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1.
Eur J Cancer ; 203: 114043, 2024 May.
Article En | MEDLINE | ID: mdl-38598921

BACKGROUND: Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients. METHODS: We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated. RESULTS: Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex. CONCLUSIONS: This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC.


Esophagogastric Junction , Microsatellite Instability , Randomized Controlled Trials as Topic , Stomach Neoplasms , Humans , Male , Female , Esophagogastric Junction/pathology , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Prognosis , Sex Factors , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Esophageal Neoplasms/therapy , Esophageal Neoplasms/drug therapy , Middle Aged , Aged , Chemotherapy, Adjuvant
2.
Sci Rep ; 14(1): 7030, 2024 03 25.
Article En | MEDLINE | ID: mdl-38528113

The enhanced recovery after surgery (ERAS) protocol, including prokinetic medications, is commonly used to prevent postoperative ileus. Prospective studies evaluating the effectiveness of mosapride citrate, a prokinetic 5-hydroxytryptamine 4 receptor agonist, in patients undergoing gastrectomy within the ERAS framework are lacking. This double-blind randomized trial included patients who were scheduled for laparoscopic or robotic gastrectomy for gastric cancer. Participants were randomly assigned to either a control (placebo) or experimental (mosapride citrate) group, with drugs administered on postoperative days 1-5. Bowel motility was evaluated based on bowel transit time measured using radiopaque markers, first-flatus time, and amount of food intake. No significant differences were observed in baseline characteristics between the two groups. On postoperative day 3, no significant difference was observed in the number of radiopaque markers visible in the colon between the groups. All factors associated with bowel recovery, including the time of first flatus, length of hospital stay, amount of food intake, and severity of abdominal discomfort, were similar between the two groups. Mosapride citrate does not benefit the recovery of intestinal motility after minimally invasive gastrectomy in patients with gastric cancer. Therefore, routine postoperative use of mosapride citrate is not recommended in such patients.


Benzamides , Gastrectomy , Morpholines , Stomach Neoplasms , Humans , Benzamides/therapeutic use , Flatulence , Gastrectomy/adverse effects , Gastrectomy/methods , Laparoscopy/methods , Length of Stay , Morpholines/therapeutic use , Postoperative Complications/prevention & control , Prospective Studies , Stomach Neoplasms/surgery , Treatment Outcome
3.
Adv Mater ; 36(21): e2310671, 2024 May.
Article En | MEDLINE | ID: mdl-38279779

Zinc pnictides, particularly Zn3As2, hold significant promise for optoelectronic applications owing to their intrinsic p-type behavior and appropriate bandgaps. However, despite the outstanding properties of colloidal Zn3As2 nanocrystals, research in this area is lacking because of the absence of suitable precursors, occurrence of surface oxidation, and intricacy of the crystal structures. In this study, a novel and facile solution-based synthetic approach is presented for obtaining highly crystalline p-type Zn3As2 nanocrystals with accurate stoichiometry. By carefully controlling the feed ratio and reaction temperature, colloidal Zn3As2 nanocrystals are successfully obtained. Moreover, the mechanism underlying the conversion of As precursors in the initial phases of Zn3As2 synthesis is elucidated. Furthermore, these nanocrystals are employed as active layers in field-effect transistors that exhibit inherent p-type characteristics with native surface ligands. To enhance the charge transport properties, a dual passivation strategy is introduced via phase-transfer ligand exchange, leading to enhanced hole mobilities as high as 0.089 cm2 V-1 s-1. This study not only contributes to the advancement of nanocrystal synthesis, but also opens up new possibilities for previously underexplored p-type nanocrystal research.

5.
Exp Mol Med ; 55(5): 974-986, 2023 05.
Article En | MEDLINE | ID: mdl-37121972

The mesenchymal cancer phenotype is known to be clinically related to treatment resistance and a poor prognosis. We identified gene signature-based molecular subtypes of gastric cancer (GC, n = 547) based on transcriptome data and validated their prognostic and predictive utility in multiple external cohorts. We subsequently examined their associations with tumor microenvironment (TME) features by employing cellular deconvolution methods and sequencing isolated GC populations. We further performed spatial transcriptomics analysis and immunohistochemistry, demonstrating the presence of GC cells in a partial epithelial-mesenchymal transition state. We performed network and pharmacogenomic database analyses to identify TGF-ß signaling as a driver pathway and, thus, a therapeutic target. We further validated its expression in tumor cells in preclinical models and a single-cell dataset. Finally, we demonstrated that inhibition of TGF-ß signaling negated mesenchymal/stem-like behavior and therapy resistance in GC cell lines and mouse xenograft models. In summary, we show that the mesenchymal GC phenotype could be driven by epithelial cancer cell-intrinsic TGF-ß signaling and propose therapeutic strategies based on targeting the tumor-intrinsic mesenchymal reprogramming of medically intractable GC.


