Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis because it is often detected at an advanced stage, and drug resistance interferes with treatment. However, the mechanism underlying drug resistance in PDAC remains unclear. Here, we investigated metabolic changes between a parental PDAC cell line and a gemcitabine (GEM)-resistant PDAC cell line. We established a GEM-resistant cell line, MIA-G, from MIA-PaCa-2 parental (MIA-P) cells using continuous therapeutic-dose GEM treatment. MIA-G cells were also more resistant to 5-fluorouracil in comparison to MIA-P cells. Metabolic flux analysis showed a higher oxygen consumption rate (OCR) in MIA-G cells than in MIA-P cells. Notably, OCR was suppressed by GEM treatment only in MIA-G cells. GEM treatment increased mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS) in MIA-P cells, but not in MIA-G cells. Glutamine uptake and peroxidase levels were elevated in MIA-G cells. The antioxidants N-acetyl-L-cysteine and vitamin C increased the sensitivity to GEM in both cell lines. In MIA-G cells, the expression of the mitochondrial transcription factor A also decreased. Furthermore, rotenone reduced the sensitivity of MIA-P cells to GEM. These findings suggest that the suppression of oxidative phosphorylation contributes to GEM resistance by reducing ROS production. Our study provides a new approach for reducing GEM resistance in PDAC.

Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl₂-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future.

Aim: There is an urgent need to establish biomarkers for the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the usefulness of the combined assessment of carbohydrate antigen 19‐9 (CA19‐9), carcinoembryonic antigen (CEA), and duke pancreatic monoclonal antigen type 2 (DUPAN‐2) in PDAC.Methods: We retrospectively investigated the impact of three tumor markers on overall survival (OS) and recurrence‐free survival (RFS). Patients were classified into two groups: upfront surgery (US) and neoadjuvant chemoradiation (NACRT) groups.Results: In total, 310 patients were evaluated. In the US group, patients who had all three elevated markers showed a significantly worse prognosis than the others (median: 16.4 months, P = .005). In the NACRT group, patients who had elevated CA 19‐9 and CEA levels after NACRT had significantly worse prognosis than the others (median: 26.2 months, P < .001). The elevated DUPAN‐2 levels before NACRT were associated with significantly worse prognosis than normal levels (median: 44.0 vs 59.2 months, P = .030). Patients who had elevated DUPAN‐2 levels before NACRT with elevated CA 19‐9 and CEA levels after NACRT showed extremely poor RFS (median: 5.9 months). Multivariate analysis revealed that a modified triple‐positive tumor marker indicating elevated DUPAN‐2 levels before NACRT and elevated CA19‐9 and CEA levels after NACRT was an independent prognostic factor of OS (hazard ratio: 2.49, P = .007) and RFS (hazard ration: 2.47, P = .007).Conclusions: The combined evaluation of three tumor markers may provide useful information for the treatment of patients with PDAC.

Gastric cancers are strongly associated with Helicobacter pylori infection, with intestinal metaplasia characterizing the background mucosa in most cases. However, only a subset of intestinal metaplasia cases proceed to carcinogenesis, and the characteristics of high-risk intestinal metaplasia that link it with gastric cancer are still unclear. We examined telomere reduction in five gastrectomy specimens using fluorescence in situ hybridization, and identified areas with localized telomere loss (outside of cancerous lesions), which were designated as short telomere lesions (STLs). Histological analyses indicated that STLs were characteristic of intestinal metaplasia accompanied by nuclear enlargement but lacking structural atypia, which we termed dysplastic metaplasia (DM). A review of gastric biopsy specimens from 587 H. pylori-positive patients revealed 32 cases of DM, 13 of which were classified as high-grade based on the degree of nuclear enlargement. All high-grade DM cases exhibited a telomere volume reduced to less than 60% of that of lymphocytes, increased stemness, and telomerase reverse transcriptase (TERT) expression. Two patients (15%) exhibited low levels of p53 nuclear retention. After a 10-year follow-up, 7 (54%) of the high-grade DM cases had progressed to gastric cancer. These results suggest that DM is characterized by telomere shortening, TERT expression, and stem cell proliferation, and high-grade DM is a high-grade intestinal metaplasia that likely represents a precancerous lesion of gastric cancer. High-grade DM is expected to effectively prevent progression to gastric cancer in H. pylori-positive patients.

Introduction: Studies on neoadjuvant treatment have been actively conducted in patients with resectable pancreatic cancer. However, neoadjuvant treatment effectiveness, especially in clinical T1 stage patients, still needs to be determined. We comparatively evaluated the oncologic benefit of preoperative neoadjuvant treatment in clinical T1 stage pancreatic cancer. Methods: Data from two centers were included in the comparative analysis, with overall and recurrence-free survival as primary outcomes, between January 2010 and December 2017. Results: In total, 45 patients were retrospectively reviewed in this study. Two patients in the neoadjuvant group were excluded because of distant metastasis during neoadjuvant treatment. Finally, 43 patients underwent a pancreatectomy for clinical T1 pancreatic cancer, of whom, 35 and 8 patients underwent upfront surgery and neoadjuvant treatment, respectively. Overall survival was similar in the two study groups (5-year overall survival rate: neoadjuvant group, 75%; upfront surgery group, 43.9%, p = 0.066). Conclusions: In our study on patients with clinical T1 stage pancreatic cancer, no significant differences were reported in the oncological outcome in the neoadjuvant therapy group. Large-scale prospective studies are needed to determine the survival benefits of neoadjuvant treatment for early-stage pancreatic cancer.

A 71‐year‐old obese woman was referred to our hospital with lower left abdominal pain. Computed tomography showed a 46 mm elliptic calcification lodged in the sigmoid‐descending colon junction (SDJ), which had been detected 5 years prior but was not within the gall bladder at presentation. Therefore, we diagnosed colonic gallstone ileus with obstructive colitis caused by a gallstone. Colonoscopy revealed a smooth gallstone impacted at the sigmoid‐descending colon junction, which was not fixed and could be pushed proximally with the endoscope. Dislodgement of the stone was unsuccessful with both a large polypectomy snare and a retrieval basket. Considering the high risk of surgery, we chose a non‐surgical treatment strategy for obstructive colitis. Accordingly, a transanal ileus tube was placed to drain the proximal portion of the gallstone. The drainage of the colon by the ileus tube was satisfactory; the proximal colon was decompressed, ameliorating the obstructive colitis. Five days after tube placement, a colonoscopy revealed spontaneous passage of the gallstone into the rectum where it was finally removed. Cholecystocolonic fistula formation was confirmed by magnetic resonance imaging. We decided to surgically close the cholecystocolonic fistula to prevent future retrograde biliary infections. The surgery used a surgical stapler and was successful, with an uneventful postoperative course. Since radical surgical treatment of colonic gallstones and cholecystoenteric fistulas has a risk of postoperative morbidity and mortality, this case illustrates the importance of thoroughly considering nonsurgical interventions and surgeries for the safe treatment of colonic gallstone ileus.