Laparoscopic curative resection following perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel and its influence on Claudin18.2 expression in advanced gastric or gastroesophageal junction adenocarcinoma: A two-case report

Laparoscopic curative resection following perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel and its influence on Claudin18.2 expression in advanced gastric or gastroesophageal junction adenocarcinoma: A two-case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Laparoscopic curative resection following perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel and its influence on Claudin18.2 expression in advanced gastric or gastroesophageal junction adenocarcinoma: A two-case report Tohru Takahashi, Takahiro Ishii, Taku Maejima, Eriko Aimono, Dai Miyazaki, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5245561/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel has improved survival in patients with locally advanced resectable gastric or gastroesophageal junction adenocarcinomas in Europe. Methods We report two cases of laparoscopic curative resection with perioperative docetaxel-based chemotherapy for advanced gastroesophageal junction or gastric adenocarcinoma and investigated variations in Claudin18.2 expressions associated with chemotherapy. Results Preoperative four-cycle docetaxel-based chemotherapy enabled laparoscopic total gastrectomy with distal esophagectomy via trans-hiatal approach or laparoscopic distal gastrectomy with extensive lymph node dissection. Postoperative left inferior pulmonary arterial thrombosis and chylous ascites recovered with pharmacotherapy and lipiodol lymphatic embolization. Despite discontinuing postoperative one-cycle chemotherapy, no recurrence was observed for over 1.5 years and 1 year. Immunohistochemical staining showed increased Claudin18.2 expression in undifferentiated adenocarcinomas in the resected specimens than in pre-chemotherapeutic biopsies. Conclusion Perioperative docetaxel-based chemotherapy was effective for Japanese patients with gastroesophageal junction and gastric adenocarcinoma, suggesting a combination treatment with anti-Claudin18.2 antibody as neoadjuvant or first-line chemotherapy. Gastroesophageal junction adenocarcinoma perioperative chemotherapy FLOT Claudin18.2 laparoscopic curative resection Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Gastric cancer is the fifth most commonly diagnosed cancer (5.6%) and the fourth leading cause of cancer death (7.7%), with an estimated 769,000 deaths worldwide in 2020 [ 1 ]. In Western countries, perioperative chemotherapy is standard strategy for patients with locally advanced, resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma since the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial demonstrated improved progression-free survival (PFS) and overall survival (OS) with epirubicin, cisplatin, and 5-fluorouracil (ECF) regimen compared to surgery alone [ 2 ]. More effective perioperative chemotherapeutic regimens, such as the 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen, have shown significantly improved OS compared to ECF [ 3 ]. Advanced surgical techniques have enabled gastrectomies with extended lymph node dissection (ELND), leading to better outcomes and a focus on postoperative chemotherapy in Japan. However, preoperative chemotherapy has also been administered to patients with advanced gastric cancers, including extensive lymph node metastasis (ELM) or resectable large tumors, although the optimal regimen remains undetermined [ 4 – 6 ]. We report two cases of laparoscopic curative resection following perioperative FLOT chemotherapy for locally advanced GEJ and advanced gastric cancer with ELM and investigated variations in Claudin18.2 (CLDN18.2) expressions associated with chemotherapy. Case presentation Case 1: A man in his thirties with epigastric discomfort was referred for examination of a GEJ tumor. Esophagogastroduodenoscopy (EGD) revealed gastric wall thickening with scirrhous changes in the GEJ region extending to the gastric and esophageal mucosa, resembling a submucosal tumor (Fig. 1a-c). Biopsy revealed signet-ring cell carcinoma with equivocal human epidermal growth factor receptor 2 (HER2) expression. Contrast radiography revealed gastric wall deformity along the lesser curvature with a 4-cm longitudinal esophageal distortion suggesting invasion (Fig. 1d). Enhanced computed tomography (CT) revealed gastric wall thickening extending to the esophageal wall, without adjacent tissue invasion (diaphragm and pancreas), accompanied by several lymphadenopathies around the lesser curvature (Fig. 1e-f). He was diagnosed with resectable Siewert type III GEJ adenocarcinoma, classified as cT4aN2M0 and cStage III by the Union for International Cancer Control. Large tumor resection with extensive esophageal invasion in the narrow mediastinal space was considered a high-risk complication owing to poor visibility; therefore, intensified perioperative chemotherapy for resectable GEJ adenocarcinoma was recommended at our multidisciplinary conference. He received preoperative four-cycle FLOT chemotherapy [docetaxel (50 mg/m 2 ), leucovorin (200 mg/m 2 ), and oxaliplatin (85 mg/m 2 ) on day 1, and 5-fluorouracil (2600 mg/m 2 ) as a 24-hour continuous infusion] biweekly. Tumor marker levels decreased during chemotherapy (carcinoembryonic antigen, 12.5–1.7 ng/mL; carbohydrate antigen 19-9, 81.9–4.1 IU/mL). Post-chemotherapy EGD and radiography showed reduced gastric wall thickening and a smooth-surfaced esophageal wall (Fig. 1g-j), identical