neoadjuvant DOS chemotherapy for Japanese patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG)., Methods: Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m 2 , day 1), oxaliplatin (mg/m 2 , day 1), and S-1 (mg/day, days 1-14) were: 50/100/80-120 at level 1, and 60/100/80-120 at level 2, respectively. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered in the UMIN Clinical Trial Registry (UMIN 000022210)., Results: We enrolled 12 patients with locally advanced AEG in this study. At dose level 1, one of the six patients experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and grade 3 febrile neutropenia. Two of the next six patients also experienced DLT of need for more than 2-week delay of the start of the second cycle due to adverse events at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen., Conclusion: Recommended doses of docetaxel (mg/m 2 ), oxaliplatin (mg/m 2 ), and S-1 (mg/day) were 60/100/80-120. This chemotherapy scheme showed good preliminary efficacy with acceptable toxicity warranting a further phase II trial to investigate the efficacy of this regimen.

Purpose: Transthoracic esophagectomy for esophageal cancer is one of the most invasive procedures in surgery for gastrointestinal cancer. Serious complications sometimes occur after esophageal cancer surgery, including recurrent laryngeal nerve injury and pneumonia. The purpose of this study was to access the possibility of robot-assisted thoracoscopic esophagectomy for esophageal cancer in terms of preventing recurrent laryngeal nerve injury., Methods: Operations in thoracic part were performed in prone position with bilateral ventilation. During dissection of the recurrent laryngeal nerve lymph nodes, thin blood vessels were coagulated with Maryland bipolar forceps in the left hand and then dissected with monopolar scissors in the right hand. Especially when dissecting left recurrent laryngeal nerve lymph nodes, the nerve was left unisolated from the vascular sheath that involves the aortic arch. Short-term outcomes including operative time, estimated blood loss, and postoperative complications including recurrent laryngeal nerve injury were accessed., Results: From November 2018 to January 2020, 20 patients underwent robot-assisted thoracoscopic esophagectomy for esophageal cancer. Thoracic operative time was 242 min, estimated blood loss in the thoracic part was minimal, the number of dissected mediastinal lymph nodes was 19 (all median), and the incidence rates of recurrent laryngeal nerve injury and pneumonia were 10% (2 case) and 10% (2 cases), respectively., Conclusion: Robot-assisted thoracoscopic esophagectomy for esophageal cancer has the possibility of reducing recurrent laryngeal nerve injury even in the introductory period. Randomized controlled trials are required to confirm this advantage of the robotic surgery.

Background: It is elusive which subtypes of immune cells are pivotal in cancer progression and prognosis in gastric cancer (GC). The aim of this study is to clarify clinical impact of immature myeloid-derived immune cells in patients with GC who underwent curative gastrectomy with curative lymphadenectomy and treated with S-1 (tegafur/gimeracil/oteracil) postoperatively., Methods: The prognostic impact of recruited CD33+ immature myeloid-derived cells were clinicopathologically analyzed in curatively resected stage II and III GC. Correlation of preoperative peripheral leukocyte fractions with recruited CD33+ immature cells was also assessed., Results: Patients with high CD33+ cell counts in primary tumor showed dramatically worse prognosis (5-y recurrence-free survival 29.0%) than that of the counterparts (79.4%). High CD33+ cell counts independently predicted poor prognosis in stage II/III (hazard ratio, 4.34; P < 0.001). In analyses of each stage, high CD33+ cell count was pivotally associated with poor prognosis in both stages. There was no significant correlation of each peripheral leukocyte fraction with CD33+ cell recruitment. Of note, high CD33+ cell count was significantly correlated with hematogenous recurrence., Conclusions: Recruitment of CD33+ immature myeloid cells critically predict hematogenous recurrences in curatively resected advanced GC. These results give rational to focusing on CD33+ myeloid-derived cells as a novel approach to tackle advanced GC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report a case of a 61-year-old man who underwent open total gastrectomy and D2 lymph node dissection for gastric cancer. The pathological findings were suggestive of pT2N3M0, fStage ⅢA. S -1 was administered for 1 year post-surgery. One year and 9 months after the operation, an epigastralgia was found, and the PET-CT showed an increase of SUVmax 3.80 around the celiac artery. S -1 plus CDDP therapy was initiated. However, due to the occurrence of neutropenia, the therapy was changed to ramucirumab plus paclitaxel. After 20 courses of the same regimen, no PET-CT uptake was observed. We thus considered it cCR and discontinued further chemotherapy. The patient has been alive for 15 months without recurrence. By performing effective chemotherapy at an early stage, cCR could be observed after a secondary treatment. Therefore, longterm survival could be expected for post-operative recurrence of gastric cancer.