Stomach Neoplasms , Animals , Mice , Humans , Stomach Neoplasms/pathology , Epithelial-Mesenchymal Transition/genetics , Gene Expression Profiling , Transcriptome , Disease Models, Animal , Transforming Growth Factor beta/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Tumor Microenvironment/genetics
6.
BMC Med ; 21(1): 38, 2023 02 01.
Article En | MEDLINE | ID: mdl-36726166

BACKGROUND: Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1α in regulating cancer cell viability under metabolic and genotoxic stress remains elusive. METHODS: We investigated the PGC1α-mediated survival mechanisms in metabolic stress (i.e., glucose deprivation-induced metabolic stress condition)-resistant cancer cells. We established glucose deprivation-induced metabolic stress-resistant cells (selected cells) from parental tumor cells and silenced or overexpressed PGC1α in selected and parental tumor cells. RESULTS: Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1α to cell viability in metabolic stress conditions. Interestingly, in the mouse xenograft model of patient-derived drug-resistant cancer cells, each group treated with an anti-cancer drug alone showed no drastic effects, whereas a group that was co-administered an anti-cancer drug and a specific PMCA inhibitor (caloxin or candidate 13) showed marked tumor shrinkage. CONCLUSIONS: Our results suggest that PGC1α is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, inducing PMCA expression and allowing survival in glucose-deprived conditions. We have discovered a novel therapeutic target candidate that could be employed for the treatment of patients with refractory cancers.


Neoplasms , Mice , Humans , Animals , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Neoplasms/drug therapy , Stress, Physiological , Drug Resistance , Tumor Microenvironment
7.
Gut Liver ; 17(5): 753-765, 2023 09 15.
Article En | MEDLINE | ID: mdl-36789575

Background/Aims: AT-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancer (GC), especially Epstein-Barr virus (EBV)-associated and microsatellite instability high GC. The loss of ARID1A expression has been reported as a poor prognostic marker in GC. However, the relationships between ARID1A alteration and EBV-associated and microsatellite instability high GC, which are known to have a favorable prognosis, has hampered proper evaluation of the prognostic significance of ARID1A expression in GC. We aimed to analyze the true prognostic significance of ARID1A expression by correcting confounding variables. Methods: We evaluated the ARID1A expression in a large series (n=1,032) of advanced GC and analyzed the relationships between expression pattern and variable parameters, including clinicopathologic factors, key molecular features such as EBV-positivity, mismatch repair protein deficiency, and expression of p53 and several receptor tyrosine kinases including human epidermal growth factor receptor 2, epidermal growth factor receptor, and mesenchymal-epithelial transition factor. Survival analysis of the molecular subtypes was done according to the ARID1A expression patterns. Results: Loss of ARID1A expression was found in 52.5% (53/101) of mutL homolog 1 (MLH1)-deficient and 35.8% (24/67) of EBV-positive GCs, compared with only 9.6% (82/864) of the MLH1-proficient and EBV-negative group (p<0.001). The loss of ARID1A expression was associated only with MLH1 deficiency and EBV positivity. On survival analysis, the loss of ARID1A expression was associated with worse prognosis only in MLH1-proficient and EBV-negative GC. Multivariate analysis revealed that both loss of ARID1A and decreased ARID1A expression were independent worse prognostic factors in patients with advanced GC. Conclusions: Only in MLH1-proficient and EBV-negative GC, the loss of ARID1A expression is related to poorer prognosis.


