Clinical Significance of HRNR Expression in Patients With Stage II/III Gastric Cancer After Curative Gastrectomy.

BACKGROUND/AIM: The function of the S-100 protein family member hornerin (HRNR) in gastric cancer (GC) tissues is largely unknown. We researched the clinical significance of HRNR expression in GC tissues of patients with pathological (p)Stage II/III GC after curative resection. PATIENTS AND METHODS: We included patients with pStage II/III GC who underwent curative gastrectomy (n=253). Expression levels of HRNR in GC tissue and in the adjacent normal mucosa were determined using quantitative real-time polymerase chain reaction. Clinicopathological features and overall survival (OS) were compared in patients with different HRNR expression levels in GC tissue. RESULTS: HRNR expression levels were significantly higher in GC tissues than in the adjacent normal mucosa. HRNR expression level in GC tissue showed sex differences. The 5-year OS rate in the high-HRNR expression group was significantly worse than that in the low-expression group (5-year survival 53.6% vs. 74.9%; p=0.004). Furthermore, on multivariate analysis, high-HRNR expression was an independent predictor of poor OS (hazard ratio=1.534; 95% confidence interval=1.130-2.618; p=0.011). CONCLUSION: In patients with pStage II/III GC after curative gastrectomy, HRNR expression in GC tissue may be a useful prognostic marker.

Clinical Significance of Granzyme B Gene Expression in Pathological Stage II/III Gastric Cancer After Curative Gastrectomy.

BACKGROUND/AIM: Granzyme B (GZMB) is mainly produced by natural killer (NK) cells and activated CD8-positive T cells to induce tumor cell apoptosis. We analyzed the significance of GZMB expression in gastric cancer (GC) tissues from patients with pathological (p)Stage II/III GC after curative resection. PATIENTS AND METHODS: Patients with pStage II/III GC who received curative resection (n=253) were included and the expression levels of GZMB in GC tissues and in the adjacent normal mucosa were measured using quantitative real-time polymerase chain reaction. The expression levels in GC tissues and clinicopathological features and overall survival (OS) were compared in these patients. RESULTS: GZMB expression levels were significantly higher in GC tissues than in the adjacent normal mucosa. GZMB expression levels in GC tissues were not associated with any clinicopathological features. The 5-year OS rate in the high-GZMB expression group was significantly better than that in the low-expression group (5-year survival rate 72.0% vs. 55.7%; p=0.009). Furthermore, on multivariate analysis, high-GZMB expression was an independent factor for better OS (hazard ratio=0.652; 95% confidence interval=0.432-0.987; p=0.043). CONCLUSION: In patients with locally advanced GC after curative resection, GZMB expression in GC tissue may be a useful prognostic marker.

Efficacy of chemotherapy for patients with gastric cancer with early recurrence during or after adjuvant chemotherapy with S-1 alone: a multicenter retrospective study.

This study aimed to survey the efficacy of chemotherapy regimens in the real world setting and explore the most promising regimen for patients experiencing early recurrence for gastric cancer. We retrospectively reviewed the clinical course of 207 patients with gastric cancer, who developed early recurrence during or within 6 months after completing S-1 adjuvant therapy at 19 Japanese institutions between 2012 and 2016. The treatment regimens after recurrence were fluoropyrimidines plus platinum-based regimens (FP) in 91 (44%) patients, paclitaxel-based regimens (PTX) in 102 (49%), and irinotecan-based regimens (IRI) in 14 (7%). The overall response and disease control rates were 28.7% and 54.1%. Median progression-free survival (PFS) and overall survival (OS) were 5.1 and 12.9 months, respectively. In the FP, PTX, and IRI regimens, the median PFS and OS were 5.9, 4.1, 4.1 months and 12.8, 12.9, and 11.8 months, respectively. The combination of PTX and ramucirumab showed survival comparable to capecitabine plus platinum. Multivariate analyses for OS showed that recurrence during adjuvant chemotherapy and undifferentiated histological type were independent poor prognostic factors. Although the prognosis of patients with early recurrence even with adjuvant S-1 was poor, PTX plus ramucirumab therapy could be a potential treatment option.

Prognostic value of computed tomography­derived skeletal muscle index and radiodensity in patients with gastric cancer after curative gastrectomy.