Background: OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer., Methods: OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC)., Results: OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance., Conclusion: Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.

DNA markers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed for detection of minimally invasive disease. The epigenetic relevance of the cysteine dioxygenase 1 gene (CDO1) has been never investigated in PDAC. Three studies, including cellular experiments, tissue validation, and pilot testing for pancreatic cytology, were carried out. Promoter DNA methylation value (MV) of CDO1 was quantified by quantitative methylation-specific PCR. CDO1 expression was consistent with its promoter DNA methylation in 7 PDAC cell lines. In 160 retrospectively collected primary PDAC tumor tissues, MV was significantly higher compared to the corresponding noncancerous pancreas (area under the receiver operating characteristic curve [AUC] = 0.97, P < .0001), and CDO1 hypermethylation was highly specific to PDAC tumor tissues. CDO1 hypermethylation group (MV over 19) was significantly associated with diverse prognostic factors in PDAC. Surprisingly, it was significantly higher in prospectively collected PDAC cytology samples (n = 37), including both pancreatic juice (n = 12) and endoscopic ultrasound-fine needle aspiration (EUS-FNA) cytology (n = 25) compared to pancreatic benign diseases (AUC = 0.96, P < .0001). Detection of PDAC was confirmed by DNA testing in 35 of 37 patients (95% sensitivity); thus, it was more sensitive than cytology (33%) or EUS-FNA cytology (88%). Promoter DNA methylation of CDO1 is extremely specific for PDAC tumors, and accumulates with PDAC tumor progression. It could be a definitive diagnostic marker of PDAC in pancreatic juice or EUS-FNA cytology., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Conventional laparoscopic and open distal gastrectomy procedures have inherent limitations such as restricted movement of straight forceps and tremor of the tip of the devices that can potentially be overcome using robotic distal gastrectomy (RDG). This single-institutional phase II trial aimed to evaluate the safety and feasibility of RDG with lymph node dissection for clinical stage IA gastric cancer., Methods: The study included patients with clinical stage IA gastric cancer in the lower two-thirds of the stomach considered to be curatively resected via distal gastrectomy. The primary end point was the proportion of patients who developed intra-abdominal complications, requiring medical or interventional treatment. The planned sample size was 25, calculated based on an expected complication rate of 3% and a threshold complication rate of 15%, with a one-sided alpha of 10%, power of 70%., Results: Overall postoperative complications rate was 16%. The proportion of patients who developed intra-abdominal complications, requiring treatment was 0% (90% confidence interval, 0-9.8%). No patient developed in-hospital adverse events of grade 3 or higher. The short-term clinical outcomes were as follows: the median duration of postoperative hospital stay was 7 d, and 10 patients (40.0%) had a body temperature of 38°C or higher during their hospital stay., Conclusions: This trial confirmed the safety of RDG with limitation by the restriction of dedicated surgeons. A phase III trial to confirm the superiority of RDG to conventional laparoscopic distal gastrectomy is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Complete visceral inversion occurs in 1/5,000 individuals. In 64%of cases, complete visceral inversion is complicated by the malformation of other organs. Careful attention is required when performing surgeries. In recent years, with the development of laparoscopic surgery, some cases of laparoscopic surgery with complete visceral inversion have been reported. Herein, we report a case of safely performed laparoscopic surgery for sigmoid colon cancer with complete visceral inversion along with a relevant discussion.

Background: The prognosis of patients with gastric cancer with bulky node metastasis, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) remains poor. We conducted a phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 (DCS) for establishing a new treatment modality that improves prognosis., Methods: Patients received up to four 28-day cycles of DCS therapy (docetaxel at 40 mg/m 2 , cisplatin at 60 mg/m 2 on day 1, and S-1 at 40 mg/m 2 twice daily for 2 weeks) followed by gastrectomy with D2 nodal dissection. S-1 chemotherapy was administered for 1 year after surgical resection. The primary endpoint was the percentage of complete resections of the primary tumor with clear margins (R0 resection). The planned sample size was 40; this was calculated based on an expected R0 rate of 85% and a threshold R0 rate of 65%, with a one-sided alpha of 5% and a power of 90%., Results: Between 2010 and 2017, 40 patients were enrolled. The R0 resection rate was 90%. The most common grade 3 or 4 adverse events during DCS therapy were leukocytopenia (27.5%), neutropenia (55.0%), and hyponatremia (22.5%). The most common grade 3 or 4 surgical morbidity was pancreatic fistula (12.5%); mortality was 0%. The pathological response rate was 57.5% with a grade 3 histological response rate of 8%., Conclusions: Neoadjuvant chemotherapy with DCS was feasible and showed a sufficient R0 resection rate. A future study with a sufficient follow-up period should confirm survival outcomes.

