**4. Discussion**

We examined the prognostic significance of GLUT1 expression in patients with surgically resected PPC. We found that overexpression of GLUT1 is an independent factor for predicting poor outcomes and is useful as a prognostic marker in patients with a non-AC component. In the patients with non-AC, OS and DFS showed the highest difference between low-GLUT1 and high-GLUT1 compared with all patients and subgroup patients with AC component. The value of GLUT1 as a prognostic marker differed according to the epithelial histology of PPC.

A previous meta-analysis of 1423 patients with lung cancer revealed a relationship between GLUT1 expression and clinicopathological parameters [5]. This study described that positive expression of GLUT1 was significantly associated with squamous cell carcinoma, poorly differentiated tumors, lymph node metastases, large tumor size, and advanced tumor stage. In the present study, no significant difference in the frequency of high GLUT1 expression was observed between patients with non-AC and AC components. In our analysis according to epithelial histology, however, high expression of GLUT1 was identified as a significant factor for predicting worse outcomes in patients with a non-AC component compared to those with an AC component. A previous study reported that the accumulation of FDG was closely linked to poor prognosis in patients with AC, indicating the prognostic role of glucose metabolism as a significant prognostic predictor [10]. Although the limited sample size may have biased our results, our study suggests that the role of GLUT1 as a prognostic predictor in the histology of the AC component differs between patients with PPC and NSCLC. Here, we demonstrated that high expression of GLUT1 was strongly correlated with advanced stage, vascular invasion, pleural invasion, and tumor cell proliferation. These findings correspond to those of a study on NSCLC [5].

Recently, we reported the prognostic significance of amino acid transporter 1 (LAT1) expression in patients with surgically resected NSCLC [7]. LAT1 was highly expressed in patients with PPC, and there was a close relationship between high LAT1 expression and a worse prognosis. In the analysis according to histological type, the expression of LAT1 was significantly lower in patients with an AC component than in those without an AC component; however, the role of LAT1 as a predictive marker related to poor prognosis did not differ between patients with AC and non-AC. This contradicts the findings of the current study.

There were several limitations to our study. First, the sample size was small because PPC is a rare entity, which may have biased the results. However, compared to previous studies, this was a large-scale investigation using tumor samples collected from multiple institutions. As it is difficult to definitively diagnose PPC using biopsy samples, we collected tumor samples from patients with surgically resected PPC. Second, the expression of GLUT1 has been shown to be closely associated with tumor progression, metastases, and survival of PPC; however, it remains unknown whether GLUT1 expression is correlated with the uptake of 18F-FDG within PPC tumor cells. Although a previous exploratory study indicated a close relationship between GLUT1 expression and 18F-FDG accumulation in patients with PPC, it is necessary to validate this correlation using different cohorts with more than 100 tumor samples. Finally, GLUT1 is found to be a targeting molecule for PPC; however, inhibition of glucose metabolism may be harmful to normal cells rather than cancer cells. Therefore, it may be difficult to administer inhibitors of GLUT1 as a treatment for PPC with a non-AC component in clinical practice. Further studies are needed to develop a selective inhibitor of GLUT1 to diminish the tumor growth and metastases of PPC.

#### **5. Conclusions**

GLUT1 is an independent predictor of poor prognosis in patients with surgically resected PPC, particularly in those with an AC component. Although GLUT1 is widely expressed in human cancers, tumor glucose metabolism was identified as an essential factor related to tumor cell proliferation, survival, and pathogenesis. Additional studies are needed to determine the therapeutic potential of GLUT1 inhibitors in patients with advanced PPC.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2077-0383/9/2/413/s1, Figure S1. Each percentage of epithelial and sarcomatous components.

*J. Clin. Med.* **2020**, *9*, 413

**Author Contributions:** Conceptualization, H.I. and K.K.; methodology, K.K.; software, K.K.; validation, H.I.; formal analysis, K.K.; investigation, H.I. and K.K.; resources, H.E., K.I., Y.G., M.K., T.K., T.Y., Y.O., T.O. (Takashi Osaki), Y.K., S.T., and A.F.; data curation, H.I.; writing—original draft preparation, H.I., K.K., H.E., K.I., Y.G., M.K., T.K., T.Y., Y.O., T.O. (Takashi Osaki), Y.K., S.T., and A.F.; writing—review and editing, H.I., K.K., H.E., K.I., Y.G., M.K., T.K., T.Y., Y.O., T.O. (Takashi Osaki), Y.K., S.T., A.F., and T.O. (Tetsunari Oyama); visualization, T.O. (Tetsunari Oyama); supervision, T.A. and K.S.; project administration, K.K.; funding acquisition, K.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** We thank Kimihiro Shimizu and Akira Mogi with Gunma University Hospital, Osamu Kawashima with Shibukawa Medical Center, Masayuki Sugano with Takasaki Medical Center, Ryohei Yamamoto with Saku Central Hospital Advanced Care Center, and Yukio Seki with Nagoya Medical Center for the collection of materials and patient treatment information. We would also like to thank Editage (www.editage.jp) for English language editing.

**Conflicts of Interest:** The authors declare no conflict of interest.