The association of computed tomography (CT)-derived skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) with postoperative prognosis in patients with gastric cancer (GC) remains unknown. Therefore, the present study aimed to assess the association between SMI and SMD with 5-year overall survival (OS) and recurrence-free survival (RFS) in patients with GC. SMI and SMD were measured preoperatively in patients who underwent gastrectomy. Patients were categorized into Groups 1 (high SMI and SMD), 2 (high SMI or SMD) and 3 (low SMI and SMD). OS and RFS rates were assessed using Kaplan-Meier analysis and the log-rank test. Among 459 patients, OS and RFS rates were significantly lower in the low-SMD group than in the high-SMD group (OS, 83.4% vs. 88.8%, respectively; P=0.04 and RFS, 80.5% vs. 87.2%, respectively; P=0.02). OS and RFS rates were also significantly lower in Group 3 than in Groups 2 and 1 (P=0.006). Multivariate analysis revealed that a low SMI and SMD (Group 3) was a significant independent prognostic factor for OS [hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.17-4.59; P=0.016] and RFS (HR, 2.28; 95% CI, 1.19-4.37; P=0.013). In summary, low SMI and SMD values may be useful postoperative prognostic indicators for patients with GC.

Inflammatory Burden Index Prognostic Impact in Patients With Gastric Cancer After Gastrectomy: A Propensity Score-matched Analysis.

BACKGROUND/AIM: The Inflammatory Burden Index (IBI) has been reported as a novel prognostic indicator in several cancers and diseases. However, research on the IBI in patients with gastric cancer (GC) after gastrectomy is insufficient. This study investigated the utility of the preoperative IBI as a prognostic indicator in patients with GC. PATIENTS AND METHODS: This retrospective study enrolled 459 patients undergoing gastrectomy for GC between 2013 and 2017 at the Kanagawa Cancer Center, Kanagawa, Japan. The IBI was calculated from preoperative blood test data. We evaluated the relationship between the preoperative IBI and clinicopathologic factors, overall survival (OS), and recurrence-free survival (RFS) after gastrectomy for GC, using propensity score matched analysis. RESULTS: Regarding the association between IBI and clinicopathologic features, the high-IBI group was significantly older and had more lymphatic invasion and more progressive pT status than the low-IBI group before propensity score-matched analysis. OS and RFS after curative surgery were significantly lower in patients with a high IBI than in those with a low IBI (77.5% vs. 86.1%; p=0.02 and 74.3% vs. 85.1%; p=0.03, respectively). Multivariate analysis identified high IBI as an independent predictor of both OS and RFS. CONCLUSION: Preoperative IBI may serve as a valuable prognostic indicator for patients undergoing curative gastrectomy for GC.

Preoperative Visceral-to-Subcutaneous Fat Ratio by Sex as a Predictor of Postoperative Survival in Patients With Gastric Cancer.

BACKGROUND/AIM: The sex-specific effect of the visceral-to-subcutaneous fat ratio (VSR) before gastrectomy on postoperative survival in patients with gastric cancer (GC) remains unclear. This study measured the preoperative VSR in patients with GC and analyzed its relationship with 5-year overall survival (OS) and relapse-free survival (RFS) by sex. PATIENTS AND METHODS: This prospective study included 540 patients with GC undergoing gastrectomy. Preoperative visceral and subcutaneous fat volumes were measured using computed tomography, and the VSR was calculated. A cutoff value for the VSR was established using 5-year survival data, and its association with survival was analyzed using the Kaplan-Meier method, log-rank tests, and multivariate regression analysis. RESULTS: Among the 459 patients analyzed (300 males and 159 females), OS and RFS were significantly lower in the low-VSR group than in the high-VSR group in males (OS: 76.2% vs. 88.1%, p=0.01; RFS: 74.6% vs. 86.0%, p=0.02). In females, no difference in OS was observed between the groups, whereas the high-VSR group had significantly lower RFS than that of the low-VSR group (RFS: 74.7% vs. 88.9%, p=0.01). Multivariate analysis showed that a low VSR was an independent poor predictor of OS in males and a high VSR was an independent poor predictor of RFS in females. CONCLUSION: In patients with GC, the sex-dependent preoperative VSR was a potentially useful predictor of postoperative survival.

Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Complete response induced by nivolumab monotherapy in gastric neuroendocrine carcinoma: a case report.

No standard treatment has been established for gastric neuroendocrine carcinoma (G-NEC). We present the case of a patient with recurrent G-NEC who achieved a complete response (CR) with nivolumab. A woman in her 70 s, with no significant medical or family history of illness, underwent an upper gastrointestinal endoscopy, which revealed a Borrmann type 2 tumor in the gastric antrum. Malignant tumor cells were not detected in the endoscopic biopsy samples; however, a malignant gastric tumor was strongly suspected. Therefore, surgical resection was performed, and the tumor was pathologically diagnosed as a G-NEC with liver metastases. Adjuvant etoposide plus carboplatin was administered for four cycles, but recurrence in the liver was observed 5 months after the completion of adjuvant chemotherapy. Ramucirumab plus paclitaxel and irinotecan were introduced as second and third-line treatments. After these treatments, the mesenteric lymph node metastases expanded. Tumor mutation burden (TMB) was low (five mutations/megabase), and microsatellite instability remained stable. However, programmed death-ligand 1 Combined Positive Score (CPS) was ≥ 5 in the resected sample. Therefore, nivolumab monotherapy was introduced as a fourth-line treatment. The mesenteric lymph node metastases exhibited swelling 3 weeks after the initiation of nivolumab; however, they rapidly shrank, and CR was later achieved. Treatment with nivolumab is currently ongoing for 12 months. This is the first report of nivolumab monotherapy in a patient with G-NEC who showed pseudo-progression. Even in TMB-low and microsatellite stable cases, nivolumab may be a viable option for patients with G-NEC.

Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting. METHODS: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed. FINDINGS: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy. INTERPRETATION: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer. FUNDING: Ono Pharmaceutical and Bristol Myers Squibb.

Comparison of the Dietary Intake After Gastrectomy Between Male and Female Patients With Gastric Cancer.

BACKGROUND/AIM: This study aimed to investigate the differences in the postoperative dietary intake (DI) loss between men and women after radical resection for early gastric cancer (GC), and to identify effective nutritional support for both sexes. PATIENTS AND METHODS: This prospective, observational study enrolled patients who underwent gastrectomy for GC. DI was assessed using the food frequency questionnaire containing 82 food items (FFQW82) during nutritional counseling before surgery and one and three months postoperatively. RESULTS: The median preoperative DI of all participants was 1,856.3 kcal/day, and DI at 1 and 3 months were 1,532.5 kcal/day and 1,637 kcal/day, respectively. The median preoperative DI was 1805 kcal/day (1,300-2,330 kcal/day) and 1481 kcal/day (1,126-1,957 kcal/day) in men and women, respectively (p<0.0001). The median DI at 1 month was 1627 (1,101-2,195) kcal/day and 1,308 (986-1,915) kcal/day in men and women, respectively (p<0.0001). At 3 months postoperatively, the median DI was 1737 (1,130-2,443) kcal/day in men and 1428 (816-2,005) kcal/day in women (p<0.0001). However, there was no significant difference in the DI loss rate at 1 month (median: -9.7% vs. -9.3%, p=0.765) and 3 months (median: -3.5% vs. -4.8%, p=0.137) between men and women. CONCLUSION: Although the DI loss rate in men and women after gastrectomy for GC was almost similar, the postoperative DI and DI loss differed significantly. Therefore, differences in DI loss after gastrectomy between men and women should be considered while assessing the efficacy of additional nutritional support such as oral nutritional supplements after gastrectomy.

A propensity­matched analysis of the prognostic value of advanced lung cancer inflammation index in patients with gastric cancer after curative resection.