Epstein-Barr Virus Infections , Stomach Neoplasms , Humans , Prognosis , DNA-Binding Proteins , Transcription Factors/genetics , Transcription Factors/metabolism , Epstein-Barr Virus Infections/complications , Stomach Neoplasms/metabolism , Microsatellite Instability , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Biomarkers, Tumor/genetics
8.
Gastric Cancer ; 25(6): 1039-1049, 2022 11.
Article En | MEDLINE | ID: mdl-35920999

BACKGROUND: In this post hoc analysis of the PRODIGY study, we aimed to investigate factors associated with survival outcomes and provide evidence for designing optimal perioperative treatment strategies for gastric cancer patients receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 212 patients in the neoadjuvant chemotherapy group of the PRODIGY study were included as the study population. The prognostic impact of clinicopathologic factors, including the initial radiological clinical stage (cStage) and post-neoadjuvant chemotherapy pathological stage (ypStage), was analyzed. RESULTS: The median age was 58 years. The majority of patients (77.4%) had cStage III disease, and about 10% and 25% had ypStage 0 and I disease, respectively. According to the initial cStage, progression-free survival (PFS) and overall survival (OS) were significantly different (P < 0.01). PFS and OS were also different according to the ypStage (P < 0.01). In multivariate analyses, cStage IIIC disease (vs. cStage II) and ypStage II and III disease (vs. ypStage 0/I) were independent factors for poor survival outcomes. Based on the patterns of PFS and OS according to both cStage and ypStage, three patient groups were defined. These groups showed distinct PFS and OS (P < 0.01) with 5-year PFS rates of 95.7%, 77.9%, and 31.3% and 5-year OS rates of 95.7%, 82.4%, and 42.5%, respectively. CONCLUSIONS: Both initial cStage and ypStage were independent factors for survival outcomes of gastric cancer patients treated with neoadjuvant chemotherapy. Efforts should be made to develop optimal peri-operative treatment strategies for patients at different risks according to cStage and ypStage.


Neoadjuvant Therapy , Stomach Neoplasms , Humans , Middle Aged , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Neoplasm Staging , Prognosis , Survival Rate , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
9.
J Clin Med ; 11(11)2022 May 29.
Article En | MEDLINE | ID: mdl-35683460

Extragastric recurrence of early gastric cancer (EGC) after curative resection is rare, but prognosis has been poor in previous reports. Recently, single patient classifier (SPC) genes, such as secreted frizzled-related protein 4 (SFRP4) and caudal-type homeobox 1 (CDX1), were associated with prognosis and chemotherapy response in stage II-III gastric cancer. The aim of our study is, therefore, to elucidate predictive factors for extragastric recurrence of EGC after curative resection, including with the expression of SPC genes. We retrospectively reviewed electronic medical records of 1974 patients who underwent endoscopic or surgical curative resection for EGC. We analyzed clinicopathological characteristics to determine predictive factors for extragastric recurrence. Total RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue and amplified by real-time reverse transcription polymerase chain reaction to evaluate expression of SPC genes. Overall incidences of extragastric recurrence were 0.9%. In multivariate analysis, submucosal invasion (odds ratio [OR] = 6.351, p = 0.032) and N3 staging (OR = 171.512, p = 0.012) were independent predictive factors for extragastric recurrence. Mean expression of SFRP4 in extragastric recurrence (-2.8 ± 1.3) was significantly higher than in the control group (-4.3 ± 1.6) (p = 0.047). Moreover, mean expression of CDX1 in extragastric recurrence (-4.6 ± 2.0) was significantly lower than in the control group (-2.4 ± 1.8) (p = 0.025). Submucosal invasion and metastasis of more than seven lymph nodes were independent predictive factors for extragastric recurrence. In addition, SFRP4 and CDX1 may be novel predictive markers for extragastric recurrence of EGC after curative resection.

10.
Nat Commun ; 13(1): 774, 2022 02 09.
Article En | MEDLINE | ID: mdl-35140202

Genomic profiling can provide prognostic and predictive information to guide clinical care. Biomarkers that reliably predict patient response to chemotherapy and immune checkpoint inhibition in gastric cancer are lacking. In this retrospective analysis, we use our machine learning algorithm NTriPath to identify a gastric-cancer specific 32-gene signature. Using unsupervised clustering on expression levels of these 32 genes in tumors from 567 patients, we identify four molecular subtypes that are prognostic for survival. We then built a support vector machine with linear kernel to generate a risk score that is prognostic for five-year overall survival and validate the risk score using three independent datasets. We also find that the molecular subtypes predict response to adjuvant 5-fluorouracil and platinum therapy after gastrectomy and to immune checkpoint inhibitors in patients with metastatic or recurrent disease. In sum, we show that the 32-gene signature is a promising prognostic and predictive biomarker to guide the clinical care of gastric cancer patients and should be validated using large patient cohorts in a prospective manner.


Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Stomach Neoplasms/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fluorouracil/therapeutic use , Gastrectomy , Gene Expression Profiling , Humans , Kaplan-Meier Estimate , Prognosis , Retrospective Studies , Risk Factors , Stomach Neoplasms/pathology , Transcriptome
11.
Gastric Cancer ; 25(1): 170-179, 2022 01.
Article En | MEDLINE | ID: mdl-34476643

BACKGROUND: In this exploratory analysis from the PRODIGY study, we aimed to define the radiological criteria to identify patients with gastric cancer who may derive maximal clinical benefit from neoadjuvant chemotherapy. PATIENTS AND METHODS: There were 246 patients allocated to receive surgery followed by adjuvant S-1 (SC group) and 238 allocated to receive neoadjuvant chemotherapy (CSC group). As the PRODIGY's radiological method of lymph node (LN) evaluation considers short diameter and morphology (the size and morphology method), a method considering only short diameter was also employed. In the SC group, the correlation between radiologic and pathologic findings was analyzed. The hazard ratio (HR) for the progression-free survival (PFS) of the CSC group was analyzed in subgroups with different cT/N stages. RESULTS: cT4 disease showed a sensitivity of 85.6% for detecting pT4 and had a low proportion of pathologic stage (pStage) I disease (4.5%). Among the criteria determined by different cT/N stages by each method of LN positivity, those involving cT4Nany or cT4N + by both methods had a minimal proportion of pStage I disease (≤ 5%), while cT4Nany by both methods and cT4N + by the size and morphology method exhibited ≥ 75.9% sensitivity for detecting pStage III disease. The relative risk reduction in PFS of the CSC group was greatest in patients meeting the cT4Nany criterion defined by both methods (HR 0.67, 95% confidence interval 0.48-0.93). CONCLUSIONS: The cT4Nany criterion, regardless of the radiological method used for LN evaluation, may help select patients with resectable gastric cancer for neoadjuvant chemotherapy.


Neoadjuvant Therapy , Stomach Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant , Humans , Lymph Nodes/pathology , Neoadjuvant Therapy/adverse effects , Neoplasm Staging , Stomach Neoplasms/diagnostic imaging , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology
12.
Chin J Cancer Res ; 33(5): 583-591, 2021 Oct 31.
Article En | MEDLINE | ID: mdl-34815632

OBJECTIVE: Benefits of adjuvant treatment in pT1N1 gastric cancer (GC) remain controversial. Additionally, an effective biomarker for early GC is the need of the hour. The prognostic and predictive roles of single patient classifier (SPC) were validated in stage II/III GC. In this study, we aimed to elucidate the role of SPC as a biomarker for pT1N1 GC. METHODS: The present retrospective biomarker study (NCT03485105) enrolled patients treated for pT1N1 GC between 1996 and 2012 from two large hospitals (the Y cohort and S cohort). For SPC, mRNA expression of four classifier genes (GZMB, WARS, SFRP4 and CDX1) were evaluated by real-time reverse transcription-polymerase chain reaction assay. The SPC was revised targeting pT1 stages and the prognosis was stratified as high- and low-risk group by the expression of SFRP4, a representative epithelial-mesenchymal transition marker. RESULTS: SPC was evaluated in 875 patients (n=391 and 484 in the Y and S cohorts, respectively). Among 864 patients whose SPC result was available, 41 (4.7%) patients experience GC recurrence. According to revised SPC, 254 (29.4%) patients were classified as high risk [123 (31.5%) and 131 (27.1%) in the Y and S cohorts, respectively]. The high risk was related to frequent recurrence in both Y and S cohort (log-rank P=0.023, P<0.001, respectively), while there was no difference byGZMB and WARS expression. Multivariable analyses of the overall-cohort confirmed the high risk of revised SPC as a significant prognostic factor [hazard ratio (HR): 4.402 (2.293-8.449), P<0.001] of GC. A significant difference was not detected by SPC in the prognosis of patients in the presence and absence of adjuvant treatment (log-rank P=0.670). CONCLUSIONS: The present study revealed the revised SPC as a prognostic biomarker of pT1N1 GC and suggested the use of the revised SPC for early-stage GC as like stage II/III.