Background: Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC., Methods: Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples., Results: Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy., Conclusions: ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.

Background: There have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer., Methods: Quantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010., Results: (1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability., Conclusions: Promoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The aim of this study is to elucidate the optimized lymph node dissection range in middle thoracic (Mt) esophageal squamous cell carcinoma (ESCC) requiring surgery., Patients and Methods: We retrospectively analyzed 165 ESCC patients who underwent surgery with curative intent between 2009 and 2016, including 99 (60%) with MtESCC. Preoperative chemotherapy was administered in more than 80% of cStage II/III MtESCC patients. The rates of pathological and potential metastasis (representing recurrences) to lymph nodes and prognosis (median follow-up 52 months) were clarified. Lymph node dissection efficacy was assessed by calculating the efficacy index (EI) for each lymph node., Results: No. 2R had the highest rate of metastasis, with frequencies of 13/38/46% in cStage I/II/III, respectively, with the highest EI in MtESCC. Recurrences were seen in about 2-10% in the regional (nos. 1, 2L, 4R, and 10) and extraregional lymph nodes (paraaortic lymph node). The EI of lymph nodes was found to exhibit the highest score of 15 for no. 2R, followed by 11.5 for no. 17. The 5-year overall survival (OS) in MtESCC patients who underwent no. 2R lymph node dissection was 73.8%, while those who did not undergo no. 2R dissection did never reach 5-year OS (P = 0.002)., Conclusions: Meticulous lymph node dissection of no. 2R is the most important for long-term survival, and mandatory with the highest priority in MtESCC.

Background: Early detection of remnant gastric cancer (RGC) is required to reduce the risk of death, but long-term endoscopic surveillance is difficult after gastrectomy. In this study, data for the methylation status of 4 methylation genes ( CDO1, HOPX, Reprimo, and E-cadherin ) to predict the onset of RGC are presented., Results: The 4 genes showed hypermethylation in RGC tumors in contrast to the corresponding non-cancerous mucosa tissues. The methylation level in the non-cancerous mucosa tissues of the initial surgery was obviously high in initial malignant disease for CDO1 ( P = 0.0001), while in initial benign one for E-cadherin ( P = 0.003). Promoter DNA methylation status in the remnant non-cancerous mucosa tissues together with the basic clinical data in turn predicted either initial malignant disease or initial benign disease with a high AUC score of 0.94, suggesting that methylation events are differentially recognized between the initial malignant and benign disease. We then finally confirmed that 4 genes hypermethylation of the non-cancerous tissues by biopsy prior to onset of RGC could predict terms until RGC occurred ( P < 0.0001)., Methods: A total of 58 RGC patients were used to establish the model. The 4 genes promoter methylation were analyzed for DNA obtained from the patient's specimens using quantitative methylation specific polymerase chain reaction., Conclusions: This risk model would help provide guidance for endoscopic surveillance plan of RGC after gastrectomy., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

We previously reported that the dissected pancreatic tissue margin (DPM) and the preoperative serum level of carbohydrate antigen 19-9 (preCA19-9) were independent prognostic factors in pancreatic ductal adenocarcinoma (PDAC). In the current study, the prognostic relevance of these factors, including their molecular associations, were validated. A total of 161 patients with PDAC underwent a pancreatectomy between 1986 and 2013, and a multivariate Cox proportional hazards model and a propensity score-based model validated the prognostic importance of DPM. The prognostic factors were compared with the mutation profiles of the K-ras and TP53 genes. Univariate prognostic analysis of disease-specific survival (DSS) demonstrated that DPM (P<0.0001), preCA19-9 (P<0.0001) and Union for International Cancer Control (UICC) stage (P<0.0001), were all significantly associated with poor outcome in PDAC. A multivariate Cox proportional hazards model confirmed that preCA19-9 (P=0.0002) and DPM (P=0.0002) remained as prognostic factors independent of UICC stage (P=0.0015). The combination of preCA19-9 and DPM to predict prognosis could accurately identify the long-term survivors of PDAC (70% 5-year DSS), and a multivariate logistic regression model identified that DPM was the most effective predictor of mortality. The prognostic relevance of DPM was also confirmed (P=0.0008) through propensity score-based background adjustment of patient bias. K-ras gene mutation was significantly associated with DPM (P=0.0002), and DPM-positive patients demonstrated recurrence of distant metastasis in 67% of cases. Therefore, DPM is a critical prognostic indicator in PDAC. In combination with preCA19-9, DPM may be useful to identify long-term survivors of PDAC. Furthermore, to the best of our knowledge, the current study was the first to discover that DPM can represent a poor prognosis based putatively on its association with the K-ras gene mutation.

