Background We previously demonstrated the potential of circulating tumor DNA (ctDNA) for the amplification of detecting HER2 in patients with gastric cancer (GC). In the present study, we focused on the clinical courses of patients who developed recurrence with GC, and investigated the potential clinical utility of the ddPCR-based HER2 copy number (CN) as a marker for the temporal and/or spatial heterogeneities of GC during treatment progress. Method We enrolled 30 healthy volunteers and 60 patients with GC who underwent surgery, including 17 patients who developed recurrence. Using ribonuclease P RNA component H1 (RPPH1) as a reference gene, plasma HER2 to RPPH1 ratios (the HER2 ratio) were determined using ddPCR. Results The preoperative plasma HER2 ratio correlated with the tumor HER2 status (p \ 0.001), and sensitivity and specificity were 0.733 and 0.933, respectively.Analyses of plasma samples during the postoperative follow-up periods revealed that high plasma HER2 ratios were detected at the time of recurrence in 7 of 13 cases, which were diagnosed as being HER2 negative at the time of surgery. These results were supported by continuously increasing HER2 ratios thereafter with the progression of recurrent cancer. Conclusion The plasma HER2 ratio determined by ddPCR is a repeatable and noninvasive approach for realtime evaluations of the HER2 status to monitor the effects of treatments for patients with HER2-positive GC and enable treatment options for patients with HER2-negative GC but positive conversion of the HER2 status after recurrence.

Background Gastric cancer (GC) patients with peritoneal metastasis are defined as stage IV in the Japanese classification of GC. For patients with peritoneal metastasis limited to positive peritoneal lavage cytology (CY1) and/or localized peritoneal metastasis (P1a), gastrectomy followed by S1 monotherapy is one of the most widely accepted therapeutic strategy in Japan. This study investigated the efficacy of preoperative chemotherapy as initial treatment in GC patients with CY1 and/or P1a. Methods We retrospectively reviewed GC patients diagnosed with CY1 and/or P1a at 34 institutions in Japan between 2008 and 2012. Selection criteria were: adenocarcinoma, no distant metastasis except CY1 or P1a, and no prior treatment. The subjects were divided into an Initial-Chemotherapy group and an Initial-Surgery group, according to the initial treatment. Results A total of 824 patients were collected and 713 eligible patients were identified for this study. As the initial treatment, 150 patients received chemotherapy (Initial-Cx), and 563 patients underwent surgery (Initial-Sx). Initial-Cx regimens were cisplatin plus S1/docetaxel plus cisplatin plus S1/others (n = 90/37/23). Both overall survival (OS) and progressionfree survival (PFS) were similar between the Initial-Cx and Initial-Sx groups (median OS 24.8 and 24.0 months, HR 1.07, 95% CI 0.87-1.3; median PFS 14.9 and 13.9 months, HR 1.04, 95% CI 0.85-1.27). The 5-year OS rates were 22.3% in the Initial-Cx group and 21.5% in the Initial-Sx group. Conclusions Although, the preoperative chemotherapy did not show a survival benefit for GC patients with CY1 and/or P1a, initial-Cx showed favorable survival in patients who converted to P0 and CY0.

Objective: A phase I study of weekly intravenous paclitaxel combined with a fixed dose of S-1, a dihydropyrimidine-dehydrogenase-inhibitory oral fluoropyrimidine, was conducted for patients with advanced or recurrent gastric cancer (ARGC). Endpoints of this study were to examine the toxicity profile of this regimen and to determine the recommended dose (RD) of paclitaxel. Methods: S-1 was fixed at a dose of 80 mg/m² per day and was administered for 2 weeks (days 1–14) followed by a 2-week rest. Two dose levels of paclitaxel (level 1: 60 mg/m², level 0: 50 mg/m²) were studied. Paclitaxel was infused over 1 h on days 1, 8, and 15. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel in some patients. Fifteen patients were enrolled (6 patients in level 1, and 9 patients in level 0). Dose-limiting toxicities were defined as grade 4 hematological (including grade 3 febrile neutropenia) and grade 3 non-hematological (except anorexia, nausea, vomiting and depilation) toxicities. Results: Three of 6 patients in level 1 developed grade 4 neutropenia or grade 3 febrile neutropenia, and 1 of them also showed grade 3 diarrhea, which settled the maximum-tolerated dose at this level. At level 0, 2 of 9 patients developed grade 4 neutropenia or grade 3 febrile neutropenia, and the RD of paclitaxel for this protocol was set at this level. Pharmacologic studies demonstrated the persistence of significant serum paclitaxel levels over 24 h after drug administration at both levels. Objective responses according to Response Evaluation Criteria in Solid Tumors were observed in 3 of 6 patients who had measurable disease. Conclusion: A combination of S-1 and weekly paclitaxel was feasible and well tolerated, and is suggested to produce a worthwhile response in ARGC. These results warrant further investigation, and a phase II study has already been started.