13.
J Clin Oncol ; 39(34): 3884-3886, 2021 12 01.
Article En | MEDLINE | ID: mdl-34591598
15.
Ann Surg Oncol ; 28(13): 8908-8915, 2021 Dec.
Article En | MEDLINE | ID: mdl-34401986

BACKGROUND: Microsatellite status is a prognostic biomarker in advanced gastric cancer. This retrospective study aimed to investigate the usefulness of microsatellite status in predicting prognosis and response to adjuvant treatment in pT1N1 gastric cancer. PATIENTS AND METHODS: Among 875 patients who underwent radical gastrectomy for pT1N1 gastric cancer at two tertiary hospitals, 838 with available microsatellite instability (MSI) data were included and classified into two groups according to microsatellite status: microsatellite stable (MSS) and MSI-high (MSI-H). Recurrence-free survival rate and risk factors for tumor recurrence were analyzed. RESULTS: Of 838 gastric cancer patients, 100 (11.9%) were MSI-H and 307 (36.6%) received adjuvant treatment. During median follow-up of 70 months, 42 (5.0%) patients experienced gastric cancer recurrence; hematogenous recurrences were the most common (45.2%). Recurrence-free survival was similar in the MSS and MSI-H groups (p = 0.27), and adjuvant treatment did not show an oncological benefit over surgery alone for pT1N1 gastric cancer (p = 0.53). On univariate analysis, age, operation period, and Lauren classification were significantly associated with tumor recurrence, while adjuvant treatment and MSI status were not associated with tumor recurrence. On multivariate analysis, MSI status was not associated with tumor recurrence, and adjuvant treatment worsened the tumor recurrence risk [hazard ratio (HR) 2.373, 95% confidence interval (CI) 1.125-5.006, p = 0.023). CONCLUSION: MSI status may not be a prognostic factor for tumor recurrence or a predictor of response to adjuvant treatment in pT1N1 gastric cancer patients. Considering that the effect of adjuvant treatment to decrease the risk of tumor recurrence is not clear, it may not be indicated in pT1N1 patients.


Microsatellite Instability , Stomach Neoplasms , Chemotherapy, Adjuvant , Humans , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/surgery , Neoplasm Staging , Prognosis , Retrospective Studies , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/surgery
16.
Sci Rep ; 11(1): 14807, 2021 07 20.
Article En | MEDLINE | ID: mdl-34285288

Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73-1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.


Biomarkers, Tumor/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms/genetics , Endometrial Neoplasms/genetics , Stomach Neoplasms/genetics , Adult , Age of Onset , Aged , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Loss of Function Mutation , Male , Microsatellite Instability , Middle Aged , Prevalence , Retrospective Studies , Exome Sequencing
17.
J Clin Oncol ; 39(26): 2903-2913, 2021 09 10.
Article En | MEDLINE | ID: mdl-34133211

PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.


Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Docetaxel/therapeutic use , Esophagogastric Junction/drug effects , Esophagogastric Junction/surgery , Gastrectomy , Neoadjuvant Therapy , Oxaliplatin/therapeutic use , Oxonic Acid/therapeutic use , Stomach Neoplasms/therapy , Tegafur/therapeutic use , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant , Docetaxel/adverse effects , Drug Combinations , Esophagogastric Junction/pathology , Female , Gastrectomy/adverse effects , Gastrectomy/mortality , Humans , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoadjuvant Therapy/mortality , Neoplasm Staging , Oxaliplatin/adverse effects , Oxonic Acid/adverse effects , Progression-Free Survival , Republic of Korea , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Tegafur/adverse effects , Time Factors , Young Adult
18.
Cancer Med ; 10(10): 3249-3260, 2021 05.
Article En | MEDLINE | ID: mdl-33932104

BACKGROUND: The effect of long-term surveillance for asymptomatic patients after curative resection of gastric cancer is being debated. We compared the prognosis of Korean patients with recurrent gastric cancer according to the presence or absence of cancer-related symptoms at the time of recurrence detection. METHODS: We retrospectively reviewed the medical records of 305 Korean patients who experienced recurrence after curative resection of primary gastric cancer between March 2002 and February 2017 at Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. RESULTS: The median follow-up duration was 169.8 months (1-267.2), and the median age at first recurrence was 58.1 years (23.4-81.9). Among 305 patients with recurrence, 97 of 231 (42.0%) patients with early recurrence (≤5 years after curative surgical resection) and 47 of 74 (63.5%) patients with late recurrence (>5 years after curative surgical resection) had cancer-related symptoms at recurrence (p = 0.001). For survival after recurrence, detection of asymptomatic recurrence was an independent favorable factor (hazard ratio, 0.527; 95% confidence interval, 0.409-0.681; p < 0.001) accompanied with the possibility of subsequent treatment, targeted-, or immunotherapy for recurrent disease, and locoregional recurrence only. In the late-recurrence group, the patients with asymptomatic detection of recurrence showed favorable post-recurrence survival (median, 33.3 months vs. 14.7 months; p = 0.002), overall survival (median, 136.3 months vs. 106.1 months; p = 0.010), and cancer-specific survival (median, 177.5 months vs. 106.1 months; p = 0.005) than the patients with symptomatic detection. CONCLUSION: The detection of gastric cancer recurrence in patients without cancer-related symptoms may be related to improved survival, suggesting the potential benefit of long-term surveillance.