The prognostic significance of inflammation, immune response and nutritional status in patients with cancer is well-documented. The advanced lung cancer inflammation index (ALI) has emerged as a novel prognostic indicator, reflecting both inflammation and nutritional status. This study aimed to assess the prognostic relevance of preoperative ALI in patients with gastric cancer (GC). Data of 459 patients who underwent curative gastrectomy for GC between December 2013 and November 2017 at the Kanagawa Cancer Center (Yokohama, Japan) were retrospectively analyzed. Preoperative ALI was calculated from blood tests. Patients were divided into the high- and low-ALI groups. This study investigated the association between preoperative ALI, clinicopathological features, overall survival (OS) and relapse-free survival (RFS) after propensity-matched analysis. Comparative analysis revealed that patients in the low-ALI group tended to be older, were predominantly female, had lower body mass index and had a higher incidence of lymphatic invasion compared with those in the high-ALI group before propensity-matched analysis. Notably, the low-ALI group exhibited significantly reduced OS and RFS post-gastrectomy (85.5% vs. 93.8%, P=0.01; and 82.1% vs. 91.8%, P=0.02, respectively). Multivariate analysis identified low ALI as an independent prognostic factor for both OS and RFS. In conclusion, preoperative ALI could provide a valuable prognostic tool for patients with GC undergoing curative resection, offering insights into patient survival outcomes based on their inflammatory and nutritional status.

Comparison of Survival Between ypStage and pStage in Gastric Cancer.

BACKGROUND/AIM: In East Asia, the standard treatment for resectable advanced gastric cancer involves gastrectomy and postoperative adjuvant chemotherapy; nevertheless, neoadjuvant chemotherapy is also expected to improve survival rates. However, it remains unclear whether the same criteria can be used to select adjuvant chemotherapy for patients treated with neoadjuvant chemotherapy, or how survival varies between post-chemotherapy pathological Stage (ypStage) and pathological Stage without chemotherapy (pStage). This study evaluated the long-term outcomes of ypStage and pStage in gastric cancers and investigated the optimal intensity of adjuvant chemotherapy for patients who have received preoperative chemotherapy. PATIENTS AND METHODS: From January 2007 to November 2019, 1,585 patients underwent radical gastrectomy for gastric cancer at the Kanagawa Cancer Center. The patient background was adjusted by propensity score matching, and recurrence-free survival was compared between the two groups. In addition, a prognostic factor analysis was conducted for each yp/pStage. RESULTS: The 5-year recurrence-free survival rates for yp/pStage I were 77.1% and 90.9%, respectively, with no significant difference (p=0.342). The 5-year recurrence-free survival rates for yp/pStage II were 50.4% and 69.1%, respectively, with no significant difference (p=0.062). The 5-year recurrence-free survival rates for yp/pStage III were 42.9% and 68.7%, respectively, with a significant difference observed (p=0.016). In the prognostic factor analysis for each stage, the presence or absence of preoperative chemotherapy was selected as an independent prognostic factor for yp/pStage I [hazard ratio (HR)=17.72; p=0.001] and yp/pStage II (HR=2.655, p=0.003). CONCLUSION: ypStage tends to have a worse prognosis than pStage, and further development of multidisciplinary treatment is necessary.

Comparison of Dietary Intake After Gastric Cancer Gastrectomy Between Patients With and Without Postoperative Surgical Complications.

BACKGROUND/AIM: This study aimed to compare dietary intake (DI) after gastrectomy for gastric cancer between patients with (C group) and without (NC group) postoperative surgical complications. PATIENTS AND METHODS: This prospective observational study enrolled patients who underwent gastrectomy for gastric cancer. DI was assessed using a food frequency questionnaire with 82 food items (FFQW82) during nutritional counseling before surgery and at one and three months after surgery. RESULTS: A total of 225 patients participated in this study. Of the 225 patients, 193 had no postoperative complications, and 32 had postoperative complications (Clavien-Dindo grade ≥2). The median DI at 1 month postoperatively was 1508 kcal/day in the NC group and 1,470.5 kcal/day in the C group (p=0.175). The median DI at 3 months postoperatively was 1,623 kcal/day in the NC group and 1575 kcal/day in the C group (p=0.473). There was a significant difference between the NC and C groups in the rate of decrease in DI at one month (median: -8.44% vs. -15.37%, p=0.032) and at three months postoperatively (median: -3.58% vs. -6.12%, p=0.038). CONCLUSION: There was a statistically significant difference in the rate of decrease in DI after gastrectomy between the C and NC groups at 1 and 3 months postoperatively. Our results suggest that patients with postoperative surgical complications require additional nutritional treatment for decreased DI.

