PURPOSE Trifluridine/tipiracil (FTD/TPI) plus ramucirumab may improve survival as a later-line therapy for advanced gastric cancer (GC); however, prospective evidence is limited. PATIENTS AND METHODS We conducted a multicenter, prospective phase II trial of FTD/TPI plus ramucirumab in patients with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma who had received at least two previous systemic regimens for advanced disease, including a ramucirumab-containing regimen. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function. Patients received oral FTD/TPI (35 mg/m 2 , days 1-5 and 8-12) and ramucirumab (8 mg/kg, days 1 and 15) every 28 days. The primary end point was time to treatment failure (TTF), and the secondary end points were progression-free survival (PFS), overall survival (OS), response, disease control rate (DCR), relative dose intensity (RDI), and safety. RESULTS Between February 2022 and March 2024, 32 patients were enrolled (median age, 72.5 years; 53.1% male). The median TTF was 4.0 months (95% CI, 2.8 to 5.0), meeting the primary end point. Median PFS and OS were 4.8 (95% CI, 2.8 to 8.3) and 12.2 months (95% CI, 7.8 to 17.2), respectively. Among 26 patients with measurable disease, objective response rate was 11.5%, and DCR was 76.9%. Mean RDI was 78.6% for FTD/TPI and 93.1% for ramucirumab, supporting feasibility in this cohort. Grade ≥3 neutropenia occurred in 53.1% and febrile neutropenia in 9.4%. Frequent nonhematologic events were anorexia (68.8%) and fatigue (59.4%), mostly grade 1 to 2. A modified FTD/TPI schedule was introduced in 15 patients and maintained dose delivery while reducing neutropenia, with no febrile events. CONCLUSION FTD/TPI plus ramucirumab met its primary end point and was feasible with manageable safety in heavily pretreated advanced GC. Given the single-arm design, the efficacy findings are hypothesis-generating and warrant confirmation in larger randomized trials.

Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy, and reliable biomarkers for predicting metastasis and prognosis are urgently needed. Through comprehensive transcriptomic profiling, we identified Bardet–Biedl syndrome 5 (BBS5) as a potential biomarker of clinical significance. Transcriptome analysis was performed on surgical specimens from eight ESCC patients with distant metastatic recurrence (discovery cohort, n = 8). BBS5 mRNA expression was quantified by Reverse Transcription Quantitative PCR (RT-qPCR) across 18 ESCC cell lines, and siRNA-mediated knockdown was conducted in two independent high-expressing lines (KYSE1260 and KYSE590) to assess proliferation in both cell lines and migration and invasion in KYSE1260. In 266 patients who underwent curative esophagectomy, BBS5 mRNA levels were measured by RT-qPCR and correlated with clinicopathological features and survival outcomes. Among these, 98 cases additionally underwent immunohistochemical (IHC) assessment of BBS5 protein expression. A second (independent) cohort of 175 ESCC patients was further analyzed using tissue microarray (TMA)–based IHC to validate prognostic relevance. BBS5 knockdown significantly inhibited proliferation of the BBS5-high ESCC cell lines KYSE1260 and KYSE590, markedly suppressed invasion in KYSE1260 and reduced the migratory capacity of KYSE1260. Tumors exhibited significantly higher BBS5 mRNA expression than adjacent normal tissues. High BBS5 expression was associated with significantly shorter overall survival (P = 0.025), and multivariate analysis identified BBS5 expression as an independent predictor of overall and disease-free survival. IHC analysis confirmed the association between high BBS5 expression and poor prognosis, which was further validated in the second (independent) TMA cohort, in which high BBS5 protein expression independently predicted both overall and disease-free survival. BBS5 promotes ESCC cell proliferation, migration and invasion and serves as a robust prognostic indicator in two independent patient cohorts, highlighting its potential utility as a clinically relevant biomarker.

