胃

Thymidine phoshorylase阻害による5FU耐性の克服

演　　者：: 森龍太郎¹，末次智成¹, 棚橋利行¹, 山口和也¹, 二村学¹, 吉田和弘¹
所属機関：: ¹岐阜大学・腫瘍外科

Introduction: 5FU can be converted to its active metabolite fluoro-deoxyuridine monophosphate (FdUMP) through two pathways: the orotate phosphoribosyl transferase-ribonucleotide reductase (OPRT-RR) pathway and the thymidine phosphorylase-thymidine kinase (TP-TK) pathway. We investigated the mechanism underlying 5FU-resistance, focusing on the changes in the 5FU metabolisms. Materials and methods: MKN45 and 5FU-resistant MKN45/F2R cells were treated with 5FU or fluoro-deoxyuridine (FdU) in combination with hydroxyurea (HU) or tipiracil (TPI). The amount of FdUMP was determined by the density of the upper band of thymidylate synthase (TS) on Western blotting, and the cell viability was calculated using an MTT assay. Results: The MKN45/F2R cells exhibited 5FU resistance (13.3-fold) and showed decreased OPRT and increased TP levels. In both cell lines, the FdUMP after treatment with 5FU was decreased when RR was inhibited by HU but not when TP was inhibited by TPI, indicating that FdUMP was synthesized from 5FU only through the OPRT-RR pathway. A metabolome analysis revealed the loss of intracellular deoxyribose 1-phosphate (dR1P) in both cells, which is required for the synthesis of FdU from 5FU by TP. The knockdown of OPRT caused decreased FdUMP and resistance to 5FU in MKN45 cells. After the knockdown of TK, the FdUMP after treatment with FdU was decreased in MKN45 cells. However, it was not changed in MKN45/F2R cells, indicating that FdUMP could not be synthesized from FdU by TK in MKN45/F2R cells. Interestingly, TP inhibition caused increased FdUMP after treatment with 5FU and reversed the resistance to 5FU in MKN45/F2R cells. However, TP inhibition did not affect the sensitivity to 5FU in MKN45 cells. Conclusions: In MKN45/F2R cells, FdUMP can easily be reduced through TP-TK pathway, leading to 5FU resistance. The inhibition of TP reversed the resistance to 5FU, suggesting that combination of 5FU and TPI is a promising cancer therapy.

胃癌手術における術前個別立体解剖の理解とその術後合併症に与える影響

演　　者：: 大内田研宙^1,2，進藤幸治¹, 森山大樹¹, 永井俊太郎¹, 大塚隆生¹, 永井英司³, 清水周次¹, 江藤正俊², 橋爪誠², 中村雅史¹
所属機関：: ¹九州大学・臨床・腫瘍外科, ²九州大学病院・先端医工学診療部, ³日本赤十字社福岡赤十字病院・外科

Previously, we focused on the mobility of gastro-pancreatic fold, introduced three approaches, such as medial, right sided, and left sided approaches, and selected the appropriate approach depending on the case-specific personalized anatomy. Now, we preoperatively select the appropriate approach based on the preoperative 3D simulation. Using 3D simulation, we can observe the operative view at the same angle as laparoscopic view, intuitively image the intraoperative view, and decide the appropriate approach depending on each case-specific anatomy. So far, we preoperatively analyzed 220 cases of laparoscopic gastrectomies (LG) and investigated the objective parameters to select the suitable approach for suprapancreatic LN dissection based on the 3D simulation images. We then found the several parameters, which are correlated with the difficulties of suprapancreatic LN dissection, such as the angles and the distances of the celiac artery and its branches and the relative positions between pancreas and these arteries. Furthermore, to investigate the impacts of preoperative 3D simulation on the postoperative complications after LG, we reviewed the 458 LG cases including 300 cases before 3D introduction and 158 cases after 3D introduction. Then, we found that blood loss, drain-amylase on postoperative day 1, and pancreatic fistula Grade I and Grade II (Clavien-Dindo classification) were significantly reduced after introduction of 3D simulation. In this presentation, we will report the novel 3D specific surgical anatomy based on the 3D simulation, which may be involved in the safety and the accuracy of lymph node dissection in LG as well as the results of the reviews and the movie regarding the procedures based on the 3D specific surgical anatomy.