Clinical Significance of Tryptophanyl-tRNA Synthetase 1 Gene Expression in Patients With Locally Advanced Gastric Cancer.

BACKGROUND/AIM: The tryptophanyl-tRNA synthetase 1 gene (WARS1), encodes a tryptophan-tRNA synthetase involved in the amino acidification of tryptophan-tRNA and has been reported to be involved in cancer cell growth, metastasis promotion, and drug resistance in a variety of cancers. This study investigated the clinical significance of WARS1 expression as a biomarker in gastric cancer tissues obtained from patients with locally advanced gastric cancer (GC) who underwent radical resection. PATIENTS AND METHODS: WARS1 expression in GC tissues and adjacent normal gastric mucosa of 253 patients with pStage II/III GC who underwent curative resection was determined using quantitative polymerase chain reaction (PCR). Association of WARS1 expression levels, categorized into high and low expression based on the median expression levels, with clinicopathological factors and overall survival (OS) of these patients was assessed. RESULTS: The low-WARS1 expression group had significantly higher serosal invasion, lymph node metastasis, lymphatic invasion, venous invasion, and pathological stage than did the high-WARS1 expression group. OS was significantly worse in the low- than in the high-WARS1 expression group (5-year survival 52.2% vs. 75.9%; p=0.0001). Furthermore, in multivariate analysis, low WARS1 expression was an independent predictor for poor OS (hazard ratio=2.101; 95% confidence interval=1.328-3.322; p=0.002). CONCLUSION: In patients with locally advanced GC, after curative resection, WARS1 expression in GC tissue may be a useful prognostic marker.

Clinical Impact of the C-reactive Protein-albumin-lymphocyte Index in Post-gastrectomy Patients With Gastric Cancer.

BACKGROUND/AIM: Recently, preoperative inflammatory, immune, and nutritional statuses have attracted attention as prognostic factors in post-curative gastrectomy patients with gastric cancer (GC). The usefulness of the C-reactive protein-albumin-lymphocyte (CALLY) index as a prognostic factor in patients with various cancers, has been reported. However, reports on the clinical significance of the CALLY index in patients with GC after gastrectomy remain inadequate. In this prospective study, we focused on the preoperative CALLY index and investigated its usefulness as a prognostic factor in patients with GC. PATIENTS AND METHODS: This study included 459 patients who underwent gastrectomy for GC between December 2013 and November 2017 at Kanagawa Cancer Center, Kanagawa, Japan. The preoperative CALLY index was calculated based on the preoperative blood test data. Patients were divided into high- and low-CALLY groups. The associations of the preoperative CALLY scores with clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS) after gastrectomy for GC were evaluated. RESULTS: The low-CALLY group was significantly older, had higher venous invasion, and a more progressive pStage than did the high-CALLY group. OS and RFS after gastrectomy in the low-CALLY group were significantly worse than those in the high-CALLY group (77.9% vs. 88.9%; p<0.001 and 73.8% vs. 87.1%; p<0.001, respectively). In the multivariate analysis, a low CALLY score was an independent prognostic factor of worse OS and RFS. CONCLUSION: Preoperative CALLY levels may be a useful prognostic predictor in patients with GC after curative gastrectomy.

Survival Predictors Before Preoperative Adjuvant Chemotherapy in Patients With Locally Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: Radical resection after preoperative adjuvant chemotherapy (NAC) is a standard treatment for patients with locally advanced esophageal squamous cell carcinoma (LAESCC), but its outcome remains unsatisfactory. In order to develop a personalized treatment program for LAES, we herein compared the survival prediction utility of five pre-NAC nutritional, inflammatory, and immune indexes in patients with LAESCC. PATIENTS AND METHODS: We evaluated the survival of 203 patients with LAESCC who underwent radical resection after NAC from January 2011 to September 2019 for the following representative pre-NAC nutritional, inflammatory, and immune indices: modified Glasgow Prognostic Score, Prognostic Nutritional Index, C-reactive protein/albumin ratio, serum neutrophil/lymphocyte ratio, and Geriatric Nutrition Risk Index (GNRI) were evaluated for their impact on survival. RESULTS: Of the five indices, GNRI was the best predictor of survival as determined by the area under the curve (p<0.05). When patients were divided into three groups according to the nutritional risk assessment of Bouillanne et al. using the pre-NAC GNRI, the 5-year overall survival (OS) and recurrence-free survival (RFS) were significantly stratified (p<0.001). On multivariate analysis, the GNRI independently identified a poor OS group [group 1: hazard ratio (HR)=2.598, p=0.002; group 2: HR=6.257, p<0.001] and a high recurrence risk group (group 1: HR=1.967, p=0.016; group 2: HR=4.467, p<0.001). CONCLUSION: In patients with LAESCC, GNRI may be the most accurate, reliable, and useful prognostic factor among the five major systemic inflammatory and nutritional indices.