to the remarkable tumor shrinkage on CT (Fig. 1k-l), resulting in a preoperative diagnosis of ycT3N1M0, ycStage III. He underwent laparoscopic total gastrectomy with distal esophagectomy via a trans-hiatal approach, accompanied by ELND (Fig. 2a-c). He developed bilateral atelectasis and left inferior pulmonary arterial thrombosis but recovered with pharmacotherapy and was discharged on postoperative day 14. Histopathology revealed that over 90% of the tumor cells had disappeared from the gastric wall, replaced by mucinous changes and hyaline fibrosis, without lymph node metastasis. However, a few viable cells showed intramural esophageal invasion (Fig. 2d). Immunohistochemical staining for CLDN18.2 was positive in moderately differentiated adenocarcinoma cells but negative in signet-ring cells from the pre-chemotherapeutic biopsy (Fig. 2e-f). However, CLDN18.2 was positive in signet ring cells from the resected specimen with neural invasion (Fig. 2g-h). The patient was diagnosed with ypT3N0M0 and ypStage IIA. Despite discontinuing one cycle of postoperative chemotherapy at his request, he remained recurrence-free for over 1.5 years postoperatively. Case 2: A man in his sixties presented with palpitations and underwent further examination because of severe anemia (3.1 g/dL). EGD showed a well-defined tumor with ulceration in the lesser curvature of the antrum. This was consistent with gastric wall deformity with pyloric stenosis on contrast radiography, revealing moderately to poorly differentiated adenocarcinoma (Fig. 3a-b). CT revealed gastric wall thickening with subserous edema and bulky lymphadenopathies, which showed 18 F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)-CT (Fig. 3c-f). He was diagnosed with cT4aN3M0 and cStage III. Initially, laparoscopic gastrojejunostomy was performed to address severe undernutrition (albumin, 2.0 g/dL; prealbumin, 15.1 mg/dL; cholinesterase level, 117 U/L), followed by perioperative four-cycle FLOT chemotherapy to facilitate elective minimally invasive gastrectomy. EGD and CT revealed tumor shrinkage and reduced lymphadenopathies (Fig. 3g-j) with decreased FDG uptake on PET-CT (Fig. 3k), leading to a preoperative diagnosis of ycT3N2M0 and ycStageIII. He underwent laparoscopic distal gastrectomy with ELND (Fig. 4a). Three days postoperatively, a continuous lymphatic fistula developed but was successfully treated with lipiodol lymphography, resulting in reduced ascites and discharge on postoperative day 24. Histopathology of the resected specimen revealed sparse tubular adenocarcinoma invading the muscular layer in a highly inflammatory area and a new polypoid lesion with tubular adenoma and poorly differentiated adenocarcinoma foci at its base (Fig. 4b-d). Immunohistochemical staining for CLDN18.2 showed higher positive intensity in well-differentiated adenocarcinoma cells than in poorly differentiated adenocarcinoma cells from the pre-chemotherapeutic specimen (Fig. 4e-f). After chemotherapy, positive intensity increased in poorly differentiated adenocarcinoma cells of the resected specimen (Fig. 4g-h) despite decreased staining in the polypoid lesion (Fig. 4i-j). He was diagnosed with ypT2N1M0 and ypStage IIA and underwent postoperative one-cycle FLOT chemotherapy, which was discontinued at his request. He has been recurrence-free for over 1 year. Discussion FLOT chemotherapy is the standard perioperative treatment for patients with locally advanced resectable gastric cancer or GEJ adenocarcinoma in Europe [ 3 ]. Combining molecular-targeted antibody treatment with FLOT chemotherapy has been investigated to improve outcomes. HER2-targeted therapy with trastuzumab and pertuzumab [ 7 ] and the immune checkpoint inhibitor atezolizumab [ 8 ] demonstrated higher pathological complete response (pCR) rates with FLOT. However, the anti-angiogenic ramucirumab with FLOT did not improve pCR rates and increased anastomotic leakage despite a higher complete resection (R0) rate [ 9 ]. In Japan, preoperative chemotherapy with cisplatin and oral fluoropyrimidine titanium silicate (TS-1) is the provisional standard treatment for patients with locally advanced gastric cancer with ELM, including bulky or para-aortic lymph nodes [ 4 ]. A recent study showed that preoperative triplet chemotherapy with docetaxel, oxaliplatin, and TS-1 (DOS) improved pCR (24%) and R0 (98%) in patients with gastric cancer complicated by ELM [ 10 ] compared with other regimens (pCR, 2%; R0, 82–84.6%) [ 4 , 5 ]. New trials are comparing DOS with FLOT to determine the optimal regimen for patients with GEJ adenocarcinoma [ 11 ] or macroscopic extended large gastric cancer [ 12 ]. A retrospective study comparing perioperative FLOT with other regimens demonstrated a higher overall response (84.4%) and R0 rates (93.8%), resulting in better OS and PFS (39 and 24 months, respectively) compared to ECF (56.3%, 75%, 21, and 14 months), docetaxel, cisplatin, and 5-fluorouracil (76.4%, 94.1%, 28, and 18 months), and 5-fluorouracil, leucovorin, and oxaliplatin (75.7%, 81.8%, 25, and 17 months) in patients with resectable gastric cancer [ 13 ]. However, a phase II randomized controlled trial in China found no difference in the R0 rate or pathological response between perioperative FLOT and TS-1 plus oxaliplatin for patients with advanced gastric cancer, suggesting racial differences [ 14 ]. Some network meta-analyses demonstrated that perioperative FLOT chemotherapy was associated with better OS in patients with gastric cancer [ 15 ] or adenocarcinoma in the stomach or GEJ [ 16 ]. However, preoperative