胃癌腹膜播種に対する全身化学療法と腹腔内化学療法および胃切除術による集学的治療

演　　者：: 小林大介^1,15, 石神浩徳^2,15, 藪崎裕^3,15, 大森健^4,15, 小寺泰弘^1,15, 福島亮治^5,15, 今野元博^6,15, 有上貴明^7,15, 富田寿彦^8,15, 岸健太郎^9,15, 松村卓樹^10,15, 三澤一成^11,15, 廣野靖夫^12,15, 山口博紀^13,15, 北山丈二^14,15
所属機関：: ¹名古屋大学・消化器外科, ²東京大学附属病院・外来化学療法部, ³新潟県立がんセンター新潟病院・消化器外科, ⁴大阪国際がんセンター・消化器外科, ⁵帝京大学医学部・外科, ⁶近畿大学・外科, ⁷鹿児島大学・消化器・乳腺甲状腺外科, ⁸兵庫医科大学・消化器内科, ⁹大阪警察病院・外科, ¹⁰愛知医科大学医学部・消化器外科, ¹¹愛知県がんセンター中央病院・消化器外科, ¹²福井大学・消化器外科, ¹³自治医科大学附属病院・臨床腫瘍科, ¹⁴自治医科大学附属病院・臨床研究支援センター, ¹⁵腹腔内化学療法研究会

Background
Peritoneal metastasis (P1) is the most frequent and crucial factor for advanced gastric cancer (GC). Intraperitoneal (IP) chemotherapy with taxanes has local effects due to high concentrations in the peritoneal cavity. Combination of IP and systemic chemotherapy followed by gastrectomy after response is a promising option for GC with P1.
Methods
We evaluated the safety and efficacy of surgery in 4 clinical trials of chemotherapy regimens, 3 regimens (S-1/paclitaxel [PTX] + IP PTX, S-1/oxaliplatin + IP PTX, capecitabine/cisplatin + IP docetaxel) in P1 patients and 1 regimen (S-1/PTX + IP PTX) in positive peritoneal cytology (P0CY1) patients. Gastrectomy was recommended when peritoneal cytology turned negative, and the disappearance or marked shrinkage of P1 was confirmed by laparoscopy. Combination chemotherapy was restarted after surgery and repeated with appropriate modification.
Results
A total of 260 (P1 222, P0CY1 38) patients were enrolled in the clinical trials. Gastrectomy was performed in 124 (P1 93, P0CY1 31) after response to chemotherapy. The mean peritoneal cancer index was 9.4 (SD 9.7) in 93 P1 patients. Total and distal gastrectomy were performed in 100 and 24 patients, respectively. Curative (R0) resection was achieved in 80 patients (65%). Histological response of grade Ib or higher (viable tumor cells ≦2/3) was obtained in 55 patients (44%). The MSTs of P0CY1 and P1 patients were 31.0 months (95% CI 25.7 months-not reached) and 26.3 months (95% CI 21.3-34.2 months) since the initiation of chemotherapy, respectively. The MST and median PFS of all patients were 21.3 months (95% CI 15.6-26.3 months) and 14.2 months (95% CI 9.9-17.3 months) since the gastrectomy. Postoperative complications of Clavien-Dindo grade II-IVa occurred in 11 patients (9%). There were no treatment-related deaths.
Conclusions
Gastrectomy after confirming the elimination of P1 or CY1 by IP plus systemic chemotherapy is safe and could achieve more prolonged survival.

経口摂取困難な腹膜播種陽性胃癌症例に対するmFOLFOX6+paclitaxel腹腔内投与併用療法

演　　者：: 廣野靖夫^1,15，石神浩徳^2,15, 室圭^3,15, 門脇重憲^3,15, 吉田俊太郎^4,15, 富田寿彦^5,15, 藪崎裕^6,15, 楠本哲也^7,15, 太田光彦^8,15, 小寺泰弘^9,15, 辻靖^10,15, 秀村晃生^11,15, 蜂谷修^12,15, 大庭幸治¹³, 北山丈二^14,15
所属機関：: ¹福井大学・第一外科, ²東京大学附属病院・外来化学療法部, ³愛知県がんセンター中央病院・薬物療法部, ⁴東京大学・消化器内科, ⁵兵庫医科大学病院・消化器内科, ⁶:新潟県立がんセンター新潟病院・消化器外科, ⁷九州医療センター・消化器外科, ⁸九州がんセンター・消化器外科, ⁹名古屋大学・消化器外科, ¹⁰斗南病院・腫瘍内科, ¹¹関東労災病院・外科, ¹²山形大学・第一外科, ¹³東京大学・情報学環, ¹⁴自治医科大学附属病院・臨床研究支援センター, ¹⁵腹腔内化学療法研究会

Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously reported the safety and efficacy of IP paclitaxel (PTX) plus S-1 based regimens in clinical trials. However, some patients with peritoneal metastasis cannot take oral anticancer drugs because of obstruction or dysfunction of the gastrointestinal tract. Therefore, we designed a regimen combining IP PTX with mFOLFOX6, and performed a multicenter, single-arm phase I/II study.
Methods: Eligibility criteria included: pathologically proven gastric adenocarcinoma; peritoneal metastasis; inadequate oral intake; adequate organ functions and age between 20-80 years. mFOLFOX6 was administered at the standard doses on days 1 and 15, and PTX was administered at 20 mg/m² on days 1, 8 and 15 every 4 weeks. The primary endpoint was 1-year overall survival (OS) rate. Secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), response rate, negative conversion rate on peritoneal cytology and safety.
Results: We enrolled 36 patients and evaluated efficacy and safety in 34 patients who received at least one dose of protocol treatment. Sixteen patients had malignant ascites before treatment. The median number of courses was 6 (range 1-17). The 1-year OS rate was 55.9% (95% confidence interval [CI], 37.9%-72.8%). The median PFS was 7.5 months (95% CI, 5.1-12.5 months). The median TTF was 5.6 months (95% CI, 4.4-7.7 months). The best overall response was stable disease in all three patients with target lesions. The negative conversion rate on peritoneal cytology was 73.1% (95% CI, 52.2%-88.4%). The frequent grade 3/4 toxicities included neutropenia, leukopenia, hypokalemia and elevation of alanine transaminase. There were no treatment-related deaths.
Conclusions: Combination chemotherapy of mFOLFOX6 plus IP PTX is well tolerated and active in gastric cancer patients with peritoneal metastasis and inadequate oral intake.

胃癌や膵癌治癒手術後の再発バイオマーカーとしての腹腔内リキッドバイオプシー

演　　者：: 村田聡^1,2，竹林克士², 山口剛², 貝田佐知子², 児玉泰一^2,3, 赤堀浩也^2,4, 飯田洋也², 前平博充², 森治樹², 三宅亨², 園田寛道², 北村直美², 谷総一郎², 清水智治², 谷眞至²
所属機関：: ¹滋賀医科大学・腫瘍センター, ²滋賀医科大学・外科, ³日野記念病院・外科, ⁴東近江総合医療センター・外科

Background
To elucidate recurrence pathophysiology,the prognostic effect of peritoneal cancer cell spillage during surgery was evaluated in patients (pts) who underwent potentially curative (R0) gastric cancer (GC) or pancreatic cancer (PC) surgery.

Methods
Pts with advanced GC (≧pT2 MP) or PC who underwent R0 surgery between 2010 and 2017 were enrolled. Peritoneal washing (PW) fluid before (PW-Pre) and after surgery (PW-Post) was collected and cultured to detect viable cancer cells.

Results
In 100 consecutive pts with advanced GC negative for PW-Pre-cytology (CY0) and PW-Pre cancer cell culture [CCC(-)], 53 pts showed PW-Post CCC(+) and 47 had PW-Post CCC(-). No clinicopathological difference was observed between the two cohorts. Recurrences (peritoneum:7, liver:3, distant lymph node:9, local:1) occurred in 20 (37.7%) pts with PW-Post CCC(+). No recurrence was observed in pts with PW-Post CCC(-). Multivariate logistic analysis showed that PW-Post CCC(+) was an independent risk factor for recurrence (Odds 60.3, P = 0.005). The 5-year relapse-free survival rate was 45.4% in pts with PW-Post CCC(+), and 100% in pts with PW-Post CCC(-) (P < 0.0001).
In 53 consecutive pts with PC with CY0, 19 (36.5%) showed PW-Pre CCC(+). In 33 pts with PW-Pre CCC(-), 25 (75.7%) developed PW-Post CCC(+), and 8 (24.3%) remained at PW-Post CCC(-). No clinicopathological difference was observed between pts with PW-CCC(+) and PW-CCC(-). Recurrences (peritoneum:8, liver:16, lung:4, distant lymph node:2, local:9) occurred in 32/44 (72.7%) pts with PW-CCC(+). One (12.5%) of 8 pts with PW-CCC(-) developed local recurrence. Multivariate logistic analysis showed PW-CCC(+) as an independent risk factor for recurrence after PC surgery (Odds 38.7, P = 0.003).

Conclusion
PW-CCC as peritoneal liquid biopsy is a promising predictive biomarker for recurrence after R0 GC or R0 PC surgery. This may rationalize intra-operative intra-peritoneal therapy, and help determine adjuvant chemotherapy intensity.