Background: Laparoscopy-assisted proximal gastrectomy (LAPG) with esophagogastrostomy using the double-flap technique has been reported to rarely cause gastroesophageal reflux. However, quantitative evaluation of the reflux has hardly been performed. The aim of this study was to clarify the superiority of the double-flap technique of LAPG with esophagogastrostomy compared with the OrVil technique in terms of preventing gastroesophageal reflux., Methods: A total of 40 and 51 patients who underwent LAPG with esophagogastrostomy using the double-flap and OrVil techniques, respectively, for upper one-third gastric cancer were included in this study. Of these, 22 and 13 patients in the double-flap and OrVil groups, respectively, consented to undergo a 24-h impedance-pH monitoring test at 3 months postoperatively. Postoperative complications, including gastroesophageal reflux and anastomotic stricture, were assessed retrospectively., Results: No significant differences were observed in the patients' background between both groups, except for a higher D1+ dissection rate observed in double-flap group than in the OrVil group (93% vs 25%, P < 0.001). Operative time was significantly longer in the double-flap group than in the OrVil group (353 min vs 280 min, P < 0.001). All reflux % time was significantly lower in the double-flap group than in the OrVil group (1.29% vs 2.62%, P = 0.043). On the other hand, the proportion of anastomotic stricture requiring endoscopic balloon dilatation was lower in the double-flap group than in the OrVil group but without statistical significance (18% vs 27%; P = 0.32)., Conclusions: Despite its longer operative time and still relatively high anastomotic stricture rate, the double-flap technique would be better than the OrVil technique in terms of preventing gastroesophageal reflux in patients who underwent LAPG with esophagogastrostomy.

Introduction: Despite technical improvements in laparoscopic gastrectomy, gastric stasis is still a serious problem in laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG). The aim of this study was to investigate the factors that might cause gastric stasis in LAPPG., Methods: From April 2004 through November 2012, 85 patients with cT1N0 middle-third gastric cancer who underwent LAPPG at Kitasato University Hospital; these patients were included in the present study. Infra-pyloric vein (IPV)-preserving LAPPG was performed in 41 patients. We compared the rate of gastric stasis in the IPV-preserving and the IPV-non-preserving groups, and analyzed the clinicopathological factors that might have caused gastric stasis., Results: We did not demonstrate that preservation of the IPV could prevent gastric stasis in the early and late postoperative periods. Symptoms of gastric stasis were most frequently recognized 1 year after surgery. A significantly higher proportion of preoperative ASA class 2 patients had gastric stasis than did not (80.0% [12/15] vs 48.6% [34/70], P=0.02). Among the ASA class 2 patients, a significantly greater proportion of those with depressed activities of daily living than those with normal activities of daily living had gastric stasis (66.7% [4/6] vs 20.0% [8/40], P = 0.015)., Conclusions: The clinical significance of the IPV preservation in LAPPG could not be demonstrated. LAPPG should be performed for ASA class 1 patients or those with maintained preoperative activities of daily living., (© 2018 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen (CTA) and predominant target for cancer immunotherapy. Our previous study indicated that KK-LC-1 was expressed in 82% of gastric cancers, and also in 79% of early stage of gastric cancers, with a correlation to Helicobacter pylori (H. pylori) infection. In addition, we found that KK-LC-1 was occasionally expressed at non-tumour sites of stomachs carrying tumours. Here, we investigated the characteristics of KK-LC-1 expression at non-tumour sites and the clinical utility of these phenomena. The gene expression of KK-LC-1 was detected at the non-tumour sites including pyloric glands. The most detectable corpus/gland subset had a KK-LC-1 expression rate of 77% in the pyloric gland of the lower corpus where H. pylori preferentially exists. KK-LC-1 expression rates were 67% or 32% with or without intestinal metaplasia, which also induced by H. pylori, respectively. Consequently, KK-LC-1 would be detected at the pre-cancerous condition of the stomach, and may be a useful marker to predict gastric cancer.

