Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant disease, which has an extremely low survival rate of <9% in the United States. As a new hallmark of cancer, metabolism reprogramming exerts crucial impacts on PDAC development and progression. Notably, arginine metabolism is altered in PDAC cells and participates in vital signaling pathways. In addition, arginine and its metabolites including polyamine, creatine, agmatine, and nitric oxide regulate the proliferation, growth, autophagy, apoptosis, and metastasis of cancer cells. Due to the loss of argininosuccinate synthetase 1 (ASS1) expression, the key enzyme in arginine biosynthesis, arginine deprivation is regarded as a potential strategy for PDAC therapy. However, drug resistance develops during arginine depletion treatment, along with the re-expression of ASS1, metabolic dysfunction, and the appearance of anti-drug antibody. Additionally, arginase 1 exerts crucial roles in myeloid-derived suppressor cells, indicating its potential targeting by cancer immunotherapy. In this review, we introduce arginine metabolism and its impacts on PDAC cells. Also, we discuss the role of arginine metabolism in arginine deprivation therapy and immunotherapy for cancer.
Arginine/metabolism* ; Argininosuccinate Synthase ; Carcinoma, Pancreatic Ductal/drug therapy* ; Cell Line, Tumor ; Humans ; Pancreatic Neoplasms/drug therapy*

To investigate whether chemotherapy could prolong the postoperative survival time in patients with early stages pancreatic ductal adenocarcinoma (PDAC). A total of 5280 stage ⅠA -ⅡB PDAC patients diagnosed from 2010 to 2015 were selected from surveillance，epidemiology，and end results (SEER) database. Propensity score matching (PSM) analysis was adopted to reduce the baseline differences between the groups. Univariate survival analysis was conducted with the Kaplan-Meier method. Multivariate survival analysis was performed with the Cox proportional hazards model. Univariate and multivariate survival analyses showed that age, differentiation, stage, chemotherapy were independent risk factors for the survival of PDAC patients. After PSM, it is found that adjuvant chemotherapy could prolong the median overall survival time (mOS) for stage ⅠB, ⅡA and ⅡB patients. However, for stage ⅠA patients, there were no significant differences in 3-year survival rate and mOS between patients with chemotherapy (=283) and without chemotherapy (=229) (57.4% vs 55.6%, vs all >0.05). Further analyses show that among 101 patients with well differentiated PDAC and 294 patients with moderately differentiated PDAC, there were no significant differences in survival rate and mOS between patients with and without chemotherapy (all >0.05). Among 117 patients with low-differentiated + undifferentiated PDAC, 3-year survival rate and mOS in patients with chemotherapy were significantly better than those without chemotherapy (48.5% vs 34.1%, vs all <0.05). Chemotherapy regimen used currently is not beneficial for patients with moderately and well differentiated stage ⅠA PDAC, but it is an independent prognostic factor for low-differentiated + undifferentiated PDAC patients.
Adenocarcinoma/pathology* ; Carcinoma, Pancreatic Ductal/surgery* ; Chemotherapy, Adjuvant ; Humans ; Neoplasm Staging ; Pancreatic Neoplasms/drug therapy* ; Prognosis ; Propensity Score

Pancreatic carcinoma constitutes to be a major unsolved health problems worldwide. Because of difficulties in diagnosis, the aggressiveness of pancreatic cancers, and the lack of effective systemic therapies, only less than 5% of patients with pancreatic cancer will be alive 5 years after diagnosis. At the time of diagnosis of pancreatic cancer, less than 20% of patients present with tumors that are confined to the pancreas, and therefore only 10~20% undergo resection with curative intent. The majority of patients present with locally advanced and metastatic disease, whose median survival is only 6~9 months and 3~6 months, respectively. The result of chemotherapy, mainly based on 5-FU, have documented low response rate and little impact on survival or quality of life. However, during the past 10 years, a real progress has been made in the area of chemotherapy for pancreatic cancer with the introduction of gemcitabine. Gemcitabine have shown improved overall survival (5.65 months vs. 4.41 months) and clinical benefit response (23.8% vs. 4.8%) compared with standard 5-FU-based chemotherapy. Therefore, gemcitabine has replaced 5-fluorouracil-based chemotherapy as the standard of care. Subsequent trials have also suggested that combinations of gemcitabine with other agents, such as cisplatin, irinotecan or capecitabine, may further improve clinical benefits in patients with advanced pancreatic cancers. One promising combination is gemcitabine plus oxaliplatin (GEMOX), that was reported in 2003. The response rate of GEMOX and gemcitabine alone was 25.8% and 16.1% (p=0.05). The time to progression was also significantly prolonged in GEMOX arm compared to gemctabine (25 weeks vs 16 weeks). In addition, other several efforts including alternative method of gemibitabine infusion as well as novel drug-combination have been made to improve the prognosis. Novel drugs include pemetrexed, S-1, cetuximab, and bevacizumab, etc. For instance, the response rate and 1-year survival of patients who treated with gemicitabine plus bevacizumab, a monoclonal blocking antibody of VEGF, was 38% and 54%, respectively. In conclusion, a shift in paradigms has occurred in the management of pancreatic cancer with respect to systemic therapy. The use of chemotherapy improved survival, reduced tumor-related symptoms, and achieved significant clinical benefit response in one third of patients. New targets for therapy through rapidly evolving understanding of the molecular biology of pancreatic cancer hold promise for even more effective treatment in the near future.
Arm ; Carcinoma, Pancreatic Ductal ; Cisplatin ; Diagnosis ; Drug Therapy* ; Fluorouracil ; Humans ; Molecular Biology ; Pancreas ; Pancreatic Neoplasms* ; Prognosis ; Quality of Life ; Standard of Care ; Vascular Endothelial Growth Factor A ; Bevacizumab ; Capecitabine ; Cetuximab ; Pemetrexed

