The impact of CLDN18.2 expression on effector cells mediating antibody-dependent cellular cytotoxicity in gastric cancer

Abstract Activating antibody-dependent cellular cytotoxicity (ADCC) by targeting claudin-18 isoform 2 (CLDN18.2) using zolbetuximab, a monoclonal antibody against CLDN18.2, has been considered a promising novel therapeutic strategy for gastric cancer (GC). However, the impact of CLDN18.2 expression on natural killer (NK) cells and monocytes/macrophages—crucial effector cells of ADCC—in GC has not been fully investigated. In the present study, we assessed the impact of CLDN18.2 expression on clinical outcomes, molecular features, and the frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, in GC by analyzing our own GC cohorts. The expression of CLDN18.2 did not significantly impact clinical outcomes of GC patients, while it was significantly and positively associated with Epstein–Barr virus (EBV) status and PD-L1 expression. The frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, were comparable between CLDN18.2-positive and CLDN18.2-negative GCs. Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC

Clinical usefulness of ramucirumab plus paclitaxel for unresectable and recurrent gastric cancer

Introduction Recently in Japan, Ramucirumab (RAM) became the first anti-angiogenic agent to be approved for second-line treatment of gastric cancer. In the present study, we aimed to evaluate the efficacy and safety of RAM plus paclitaxel (PTX) in patients with unresectable and recurrent gastric cancer in our institution. Patients and Methods The subjects were 11 patients with unresectable and recurrent gastric cancer who received RAM plus PTX as a second- or later-line treatment at our hospital between June 2015 and September 2017, after the failure of previously-attempted treatments. We assessed the efficacy and safety of RAM plus PTX, and also compared them between patients aged <75 years (n=6) and those aged ≥75 (n=5), by performing a retrospective analysis based on the data obtained from daily clinical practice for gastric cancer treatment. Results Objective tumor response was observed in one of the 11 patients (9.1%) with partial response, and disease control was seen in the remaining 10 (90.9%). The median overall survival (OS) and progression-free survival (PFS) of the patients were 20.8 months (95% CI 7.8-NA (not applicable)) and 11.3 months (95% CI 6.5-NA), respectively. There were no serious adverse events. The median OS for the <75 years group and ≥75 years group was NA (due to short follow-up period) and 20.8 months (p = 0.336), respectively, and their respective median PFS rates were 9.4 and 11.3 months (p = 0.492). The difference of rate of adverse events was not significant between the two age groups in the present study, though the number of adverse events was not sufficient. Conclusion The results of the present study suggest that the combination chemotherapy of RAM and PTX was effective in unresectable and recurrent gastric cancer patients as a second- or later-line therapy, and has been shown to be safe and feasible in elderly patients

腹腔鏡下に切除した腫瘍内感染を伴う胃gastrointestinal stromal tumorの1例

胃消化管間質腫瘍（gastrointestinal stromal tumor, GIST）は腫瘍径の増大に伴い内部の変性，出血，壊死をきたすことがあり，腫瘍内部の感染を呈する場合がある。症例は82歳女性。近医で施行された上部消化管内視鏡検査（esophagogastroduodenoscopy, EGD）で穹窿部に粘膜下腫瘍を指摘され，当院紹介となった。当院で施行したEGDでは穹窿部にdelleを伴う56×47mmの粘膜下腫瘍を認めた。超音波内視鏡下穿刺吸引法を施行しGISTの診断となり手術待機中であったが，意識障害，体動困難のため前医に救急搬送された。造影CT検査で腫瘍径の増大および内部のairを伴う液体貯留を認めた。血液検査では著明な炎症反応の上昇を認め，胃GISTの腫瘍内感染の診断で抗菌薬による加療を開始した。当院転院後にEGDを行ったがすでに胃内に穿通し膿性の排液が認められたため追加でのドレナージは施行しなかった。感染のコントロールが得られ，待機的に腹腔鏡下胃局所切除術を施行した。術後経過は良好で術後14日目にリハビリ目的に転院した。病理組織学的検査では腫瘍径は4.0×3.0mmで断端は陰性だった。modified Fletcher分類で再発超低リスク群の胃GISTの診断となり術後補助療法は施行せず，術後4ヶ月再発なく経過している。今回，腫瘍内感染から敗血症に至ったものの，保存的加療により腫瘍の縮小が得られたため腹腔鏡下胃局所切除術を施行した胃GISTの症例を経験した。胃GISTの腫瘍内感染は適切にドレナージが施行され，感染コントロールが得られれば腹腔鏡下に安全に低侵襲な手術が可能である。胃GISTの腫瘍内感染を発症した症例のうち待機的に手術を行った症例について文献的考察を含めて報告する。Gastrointestinal stromal tumors (GISTs) can undergo degeneration, bleeding, and necrosis as they grow, sometimes leading to intra-tumoral infection. We present the case of an 82-year-old woman who was referred to our hospital after a submucosal tumor was discovered in her gastric fornix during an esophagogastroduodenoscopy (EGD) conducted at a nearby medical facility. During the EGD at our hospital, we observed a submucosal tumor measuring 56×47 mm with a delle in the gastric fornix. Endoscopic ultrasound-guided fine needle aspiration confirmed the diagnosis of GIST. While awaiting surgery, the patient was transferred back to the previous medical facility due to altered consciousness and difficulty in movement. A contrast-enhanced CT scan revealed an enlarged tumor with fluid accumulation and air inside, indicating infection. Blood tests showed significantly elevated inflammatory markers, confirming the diagnosis of intra-tumoral infection in the gastric GIST. Antibiotic therapy was initiated accordingly. Upon returning to our hospital, repeat upper gastrointestinal endoscopy revealed pus drainage into the stomach. Infection was successfully controlled, and the patient underwent laparoscopic local resection of the gastric GIST. Postoperative recovery was uneventful, and the patient was transferred for rehabilitation on postoperative day 14. Pathological examination of the resected tumor revealed negative margins, indicating a very low risk for recurrence according to the modified Fletcher classification. No adjuvant therapy was administered, and the patient remained recurrence-free at the 4-month follow-up. Despite the development of sepsis from intra-tumoral infection, conservative management led to tumor reduction, enabling a safe and minimally invasive laparoscopic local resection of the gastric GIST. This case highlights the successful treatment of gastric GIST with intra-tumoral infection using a conservative approach followed by surgical intervention