Asymptomatic Diseases/mortality , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Proportional Hazards Models , Republic of Korea , Retrospective Studies , Young Adult
19.
Dis Markers ; 2021: 8870562, 2021.
Article En | MEDLINE | ID: mdl-33854651

BACKGROUND: Several studies have been conducted to investigate the association between the presence of perineural invasion (PNI) and overall survival (OS) of gastric cancer (GC) patients who underwent curative resection, but no consensus has been reached. This study is aimed at determining the prognostic significance of PNI in gastric cancer. Study Design. The data of 2969 patients with gastric cancer and who had undergone curative gastrectomy from 2006 to 2010 in two high-volume hospitals of China and Korea were retrospectively analyzed. PNI positivity was identified when carcinoma cells were found to infiltrate into the perineurium or neural fascicles. The relationships between PNI and other clinicopathological factors were evaluated, and survival analyses were performed. RESULTS: The presence of PNI was detected in 1055 of the 2969 patients (35.5%). Nationality, age, tumor location, size of tumor, differentiation of the tumor, pT stage, pN stage, lymphatic invasion, and vascular invasion had been associated with PNI positivity. The mean survival time of patients with and without PNI was 62.5 months and 87.3 months, respectively (P < 0.001). However, the presence of PNI was not an independent prognostic factor for gastric cancer, except for patients in stage III (P = 0.037, hazard ratio: 1.21, 95% confidence interval: 1.01-1.44). CONCLUSION: PNI occurs frequently in patients with gastric cancer, and the incidence of PNI increases with the staging of the tumor. The presence of PNI can provide additional information in predicting the survival outcome for those with stage III tumors.


Carcinoma/pathology , Gastrectomy/adverse effects , Peripheral Nerves/pathology , Postoperative Complications/epidemiology , Stomach Neoplasms/pathology , Aged , Carcinoma/surgery , Female , Humans , Male , Middle Aged , Neoplasm Invasiveness , Prognosis , Stomach Neoplasms/surgery
20.
Yonsei Med J ; 62(2): 109-117, 2021 Feb.
Article En | MEDLINE | ID: mdl-33527790

PURPOSE: This study aimed to investigate the effectiveness of postoperative chemotherapy in pT1bN0 and pT2N0 gastric cancer patients with high risk factors. MATERIALS AND METHODS: Clinicopathological data of gastric cancer patients, who had undergone gastrectomy in high volume centers in Korea and China and were finally diagnosed with pT1bN0 and pT2N0 between 2006 and 2010, were analyzed retrospectively. Survival analyses stratified by risk factors and multivariable analyses were performed. RESULTS: A total of 1509 patients were enrolled, with 41 (2.7%) patients receiving adjuvant chemotherapy after gastrectomy and 1468 (97.3%) patients undergoing surgery alone. The adjuvant chemotherapy group showed higher percentages of tumor with maximal diameter >3 cm (51.2% vs. 25.8%), poor differentiation (68.3% vs. 49.8%), and less harvested lymph nodes (17.1% vs. 5.2%) compared to the surgery alone group. The overall survival rates were 95.1% in the adjuvant chemotherapy group and 93.3% in the surgery alone group, without significant difference. In multivariable analysis, age was found to be an independent prognostic factor. However, there were no difference in the overall survival between patients with risk factors and those without risk factors, even in terms of age. Meanwhile, patients with more than two risk factors who received chemotherapy showed better survival trend, especially for pT2N0 patients, compared to the surgery alone group, although no significant differences were observed. CONCLUSION: In pT1bN0 and pT2N0 patients, age was found to be an independent prognostic factor. However, adjuvant chemotherapy seemed to be unnecessary, while postoperative chemotherapy might offer survival benefits to pT2N0 patients with more than two risk factors.


Internationality , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Chemotherapy, Adjuvant , China , Female , Humans , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Prognosis , Republic of Korea , Retrospective Studies , Risk Factors , Stomach Neoplasms/pathology , Survival Analysis
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