Overcoming drug resistance is one of the biggest challenges in cancer chemotherapy. In this study, we examine whether targeting the long noncoding RNA taurine upregulated gene 1 (TUG1) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). TUG1 was expressed at significantly higher levels across 197 PDAC tissues compared with normal pancreatic tissues. Overall survival of patients with PDAC who had undergone 5-FU–based chemotherapy was shorter in high TUG1 group than in low TUG1 group. Mechanistically, TUG1 antagonized miR-376b-3p and upregulated dihydropyrimidine dehydrogenase (DPD). TUG1 depletion induced susceptibility to 5-FU in BxPC-3 and PK-9 pancreatic cell lines. Consistently, the cellular concentration of 5-FU was significantly higher under TUG1-depleted conditions. In PDAC xenograft models, intravenous treatment with a cancer-specific drug delivery system (TUG1-DDS) and 5-FU significantly suppressed PDAC tumor growth compared with 5-FU treatment alone. This novel approach using TUG1-DDS in combination with 5-FU may serve as an effective therapeutic option to attenuate DPD activity and meet appropriate 5-FU dosage requirements in targeted PDAC cells, which can reduce the systemic adverse effects of chemotherapy. Significance: Targeting TUG1 coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in TUG1-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment.

Background/Aim: Predicting the prognosis of metastatic urothelial carcinoma (mUC) patients is needed for clinical decisions. We examined the value of a modified Glasgow prognostic score (mGPS) as a predictive marker for mUC patients. Patients and Methods: In a multicenter study, 68 mUC patients received short hydration gemcitabine/ cisplatin (shGC) and 74 received pembrolizumab (PEM). Patients were allocated according to mGPS. Progression-free (PFS) and cancer-specific (CSS) survival were examined. Results: Higher mGPS reflected poorer PFS and CSS in shGC (p=0.03, p<0.0001, respectively) and PEM (p=0.02, p<0.001, respectively) patients. PFS for the high mGPS group was longer than that of the low mGPS group in the two cohorts (p <0.0001 for both), with similar CSS results (p<0.0001 and p<0.001, respectively). Multivariate analyses revealed high mGPS was a risk factor for poor CSS in both cohorts (HR=3.55, p<0.001, and HR=2.21, p<0.01, respectively). Conclusion: In the mUC patients receiving shGC or PEM, mGPS was a predictive prognostic marker.The incidence of bladder cancer is rising but the mortality rate has recently become reduced with improved treatment (1). However, for patients with metastatic urothelial carcinoma (mUC) the 5-year survival rate is approximately 5% and its prognosis appears poor (2). Evidence from several regimens has been used to improve the prognosis of mUC. Cisplatin-based chemotherapy is recommended as first-line treatment for mUC in National Comprehensive Cancer Network (NCCN) guidelines (3, 4). For decades, evidence from second-line therapy has been lacking. Recently, the efficacy of pembrolizumab (PEM) was described (5), which became the preferred regimen of second-line therapy for mUC under NCCN guidelines (4). However, the optimal timing of a switch in drug has not been established and a definitive prognostic marker for supporting drug selection is lacking. In this regard, useful biomarkers have appeared to assist physicians in identifying the timing of the cessation of the administration of drugs that lost their efficacy over time in patients with advanced cancers.Several evaluation methods related to nutrition or inflammation have been identified that can be used to assess the prognosis of cancer patients. Useful prognostic markers for mUC based on drugs have been reported previously. Predictive factors for the prognosis of patients with mUC who received cisplatin-based chemotherapy are: performance status (PS), hemoglobin levels, and liver metastasis (6). Sarcopenia, a quantitative measure of a loss in muscle mass and strength, is as a prognostic marker of patients with mUC who received gemcitabine and cisplatin (GC) (7). In a previous report, we described how the progression of sarcopenia was also considered a predictive marker of overall survival as found in patients with mUC who underwent gemcitabine and docetaxel treatment as secondline therapy (8). In research on biomarkers using blood samples, the neutrophil-lymphocyte ratio was also shown to reflect the response of pat...

<b><i>Background:</i></b> We evaluated the prognostic efficacy of the Geriatric Nutritional Risk Index (GNRI) in second-line pembrolizumab (PEM) therapy for patients with metastatic urothelial carcinoma (mUC). <b><i>Patients and Methods:</i></b> From January 2018 to October 2019, 52 mUC patients, treated previously with platinum-based chemotherapy, underwent second-line PEM therapy. Peripheral blood parameters were measured at the start of treatment: serum neutrophil-to-lymphocyte ratio (NLR), serum albumin, serum C-reactive protein (CRP), and body height and weight. PEM was intravenously administered (200 mg every 3 weeks). The patients were organized into two groups based on their GNRI (&#x3c;92 [low GNRI] and ≥92 [high GNRI]), and the data were retrospectively analyzed. Adverse events (AEs) were evaluated and imaging studies assessed for all patients. Analyses of survival and recurrence were performed using Kaplan-Meier curves. Potential prognostic factors affecting cancer-specific survival (CSS) were assessed by univariate and multivariate Cox regression analyses. <b><i>Results:</i></b> patients’ baseline characteristics, except for their BMI and objective response rate, did not significantly differ between the two groups. The median total number of cycles of PEM therapy was significantly higher for the high-GNRI group (<i>n</i> [range]: 6 [2–20] vs. 3 [1–6]). The median CSS with second-line PEM therapy was 3.6 months (95% confidence interval [CI]: 2.5–6.1) and 11.8 months (95% CI: 6.2–NA) in the low-GNRI and the high-GNRI group (<i>p</i> &#x3c; 0.01), respectively. Significant differences in CSS between the low- and high-CRP or -NRL groups were not found. Multivariate Cox proportional-hazards regression analysis revealed that a poor Eastern Cooperative Oncology Group performance status, visceral metastasis, and a low GNRI were significant prognostic factors for short CSS (95% CI: 1.62–6.10, HR: 3.14; 95% CI: 1.13–8.11, HR: 3.03; 95% CI: 1.32–8.02, HR: 3.25, respectively). Of the AEs, fatigue showed a significantly higher incidence in the low-GNRI group. <b><i>Conclusions:</i></b> For mUC patients receiving second-line PEM therapy, the GNRI is a useful predictive biomarker for survival outcome.

Tapentadol appears to have an acceptable safety margin and promising efficacy to relieve cancer-related neuropathic pain that is refractory to first-line opioid treatment.