Equal short-term outcomes of intracorporeal mechanical gastrogastrostomy in laparoscopic pylorus-preserving gastrectomy for cT1N0 gastric cancer in the middle stomach compared with the extracorporeal hand-sewing method.

BACKGROUND: Intracorporeal mechanical gastrogastrostomy (IMG) techniques have recently been developed and their short-term safety was presented in their initial evaluation. However, whether they are comparable to extracorporeal hand-sewing gastrogastrostomy (EHG) remains unclear. The aim of the study is to establish the safety of IMG in totally laparoscopic pylorus-preserving gastrectomy (TLPPG) compared to EHG in laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG). METHODS: We retrospectively analyzed the short-term outcomes of patients with middle-third early gastric cancer who underwent LAPPG or TLPPG between 2005 and 2022. The primary objective of this study was to evaluate the non-inferiority of IMG to EHG in terms of safety, with the primary endpoint being the risk difference in anastomosis-related complications (ARCs). The sample size required to achieve a statistical power of 80% for the non-inferiority test was 971 with a one-sided alpha level of 5% and non-inferiority of 5%. RESULTS: The analysis included a total of 1,021 patients who underwent LAPPG or TLPPG during the study period. Among them, 488 patients underwent EHG, while 533 underwent IMG. The incidences of ARCs were 11.3% and 11.4% in EHG and IMG, respectively. The observed difference in incidence was 0.0017 (90% confidence interval - 0.0313 to 0.0345), which statistically demonstrated the non-inferiority of IMG to EHG in the incidence of ARCs. Among other complications, the incidence of wound infection in IMG was lower than that in EHG. CONCLUSION: IMG is safe regarding ARCs compared with EHG. These results will encourage surgeons to introduce IMG for patients with early middle gastric cancer.

Mural infective endocarditis with a mass on the fossa ovalis in the right atrium.

Infective endocarditis (IE) is a life-threatening disease that affects the endocardial surface of the heart. Although heart valves are commonly involved in IE, in rare cases, vegetation is attached to the cardiac walls without valvular endocardial involvement, which is referred to as mural IE. In this case, a 60-year-old female presented with a seven-day history of fever associated with worsening pain in the right shoulder and left hip. Streptococcus dysgalactiae subsp. Equisimilis was detected in both blood and joint fluid cultures. Although transthoracic echocardiography revealed no mass, transesophageal echocardiography revealed a mobile mass in the fossa ovalis of the right atrium. She was subsequently diagnosed with mural IE and successfully treated with antibiotics without cardiac surgery. To our knowledge, only a few reports have described mural IE with vegetation in or around the fossa ovalis of the right atrium. This case highlights the importance of transesophageal echocardiography in diagnosing mural IE. The treatment strategy for mural IE should be discussed individually and in a multidisciplinary manner because current IE guidelines may not be applicable to mural IE cases due to differences in disease characteristics and clinical course between mural and valvular IE.

Arid5a/IL-6/PAI-1 Signaling Is Involved in the Pathogenesis of Lipopolysaccharide-Induced Kidney Injury.

A systemic inflammatory response leads to widespread organ dysfunction, such as kidney dysfunction. Plasminogen activator inhibitor-1 (PAI-1) is involved in the pathogenesis of inflammatory kidney injury; however, the regulatory mechanism of PAI-1 in injured kidneys remains unclear. PAI-1 is induced by interleukin (IL)-6 in patients with sepsis. In addition, the stabilization of IL-6 is regulated by the adenine-thymine-rich interactive domain-containing protein 5a (Arid5a). Therefore, the aim of the present study was to examine the involvement of Arid5a/IL-6/PAI-1 signaling in lipopolysaccharide (LPS)-induced inflammatory kidney injury. LPS treatment to C57BL/6J mice upregulated Pai-1 mRNA in the kidneys. Enzyme-linked immunosorbent assay (ELISA) revealed that PAI-1 expression was induced in the culture supernatants of LPS-treated human umbilical vein endothelial cells, but not in those of LPS-treated human kidney 2 (HK-2) cells, a tubular cell line. Combined with single-cell analysis, endothelial cells were found to be responsible for PAI-1 elevation in LPS-treated kidneys. Administration of TM5441, a PAI-1 inhibitor, reduced the urinary albumin/creatinine ratio, concomitant with downregulation of Il-6 and Arid5a mRNA expressions. IL-6 treatment in LPS model mice further upregulated Pai-1 mRNA expression compared with LPS alone, accompanied by renal impairment. Furthermore, the expression of Il-6 and Pai-1 mRNA was lower in Arid5a knockout mice than in wild-type mice after LPS treatment. Taken together, the vicious cycle of Arid5a/IL-6/PAI-1 signaling is involved in LPS-induced kidney injury.

A sandwiching method that simplifies hepatic left lateral segment inversion to secure an optimal surgical view around the esophageal hiatus in laparoscopic and robotic gastrectomy for upper gastric and esophagogastric junction cancers.