Curative gastrectomy and adjuvant chemotherapy using S-1 is a standard treatment for stage II/III gastric cancer in Japan. The purpose of the present study was to evaluate the prognostic relevance of fibroblast growth factor receptor (FGFR)2 expression in patients with stage II/III gastric cancer that underwent postoperative adjuvant chemotherapy with S-1. Formalin-fixed paraffin-embedded surgical specimens were retrospectively examined in 167 patients with stage II/III gastric cancer that underwent curative gastrectomy followed by adjuvant S1 chemotherapy. FGFR2 expression was measured using immunohistochemistry (IHC) staining. The IHC results for FGFR2 were as follows: Grade 1+, 32; grade 2+, 80; grade 3+, 55 patients. The FGFR2 expression level was not significantly associated with relapse-free or overall survival rates. However, in the diffuse type, the FGFR2 expression level tended to be negatively correlated with relapse-free survival. In particular, the proportion of patients who recurred >5 years following surgery was significantly larger in the FGFR2 grade 3+ group than in the grade 1+, 2+ group (4/22 vs. 1/35; P=0.047). The recurrent sites of long-term failure were mostly peritoneum among the diffuse type. To the best of our knowledge, the present study indicated for the first time that FGFR2 could predict long-term failure of adjuvant S-1 chemotherapy in curative advanced gastric cancer. There was no interaction between FGFR2 expression and patient survival outcomes in stage II/III gastric cancer. Patients with FGFR2 3+ in stage II/III gastric cancer should carefully be followed-up for >5 years after surgery.

Introduction: Although chemotherapy is the main treatment for recurrent colorectal cancer, the utility of radiotherapy as a local treatment has been widely reported. We performed chemoradiotherapy with S-1 for cases with recurrence after surgery, and the outcomes are reported herein., Materials and Methods: Chemoradiotherapy with S-1 was performed in 4 cases. S-1 was administered for 2 weeks during the irradiation period, and the off period provided was 1 week., Results: X-ray irradiation was performed in 2 cases and proton beam irradiation in the other 2. The progression free periods of the 2 cases receiving proton beam irradiation were 31 months and 36 months. In contrast, the progression free periods of the 2 cases given X-ray irradiation were 24 months and 21 months., Discussion: It is known that S-1 not only achieves a high anticancer effect via dihydropyrimidine dehydrogenase(DPD)inhibition, which is a major metabolic pathway of 5-FU, but also increases the radiation susceptibility of malignancies. S-1 is regarded as an ideal anticancer agent when used in combination with radiation therapy. Since the local control achieved in our 4 cases was good, chemoradiotherapy with S-1 was considered to be a useful treatment.

Objectives: Resection of liver metastasis from colorectal cancer is known to improve prognosis; therefore, surgical treatment is recommended for resectable metastases in the Japanese Society for Cancer of the Colon and Rectum Guidelines for the Treatment of Colorectal Cancer. In this study, we investigated factors that affect the prognosis of resection of such metastatic liver tumors., Results: Thirty-three cases of liver resection performed during the period from 1998 to 2017 were investigated. The 5-year overall survival rate after liver resection was 47.3%, and the 5-year recurrence-free survival rate after liver resection was 29.9%. Univariate analysis identified CA19-9(p=0.02)and operative procedure(p=0.0046)as prognostic factors, while multivariate analysis revealed operative procedure(p=0.03)to be a prognostic factor. When prognosis was examined in terms of operative procedure(ie, lobectomy, segmental resection, or partial resection), the prognosis of patients undergoing lobectomy was significantly poorer compared to those undergoing segmental resection(p=0.0092, RR=28.94)and partial resection(p=0.0092, RR=25.37)., Conclusion: In this study, operative procedure was identified as a poor prognostic factor. The prognosis of liver metastasis requiring lobectomy is considered to be poor. Further accumulation of cases is needed to investigate the effects of other factors in the choice of operative procedure.

