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.

The Clinical Impact of the Pretreatment Albumin to Fibrinogen Ratio in Esophageal Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: The albumin to fibrinogen ratio (AFR) has been identified as a promising prognostic marker for some malignancies. The aim of the present study was to evaluate the clinical impact of AFR in esophageal cancer patients who received curative resection. PATIENTS AND METHODS: The present study included 123 patients who underwent curative treatment for esophageal cancer between 2005 and 2020. The prognosis and clinicopathological parameters were compared between patients with high and low AFRs. RESULTS: The overall survival (OS) stratified by each clinical factor was compared using the log-rank test, and a significant difference was observed when using a pretreatment AFR of 1.23. When comparing the patient backgrounds between the high-AFR (AFR ≥12.3) and low-AFR (AFR<12.3) groups, significant differences were noted in the pathological T status. The high-AFR group had significantly higher OS rates at 3 years (70.8%) and 5 years (59.3%) after surgery in comparison to the low-AFR group (46.6% and 37.4%, respectively). Univariate and multivariate analyses for OS showed that the AFR was a significant prognostic factor. In addition, when comparing the site of first recurrence, a marginally significant difference was noted in hematological recurrence. CONCLUSION: The AFR is a significant risk factor in patients with esophageal cancer, holding promise as a valuable prognostic factor.

The Prognostic Immune and Nutritional Indices Are Independent Prognostic Factors for Esophageal Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: Recently, the prognostic immune and nutritional index (PINI) was developed and reported to be a promising nutritional and inflammatory prognostic marker. The aim of the present study was to clarify the clinical impact of the PINI for esophageal cancer patients who received curative treatment. PATIENTS AND METHODS: We conducted a retrospective review of medical records and collected data on consecutive esophageal cancer patients who underwent curative resection at Yokohama City University between 2005 and 2020. The PINI was calculated by dividing the serum ALB concentration (g/dl) by the serum monocyte concentration, both of which were measured before surgery. RESULTS: A total of 180 patients were included in this study. The cutoff value of the PINI was 3.0 in the present study. The 3- and 5-year overall survival rates were 45.2% and 33.5%, respectively, in the PINI-low subgroup, and 69.1% and 61.8%, respectively, in the PINI-high subgroup. A multivariate analysis demonstrated that the PINI was an independent prognostic factor for overall survival (hazard ratio=2.091, 95% confidence interval=1.287-3.399, p=0.003). Similar results were observed for recurrence-free survival. When comparing the sites of recurrence between the two groups, the incidence of hematological recurrence was significantly greater in the PINI-low subgroup compared to the PINI-high subgroup (46.8% vs. 21.1%, p<0.001). CONCLUSION: The PINI is a promising nutritional and inflammatory marker for esophageal cancer patients. The PINI might be a useful marker for the treatment and management of esophageal cancer patients.

The Clinical Impact of the Prognostic Immune and Nutritional Index in Gastric Cancer Patients Who Received Curative Treatment.

BACKGROUND/AIM: The prognostic immune and nutritional index (PINI) was developed and reported as a promising prognostic factor. This study aimed to clarify the clinical impact of the PINI in gastric cancer (GC) patients who received curative treatment. PATIENTS AND METHODS: Patients who underwent curative resection for GC at Yokohama City University between 2005 and 2020 were selected based on their medical records. The PINI was calculated by dividing the serum albumin concentration (g/dl) by the serum monocyte concentration. Both measurements were performed prior to surgery. RESULTS: A total of 262 patients were included in this study. Based on the 3- and 5-year overall survival (OS), we set the cutoff value of the PINI at 3.4 in the present study. The 3- and 5-year OS rates were 69.0% and 66.1%, respectively, in the PINI-low group and 90.5% and 82.8% in the PINI-high group. There were significant differences between the two groups (p<0.001). A multivariate analysis of factors associated with OS identified PINI as an independent prognostic factor (hazard ratio=1.996; 95% confidence interval=1.096-3.636, p=0.024). Similar results were observed for RFS. In addition, the PINI status affected the recurrence pattern, postoperative anastomotic leakage, and the introduction of postoperative adjuvant chemotherapy. CONCLUSION: The PINI is a promising nutritional and inflammatory marker for patients with GC and might be a useful marker for the treatment and management of patients with GC.