PURPOSE: In laparoscopic surgery for upper gastric and esophagogastric junction (EGJ) cancer, it is important to achieve optimal exposure of the esophageal hiatus to secure an appropriate workspace. In recent years, hepatic left lateral segment (HLLS) inversion has been used to achieve an optimal surgical field. We present a simple technique to perform a modified HLLS inversion. METHODS: As a simple modified method, suturing a 2-0 straight needle to the peritoneum of the round ligament and pulling it to the outside of the abdominal cavity, the falciform, left triangular, and coronary ligaments were dissected. The HLLS was inverted by moving it to the right through the space of the transected falciform ligament. By ligating the thread through the round ligament, the HLLS was sandwiched between the rest of the liver and abdominal wall. The short-term surgical outcomes of patient who underwent simple modified HLLS inversion were retrospectively reviewed. RESULTS: This study investigated consecutive 24 patients who underwent laparoscopic proximal and total gastrectomies using the simple modified HLLS inversion technique between June 2021 and April 2022. This series of procedures could be completed in approximately 16 min. A Nathanson liver retractor was used in three patients due to difficulties in completing the HLLS inversion in our institution. Postoperative serum liver enzyme levels indicated there was a small effect on the liver. CONCLUSIONS: The simple modified HLLS inversion technique may be a safe and useful procedure and can provide an enhanced surgical field during laparoscopic surgery for upper gastric and EGJ cancers.

Pancreas-contactless gastrectomy for gastric cancer prevents postoperative inflammation.

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.

Related factors associated with exercise behavior in patients with peripheral arterial disease.

[Purpose] This study aimed to identify the factors associated with exercise behavior in patients with peripheral arterial disease. [Participants and Methods] The study included 43 patients with peripheral arterial disease (mean age, 75.2 ± 5.6 years) who were admitted for endovascular treatment from January 2020 to June 2021. Participants were surveyed through questionnaires to assess their physical function for determining their exercise behavior and the presence of physical, personal, and environmental factors that might have affected their stage of change regarding exercise behavior. [Results] A comparison of physical, personal, and environmental factors between the two groups classified by the presence or absence of exercise behavior showed that subjective health and exercise self-efficacy were significantly lower in the group without exercise. Furthermore, a difference was noted in the presence or absence of work. The adjusted binomial logistic regression analysis results using each of the factors differing between the groups, plus the walking impairment questionnaire total score as explanatory variables, showed a significant relationship with exercise self-efficacy only. [Conclusion] The results of this study showed that exercise self-efficacy presented a useful predictive relationship with the presence of exercise behavior in patients with peripheral arterial disease.

Prospective study to validate the clinical utility of DNA diagnosis of peritoneal fluid cytology test in gastric cancer.

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.

Preoperative chemotherapy could modify recurrence patterns through postoperative complications in patients with gastric cancer.

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.

Randomized study of prevention of gastrointestinal toxicities by nutritional support using an amino acid-rich elemental diet during chemotherapy in patients with esophageal cancer (KDOG 1101).

BACKGROUND: This randomized study was designed to evaluate the clinical effect of an elemental diet during chemotherapy in patients with esophageal cancer. METHODS: The inclusion criteria were as follows: (1) esophageal squamous cell carcinoma, (2) stage IB-IV, (3) schedule to receive docetaxel, cisplatin, and 5-fluorouracil (DCF chemotherapy), (4) 20-80 years old, (5) performance status of 0-2, (6) oral intake ability, and (7) written informed consent. Patients were divided into two groups: the elemental supplementary group and the non-supplementary group. Patients received ELENTAL® (160 g/day) orally 9 weeks after the start of chemotherapy. Primary endpoint was the incidence of grade 2 or higher gastrointestinal toxicity according to the Common Terminology Criteria for Adverse Events, version 4.0. Secondary endpoints were the incidence of all adverse events and the evaluation of nutritional status. RESULTS: Thirty-six patients in the elemental supplementary group and 35 patients in the non-supplementary group were included in the analysis. The incidence of grade 2 or higher gastrointestinal toxicity and all grade 3 or 4 adverse events did not differ significantly between the groups. In the elemental supplementary group, the body weight (p = 0.057), muscle mass (p = 0.056), and blood levels of transferrin (p = 0.009), total amino acids (p = 0.019), and essential amino acids (p = 0.006) tended to be maintained after chemotherapy. CONCLUSION: Nutritional support provided by an amino acid-rich elemental diet was ineffective for reducing the incidence of adverse events caused by DCF chemotherapy in patients with esophageal cancer.

Promoter DNA Hypermethylation of the Cysteine Dioxygenase 1 (CDO1) Gene in Intraductal Papillary Mucinous Neoplasm (IPMN).

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers of IPMN are required for detection of invasive disease, and cysteine dioxygenase 1 (CDO1) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN. PATIENTS AND METHODS: A total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied. CDO1 promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy. RESULTS: The methylation values (TaqMeth Vs) of CDO1 increased when noncancerous pancreas tissues were compared with IPMA and HGD (p < 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (p = 0.0016), which were in turn higher than the corresponding noncancerous tissues (p < 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (p < 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (p = 0.0277). CONCLUSIONS: CDO1 promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma-carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases.