chemoradiotherapy showed better OS for GEJ cancer than other preoperative or perioperative neoadjuvant treatments [ 17 ]. Recent data have indicated that perioperative FLOT chemotherapy offers superior OS compared to preoperative chemoradiation in patients with GEJ adenocarcinoma [ 18 ], confirming FLOT as the preferred perioperative regimen. Clinicopathological and biological features of gastric or GEJ adenocarcinomas help predict chemotherapy efficacy with molecular-targeted therapies. Our study performed immunohistochemical staining for CLDN18.2 and fibroblast growth factor 2 (FGFR2) to assess the potential of new monoclonal antibodies. Although FGFR2 was negative in both cancer types with no upregulation in real-time PCR (Supplementary Fig. 1), CLDN18.2 expression was higher in the well-differentiated components than in the poorly differentiated components, contrary to previous research [ 19 ]. This suggests that CLDN18.2 expression may be associated with histological differentiation [ 20 ]. Since CLDN18.2 is upregulated after chemotherapy in gastric cancer cell lines [ 21 ], chemotherapy-induced CLDN18.2 upregulation was observed in poorly differentiated adenocarcinoma in this study. This suggests that the monoclonal antibody zolbetuximab targeting CLDN18.2 might be more effective for highly malignant cancers and could be used in neoadjuvant or recurrent first-line treatments with chemotherapy. However, careful interpretation is needed, as evaluating only two samples for CLDN18.2 expression is insufficient to confirm variations based on tumor differentiation or chemotherapy. This study has limitations. We report two cases with different biological features: GEJ adenocarcinoma and gastric cancer with bulky lymph nodes, which limited our ability to examine the FLOT chemotherapy efficacy comprehensively. Additionally, our findings may not be comparable with other studies in Asian populations, where neoadjuvant chemotherapy regimens mainly consist of fluorouracil and platinum, with limited FLOT data in China [ 14 , 22 ]. In conclusion, perioperative FLOT chemotherapy is effective for advanced resectable gastric or GEJ adenocarcinoma, even in Asian populations, leading to R0 resection with minimally invasive surgery. CLDN18.2 detection may help predict chemotherapy efficacy and guide the combination of chemotherapy with zolbetuximab in various treatment settings. Declarations Acknowledgments We would like to thank Editage (www.editage.jp) for English language editing and Kohei Yamaguchi for assistance with pathological data curation. Statements and Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interest The authors have no relevant financial or non-financial interests to disclose. Author Contribution Tohru Takahashi, Takahiro Ishii, Hagiwara Masahiro, and Yusuke Mizukami contributed to the conception and design of the study. Tohru Takahashi, Takahiro Ishii, Taku Maejima, Dai Miyazaki, Susumu Fukahori, and Yusuke Ono contributed to acquisition, analysis, and interpretation of data. Eriko Aimono, Taichi Kimura, and Mitsuru Yanai performed histological analysis. Tohru Takahashi drafted the first manuscript. Yusuke Mizukami provided administrative support. Takahiro Ishii was responsible for systemic chemotherapy. Tohru Takahashi performed laparoscopic resections for gastric or gastroesophageal junction adenocarcinomas, and Taku Maejima supported the operations as an assistant. All authors critically revised the manuscript, agreed to be fully accountable for ensuring integrity, and have read and approved the final version. Data Availability The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Ethics Approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Tokushukai Group Ethics Committee (Aug 29, 2024/No: TGE02602-012). Consent Informed consent to participate and to publish was obtained from all individual participants included in the study. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660 Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. 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J Clin Oncol 42:LBA1-LBA. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA1 Wang C, Wang Y, Chen J, Wang Y, Pang C, Liang C, et al (2023) CLDN18.2 expression and its impact on prognosis and the immune microenvironment in gastric cancer. BMC Gastroenterol 23:283. https://doi.org/10.1186/s12876-023-02924-y Angerilli V, Ghelardi F, Nappo F, Grillo F, Parente P, Lonardi S, et al (2024) Claudin-18.2 testing and its impact in the therapeutic management of patients with gastric and gastroesophageal adenocarcinomas: A literature review with expert opinion. Pathol Res Pract 254:155145. https://doi.org/10.1016/j.prp.2024.155145 Nishibata T, Weng J, Omori K, Sato Y, Nakazawa T, Suzuki T, et al (2024) Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models. J Pharmacol Sci 155:84–93. https://doi.org/10.1016/j.jphs.2024.04.004 Wang K, Ren Y, Ma Z, Li F, Cheng X, Xiao J, et al (2019) Docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) as preoperative and postoperative chemotherapy compared with surgery followed by chemotherapy for patients with locally advanced gastric cancer: a propensity score-based analysis. Cancer Manag Res 11:3009–3020. https://doi.org/10.2147/CMAR.S200883 Additional Declarations No competing interests reported. Supplementary Files ESM1.docx Electronicsupplementarymaterial1.tiff Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5245561","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":365335208,"identity":"4108aae8-0e3a-4260-a03e-f598e784b87f","order_by":0,"name":"Tohru 