Background: Minimal residual disease of the peritoneum is challenging for early cancer detection in gastric cancer (GC). Utility of PCR amplification of cancer-derived DNA has been considered feasible due to its molecular stability, however such markers have never been available in GC clinics. We recently discovered cancer-specific methylation of CDO1 gene in GC, and investigated the clinical potential to detect the minimal residual disease., Methods: One hundred and two GC patients were investigated for peritoneal fluid cytology test (CY), and detection level of the promoter DNA methylation of CDO1 gene was assessed by quantitative methylation specific PCR (Q-MSP) in the sediments (DNA CY)., Results: (1) CY1 was pathologically confirmed in 8 cases, while DNA CY1 was detected in 18 cases. All 8 CY1 were DNA CY1. (2) DNA CY1 was recognized in 14.3, 25.0, 20.0, and 42.9%, in macroscopic Type II, small type III, large type III, and type IV, respectively, while it was not recognized in Type 0/I/V. (3) DNA CY1 was prognostic relevance in gastric cancer (p = 0.0004), and its significance was robust among Type III/IV gastric cancer (p = 0.006 for overall survival and p = 0.0006 for peritoneal recurrence free survival). (4) The peritoneal recurrence was hardly seen in GC patients with potent perioperative chemotherapy among those with DNA CY1., Conclusions: DNA CY1 detected by Q-MSP for CDO1 gene promoter DNA methylation has a great potential to detect minimal residual disease of the peritoneum in GC clinics as a novel DNA marker.

We previously demonstrated that the lymph node ratio (LNR) is a prognostic factor associated with EGFR expression, among first priority genes amplified or overexpressed in cancer. Here, we investigated the associations between high LNR and second, third, and fourth priority genes. We performed mRNA expression microarray analysis of tumor tissue from patients with stage III gastric cancer and high or low LNRs. Candidate high LNR-associated genes were further evaluated in 39 patients with stage III gastric cancer. The functional relevance of these genes was evaluated in gastric cancer cell lines. We focused on five genes: H19 , PEG10 , IGF2BP3 , CD177, and PGA3 . H19 and PEG10 were confirmed as high LNR-associated genes. H19 , PEG10 , and IGF2BP3 were found to promote each other's expression. Knocking down H19 or PEG10 using RNAi decreased cell proliferation, invasion, anchorage-independent growth, and chemoresistance. These genes had a mutual relationship in MKN7 cells. H19 knockdown decreased expression of epithelial-mesenchymal transition-associated genes in MKN74 cells to suppress transformation. Thus, H19 promotes epithelial-mesenchymal transition in gastric cancer and is a potential therapeutic target., Competing Interests: CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest.

Background: Growth pattern in early life is one of the most important factors affecting the pathogenesis of metabolic-associated diseases. The associations between serum uric acid (SUA) and hypertension, kidney disease, and coronary heart disease have been recognized. We investigated the association between increased BMI during childhood and adult SUA levels in Japan., Methods: We included 298 children with health examination data between 1981 and 2002 who had also undergone physical examinations after reaching early adulthood (approximately 27 y old). Subjects were divided into sex-specific tertiles based on the difference in their BMI (DBMI) over a 6-y period (6-12 y of age). The association between the three DBMI groups and SUA in adults was analyzed., Results: The predicted average SUA level in adults from the high DBMI group was 5.32 mg/dl after adjustment for related factors in a combined sex analysis. This was significantly higher than among the low DBMI group., Conclusion: Excessive BMI increases during childhood led to young adult SUA elevation even after adjusting for several factors. Lifestyle in early life may be a strong predictor of future uric acid metabolism and the resulting disease risk.

We have demonstrated that CDO1 methylation is frequently found in various cancers, including esophageal squamous cell carcinoma (ESCC), but its clinical relevance has remained elusive. CDO1 methylation was investigated in 169 ESCC patients who underwent esophagectomy between 1996 and 2007. CDO1 methylation was assessed by Q-MSP (quantitative methylation specific PCR), and its clinical significance, including its relationship to prognosis, was analyzed. (i) The median TaqMeth value of CDO1 methylation was 9.4, ranging from 0 to 279.5. CDO1 methylation was significantly different between cStage I and cStage II/III (P = 0.02). (ii) On the log-rank plot, the optimal cut-off value was determined to be 8.9; ESCC patients with high CDO1 methylation showed a significantly worse prognosis than those with low CDO1 methylation (P = 0.02). (iii) A multivariate Cox proportional hazards model identified only CDO1 hypermethylation as an independent prognostic factor (HR 2.00, CI 1.09-3.78, P = 0.03). (iv) CDO1 hypermethylation stratified ESCC patients' prognosis in cStage II/III for both neoadjuvant chemo(radio)therapy (NAC)-positive and NAC-negative cases. Moreover, the CDO1 methylation level was significantly lower in cases with Grade 2/3 than in those with Grade 0/1 (P = 0.02) among cStage II/III ESCC patients with NAC. Promoter DNA hypermethylation of CDO1 could be an independent prognostic factor in ESCC; it may also reflect NAC eradication of tumor cells in the primary tumors., (© 2016 International Society for Diseases of the Esophagus.)