BackgroundImmune checkpoint inhibitors (ICIs) have become a standard first-line treatment for unresectable esophageal squamous cell carcinoma (ESCC). However, a substantial proportion of patients have early disease progression. Reliable pretreatment biomarkers capable of predicting ICI efficacy are urgently needed. Immunoglobulin A (IgA) has been implicated in shaping an immunosuppressive tumor microenvironment, yet its clinical relevance in ESCC remains unclear.MethodsSerum IgA levels were measured in patients who had unresectable ESCC treated with first-line ICI-based therapy (n = 20) and compared with those in disease control subjects (non-ICI [n = 16] vs resectable ESCC [n = 26]) and healthy control subjects (n = 58). Associations between pretreatment serum IgA levels, survival times, and clinicopathologic variables were analyzed. The patients in each cohort were stratified into high- and low-IgA groups using cohort-specific median values.ResultsSerum IgA levels were significantly higher in all the ESCC patient groups than in the healthy control subjects. In the ICI-treated group, high pretreatment serum IgA was significantly associated with shorter progression-free survival (hazard ratio, 9.26; 95% confidence interval, 1.96-43.7; P = 0.005). No correlation between serum IgA and prognosis was observed in the non-ICI and resectable ESCC groups, indicating ICI-specific relevance. Pretreatment serum IgA did not correlate with clinicopathologic factors, including tumor markers and immune-related adverse events.ConclusionsHigh pretreatment serum IgA may serve as a novel, minimally invasive biomarker predicting poor response to ICI therapy in unresectable ESCC. Serum IgA assessment could support treatment decision-making and patient stratification in this era of expanding immunotherapy use.

BACKGROUND:Human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) presents significant therapeutic challenges due to its molecular heterogeneity. Previous studies suggest that immune checkpoint inhibitors (ICIs) may enhance the efficacy of subsequent HER2-targeted therapy. However, evidence suggesting an optimal sequence for nivolumab and trastuzumab deruxtecan (T-DXd) treatment is limited. This exploratory analysis of EN-DEAVOR evaluated the effectiveness and safety of administering T-DXd relative to the timing of prior ICI administration. METHODS:This study assessed real-world outcomes of T-DXd in patients with HER2-positive AGC stratified by prior ICI exposure: within 2 months of nivolumab (Group A), >2 months (Group B), and no prior nivolumab (Group C). The primary effectiveness endpoints included real-world progression-free survival (rwPFS) and objective response rate (ORR). Safety endpoints included grade ≥ 3 adverse events (AEs). RESULTS:Among 311 eligible patients, Group A showed the longest median rwPFS (n = 63; 6.9 months) compared with Group B (n = 63; 4.6 months) and Group C (n = 185; 4.2 months). The risk of progression was significantly lower in Group A compared with Group B (hazard ratio [95% confidence interval]: 0.6 [0.4-0.9]; P = .0074). ORR was numerically highest in Group A (54.9%) versus Group B (30.8%) and Group C (43.4%). More patients in Group B (58.7%) experienced grade ≥ 3 AEs than in Group A (50.8%) and Group C (43.8%). No new safety signals were observed. CONCLUSIONS:Initiating T-DXd within 2 months post-ICI may enhance therapeutic efficacy in HER2-positive AGC without affecting safety, supporting a potential sequencing option after ICI therapy.

Abstract Topic Esophageal Cancer: Other Background Systemic inflammation and immune status play a critical role in the development and progression of cancers. We evaluated the clinical significance of the preoperative systemic immune-inflammation index (SII) for predicting the long-term outcomes of patients who received neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). Methods The subjects of this study were 277 patients who underwent curative resection of ESCC after neoadjuvant therapy. The SII was calculated as follows: SII = neutrophil × platelet/lymphocyte counts. Patients were stratified into high and low preoperative SII groups according to the cut-off value calculated by a receiver operating characteristic curve analysis. The Kaplan–Meier method and Cox proportional regression analysis were used to evaluate the correlation of SII to prognosis. Results The optimal cutoff of the preoperative SII was set at 700. Patients were categorized into preoperative SII-low (n = 203) and SII-high (n = 74) groups. The preoperative SII was significantly associated with tumor size. The relapse-free survival of patients in the SII-high group was significantly shorter (P = 0.0087) and preoperative SII-high was identified as an independent prognostic factor (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.06–2.28, P = 0.0229). The prevalence of hematogenous recurrence was significantly higher in the SII-high group. When we stratified patients into three groups with an additional cutoff value of 1200, we observed an incremental decrease in relapse-free survival rates. Conclusion High preoperative SII was associated with shorter relapse-free survival times for ESCC patients who underwent curative resection after neoadjuvant therapy