Clinical Impact of Preoperative Prognostic Nutritional Index in Surgical Patients With Pancreatic Cancer Treated With Perioperative Adjuvant Chemotherapy.

BACKGROUND/AIM: The prognostic nutritional index (PNI) is used as a marker to evaluate the nutritional and immunological status of patients with various cancers. This study aimed to investigate whether preoperative PNI is a prognostic factor in patients with pancreatic cancer who underwent perioperative adjuvant chemotherapy and surgical resection. PATIENTS AND METHODS: We retrospectively enrolled 232 pancreatic cancer patients who underwent surgical resection with perioperative adjuvant chemotherapy between January 2013 and December 2022. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards regression models. RESULTS: The optimal cutoff value for the preoperative PNI was 44.3 in the present study. PNI <44.3 was associated with older age (p<0.001) and affected the clinical course of postoperative adjuvant chemotherapy. The PNI <44.3 had an important influence on the decreased OS (25.1 vs. 39.0 months) and RFS (13.1 vs. 22.8 months). In univariate and multivariate analyses, the preoperative PNI was an independent prognostic factor for OS [hazard ratio (HR)=1.682, 95% confidence interval (CI)=1.059-2.673, p=0.028] and RFS (HR=1.559, 95% CI=1.037-2.344, p=0.033). CONCLUSION: Preoperative PNI is a prognostic factor for both OS and RFS in patients with pancreatic cancer who underwent perioperative adjuvant chemotherapy and surgical resection. This study suggests that a low PNI may cause a lack of full-dose adjuvant chemotherapy, leading to recurrence and resulting in a poor prognosis for surgical pancreatic cancer patients treated with perioperative adjuvant chemotherapy.

Clinical Impact of the Lymphocyte-to-Monocyte Ratio in Patients With Gastric Cancer who Received Curative Treatment.

BACKGROUND/AIM: The aim of the present study was to evaluate the clinical impact of the pretreatment lymphocyte-to-monocyte ratio (LMR) on both short- and long-term oncological outcomes in patients with resectable gastric cancer (GC). PATIENTS AND METHODS: The patients were chosen based on our medical records from consecutive cases of curative resection for GC performed at Yokohama City University from 2005 to 2020. The LMR was calculated as the lymphocyte count divided by the monocyte count measured before surgery. RESULTS: The three- and five-year overall survival (OS) rates were 63.1% and 57.4%, respectively, in the low-LMR subgroup and 86.4% and 77.5%, respectively, in the high-LMR subgroup. According to multivariate analysis, the LMR was an independent prognostic factor for OS [hazard ratio (HR)=1.926, 95% confidence interval (CI)=1.143-3.245, p=0.014]. In addition, the three- and five-year RFS rates were 54.4% and 50.7%, respectively, in the low-LMR subgroup and 84.0% and 76.0% in the high-LMR subgroup. According to multivariate analysis, the LMR was an independent prognostic factor for OS (HR=2.031, 95%CI=1.266-3.258, p=0.003). When comparing the sites of recurrence between the low-LMR and high-LMR groups, there were significant differences in hematologic recurrence, lymph node recurrence, and peritoneal recurrence. CONCLUSION: Preoperative LMR might be a promising tool for the treatment and management of GC.

Protocol of a phase II study investigating the efficacy and safety of trifluridine/tipiracil plus ramucirumab as a third-line or later treatment for advanced gastric cancer.

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.

The CRP-albumin-lymphocyte (CALLY) Index Is an Independent Prognostic Factor for Gastric Cancer Patients who Receive Curative Treatment.

BACKGROUND/AIM: The CRP-albumin-lymphocyte (CALLY) index is a promising biomarker. We clarified the clinical impact of the CALLY index in gastric cancer patients who received curative treatment. PATIENTS AND METHODS: Consecutive patients who underwent curative resection for gastric cancer at Yokohama City University from 2005 to 2020 were selected based on medical records. The CALYY index was calculated as follows: serum ALB level (g/dl) × lymphocyte count (cells/µl)/C-reactive protein (mg/dl) ×104 Results: Two hundred fifty-nine patients were included in the present study. The three- and five-year overall survival (OS) rates were 64.8% and 57.0%, respectively, in the CALLY index-low group, and 86.2% and 78.2%, respectively, in the CALLY index-high group. There were significant differences between the two groups. A multivariate analysis demonstrated that the CALLY index was an independent prognostic factor for overall survival (hazard ratio=1.791; 95% confidence interval=1.067-3.009; p=0.028). When comparing the perioperative clinical course between the CALLY index-low and CALLY index-high groups, there were significant differences in postoperative surgical complications and adjuvant chemotherapy. CONCLUSION: The CALLY score was an independent prognostic factor for patients with gastric cancer. Our results suggest that the CALLY index is a promising tool for assessing inflammation and nutritional status in patients undergoing gastric cancer treatment and management.