Prediction of Efficacy of Postoperative Chemotherapy by DNA Methylation of CDO1 in Gastric Cancer.

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.

Prevention of intra-thoracic recurrent laryngeal nerve injury with robot-assisted esophagectomy.

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.

Patient selection for salvage surgery after definitive chemoradiotherapy in esophageal squamous cell carcinoma.

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.

Neoadjuvant chemotherapy plus surgery for high-risk advanced gastric cancer: long-term results of KDOG1001 trial.

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/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 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.

A phase I study of docetaxel/oxaliplatin/S-1 (DOS) combination neoadjuvant chemotherapy for patients with locally advanced adenocarcinoma of the esophagogastric junction.

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/m2, day 1), oxaliplatin (mg/m2, 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/m2), oxaliplatin (mg/m2), 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.

Diagnostic potential of hypermethylation of the cysteine dioxygenase 1 gene (CDO1) promoter DNA in pancreatic cancer.

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.

Lymph Node Progression and Optimized Node Dissection of Middle Thoracic Esophageal Squamous Cell Carcinoma in the Latest Therapeutic Surgical Strategy.

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.

WiNTRLINC1/ASCL2/c-Myc Axis Characteristics of Colon Cancer with Differentiated Histology at Young Onset and Essential for Cell Viability.

BACKGROUND: WiNTRLINC1 is a long non-coding RNA (lncRNA) that positively regulates the Wnt pathway via achaete-scute complex homolog 2 (ASCL2) in colorectal cancer. ASCL2 was recently reported to play a critical role in chemoresistance, however clinical relevance of the WiNTRLINC1/ASCL2 axis remains obscure in colon cancer. PATIENTS AND METHODS: WiNTRLINC1/ASCL2 expression was investigated at messenger RNA (mRNA) level in 40 primary colon cancer tissues and the corresponding normal mucosa tissues, together with Wnt-related genes (c-Myc/PRL-3) and other lncRNAs (H19, HOTAIR, and MALAT1). Knock-down experiments of WiNTRLINC1 clarified its role in their expression and chemoresistance. RESULTS: Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed definite overexpression of WiNTRLINC1 mRNA in primary colon cancer compared with the corresponding normal colon mucosa tissues (p = 0.0005), such as ASCL2, c-Myc, and PRL-3 (p < 0.0001). The four gene expression signatures were tightly associated in the center of the ASCL2 gene (r = 0.72, p < 0.0001) in clinical samples. WiNTRLINC1 was not significantly associated with prognostic factors in colon cancer and other lncRNAs, while the WiNTRLINC1/ASCL2/c-Myc signatures were unique to young-onset colon cancer with differentiated histology. On the other hand, undifferentiated histology was significantly associated with H19 expression. Knockdown of the WiNTRLINC1 gene reduced the expression of ASCL2/c-Myc, but rather augmented PRL-3 at mRNA level, and robustly affected cell viability in colon cancer cell lines. CONCLUSION: The enhanced WiNTRLINC1/ASCL2/c-Myc axis involved in Wnt pathway activation is a common pathway essential for differentiated colon tumorigenesis, especially with young onset, and may be essential for a viable phenotype of colon cancer.

Epigenetic Status of CDO1 Gene May Reflect Chemosensitivity in Colon Cancer with Postoperative Adjuvant Chemotherapy.

BACKGROUND: Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor gene, and its expression is regulated by promoter DNA methylation in human cancer. The metabolic product mediated by CDO1 enzyme increases mitochondrial membrane potential (MMP), putatively representing chemoresistance. The aim of this study is to investigate the functional relevance of CDO1 gene in colon cancer with chemotherapy. PATIENTS AND METHODS: We investigated 170 stage III colon cancer patients for CDO1 methylation by using quantitative methylation-specific polymerase chain reaction (PCR). To elucidate the functional role of CDO1 gene in colorectal cancer (CRC) biology, we established cell lines that stably express CDO1 gene and evaluated chemosensitivity, MMP, and tolerability assay including anaerobic environment. RESULTS: Hypermethylation of CDO1 gene was an independent prognostic factor for stage III colon cancer on multivariate prognostic analysis. Surprisingly, patients with CDO1 hypermethylation exhibited better prognosis than those with CDO1 hypomethylation in stage III colon cancer with postoperative chemotherapy (P = 0.03); however, a similar finding was not seen in those without postoperative chemotherapy. In some CRC cell lines, forced expression of CDO1 gene increased MMP accompanied by chemoresistance and/or tolerance under hypoxia. CONCLUSION: CDO1 methylation may be a useful biomarker to increase the number of stage III colon cancer patients who can be saved by adjuvant therapy. Such clinical relevance may represent the functionally oncogenic property of CDO1 gene through MMP activity.

Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma.

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.