BACKGROUND/AIM:Formimidoyltransferase cyclodeaminase (FTCD) is a folate-metabolizing enzyme involved in histidine catabolism and intracellular folate homeostasis. Although FTCD has been implicated in cancer progression and epithelial-mesenchymal transition (EMT) in several malignancies, its oncological role in colorectal cancer (CRC) remains unclear. This study investigated the biological and clinical significance of FTCD in CRC. MATERIALS AND METHODS:FTCD expression was evaluated in CRC cell lines and clinical specimens from 301 patients with resectable stage II/III CRC who underwent curative resection. Functional analyses, including proliferation, invasion, migration, and subcutaneous xenograft assays, were performed using small interfering RNA-mediated FTCD knockdown. Associations between FTCD expression and clinicopathological factors, recurrence patterns, disease-free survival (DFS), and overall survival (OS) were analyzed. External validation was performed using Kaplan-Meier Plotter and The Cancer Genome Atlas (TCGA) cohorts. RESULTS:FTCD knockdown significantly suppressed proliferation, invasion, and migration in CaR-1 and COL-3-JCK cells and reduced tumor growth in vivo. FTCD expression positively correlated with multiple EMT-related genes, particularly COL1A2, SPARC, FZD7, and BMP7. High FTCD expression was significantly associated with deeper tumor invasion and left-sided tumors. Patients with high FTCD expression showed significantly worse DFS [hazard ratio (HR)=2.00, p=0.012] and OS (HR=2.96, p=0.009). In multivariate analysis, high FTCD expression remained an independent prognostic factor for OS (HR=2.47, p=0.030), but not for DFS. Peritoneal and bone recurrences were more frequent in the high FTCD group. External validation cohorts showed similar prognostic trends. CONCLUSION:FTCD may serve as a useful prognostic biomarker associated with aggressive tumor behavior and poor survival outcomes and may be a potential therapeutic target requiring further validation in CRC.

ABSTRACT Zolbetuximab is an anti‐claudin18.2 (CLDN18.2) antibody, and the addition of zolbetuximab in combination with fluoropyrimidine and oxaliplatin as a first‐line treatment for CLDN18.2‐positive and HER2‐negative gastric or gastroesophageal junction adenocarcinoma has been shown to improve survival. However, the efficacy and safety of the combination of zolbetuximab with combinations other than fluoropyrimidine and oxaliplatin have not been elucidated. The objective of the present study is to evaluate the feasibility of combination treatment with trifluridine/tipiracil (FTD/TPI), which is effective as a third‐ or later‐line treatment, and zolbetuximab. In this study, 32 patients with CLDN18.2‐positive and HER2‐negative unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma who received two or more lines of chemotherapy will be recruited. The patients will receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and days 8–12 every 4 weeks) plus zolbetuximab (an initial dose of 800 mg/m2 or 400 mg/m2 depending on prior zolbetuximab exposure, followed by 400 mg/m2 every 3 weeks). The primary endpoint is treatment‐emergent events leading to the discontinuation of zolbetuximab. The secondary endpoints are the time to treatment failure, progression‐free survival, overall survival, response rate, incidence of adverse events, and incidence of Grade 3 or higher adverse events. The results will be used to evaluate the feasibility of the treatment and are expected to be used to evaluate whether future trials can be conducted.

367 Background: Later-line treatment options for advanced gastric cancer (AGC), including nivolumab, irinotecan, and trifluridine/tipiracil (FTD/TPI), provide limited clinical benefit. Recent studies suggest that FTD/TPI with ramucirumab (Ram) may improve outcomes, but prospective data in clinical practice is insufficient. Methods: This multicenter, prospective, single-arm, phase II trial evaluated FTD/TPI plus Ram as third-line or later therapy in unresectable or recurrent AGC. Eligible patients had prior fluoropyrimidine-, platinum-, and Ram-containing regimens. FTD/TPI (35 mg/m²) was administered orally twice daily on days 1–5 and 8–12, and Ram (8 mg/kg) intravenously on days 1 and 15, every 28 days. The primary endpoint was time to treatment failure (TTF); secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), relative dose intensity (RDI), and safety. Results: Between February 2022 and March 2024, 32 patients were enrolled (median age, 72.5 years; 53.1% male). Ram was reintroduced as a rechallenge in 18 patients (56.3%) and continued from the prior therapy in 14 (43.8%). The median TTF was 4.0 months (95% CI, 2.8–5.0), meeting the primary endpoint. Median PFS and OS were 4.8 months (95% CI, 2.8–8.3) and 12.2 months (95% CI, 7.8–17.2), respectively. Among 26 patients with measurable lesions, ORR was 11.5% and DCR was 76.9%. The mean RDI was 78.6% for FTD/TPI and 93.1% for Ram. Post-discontinuation therapy was given to 17 patients (53.1%). Grade ≥3 neutropenia occurred in 17 patients (53.1%), and febrile neutropenia in 3 (9.4%). Common non-hematologic adverse events were anorexia (68.8%), fatigue (59.4%), and proteinuria (59.4%), mostly grade 1–2. Dose modification to a biweekly FTD/TPI schedule was implemented in 15 patients at the physician’s discretion for grade ≥3 neutropenia or other adverse events. Grade ≥3 neutropenia occurred in 10 of 50 cycles (20%) under this schedule, with no febrile neutropenia observed. Conclusions: FTD/TPI plus ramucirumab demonstrated promising efficacy and manageable toxicity as third-line or later therapy for unresectable or recurrent AGC. These findings warrant further investigation in larger, randomized studies to confirm the clinical benefits. Clinical trial information: jRCTs041210105 .