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Mizukami","suffix":""}],"badges":[],"createdAt":"2024-10-11 11:08:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5245561/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5245561/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66658148,"identity":"a824d0e3-48b6-4a6b-9d96-4b149717008e","added_by":"auto","created_at":"2024-10-15 08:26:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2215820,"visible":true,"origin":"","legend":"\u003cp\u003eInitial diagnosis by EGD revealed gastric wall thickening along the lesser curvature extending beyond the gastric angle with invasion into the esophageal submucosa (a-c). Contrast radiography demonstrated a 4 cm longitudinal esophageal distortion with gastric wall deformity in the lesser curvature (d). Enhanced CT revealed esophageal and gastric wall thickening, accompanied by lymphadenopathy (yellow dotted circle) around the lesser curvature (e-f).\u003c/p\u003e\n\u003cp\u003ePreoperative diagnostic findings revealed reduced gastric wall thickening with decreased length of esophageal invasion on EGD (g-i) and smooth-surfaced esophageal and gastric walls on contrast radiography (j). CT demonstrated reduced gastric wall thickening and decreased lymphadenopathy around the lesser curvature (yellow dotted circle) (k-l).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5245561/v1/c5e56bb7df67a6c170cc43d1.png"},{"id":66658150,"identity":"f003b32d-2f78-4c51-9cc2-c6ec77f27c64","added_by":"auto","created_at":"2024-10-15 08:26:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4136127,"visible":true,"origin":"","legend":"\u003cp\u003eIntraoperative findings identified a 4cm esophageal invasion from GEJ by endoscopy, leading to the decision to perform a laparoscopic total gastrectomy with distal esophagectomy via a trans-hiatal approach, along with extended lymph node dissection, including lower mediastinal lymph nodes (a-c). Histopathological findings of the resected specimens revealed that over 90% of tumor cells had disappeared, replaced by mucinous changes and hyaline fibrosis in the gastric wall, with a few viable cells invading the esophageal submucosa (d, ×100). Immunohistochemical staining for CLDN18.2 was positive in the moderately differentiated adenocarcinoma cells but negative in the signet-ring cells from the pre-chemotherapeutic biopsy (e-f, ×100). In the resected specimen, the signet-ring cells were positive for CLDN18.2 staining with neural invasion (g-h, ×200). The scale bars represent 200 (d-f) and 100 µm (g-h).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5245561/v1/9b4f545d56003a10b42abfe6.png"},{"id":66658674,"identity":"6aab78e6-a63d-4e18-938b-44c9e398c059","added_by":"auto","created_at":"2024-10-15 08:34:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2016185,"visible":true,"origin":"","legend":"\u003cp\u003eInitial diagnosis by EGD identified a well-defined tumor with a central ulcer in the lesser curvature of the antrum (a). Contrast radiography revealed gastric wall deformity with pyloric stenosis (b), and CT showed a protruded tumor in the antrum with lymph node enlargement around the superior border of the pancreas and antrum (yellow dotted circle) (c-e). PET-CT identified the uptake of FDG in the gastric wall and bulky lymph node around the antrum (f).\u003c/p\u003e\n\u003cp\u003ePreoperative diagnostic findings showed tumor shrinkage in the antrum on EGD (g) and decreased lymph node size around the superior border of the pancreas and antrum (yellow dotted circle) despite persistent gastric wall thickening on CT (h-j). PET-CT revealed decreased FDG uptake in the gastric wall (k).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5245561/v1/ac5307f65c932fc5babf7bc0.png"},{"id":66658152,"identity":"8d88a72d-7b36-4bd6-84f0-ee60734bf06e","added_by":"auto","created_at":"2024-10-15 08:26:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3533129,"visible":true,"origin":"","legend":"\u003cp\u003eIntraoperative findings identified a bulky lymph node around the antrum without invasion in the surrounding tissues (a). The resected specimen identified the central ulcer-forming tumor with the newly formed polypoid lesion (b). Tubular adenocarcinoma was sparsely present with muscular invasion in an extensive inflammatory and necrotic area (c, ×40). The newly formed polypoid lesion (red dotted square) mainly consisted of an adenoma with poorly differentiated adenocarcinoma foci at its base, similar to the existing tumor (d, ×40). Immunohistochemical staining for CLDN18.2 was weakly positive in poorly differentiated adenocarcinoma cells from pre-chemotherapeutic biopsy (e-f, ×100), highly positive in the resected specimen after chemotherapy (g-h, ×100), and weakly positive in the newly formed polypoid lesion (i-j, ×100). The positive intensity before chemotherapy (f) increased to strong after chemotherapy in poorly differentiated adenocarcinoma cells of the main tumor (h). In contrast, the newly formed polypoid lesion (j) exhibited weaker positive staining compared to the main tumor (h). The scale bars represent 500 (c-d) and 200 µm (e-j).