トラスツズマブ不応HER2陽性進行・再発胃癌におけるHER2 status 再評価 (KSCC1604)

演　　者：: 有上貴明¹，佐伯浩司², 柏田知美³, 牧山明資⁴, 岩槻政晃⁵, 成田有季哉⁶, 佐竹悠良⁷, 松田佳子⁸, 園田英人⁹, 下川元継¹⁰, 沖英次², 前原喜彦¹¹
所属機関：: ¹鹿児島大学・消化器・乳腺甲状腺外科, ²九州大学病院・消化器・総合外科,³佐賀大学附属病院・血液・呼吸器・腫瘍内科, ⁴九州病院・血液・腫瘍内科, ⁵熊本大学附属病院・消化器外科, ⁶愛知県がんセンター・臨床腫瘍内科, ⁷神戸市立医療センター中央市民病院・腫瘍内科, ⁸神戸大学附属病院・食道胃腸外科, ⁹伊万里有田共立病院・外科, ¹⁰九州がんセンター・腫瘍情報研究部, ¹¹九州中央病院

Background. Addition of trastuzumab to chemotherapy is the standard first-line therapy of HER2-positive advanced or recurrent gastric cancer. However, anti-HER2 therapy did not demonstrate a survival advantage in second line setting of these patients. The KSCC study group conducted the study to assess the change in HER2 status and to identify possible biomarkers for acquired resistance after use of trastuzumab.
Patients and Method. Key inclusion criteria were as follows; advanced or recurrent gastric adenocarcinoma with HER2-positive status (IHC3+ or IHC2+ with FISH amplification) before trastuzumab therapy; diagnosed with progressive disease following trastuzumab therapy; pathologically confirmed adenocarcinoma within 3 months following completion of trastuzumab therapy. We collected biopsy samples from patients who had developed resistance to trastuzumab and evaluated HER2 status before and after. Amplification of EGFR and c-met, as well as PIK3CA mutation were comparatively analyzed if samples were available.
Results. Biopsy samples, clinical data and information of formalin fixing conditions were collected from 33 eligible patients as the full analysis set. HER2 loss was identified in 20 patients (60.6%) with refractory disease. IHC showed that the rate of HER2 overexpression was remarkably decreased after therapy (pre-HER2 IHC 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). It was found that non-use of 10% neutral buffered formalin for fixing significantly reduced the rate of HER2-positive status. EGFR amplification, c-met amplification, and PIK3CA gene mutation before and after trastuzumab therapy was observed in 9.4% and 3.6%, 17.2% and 4.0%, and 4.0% and 4.2% of cases, respectively.
Conclusions. It was suggested that re-evaluation of HER2 status is necessary for appropriate use of anti-HER2 targeted therapy beyond disease progression. Our results also highlighted the importance of formalin fixing conditions for HER2 testing.

トリフルリジンによる胃癌細胞内代謝変動のメタボローム解析

演　　者：: 西川敬介¹，佐々木信成¹, 今村知世¹, 谷川原祐介¹
所属機関：: ¹慶應義塾大学・臨床薬剤学

Background: TAS-102 (Lonsurf®), which contains trifluridine (FTD) and tipiracil hydrochloride, is approved for treatment of advanced colorectal cancer. TAS-102 was also reportedly effective to patients with metastatic colorectal cancer refractory to fluorouracil (5-FU)-based standard chemotherapies. However, it remains unclear about the differences in action between FTD and 5-FU. As TAS-102 is currently under development for treatment of gastric cancer, we analyzed mechanisms of action of FTD to gastric cancer cells, paying attention to behaviors of intracellular metabolisms, compared to 5-FU.
Methods: Human gastric cancer cell line, MKN45 cells were assigned to 3 groups that were 5-FU-treated cells, FTD-treated cells and control cells. Intracellular metabolites including FTD and phosphorylated FTD derived from these cells were measured by using Capillary Electrophoresis Time-of-Flight Mass Spectrometry (CE-TOFMS) system.
Results: FTD exhibited to possess anticancer effect as similar to 5-FU in human gastric cancer cells. Metabolomic analysis revealed that FTD was incorporated into gastric cancer cells and phosphorylated to triphosphate form. In pyrimidine metabolism, dUMP was increased due to the inhibition of TS activity in both 5-FU and FTD-treated cells. However, dTTP, generally reduced under the condition of TS inhibition, was increased in FTD-treated cells, suggesting that FTD exerted other effects on this pathway in gastric cancer cells. In 5-FU-treated cells, serine and glycine synthesis was accelerated, and the intermediate metabolites in tricarboxylic acid (TCA) cycle were largely increased and seemed to be supplied from glutaminolysis. On the other hand, the similar effects on metabolic profile were not observed in FTD-treated cells.
Conclusion: The metabolic fluctuation in FTD-treated gastric cancer cells was totally smaller than that in 5-FU-treated cells. It suggests that FTD has the other mechanisms than anti-metabolic action in its anticancer effect.

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