prognosis of advanced gastric cancer is still poor, chemotherapies were reported to improve the overall survival compared to the best supportive care in several studies [2][3][4]. Among the various active chemotherapeutic agents, cisplatin-based chemotherapy is the most commonly used worldwide. The V-325 study demonstrated that adding docetaxel (D) to a frequently used regimen of cisplatin and 5-fl uorouracil (CF) provided benefi ts with regard to overall survival, response rate, time to disease progression, clinical benefi t, and healthrelated quality of life [5]. Although the DCF regimen provides these advantages, it is accompanied by an increase in toxicity compared with the doublet regimen. The toxicity profi le of DCF is acceptable only with appropriately selected patients and comprehensive toxicity management strategies [6]. In this regard, the development of less toxic new combination chemotherapy has still been considered necessary to properly treat those patients with advanced gastric cancer.Paclitaxel, (Taxol; Bristol-Myers Squibb, Princeton, NJ, USA), which is derived from the bark of the Pacifi c yew, Taxus brevifolia, is one of the most active anticancer drugs for the treatment of solid tumors, effectively blocking cancer cells in the G2/M phase through the inhibition of microtubular depolymerization [7,8]. An administration schedule at doses of 175-225 mg/m 2 by intravenous infusion every 3 weeks has been widely accepted [9]. In addition, several phase II studies have shown that paclitaxel, alone or in combination with cisplatin or 5-fl uorouracil (5-FU), is also active against advanced gastric cancer [10-13]. However, a relatively high incidence of grade 3 or 4 neutropenia (14%-35%) is one of the major adverse effects.Paclitaxel is known to be a cell-cycle-specifi c agent, and in vitro experiments have suggested that prolonged Results. A total of 54 patients were registered. All of them had measurable disease and were determined to be eligible for the present study. Two complete responses and 23 partial responses were confi rmed, giving an overall response rate of 46.3%. At a fi nal follow up of 3 years, the median progressionfree survival and median overall survival were 6.0 and 14.3 months, respectively. Grade 3 neutropenia occurred in 14 patients, and grade 4 in 1 patient (total, 27.8%). The most serious nonhematological toxicity was diarrhea, where grade 3 occurred in 5 patients (9.3%). There were no treatmentrelated deaths. Conclusion. A combination of weekly paclitaxel plus S-1 was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation with comparative trials is needed for confi rmation.

AIMTo investigate the surgical therapies for gastric cancer (GC) patients of age 85 or older in a multicenter survey.METHODSTherapeutic opportunities for elderly GC patients have expanded in conjunction with extended life expectancy. However, the number of cases encountered in a single institution is usually very small and surgical therapies for elderly GC patients have not yet been standardized completely. In the present study, a total of 134 GC patients of age 85 or older who underwent surgery in 9 related facilities were retrospectively investigated. The relationships between surgical therapies and clinicopathological or prognostic features were analyzed.RESULTSEighty-nine of the patients (66%) presented with a comorbidity, and 26 (19% overall) presented with more than two comorbidities. Radical lymphadenectomy was performed in 59 patients (44%), and no patient received pre- or post-operative chemotherapy. Forty of the patients (30%) experienced perioperative complications, but no surgical or perioperative mortality occurred. Laparoscopic surgery was performed in only 12 of the patients (9.0%). Univariate and multivariate analyses of the 113 patients who underwent R0 or R1 resection identified the factors of pT3/4 and limited lymphadenectomy as predictive of worse prognosis (HR = 4.68, P = 0.02 and HR =2.19, P = 0.05, respectively). Non-cancer-specific death was more common in cStage I patients than in cStage II or III patients. Limited lymphadenectomy correlated with worse cancer-specific survival (P = 0.01), particularly in cStage II patients (P < 0.01). There were no relationships between limited lymphadenectomy and any comorbidities, except for cerebrovascular disease (P = 0.07).CONCLUSIONNon-cancer-specific death was not negligible, particularly in cStage I, and gastrectomy with radical lymphadenectomy appears to be an effective treatment for cStage II elderly GC patients.

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