Objectives: We have identified homeobox-only protein (HOPX) as a tumor suppressor gene in various human cancer, and its expression was reduced by promoter DNA hypermethylation. Homeobox-only protein is strongly expressed on pancreatic islet cells; however, clinical relevance of HOPX expression has remained elusive in pancreatic neuroendocrine tumor (pNET)., Methods: We investigated 36 patients with pNET who undertook surgical resection between 1988 and 2012 for HOPX expression and DNA methylation to reveal its clinical significance., Results: (1) Homeobox-only protein is strongly expressed on pancreatic islet cells by immunohistochemistry (IHC). Homeobox-only protein expression was recognized on pNET tumor cells for 1+ in 15, for 2+ in 16, and for 3+ in 5. (2) Homeobox-only protein IHC expression was significantly associated with prognosis (P = 0.03), and survival rate was 37.5%, 70.3%, and 100% in HOPX 1+, 2+, and 3+, respectively. (3) Promoter DNA methylation was quantitatively assessed, and HOPX hypermethylation is found in 6.3%, 11.8%, and 66.7% of G1/G2/G3 pNET, respectively (P = 0.02). (4) Multivariate Cox proportional hazards model identified HOPX IHC expression and HOPX promoter DNA hypermethylation as independent prognostic factors in pNET., Conclusions: Homeobox-only protein expression is a critical prognostic indicator of pNET, and its regulation may be made through promoter DNA methylation.

Purpose: Endoscopic therapy for clinical T1aN0 (cT1aN0) gastric cancer is an excellent therapeutic strategy; however, pathological lymph node metastasis (LNM) occasionally occurs. Patients who have a potential for LNM are subject to additional gastrectomy. Our aim was to identify predictors of LNM in additional gastrectomy., Methods: One hundred and twelve cT1aN0 gastric cancer patients undergoing additional gastrectomy after endoscopic resection were identified between 1997 and 2013. Predictors for LNM were initially selected by a univariate analysis and applied to a multivariate analysis., Results: (1) Twelve patients (10.7 %) had LNM following additional gastrectomy. (2) Clinicopathological factors significantly associated with LNM were the depth of invasion (SM2 or deeper, designated as SM2) (p = 0.0018) and rigorous lymphatic invasion (ly2,3) (p < 0.001). (3) The univariate predictors for LNM were applied to the multivariate logistic regression model, and SM2 (p = 0.0027) and ly2,3 (p = 0.0028) remained significant predictors. (4) When classified into 2 × 2 subgroups, the predictability for LNM was as follows: SM2 plus ly2,3 (46.7 %), SM2 plus ly0,1 (10.0 %), M,SM1 plus ly2,3 (0 %), and M,SM1 plus ly0,1 (0 %)., Conclusions: In cT1aN0 gastric cancer patients, both SM2 and ly2,3 are significant predictors for LNM that may be important as references for additional gastrectomy after endoscopic resection.

Using pharmacological unmasking microarray, we identified promoter DNA methylation of cysteine dioxygenase 1 (CDO1) gene in human cancer. In this study, we assessed the clinicopathological significance of CDO1 methylation in primary breast cancer (BC) with no prior chemotherapy. The CDO1 DNA methylation was quantified by TaqMan methylation specific PCR (Q-MSP) in 7 BC cell lines and 172 primary BC patients with no prior chemotherapy. Promoter DNA of the CDO1 gene was hypermethylated in 6 BC cell lines except SK-BR3, and CDO1 gene expression was all silenced at mRNA level in the 7 BC cell lines. Quantification of CDO1 methylation was developed using Q-MSP, and assessed in primary BC. Among the clinicopathologic factors, CDO1 methylation level was not statistically significantly associated with any prognostic factors. The log-rank plot analysis elucidated that the higher methylation the tumors harbored, the poorer prognosis the patients exhibited. Using the median value of 58.0 as a cut-off one, disease specific survival in BC patients with CDO1 hypermethylation showed significantly poorer prognosis than those with hypomethylation (p = 0.004). Multivariate Cox proportional hazards model identified that CDO1 hypermethylation was prognostic factor as well as Ki-67 and hormone receptor status. The most intriguingly, CDO1 hypermethylation was of robust prognostic relevance in triple negative BC (p = 0.007). Promoter DNA methylation of CDO1 gene was robust prognostic indicator in primary BC patients with no prior chemotherapy. Prognostic relevance of the CDO1 promoter DNA methylation is worthy of being paid attention in triple negative BC cancer.