A multi-institutional prospective observational study to compare postoperative quality of life of patients who undergo total or proximal gastrectomy for early gastric cancer (CCOG1602).

BACKGROUND: Proximal gastrectomy (PG) has become an increasingly preferred procedure for treating early cancer in the upper third of the stomach. However, advantages of PG in postoperative quality of life (QOL) over total gastrectomy (TG) has not fully proven. METHODS: We conducted a multi-institutional prospective observational study (CCOG1602) of patients who undergo TG or PG for cStage I gastric cancer. We used the PGSAS-37 and EORTC-QLQ-C30 to evaluate the changes in body weight and QOL over a 3-year postoperative period. The primary endpoint was the weight loss rate 3 years after surgery. RESULTS: We enrolled 109 patients from 18 institutions and selected 65 and 19 patients for inclusion in the TG and PG groups, respectively. Mean postoperative weight loss rates were 16.0% and 11.7% for the TG and PG groups, respectively (p = 0.056, Cohen's d 0.656) during postoperative year 1% and 15.0% and 10.8% for TG and PG (p = 0.068, Cohen's d 0.543), respectively, during postoperative year 3, indicating that the PG group achieved a better trend with a moderate effect size. According to the PGSAS-37, the PG group experienced a better trend in the indigestion subscale (p < 0.001, Cohen's d -1.085) and total symptom score (p = 0.050, Cohen's d -0.59) during postoperative year 3 compared with the TG group. In contrast, the EORTC-QLQ-C30 detected no difference between the groups at any time point during 3-year postoperative period. CONCLUSIONS: This prospective study demonstrates that PG tended to be more favorable compared with TG with respect to postoperative weight loss and QOL, particularly regarding indigestion.

Long-term treatment outcomes in gastric cancer with oligometastasis.

Aim: While surgery is essential for curative treatment of gastric cancer with oligometastasis, its target, timing, and possibility of combination with other treatments are unclear. We herein investigated the clinical course and long-term outcomes of gastric cancer with oligometastasis in the real world setting to determine the optimal therapeutic strategy. Methods: The present study retrospectively analyzed 992 patients who received any treatment for metastatic or recurrent gastric adenocarcinoma at Tokyo Metropolitan Komagome Hospital between 2007 and 2019. Oligometastasis was defined as any one of the following: liver metastases (HEP) <3; lung metastases (PUL) <3; unilateral adrenal gland metastasis (ADR); para-aortic lymph node metastasis (PALN); or one, distant, lymph node metastasis, excluding the regional lymph nodes (LYM). Overall survival was compared by the characteristics and treatments for the oligometastasis, and univariate and multivariate analyses were used to identify the prognostic factors of overall survival. Results: Ninety-seven patients (9.8%) with the following metastasis sites were enrolled: HEP (n = 27), PUL (n = 2), ADR (n = 3), PALN (n = 55), and LYM (n = 10). The median survival time of the cohort was 22.8 months, and the five-year overall survival rate was 28.4%. On multivariate analysis, chemotherapy for the initial treatment (hazard ratio [HR]: 0.438; p = 0.048), distal gastrectomy and/or metastasectomy (HR: 0.290; p = 0.001), and R0 resection (HR: 0.373; p = 0.005) were identified as independent, positive factors of overall survival. Conclusion: The long-term outcomes of gastric cancer in patients with oligometastasis may improve if treatment is begun with chemotherapy rather than surgery.

Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation in gastric cancer.

