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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