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5245561/v1/7ed6d05640df089f3d54fbe9.png"},{"id":66658676,"identity":"71b0bd55-ed46-4f8a-b222-52417b538ae4","added_by":"auto","created_at":"2024-10-15 08:34:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":18717941,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5245561/v1/5831276c-2fe6-4963-aa35-1c5f4bc544c6.pdf"},{"id":66658673,"identity":"50b1ed75-2192-406f-9805-02d8484cd8d1","added_by":"auto","created_at":"2024-10-15 08:34:25","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17386,"visible":true,"origin":"","legend":"","description":"","filename":"ESM1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5245561/v1/7523642634c747f5ca8949ba.docx"},{"id":66658153,"identity":"c5a925e3-1820-4dd2-a038-d811abb05247","added_by":"auto","created_at":"2024-10-15 08:26:26","extension":"tiff","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12218942,"visible":true,"origin":"","legend":"","description":"","filename":"Electronicsupplementarymaterial1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-5245561/v1/623d125df14e31125dedce1f.tiff"}],"financialInterests":"No competing interests reported.","formattedTitle":"Laparoscopic curative resection following perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel and its influence on Claudin18.2 expression in advanced gastric or gastroesophageal junction adenocarcinoma: A two-case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastric cancer is the fifth most commonly diagnosed cancer (5.6%) and the fourth leading cause of cancer death (7.7%), with an estimated 769,000 deaths worldwide in 2020 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In Western countries, perioperative chemotherapy is standard strategy for patients with locally advanced, resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma since the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial demonstrated improved progression-free survival (PFS) and overall survival (OS) with epirubicin, cisplatin, and 5-fluorouracil (ECF) regimen compared to surgery alone [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. More effective perioperative chemotherapeutic regimens, such as the 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen, have shown significantly improved OS compared to ECF [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdvanced surgical techniques have enabled gastrectomies with extended lymph node dissection (ELND), leading to better outcomes and a focus on postoperative chemotherapy in Japan. However, preoperative chemotherapy has also been administered to patients with advanced gastric cancers, including extensive lymph node metastasis (ELM) or resectable large tumors, although the optimal regimen remains undetermined [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe report two cases of laparoscopic curative resection following perioperative FLOT chemotherapy for locally advanced GEJ and advanced gastric cancer with ELM and investigated variations in Claudin18.2 (CLDN18.2) expressions associated with chemotherapy.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003e\u003cstrong\u003eCase 1:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA man in his thirties with epigastric discomfort was referred for examination of a GEJ tumor. Esophagogastroduodenoscopy (EGD) revealed gastric wall thickening with scirrhous changes in the GEJ region\u0026nbsp;extending to\u0026nbsp;the gastric and esophageal mucosa, resembling a submucosal tumor (Fig. 1a-c). Biopsy revealed signet-ring cell carcinoma with equivocal human epidermal growth factor receptor 2 (HER2) expression. Contrast radiography revealed gastric wall deformity along the lesser curvature with\u0026nbsp;a\u0026nbsp;4-cm longitudinal esophageal distortion suggesting invasion (Fig. 1d). Enhanced computed tomography (CT) revealed gastric wall thickening extending to the esophageal wall, without adjacent tissue invasion\u0026nbsp;(diaphragm and pancreas), accompanied by several lymphadenopathies around the lesser curvature (Fig. 1e-f). He was diagnosed with resectable Siewert type III GEJ adenocarcinoma, classified as cT4aN2M0 and cStage III\u0026nbsp;by\u0026nbsp;the\u0026nbsp;Union for International Cancer Control. Large tumor resection with extensive esophageal invasion in the narrow mediastinal space was considered a\u0026nbsp;high-risk complication owing to\u0026nbsp;poor visibility; therefore, intensified perioperative chemotherapy for resectable GEJ adenocarcinoma was recommended at our multidisciplinary conference.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;He received preoperative four-cycle FLOT chemotherapy [docetaxel (50 mg/m\u003csup\u003e2\u003c/sup\u003e), leucovorin (200 mg/m\u003csup\u003e2\u003c/sup\u003e), and oxaliplatin (85 mg/m\u003csup\u003e2\u003c/sup\u003e) on day 1, and 5-fluorouracil (2600 mg/m\u003csup\u003e2\u003c/sup\u003e) as a 24-hour continuous infusion] biweekly. Tumor marker levels decreased during chemotherapy (carcinoembryonic antigen, 12.5–1.7 ng/mL; carbohydrate antigen 19-9, 81.9–4.1 IU/mL). Post-chemotherapy EGD and radiography showed reduced gastric wall thickening and a smooth-surfaced esophageal wall (Fig. 1g-j), identical to\u0026nbsp;the remarkable tumor shrinkage on CT\u0026nbsp;(Fig. 1k-l), resulting in a preoperative diagnosis of ycT3N1M0, ycStage III.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;He underwent laparoscopic total gastrectomy with distal esophagectomy via a trans-hiatal approach, accompanied\u0026nbsp;by ELND (Fig. 2a-c). He developed\u0026nbsp;bilateral atelectasis and left inferior pulmonary arterial thrombosis but recovered with pharmacotherapy and was discharged on postoperative day 14.\u003c/p\u003e\n\u003cp\u003eHistopathology revealed that over 90% of\u0026nbsp;the tumor cells had disappeared\u0026nbsp;from the gastric wall, replaced by mucinous changes and hyaline fibrosis, without lymph node metastasis. However, a few viable cells showed intramural esophageal invasion (Fig. 2d). Immunohistochemical staining for\u0026nbsp;CLDN18.2\u0026nbsp;was positive in moderately differentiated adenocarcinoma cells but negative in signet-ring cells from the pre-chemotherapeutic biopsy (Fig. 2e-f). However,\u0026nbsp;CLDN18.2 was positive in signet\u0026nbsp;ring cells from the resected specimen\u0026nbsp;with neural invasion (Fig.