BACKGROUND: Tumor-associated antigen (TAA)-specific CD8(+) T cells are essential for nivolumab therapy, and irradiation has been reported to have the potential to generate and activate TAA-specific CD8(+) T cells. However, mechanistic insights of T-cell response during combinatorial immunotherapy using radiotherapy and nivolumab are still largely unknown. METHODS: Twenty patients included in this study were registered in the CIRCUIT trial (ClinicalTrials.gov, NCT03453164). All patients had multiple distant metastases and were intolerance or had progressed after primary and secondary chemotherapy without any immune checkpoint inhibitor. In the CIRCUIT trial, eligible patients were treated with a total of 22.5 Gy/5 fractions/5 days of radiotherapy to the largest or symptomatic lesion prior to receiving nivolumab every 2 weeks. In these 20 patients, T-cell responses during the combinatorial immunotherapy were monitored longitudinally by high-dimensional flow cytometry-based, multiplexed major histocompatibility complex multimer analysis using a total of 46 TAAs and 10 virus epitopes, repertoire analysis of T-cell receptor ß-chain (TCRß), together with circulating tumor DNA analysis to evaluate tumor mutational burden (TMB). RESULTS: Although most TAA-specific CD8(+) T cells could be tracked longitudinally, several TAA-specific CD8(+) T cells were detected de novo after irradiation, but viral-specific CD8(+) T cells did not show obvious changes during treatment, indicating potential irradiation-driven antigen spreading. Irradiation was associated with phenotypical changes of TAA-specific CD8(+) T cells towards higher expression of killer cell lectin-like receptor subfamily G, member 1, human leukocyte antigen D-related antigen, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, CD160, and CD45RO together with lower expression of CD27 and CD127. Of importance, TAA-specific CD8(+) T cells in non-progressors frequently showed a phenotype of CD45RO(+)CD27(+)CD127(+) central memory T cells compared with those in progressors. TCRß clonality (inverted Pielou's evenness) increased and TCRß diversity (Pielou's evenness and Diversity Evenness score) decreased during treatment in progressors (p=0.029, p=0.029, p=0.012, respectively). TMB score was significantly lower in non-progressors after irradiation (p=0.023). CONCLUSION: Oligo-fractionated irradiation induces an immune-modulating effect with potential antigen spreading and the combination of radiotherapy and nivolumab may be effective in a subset of patients with gastric cancer.

Risk factors for early recurrence after radical gastrectomy followed by adjuvant chemotherapy for stage II or III gastric cancer: a multicenter, retrospective study.

BACKGROUND: Radical gastrectomy followed by adjuvant chemotherapy is the standard treatment for stage II or III gastric cancer in Asian countries. Early recurrence during or after adjuvant chemotherapy is associated with poor prognosis; however, risk factors for early recurrence remain unclear. METHODS: In this multicenter, retrospective cohort study including six institutions, we evaluated the clinicopathological factors of 553 patients with gastric cancer undergoing gastrectomy followed by adjuvant chemotherapy between 2012 and 2016. Patients were divided into the following groups: early recurrence (recurrence during adjuvant chemotherapy or within 6 months after adjuvant chemotherapy completion) and non-early recurrence, which was further divided into late recurrence and no recurrence. Early-recurrence risk factors were investigated using multivariate Cox proportional hazard model. The chronological changes in the recurrence hazard were also examined for each factor. RESULTS: Early recurrence and late recurrence occurred in 83 (15.0%) and 73 (13.2%) patients, respectively. Based on the Cox proportional hazards model, a postoperative serum carcinoembryonic antigen level of ≥5 ng/mL (hazard ratio: 2.220, 95% confidence interval: 1.089-4.526) and a neutrophil-to-lymphocyte ratio of >1.8 (hazard ratio: 2.408, 95% confidence interval: 1.479-3.92) were identified as independent risk factors of early recurrence, but not late recurrence. The recurrence hazard ratios for neutrophil-to-lymphocyte ratio significantly decreased over time (P < 0.001) and carcinoembryonic antigen also had the same tendency (P = 0.08). CONCLUSIONS: A carcinoembryonic antigen level of ≥5 ng/mL and a neutrophil-to-lymphocyte ratio of >1.8 are predictors of early recurrence after radical gastrectomy and adjuvant chemotherapy for stage II or III gastric cancer.