PURPOSE: Most patients who undergo a curative resection of a pancreatic ductal adenocarcinoma (PDAC) develop recurrence, usually at the tumor bed or in the liver, which has been associated with the poor prognosis of a PDAC. In this study, the clinical characteristics of the recurrences following curative resection of a PDAC were analyzed to discover the surgical and adjuvant treatment strategies. METHODS: Between May 1990 and December 2002, 156 patients diagnosed with a recurrence after curative resection of a PDAC were analyzed for the pattern of recurrence, time of recurrence, associations with stage and adjuvant therapy, and survival using a retrospective review of their medical records. RESULTS: Local and systemic recurrences were found in 41.0 and 25.7%, respectively. About half of the recurrences occurred within 6 months of the operation. A local recurrence was found more frequently in the body and tail than in the head, which occurred earlier than a systemic recurrence at an advanced stage. A local recurrence occurred in 40% of patients treated with surgery alone, and in 29.4% of those treated with surgery plus radiotherapy, whereas a systemic recurrence occurred in 25.5% of patients treated with surgery alone, and in 17.4% of those treated with surgery plus chemotherapy. The patients with a local recurrence had a significantly prolonged median disease free survival time (7.8 months) than those with a systemic recurrence (5.8 months). The two-year survival rate for the locally recurred patients was greater than that for those with a systemic recurrence (23.4% vs. 17.5%). CONCLUSION: Our study showed a high rate and early occurrence of local recurrence, with a poor survival rate within 1 year, even after curative resection of the PDAC. There is still a great need for advances in meticulous surgical techniques for the control of local recurrence, especially in body and tail lesion or an advanced stage, and new adjuvant therapeutic modalities following curative resection to improve the survival rate of patients with a PDAC.
Adenocarcinoma* ; Carcinoma, Pancreatic Ductal ; Disease-Free Survival ; Drug Therapy ; Head ; Humans ; Liver ; Medical Records ; Pancreas* ; Pancreatic Ducts ; Prognosis ; Radiotherapy ; Recurrence* ; Retrospective Studies ; Survival Rate

BACKGROUND/AIMS: Second-line chemotherapy in patients with advanced pancreatic ductal adenocarcinoma (PDAC) that progresses following gemcitabine-based treatment has not been established. This study aimed to investigate the efficacy and safety of second-line combination chemotherapy with capecitabine and oxaliplatin (XELOX) in these patients. METHODS: Between August 2011 and May 2014, all patients who received at least one cycle of XELOX (capecitabine, 1,000 mg/m² twice daily for 14 days; oxaliplatin, 130 mg/m² on day 1 of a 3-week cycle) combination chemotherapy for unresectable or recurrent PDAC were retrospectively recruited. The response was evaluated every 9 weeks, and the tumor response rate, progression-free survival and overall survival, and adverse events were assessed. RESULTS: Sixty-two patients were included; seven patients (11.3%) had a partial tumor response, and 20 patients (32.3%) had stable disease. The median progression-free and overall survival were 88 days (range, 35.1 to 140.9 days) and 158 days (range, 118.1 to 197.9 days), respectively. Patients who remained stable longer with frontline therapy (≥120 days) exhibited significantly longer progression-free and overall survival. The most common grade 3 to 4 adverse events in patients were vomiting (8.1%) and anorexia (6.5%). There was one treatment-related mortality caused by severe neutropenia and typhlitis. CONCLUSIONS: Second-line XELOX combination chemotherapy demonstrated an acceptable response and survival rate in patients with advanced PDAC who had failed gemcitabine-based chemotherapy.
Adenocarcinoma ; Anorexia ; Capecitabine* ; Carcinoma, Pancreatic Ductal ; Disease-Free Survival ; Drug Therapy ; Drug Therapy, Combination* ; Humans ; Mortality ; Neutropenia ; Pancreatic Ducts ; Pancreatic Neoplasms* ; Retrospective Studies ; Salvage Therapy ; Survival Rate ; Treatment Outcome ; Typhlitis ; Vomiting

OBJECTIVETo detect changes of serum soluble Apo-1/Fas (sApo-1/Fas) in pancreatic cancer patients and to investigate its clinical value in assessing the effect of chemotherapy.

METHODSThe serum level of sApo-1/Fas in 30 normal control subjects and 58 pancreatic cancer patients were detected using enzyme-linked immunosorbent assay (ELISA), and the sApo-1/Fas level of 48 pancreatic cancer patients, before and after chemotherapy was compared.

RESULTSCompared with the level of the control group, the level of serum soluble Apo-1/Fas was significantly correlated with clinical stage but not with age, sex or pathologic type of pancreatic cancer. It was elevated gradually from stage II to IV (P < 0.01). However, it would obviously decrease in pancreatic cancer patients after chemotherapy (P < 0.01).

CONCLUSIONThe serum soluble Apo-1/Fas may be involved in the development of pancreatic cancer, and it may be used as one parameter to assess the disease status and prognosis of pancreatic cancer patient.

Adenocarcinoma, Mucinous ; blood ; drug therapy ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma, Pancreatic Ductal ; blood ; drug therapy ; Cisplatin ; administration & dosage ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Pancreatic Neoplasms ; blood ; drug therapy ; Prognosis ; Remission Induction ; fas Receptor ; blood