Non-invasive intraductal oncocytic papillary neoplasm forming a protruding lesion toward the duodenum from the accessory papilla: a case report.

BACKGROUND: Intraductal oncocytic papillary neoplasm (IOPN), previously classified as a subtype of intraductal papillary mucinous neoplasm (IPMN), has been described as an independent disease by the WHO since 2019. IOPN is a rare tumor, with few reported cases. Herein, we report a case of resected non-invasive IOPN that formed a lesion protruding toward the duodenum from the accessory papilla. CASE PRESENTATION: An 80-year-old woman was referred to our hospital because of a giant mass in the pancreatic head detected on abdominal contrast-enhanced computed tomography (CT) performed for a close examination of a mass in the right breast. CT revealed a 90-mm-sized tumor with a mixture of solid and cystic components, with contrast enhancement in the pancreatic head, and a dilated main pancreatic duct. Esophagogastroduodenoscopy revealed a semi-circumferential papillary tumor protruding toward the duodenal lumen, which did not protrude from the papilla of Vater. Transpapillary biopsy led to a preoperative diagnosis of IPMN with an associated invasive carcinoma. As there were no distant metastasis, open subtotal stomach-preserving pancreaticoduodenectomy was performed. Analysis of the surgical specimen and histopathological examination revealed that the tumor was an IOPN that protruded toward the duodenal mucosa from the accessory papilla while replacing the duodenal mucosa with no obvious stromal invasion. CONCLUSION: IOPN is a rare and poorly recognized tumor with few reported cases. There have been no reports describing IOPN forming a protruding lesion toward the duodenum from the accessory papilla. Therefore, further accumulation of cases such as this one is important to advance the study of IOPN.

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.

The Naples Prognostic Score Is an Independent Prognostic Factor for Gastric Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: This study aimed to evaluate the clinical impact of the Naples Prognostic Score (NPS) in patients with gastric cancer and to clarify the potential of the NPS as a nutritional and inflammation evaluation system. PATIENTS AND METHODS: This study included 158 patients who underwent curative treatment for gastric cancer between 2005 and 2020. The prognosis and clinical pathological parameters of the high-NPS (NPS >2) and low-NPS (NPS=0, 1) groups were analyzed. RESULTS: The overall survival (OS) rates at 3 and 5 years were 86.7% and 77.7%, respectively, in the low-NPS group and 55.4% and 47.4%, respectively, in the high-NPS group. There were significant differences in OS between the two groups. Uni- and multivariate analyses demonstrated that the NPS was an independent prognostic factor for OS (HR=2.495, 95%CI=1.240-5.451). In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 82.1% and 76.0%, respectively, in the NPS-low group, and 43.8% and 36.6% in the NPS-high group. Univariate and multivariate analyses demonstrated that the NPS was an independent prognostic factor for RFS (HR=2.739, 95%CI=1.509-4.972). When the first site of recurrence was compared between the low-NPS group and high-NPS group, there were significant differences in peritoneal recurrence (8.7% vs. 34.3%, p=0.001) and hematologic recurrence (5.6% vs. 21.9%, p=0.004). CONCLUSION: The NPS was a significant prognostic factor in patients with gastric cancer who received curative treatment. The NPS may be a promising biomarker for the treatment and management of gastric cancer.

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.

Albumin-Globulin Ratio Is an Independent Prognostic Factor for Gastric Cancer Patients who Received Curative Treatment.