Postoperative adjuvant chemotherapy using oxaliplatin in addition to 5-FU-based anticancer agents has become the standard treatment for colorectal cancer, however, there is insufficient evidence regarding the efficacy and safety of oxaliplatin combination therapy in the elderly patients. In this study, retrospective analysis of the results from the CCOG-1302 study was performed to confirm them. The patients in the CAPOX continuous (8 courses of CAPOX) and intermittent (2 courses of CAPOX + 4 courses of capecitabine + 2 courses of CAPOX) treatment arms in the CCOG-1302 study were divided into two groups, namely, the elderly (≥ 70) and non-elderly (< 70 years) groups. The adverse events, residual peripheral sensory neuropathy (PSN) and prognosis were analyzed. The incidence of grade 3 or higher hematologic and non-hematologic toxicities in the continuous and intermittent treatment arm were not significantly different between the elderly and non-elderly groups. During the follow-up period, the percentages of grade I or higher PSN residuals were significantly higher among the elderly individuals in the continuous treatment arm at years 2, 3, 4, and 5. On the other hand, PSN decreased over time in the intermittent treatment arm as well as in the elderly and non-elderly patients. The 3-year DFS was not significantly different between the elderly and non-elderly groups in the continuous and intermittent treatment arms. Oxaliplatin combination chemotherapy can be safely administered to elderly patients. In addition, intermittent administration may be more useful in elderly individuals for the prevention of PSN.

Objective:This study aimed to clarify the current status of cytological methodologies in high-volume gastric cancer centers and explore the relationship between methodology and positive rates. Background:International standards for peritoneal lavage cytological methods for collection, handling, and cytopreparation in gastric cancer have not been established yet. Methods:A questionnaire survey on cytological methodology was conducted in 61 institutions within the Japan Clinical Oncology Group in 2024. Aggregated data from patients with clinical T3 to T4 gastric cancer with cytology from 2017 to 2022 were collected to calculate positivity rates in each institution for the comparison of methodologies between institutions with high- and low-positivity rates. Results:Thirty-three institutions (64%) collected samples from 2 sites, primarily from the Douglas pouch and left subphrenic area. Fifty-eight institutions (95%) used ≤100 mL of normal saline for injection, and 51 (87%) performed intraoperative rapid cytology. Twenty-five institutions (41%) used additives in samples. Scraping glass slides and centrifugal direct smears were predominant cytopreparation methods in 31 (51%) and 22 (36%) institutions, respectively, and ethanol fixation was employed in 53 (87%). In 61 institutions (11,367 patients), the median cytological positivity rate for clinical T3 to T4 gastric cancer was 8.5% (2.1%-28.3%). Institutions with higher positivity rates more often employed ethanol fixation (97% vs. 77%, P = 0.026) and used ≤50 mL of normal saline for injection (61% vs. 37%, P = 0.074). Conclusions:Even among Japanese high-volume centers, cytological methodologies for gastric cancer lack uniformity, thereby leading to substantial variability in the proportion of positive cytology.