Phenylbutyrate (PB) is a histone deacetylase antagonist that also exhibits antitumor activity. In this study, we used 7 breast cancer cell lines to identify biomarker candidates that predict PB sensitivity in breast cancer.Comprehensive gene expression profiles were compared using microarrays, and the importance of the identified genes to PB sensitivity was confirmed in gene transfection experiments. CRL and MDAMB453 cells were identified as PB-sensitive, while MDAMB231 cells were PB-resistant.RAB25 and ESRP1 were identified as key regulators of PB sensitivity, while ANKD1, ETS1, PTRF, IFI16 and KIAA1199 acted as PB resistance-related genes. Expression of these genes was dramatically altered by DNA demethylation treatments. RAB25 expression inhibited IFI16 and PTRF, while ESRP1 expression suppressed ANKRD1, ETS1, and KIAA1199. Both RAB25 and ESRP1 were suppressed by ZEB1, which was in turn regulated via epigenetic mechanisms. Thus, PB sensitivity is influenced by epigenetic expression alteration of ZEB1. The genes associated with PB sensitivity are downstream targets of ZEB1. Epigenetic regulation of ZEB1 may prove valuable as a critical biomarker for predicting resistance to breast cancer therapies.

K-ras mutation status has remained elusive in the metastatic liver tumors of colorectal cancer (CRC) in contrast to the primary CRC tumors. In this study, K-ras mutational status of the primary and corresponding liver metastatic tumors was investigated in the 43 CRC patients. Codons 12 and 13 of K-ras were directly sequenced, and a K-ras mutation was evident in 17 cases (39.5%). In 6 cases, the K-ras mutation was evident only in the liver metastasis, but not in the primary CRC, where the mutation was found in codon 13. This discrepancy between primary and metastatic lesions with regard to codon 13 of the K-ras gene may explain the clinical discrepancy of EGFR antibody therapy. In conclusion, the current data may lead to the development of personalized medicine for recurrent CRC, although further validation study is still required., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Understanding risk factors of surgical site infections (SSIs) in gastrectomy is important to provide the best treatment for the patients with gastric cancer., Methods: This is a retrospective observational study using the medical records of 790 patients with gastrectomy from 2005 through 2009. SSIs were classified into incisional SSIs (iSSIs) and organ/space SSIs (o/sSSIs)., Results: iSSIs and o/sSSIs were detected in 41 (5.2%) patients and 68 (8.6%) patients, respectively. Open surgery was the only independent risk factor (p = 0.028) for iSSIs, while open surgery (p = 0.004), concurrent splenectomy (p < 0.001), operative time ≥220 min (p = 0.009), preoperative body mass index ≥20.8 kg/m2 (p = 0.004) and male gender (p = 0.028) were the independent risk factors for o/sSSIs. We created a risk model for o/sSSIs using these independent risk factors. The C-index model discrimination was 0.84 (p < 0.001), and the calibration of the models demonstrated a linear correlation between the predicted and observed probability., Conclusion: We reported the risk factors of SSIs for gastrectomy. The risk model developed in this study for o/sSSIs pertaining to gastric cancer surgery would contribute to provide guidance for the development of best practices., (© 2015 S. Karger AG, Basel.)

Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11-2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

The aim of this study was to clarify the relationship between long-term changes in body mass index (BMI) during childhood and adolescent blood-pressure levels in a general Japanese population. We used health report data from 900 Japanese children between 1983 and 2007. After adjusting for baseline BMI and other confounding factors multivariate linear regression analyses were performed to examine the relationship between changes in BMI (ΔBMI) over a 6-year period (6-12 years) and blood pressure once children reached ages 14 or 15. Sub-group analyses were also performed to ascertain the relationship between ΔBMI and blood pressure at 9th grade for children who had been in the bottom BMI tertile at 1st grade. Endpoint blood-pressure levels in boys (systolic and diastolic) and girls (systolic) from the group whose BMIs increased the most were significantly higher than those from the group whose BMIs increased the least (P<0.05, analysis of variance). After adjustment for baseline BMI and school-entrance year, the former group showed higher blood pressure at the endpoint than the latter (P<0.05, multiple regression analysis). Further adjustment for baseline blood pressure also showed similar results in a combined-sex analysis (n=592). Higher ΔBMI was associated with higher SBP9 even in children whose BMI was in the lowest tertile at baseline after adjustment for sex and school-entrance year (P=0.02, multiple regression analysis). Steeper BMI increases during primary school lead to adolescent increases in blood pressure even if baseline BMI is low. Growth during childhood should be carefully managed.