BACKGROUND/AIM: The albumin-globulin ratio (AGR) is a useful biomarker for predicting postoperative complications and a poor prognosis in patients with various types of cancer and can be evaluated without invasive testing or surgery. In this study, we aimed to evaluate the usefulness of the AGR in predicting the short- and long-term prognoses of patients with gastric cancer who underwent radical resection at our institution. PATIENTS AND METHODS: This study is a retrospective cohort analysis in which eligible patients were selected from the medical records of patients who underwent radical resection for gastric cancer at Yokohama City University from 2000 to 2020 and their medical records were reviewed. A total of 240 patients with gastric cancer were classified into high-AGR (>1.57) and low-AGR (≤1.57) groups and their overall survival (OS), recurrence-free survival (RFS), and postoperative complication rates were compared. RESULTS: Of the total 240 patients, 87 were classified into the high AGR group and 153 were classified into the low AGR group; the incidence of postoperative complications in the two groups did not differ to a statistically significant extent (34.4% vs. 39.2%, p=0.491). The long-term findings showed that the 5-year OS and RFS rates were significantly better in the high AGR group [84.0% vs. 64.8% (p=0.005), 80.0% vs. 61.9% (p=0.015), respectively]. CONCLUSION: Preoperative low AGR is a risk factor for OS and DFS in patients with gastric cancer who undergo surgery. The AGR may be a useful biomarker that can be applied as a prognostic indicator for patients with gastric cancer.

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.

CRP-albumin-lymphocyte (CALLY) Index Is an Independent Prognostic Factor for the Esophageal Cancer Patients Who Received Curative Treatment.

BACKGROUND/AIM: Perioperative inflammation and the nutritional status affect both short- and long-term oncological outcomes in various malignancies. We clarified the clinical impacts of the CRP-albumin-lymphocyte (CALLY) index in patients with esophageal cancer who received curative treatment. PATIENTS AND METHODS: The present study included 180 patients who underwent curative treatment for esophageal cancer between 2005 and 2020. The prognosis and clinicopathological parameters were compared between a high-fibrinogen group and a low-fibrinogen group. RESULTS: The 3- and 5-year overall survival rates were 50.0% and 42.6%, respectively, in the CALLY index-low group, and 75.9% and 66.6% in the CALLY index-high group. The differences between the two groups were statistically significant (p<0.001). Univariate and multivariate analyses demonstrated that the CALLY index was an independent prognostic factor [hazard ratio=2.310, 95% confidence interval=1.416-3.767, p<0.001]. Similar results were observed in recurrence-free survival. When comparing the details of postoperative surgical complications, there was a significant difference in the incidence of anastomotic leakage. The incidence of anastomotic leakage was 40.2% in the CALLY index-low group, while it was 27.5% in the CALLY index-high group (p=0.030). CONCLUSION: The pretreatment CALLY index is one of the independent prognostic factors for esophageal cancer. The CALLY index might become a promising biomarker for the treatment and management of esophageal cancer.

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.

Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Gastric Cancer Cohort.

PURPOSE: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin and has shown preliminary efficacy in the treatment of gastric cancer. Study 120, a phase Ib/II open-label study, assessed efficacy and safety of E7389-LF in combination with nivolumab, a programmed cell death (PD)-1 inhibitor. This report focuses on the gastric cancer cohort within the expansion phase. PATIENTS AND METHODS: Eligible patients had unresectable, measurable gastric cancer, progression following a platinum drug plus fluoropyrimidine (1L), and a taxane-containing regimen (2L). The primary objective of the expansion phase was objective response rate, secondary objectives included safety and PFS, and exploratory objectives included overall survival and biomarker evaluation. Patients received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks, both as intravenous infusions. Tumor responses were assessed every 6 weeks by the investigators per RECIST v1.1. Plasma and tumor biomarkers were assessed. RESULTS: In the 31 patients who received E7389-LF in combination with nivolumab, the objective response rate was 25.8% [confidence interval (CI), 11.9-44.6]. The median progression-free survival was 2.69 months (95% CI, 1.91-2.99) and median overall survival was 7.85 months (95% CI, 4.47-not estimable). The most common treatment-related TEAE of any grade were neutropenia (77.4%), leukopenia (74.2%), and decreased appetite (51.6%). E7389-LF in combination with nivolumab significantly increased CD8-positive cells at C2D1 (P = 0.039), and six of seven vascular markers and four IFNγ-related markers showed increases from C1D1. CONCLUSIONS: Promising antitumor activity was observed with E7389-LF in combination with nivolumab in patients with gastric cancer, and no new safety signals were observed, compared with either monotherapy.

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.

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.