Enterovesical fistula (EVF) in Crohn's disease (CD) often does not improve with medical treatment and requires surgical treatment. The surgical treatment strategy for EVF in CD is definitive resection of the intestinal tract side, and performing a leak test using dye injection into the bladder after EVF dissection to determine the appropriate surgical procedure for the bladder side. This study aimed to evaluate the outcomes of surgical treatment for EVF in CD. Twenty-one patients who underwent surgery for EVF between 2006 and 2021 were included and retrospectively evaluated for clinical background, surgical procedures, and postoperative complications. The most common origin of EVF was the ileum (17 cases; 81%), and the most common site of EVF formation was the apex (12; 57%). Surgical approaches were laparotomy in 11 (52%) cases and laparoscopy in 10 (48%). Surgical procedures on the bladder side were fistula dissection in 13 (62%) cases and sutured closure of fistula in 8 (38%). A comparison of approaches revealed no significant difference in operative time, but the amount of blood loss was significantly less in the laparoscopy (p < 0.01). There was no significant difference in the occurrence of postoperative complications between approaches. Postoperative anti-TNF-α antibody agents were used in 17 (81%) cases, and there were no cases of recurrent EVF. In conclusion, definitive resection of the intestinal tract and minimal treatment on the bladder side were sufficient to achieve satisfactory outcomes for EVF in CD.

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m2) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer.

BACKGROUND/AIM:Proximal gastrectomy (PG) is a therapy for early-stage proximal gastric cancer and offers advantages such as the preservation of food storage capacity and less body weight loss (BWL). Nevertheless, significant BWL following PG may occur, affecting the patient's well-being and survival. In this study, we aimed to identify the relevant factors for BWL following PG by analyzing an institutional database of patients.PATIENTS AND METHODS:We enrolled 58 consecutive patients who underwent PG for gastric or esophagogastric junction cancer at our institution between April 2004 and March 2021. Based on BWL at 12 months postoperatively, we retrospectively compared and examined patient characteristics, surgical details, and nutritional markers.RESULTS:The mean BWL of the 58 patients included in this analysis was 14.0±7.2%. When the patients were divided into BWL-moderate (n=29) and BWL-severe (n=29) groups using a cutoff value of 15.7%, the latter experienced early BWL within 1 month postoperatively, primarily due to body fat mass reduction, with no recovery during the 60 months of follow up. In contrast, gradual recovery was observed among patients in the BWL-moderate group after experiencing the lowest body weight 24 months postoperatively. A greater decrease in body fat mass than in muscle mass was observed in both groups. Blood hemoglobin levels did not recover in the BWL-severe group.CONCLUSION:The BWL-severe group after proximal gastrectomy demonstrated significantly greater early postoperative BWL, primarily attributed to a reduction in body fat mass, with hardly any recovery. Early postoperative nutritional intervention might be proposed to prevent long-term BWL.

274 Background: Relatively limited clinical data exists for patients who receive T-DXd treatment in the 3L+ setting for HER2-positive unresectable advanced/recurrent gastric or gastroesophageal junction cancer. Insufficient data exists on real world patient populations that are likely to be excluded from clinical trials (e.g., elderly patients, those with significant co-morbidities). Therefore, this study was designed to evaluate the real-world clinical effectiveness and safety of T-DXd in patients with HER2-positive gastric cancer. Methods: This study (UMIN000049032) was a real-world, multicenter, non-interventional, retrospective cohort study conducted in Japan. Patients with HER2-positive unresectable advanced/recurrent gastric or gastroesophageal junction cancer treated with T-DXd were enrolled. The patients were first administered T-DXd between Sep 2020, when T-DXd became available for clinical use in Japan, and Sep 2021. We followed up on these patients' records until Sep 2022. The endpoints were overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response (ORR), adverse events (AEs) of Grade ≥3, and adverse events leading to dose reduction, interruption, or discontinuation. Results: A total of 318 patients were enrolled, and 312 patients were analyzed, excluding 6 patients due to double enrollment or miss-enrollment (median age 70 years, performance status 0 or 1/≥2 [87%/12%], 43% patients with ascites). Median OS, rwPFS, and TTF were 8.90 months, 4.57 months, and 3.94 months, respectively. Overall ORR was 32.7%; it was 43.8% in the 226 patients with a target lesion. Regarding safety, the incidence of Grade ≥ 3 AEs was 48.4%. A total of 190/312 (60.9%) patients treated with T-DXd experienced dose reduction, interruption, or discontinuation of T-DXd treatment due to AEs. The most common reasons for dose reduction or interruption were neutrophil count decreased, anorexia, and malaise, while the most common reasons for discontinuation were interstitial pneumonia, anorexia, malaise, and nausea. Conclusions: This study demonstrates the effectiveness and safety of T-DXd in the 3L+ setting in real-world patients with HER2-positive gastric or gastroesophageal cancer. No new safety signals were identified on the basis of this study.

