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Matsuoka et al. J Cancer Metastasis Treat 2018;4:6  I  http://dx.doi.org/10.20517/2394-4722.2017.85                         Page 7 of 13

               phosphoserine phosphatase (L3-PP) is also one of the highly-expressed genes that have been analyzed by
               high-density microarray. L3-PP encodes the phosphatase of phosphoserine and has been said to be involved
                                    [63]
               in amino acid synthesis . The enhancement of the activity of L3-PP has been found according to the
               increased cell multiplication and frequency of mitosis . It has been reported that L3-PP overexpression of
                                                             [63]
               L3-PP in gastric cancer cells obtained from peritoneal metastasis by RT-PCR has been shown to be closely
               associated with peritoneal recurrence of gastric cancers . Combined RT-PCR analysis of CEA with L3-PP
                                                              [64]
               resulted in the reduction of false negative CEA mRNA and increased sensitivity of peritoneal metastasis
               detection from 71.4% to 85.7%. Another study performed global analysis on differential gene expression of a
               scirrhous gastric cancer cell line (OCUM-2M) and its derivative sublines with high potential for metastasis
               to the peritoneal cavity (OCUM-2MD3) in a nude mouse model . Twelve genes including rab32, trefoll
                                                                       [65]
               factor 1, α-1-antitrypsin, and gelactin4, were up-regulated by applying a high-density oligonucleotide array
               method. Besides, RT-PCR was performed in 16 representative PLF samples to classify genes specific to
               cytology-positive samples . The usefulness as markers for minimal resonant disease in 99 PLF sample
                                     [66]
               was examined using 5 genes finally selected-CK20, FABP1, MUC2, TFF1, and TFF2. Positive findings which
               were highly specific to fatal cases (91%-100%) were found by nested RT-PCR using the 5 genes. With high
               specificity, the combined use of these 5 genes resulted in identifying 6 out of 20 (30%) additional patients
               with all kinds of early relapse.

               Consequently, these genomic profiling findings suggest the critical importance of setting up a basis upon
               which to establish not only improved molecular understanding, but also better targeted strategies for gastric
               cancer treatment.



               CLINICAL APPLICATION
               Up to the present, effective therapies for peritoneal metastasis have not been established. A previous study
               found that a new oral fluorinated pyrimidine agent (S-1), used as a postoperative monotherapy, did not
               show superior effect in survival in patients with macroscopic peritoneal tumor compared with patients
                                   [67]
               with positive cytology . To improve survival, it is essential to identify high-risk patients at an earlier
               phase of peritoneal metastasis. Several experimental studies have shown that micrometastases are more
               responsive to chemotherapy than visible metastatic tumors [68,69] . Thus, in addition to make an accurate
               diagnosis, molecular diagnosis using RT-PCR analysis has an important role in starting chemotherapy
               before the development of macrometastasis. A phase II clinical trial for evaluating the prognostic impact
               of postoperative S-1 monotherapy in gastric cancer patients with CEA mRNA positivity was carried out.
               Accordingly, the 3-year survival did not show the significant difference between the study population and
               the historic control (67.3% vs. 67.1%, respectively), suggesting that S-1 may delay cancer relapse but not always
                                     [70]
               eradicate micrometastases .
               Because micrometastases are more susceptible to chemotherapy than macroscopic disease, neo-adjuvant
               chemotherapy would theoretically has a benefit in this subgroup of patients, because micrometastases are
                                                                   [71]
               more susceptible to chemotherapy than macroscopic disease . Positive cytology may serve as a guide to
               continuing chemotherapy or changing the mode of therapy. Preoperative chemotherapy protocols may
               select patients more likely to benefit from resection. A previous study analyzed the genetic diagnosis using
               PLF for detecting patients at high risk for peritoneal recurrence and for evaluating the clinical response
                                                                      [66]
               to intraperitoneal chemotherapy in patients with gastric cancer . From nineteen patients with advanced
               gastric cancer who underwent staging laparoscopy and intraperitoneal chemotherapy (MMC 20 mg on day
                                                                                                   2
               1; CDDP 20 mg on days 1-5) before surgical resection or systemic chemotherapy (docetaxel 60 mg/m on day
               1; CDDP 10 mg/m  on days 1-5; 5-fluorouracil 350 mg/m  on days 1-5), specimens of PLC were collected
                               2
                                                                 2
               and were subjected to RT-PCR. All patients except for one who showed lower level of RT-PCR and finally
               revealed negative outcome, and all but one patient who showed an values level in the period of treatment
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