\u0026nbsp;2g-h). The patient was diagnosed with ypT3N0M0 and ypStage IIA. Despite\u0026nbsp;discontinuing\u0026nbsp;one cycle of postoperative chemotherapy at his request,\u0026nbsp;he\u0026nbsp;remained recurrence-free for over 1.5 years postoperatively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA man in his sixties presented with palpitations and\u0026nbsp;underwent further examination because of severe anemia (3.1 g/dL). EGD showed a well-defined tumor with ulceration in the lesser curvature of the antrum. This was consistent with\u0026nbsp;gastric wall deformity with pyloric stenosis on contrast radiography, revealing moderately to poorly differentiated adenocarcinoma (Fig. 3a-b). CT revealed gastric wall thickening with subserous edema and bulky lymphadenopathies, which showed\u0026nbsp;\u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)-CT (Fig. 3c-f). He was diagnosed with\u0026nbsp;cT4aN3M0 and cStage\u0026nbsp;III. Initially, laparoscopic gastrojejunostomy was performed to address severe undernutrition (albumin, 2.0 g/dL; prealbumin, 15.1 mg/dL; cholinesterase\u0026nbsp;level, 117 U/L), followed by perioperative four-cycle FLOT chemotherapy to facilitate elective minimally invasive gastrectomy. EGD and CT revealed tumor shrinkage and reduced lymphadenopathies (Fig. 3g-j) with decreased FDG uptake on PET-CT (Fig. 3k), leading to a preoperative\u0026nbsp;diagnosis of\u0026nbsp;ycT3N2M0 and ycStageIII.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;He underwent\u0026nbsp;laparoscopic distal gastrectomy with ELND (Fig.\u0026nbsp;4a). Three days postoperatively, a continuous lymphatic fistula developed but was successfully treated with lipiodol lymphography, resulting in reduced ascites and discharge on postoperative day 24.\u003c/p\u003e\n\u003cp\u003eHistopathology of the resected specimen revealed sparse tubular adenocarcinoma invading the muscular layer in a highly inflammatory area and a new polypoid lesion with tubular adenoma and poorly differentiated adenocarcinoma foci at its base (Fig. 4b-d). Immunohistochemical staining for CLDN18.2 showed higher positive intensity in well-differentiated adenocarcinoma cells than in poorly differentiated adenocarcinoma cells from the pre-chemotherapeutic specimen (Fig. 4e-f). After chemotherapy, positive intensity increased in poorly differentiated adenocarcinoma cells of the resected specimen (Fig. 4g-h) despite decreased staining in the polypoid lesion (Fig. 4i-j). He was diagnosed with ypT2N1M0 and ypStage IIA and underwent postoperative one-cycle FLOT chemotherapy, which was discontinued at his request. He has been recurrence-free for over 1 year.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFLOT chemotherapy is the standard perioperative treatment for patients with locally advanced resectable gastric cancer or GEJ adenocarcinoma in Europe [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Combining molecular-targeted antibody treatment with FLOT chemotherapy has been investigated to improve outcomes. HER2-targeted therapy with trastuzumab and pertuzumab [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and the immune checkpoint inhibitor atezolizumab [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] demonstrated higher pathological complete response (pCR) rates with FLOT. However, the anti-angiogenic ramucirumab with FLOT did not improve pCR rates and increased anastomotic leakage despite a higher complete resection (R0) rate [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn Japan, preoperative chemotherapy with cisplatin and oral fluoropyrimidine titanium silicate (TS-1) is the provisional standard treatment for patients with locally advanced gastric cancer with ELM, including bulky or para-aortic lymph nodes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A recent study showed that preoperative triplet chemotherapy with docetaxel, oxaliplatin, and TS-1 (DOS) improved pCR (24%) and R0 (98%) in patients with gastric cancer complicated by ELM [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] compared with other regimens (pCR, 2%; R0, 82\u0026ndash;84.6%) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. New trials are comparing DOS with FLOT to determine the optimal regimen for patients with GEJ adenocarcinoma [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] or macroscopic extended large gastric cancer [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA retrospective study comparing perioperative FLOT with other regimens demonstrated a higher overall response (84.4%) and R0 rates (93.8%), resulting in better OS and PFS (39 and 24 months, respectively) compared to ECF (56.3%, 75%, 21, and 14 months), docetaxel, cisplatin, and 5-fluorouracil (76.4%, 94.1%, 28, and 18 months), and 5-fluorouracil, leucovorin, and oxaliplatin (75.7%, 81.8%, 25, and 17 months) in patients with resectable gastric cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, a phase II randomized controlled trial in China found no difference in the R0 rate or pathological response between perioperative FLOT and TS-1 plus oxaliplatin for patients with advanced gastric cancer, suggesting racial differences [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome network meta-analyses demonstrated that perioperative FLOT chemotherapy was associated with better OS in patients with gastric cancer [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] or adenocarcinoma in the stomach or GEJ [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, preoperative chemoradiotherapy showed better OS for GEJ cancer than other preoperative or perioperative neoadjuvant treatments [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Recent data have indicated that perioperative FLOT chemotherapy offers superior OS compared to preoperative chemoradiation in patients with GEJ adenocarcinoma [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], confirming FLOT as the preferred perioperative regimen.