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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 9 of 13

                          Macroscopically negative for metastatic disease with preoperative imaging studies

                                                    Peroperative period
                                            Staging laparoscopy PLC using RT-PCR


                                     Negative                            Positive

                                     Surgery                   Intraoperative chemothrapy (by taxane)
                                                                        EIPL HIPEC

                                Stage I     Stage > II            Neoadjuvant cemotherapy


                              Observation  Postoperative               Re-laparoscopy
                                           chemothrapy
                                                          CY positive  CY negative  CY negative


                                                        Chemotherapy    Surgery      Surgery
                                                           HIPEC
                                                        and/or palliative
                                                          resection     Postoperative
                                                                        chemothrapy
                                                EIPL: Extensive intra-operative peritoneal lavage. HIPEC : hyperthermic perioperative chemotherapy
               Figure 1: Treatment strategy for the patient with positive PLC. PLC: peritoneal lavage cytology; RT-PCR: reverse transcription-polymerase
                             Figure. Treatment strategy for the patient with positive PLC
               chain reaction; EIPL: extensive intra-operative peritoneal lavage; HIPEC: hyperthermic perioperative chemotherapy
               As previously stated, numerous efforts have been made to gain the detection rate of intraperitoneal free
               cancer cells. The main purpose of these studies must principally be an enhancement of the sensitivity of
               PLC. To eliminate diagnostic errors and the misunderstanding of molecular diagnostic results for the sake
               of determining the best treatment plan, combined multiple markers would be practical for diagnosis of
               micrometastasis. Novel markers should also be sought. Multimarker PCR would be more clinically useful
               in getting expanded broad genetic profile in the near future, but this has yet to be investigated.

               It is important to determine which genes should be analyzed for clinical decision making. Because
               personalized cancer genome analysis become more accepted and feasible, the genetic analysis of individual
               gastric tumors may provide insight into which tumor markers are the most sensitive for detection.
               Recently, The Cancer Genome Atlas Research Network (TCGA) advocated a novel classification system
               based on a genomic and molecular basis dividing gastric cancer into four major subtypes . These sub-
                                                                                              [77]
               types include Epstein Barr Virus-infected tumors (EBV), microsatellite instability-associated tumors
               (MSI), genomically stable tumors (GS) and chromosomally unstable/chromosomal instability (CIN).
               EBV reveals mutations in PIK3CA and amplifications of JAK-2, PD-L1/2 as well as hypermethylation.
               MSI demonstrate multiple mutations including PIK3CA, ERBB3, HER2, EGFR in addition to MLH1
               silencing. GS is related with CDH1 and RHOA mutations while CIN tumors harbor focal amplification
               of receptor tyrosine kinases in addition recurrent TP53 mutations. It is plausible that the relation of these
               genetic markers with peritoneal metastasis can be clarified on the basis of these molecular subtypes,
               which will lead to a future promising new candidate genetic markers in PLC for detecting intraperitoneal
               micrometastasis and a guide to new targeting agents. PLC should be considered as not just a survival
               predictor, but an important factor which can determine diagnosis and treatment of advanced gastric
               cancer after curative resection. Detection of molecular changes in PLF during chemotherapy, resulting in
               chemoresistance, could offer a promising way to shift the course of chemotherapy at the appropriate time
               as well as to find new therapeutic targets.
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