BACKGROUND/AIM:Organs of the digestive system are frequent sites of cancer development, and digestive tract cancers are the leading causes of death worldwide, including in Japan. Most of these cancers are associated with smoking or drinking habits. This study focused on the clinical and genomic characteristics of patients with these cancers using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, which comprises a large volume of data on Japanese patients who have undergone tumor profiling gene panel tests.PATIENTS AND METHODS:The genomic and clinical data from patients with digestive tract cancers registered in C-CAT between 2019 and 2023 were retrospectively reviewed. The data were derived from 412 patients with esophageal squamous cell carcinoma, 558 with gastric adenocarcinoma, 3,368 with colorectal adenocarcinoma, 139 with hepatocellular carcinoma, 2,050 with cholangiocarcinoma, and 2,552 with pancreatic ductal adenocarcinoma.RESULTS:CDKN2A, CDKN2B, and MTAP mutations were associated with both smoking and drinking history, and patients with these mutations had a worse prognosis. Almost all gene alterations in CDKN2B and MTAP were deletions, often accompanied by CDKN2A deletion. CDKN2A mutation emerged as the most decisive prognostic factor among these mutations. Although CDKN2A mutations were frequently seen in esophageal squamous cell carcinoma, cholangiocarcinoma, and pancreatic ductal adenocarcinoma, statistically significant differences in survival outcomes were only identified in the latter two.CONCLUSION:CDKN2A mutations were associated with smoking and drinking in digestive cancers. This mutation was prevalent among patients with cholangiocarcinoma and pancreatic ductal adenocarcinoma, for whom they could serve as prognostic factors.

Trastuzumab-deruxtecan (T-DXd) was approved for the treatment of HER2-positive patients with advanced gastric cancer in Japan based on the results of the DESTINY-Gastric01 trial. This study aimed to collect real-world data and evaluate the effectiveness and safety of T-DXd. Patients aged ≥ 20 years at the start of T-DXd administration with a histopathologically confirmed diagnosis of HER2-positive unresectable advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma that had worsened after chemotherapy were enrolled in this retrospective cohort study. Key outcomes included T-DXd treatment status, overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response rate and frequency of grade ≥ 3 adverse events (AEs). Of the 312 patients included in the analysis, 75.3

BACKGROUND/AIM:The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor's gene profile is crucial to avoid positive MSM. MATERIALS AND METHODS:Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets. RESULTS:Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p<0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests. CONCLUSION:Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes.

Large type 3 (diameter ≥ 8 cm) and type 4 gastric cancers have been arbitrarily combined in Japan as a single entity. However, whether these two types are oncologically similar remain unclear. This study aimed to clarify this issue. In this retrospective study, we analyzed a database of 3,575 patients from nine institutions who underwent gastrectomy between 2010 and 2014. Using propensity scores to balance significant variables, we compared prognoses and tumor recurrences. Of patients with clinical T3/T4 who underwent R0 resection, 75 and 73 had large type 3 and 4 tumors, respectively. Patients with type 4 tumors had significantly lower overall survival rates than those of patients with large type 3 tumors (hazard ratio [HR] 1.77; 95

Pancreatic fistula after gastrectomy with lymph node dissection is associated with prolonged hospital stay and critical complications such as intra-abdominal bleeding and sepsis. Polyglycolic acid (PGA) sheets are absorbable suture reinforcement materials. A randomized Phase II trial has been planned to evaluate the effect of PGA sheets on preventing postoperative pancreatic fistula. A total of 320 patients will be recruited from thirteen institutions. Patients who are scheduled to undergo distal or total gastrectomy will be randomly allocated into the PGA group or control group, and the dissected area around the pancreas will be covered by the PGA sheet in the PGA group. The primary endpoint will be the maximum value of drain amylase concentration up to 5 days after surgery. The secondary endpoints will be as follows: transition of value of amylases of drain discharge, incidence of pancreatic fistula, incidence of intra-abdominal abscess, white blood cell count, value of C-reactive protein, incidence of postoperative complication, duration of antibiotic agents administration, duration of abdominal drainage, usage of octreotide, duration of hospital stay, incidence of bleeding in abdominal cavity, mortality, and incidence of reoperation.