\u003c/p\u003e \u003cp\u003eClinicopathological and biological features of gastric or GEJ adenocarcinomas help predict chemotherapy efficacy with molecular-targeted therapies. Our study performed immunohistochemical staining for CLDN18.2 and fibroblast growth factor 2 (FGFR2) to assess the potential of new monoclonal antibodies. Although FGFR2 was negative in both cancer types with no upregulation in real-time PCR (Supplementary Fig.\u0026nbsp;1), CLDN18.2 expression was higher in the well-differentiated components than in the poorly differentiated components, contrary to previous research [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This suggests that CLDN18.2 expression may be associated with histological differentiation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Since CLDN18.2 is upregulated after chemotherapy in gastric cancer cell lines [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], chemotherapy-induced CLDN18.2 upregulation was observed in poorly differentiated adenocarcinoma in this study. This suggests that the monoclonal antibody zolbetuximab targeting CLDN18.2 might be more effective for highly malignant cancers and could be used in neoadjuvant or recurrent first-line treatments with chemotherapy. However, careful interpretation is needed, as evaluating only two samples for CLDN18.2 expression is insufficient to confirm variations based on tumor differentiation or chemotherapy.\u003c/p\u003e \u003cp\u003eThis study has limitations. We report two cases with different biological features: GEJ adenocarcinoma and gastric cancer with bulky lymph nodes, which limited our ability to examine the FLOT chemotherapy efficacy comprehensively. Additionally, our findings may not be comparable with other studies in Asian populations, where neoadjuvant chemotherapy regimens mainly consist of fluorouracil and platinum, with limited FLOT data in China [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, perioperative FLOT chemotherapy is effective for advanced resectable gastric or GEJ adenocarcinoma, even in Asian populations, leading to R0 resection with minimally invasive surgery. CLDN18.2 detection may help predict chemotherapy efficacy and guide the combination of chemotherapy with zolbetuximab in various treatment settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.jp) for English language editing and Kohei Yamaguchi for assistance with pathological data curation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatements and Declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTohru Takahashi, Takahiro Ishii, Hagiwara Masahiro, and\u0026nbsp;Yusuke Mizukami\u0026nbsp;contributed to the\u0026nbsp;conception and design of the study. Tohru Takahashi, Takahiro Ishii, Taku Maejima, Dai Miyazaki, Susumu Fukahori, and Yusuke Ono contributed to acquisition,\u0026nbsp;analysis, and\u0026nbsp;interpretation of data.\u0026nbsp;Eriko Aimono, Taichi Kimura, and Mitsuru Yanai performed\u0026nbsp;histological analysis.\u0026nbsp;Tohru Takahashi drafted the first manuscript. Yusuke Mizukami\u0026nbsp;provided administrative support.\u0026nbsp;Takahiro Ishii was responsible for systemic chemotherapy. Tohru Takahashi performed laparoscopic resections for gastric or gastroesophageal junction adenocarcinomas, and Taku Maejima supported the operations as\u0026nbsp;an assistant.\u0026nbsp;All authors critically revised the manuscript, agreed to be fully accountable for ensuring\u0026nbsp;integrity, and have read and approved\u0026nbsp;the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Tokushukai Group Ethics Committee\u0026nbsp;(Aug 29, 2024/No: TGE02602-012).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent to participate and to publish was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209\u0026ndash;249. https://doi.org/10.3322/caac.21660\u003c/li\u003e\n \u003cli\u003eCunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11\u0026ndash;20. https://doi.org/10.1056/NEJMoa055531\u003c/li\u003e\n \u003cli\u003eAl-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, et al (2019) Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393:1948\u0026ndash;1957. https://doi.org/10.1016/S0140-6736(18)32557-1\u003c/li\u003e\n \u003cli\u003eTsuburaya A, Mizusawa J, Tanaka Y, Fukushima N, Nashimoto A, Sasako M, Stomach Cancer Study Group of the Japan Clinical Oncology G (2014) Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis. Br J Surg 101:653\u0026ndash;660. https://doi.org/10.1002/bjs.9484\u003c/li\u003e\n \u003cli\u003eTakahari D, Ito S, Mizusawa J, Katayama H, Terashima M, Sasako M, et al (2020) Long-term outcomes of preoperative docetaxel with cisplatin plus S-1 therapy for gastric cancer with extensive nodal metastasis (JCOG1002). Gastric Cancer 23:293\u0026ndash;299. https://doi.org/10.1007/s10120-019-01007-w\u003c/li\u003e\n \u003cli\u003eIwasaki Y, Terashima M, Mizusawa J, Katayama H, Nakamura K, Katai H, et al (2021) Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an open-label, phase 3, randomized controlled trial. Gastric Cancer 24:492\u0026ndash;502. https://doi.org/10.1007/s10120-020-01136-7\u003c/li\u003e\n \u003cli\u003eHofheinz RD, Merx K, Haag GM, Springfeld C, Ettrich T, Borchert K, et al (2022) FLOT versus FLOT/Trastuzumab/Pertuzumab perioperative therapy of human epidermal growth factor receptor 2-positive resectable esophagogastric adenocarcinoma: a randomized phase II trial of the AIO EGA study group. J Clin Oncol 40:3750\u0026ndash;3761. https://doi.org/10.1200/JCO.22.00380\u003c/li\u003e\n \u003cli\u003eLorenzen S, Gotze TO, Thuss-Patience P, Biebl M, Homann N, Schenk M, et al (2024) Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric cancer: interim results from the randomized, multicenter, phase II/III DANTE/IKF-s633 trial. 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Gastric Cancer 27:366\u0026ndash;374. https://doi.org/10.1007/s10120-023-01453-7\u003c/li\u003e\n \u003cli\u003eKita R, Yanagimoto Y, Imazeki H, Booka E, Tsushima T, Mizusawa J, et al (2024) Protocol digest of a randomized controlled adaptive Phase II/III trial of neoadjuvant chemotherapy for Japanese patients with oesophagogastric junction adenocarcinoma: Japan Clinical Oncology Group Study JCOG2203 (NEO-JPEG). Jpn J Clin Oncol 54:206\u0026ndash;211. https://doi.org/10.1093/jjco/hyad149\u003c/li\u003e\n \u003cli\u003eHashimoto T, Nakayama I, Ohashi M, Mizusawa J, Kawachi H, Kita R, et al (2023) Randomized phase II study comparing neoadjuvant 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for patients with type 4 or large type 3 gastric cancer. 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Ther Adv Med Oncol 11:1758835919838963. https://doi.org/10.1177/1758835919838963\u003c/li\u003e\n \u003cli\u003eHoeppner J, Brunner T, Lordick F, Schmoor C, Kulemann B, Neumann UP, et al (2024) Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). J Clin Oncol 42:LBA1-LBA. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA1\u003c/li\u003e\n \u003cli\u003eWang C, Wang Y, Chen J, Wang Y, Pang C, Liang C, et al (2023) CLDN18.2 expression and its impact on prognosis and the immune microenvironment in gastric cancer. BMC Gastroenterol 23:283. https://doi.org/10.1186/s12876-023-02924-y\u003c/li\u003e\n \u003cli\u003eAngerilli V, Ghelardi F, Nappo F, Grillo F, Parente P, Lonardi S, et al (2024) Claudin-18.2 testing and its impact in the therapeutic management of patients with gastric and gastroesophageal adenocarcinomas: A literature review with expert opinion. Pathol Res Pract 254:155145. https://doi.org/10.1016/j.prp.2024.155145\u003c/li\u003e\n \u003cli\u003eNishibata T, Weng J, Omori K, Sato Y, Nakazawa T, Suzuki T, et al (2024) Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models. 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Cancer Manag Res 11:3009\u0026ndash;3020. https://doi.org/10.2147/CMAR.S200883\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gastroesophageal junction adenocarcinoma, perioperative chemotherapy, FLOT, Claudin18.2, laparoscopic curative resection ","lastPublishedDoi":"10.21203/rs.3.rs-5245561/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5245561/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel has improved survival in patients with locally advanced resectable gastric or gastroesophageal junction adenocarcinomas in Europe.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e We report two cases of laparoscopic curative resection with perioperative docetaxel-based chemotherapy for advanced gastroesophageal junction or gastric adenocarcinoma and investigated variations in Claudin18.2 expressions associated with chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e Preoperative four-cycle docetaxel-based chemotherapy enabled laparoscopic total gastrectomy with distal esophagectomy via trans-hiatal approach or laparoscopic distal gastrectomy with extensive lymph node dissection. Postoperative left inferior pulmonary arterial thrombosis and chylous ascites recovered with pharmacotherapy and lipiodol lymphatic embolization. Despite discontinuing postoperative one-cycle chemotherapy, no recurrence was observed for over 1.5 years and 1 year. Immunohistochemical staining showed increased Claudin18.2 expression in undifferentiated adenocarcinomas in the resected specimens than in pre-chemotherapeutic biopsies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e Perioperative docetaxel-based chemotherapy was effective for Japanese patients with gastroesophageal junction and gastric adenocarcinoma, suggesting a combination treatment with anti-Claudin18.2 antibody as neoadjuvant or first-line chemotherapy.\u003c/p\u003e","manuscriptTitle":"Laparoscopic curative resection following perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel and its influence on Claudin18.2 expression in advanced gastric or gastroesophageal junction adenocarcinoma: A two-case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-15 08:26:21","doi":"10.21203/rs.3.rs-5245561/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f29bf670-688b-4865-8fd1-61da7a855352","owner":[],"postedDate":"October 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-26T03:56:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-15 08:26:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5245561","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5245561","identity":"rs-5245561","version":["v1"]},"buildId":"pf3fE39SIOqb-0xH_OWvX","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}