An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells.

Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.

Automatic surgical phase recognition-based skill assessment in laparoscopic distal gastrectomy using multicenter videos.

BACKGROUND: Gastric surgery involves numerous surgical phases; however, its steps can be clearly defined. Deep learning-based surgical phase recognition can promote stylization of gastric surgery with applications in automatic surgical skill assessment. This study aimed to develop a deep learning-based surgical phase-recognition model using multicenter videos of laparoscopic distal gastrectomy, and examine the feasibility of automatic surgical skill assessment using the developed model. METHODS: Surgical videos from 20 hospitals were used. Laparoscopic distal gastrectomy was defined and annotated into nine phases and a deep learning-based image classification model was developed for phase recognition. We examined whether the developed model's output, including the number of frames in each phase and the adequacy of the surgical field development during the phase of supra-pancreatic lymphadenectomy, correlated with the manually assigned skill assessment score. RESULTS: The overall accuracy of phase recognition was 88.8%. Regarding surgical skill assessment based on the number of frames during the phases of lymphadenectomy of the left greater curvature and reconstruction, the number of frames in the high-score group were significantly less than those in the low-score group (829 vs. 1,152, P < 0.01; 1,208 vs. 1,586, P = 0.01, respectively). The output score of the adequacy of the surgical field development, which is the developed model's output, was significantly higher in the high-score group than that in the low-score group (0.975 vs. 0.970, P = 0.04). CONCLUSION: The developed model had high accuracy in phase-recognition tasks and has the potential for application in automatic surgical skill assessment systems.

A nonrandomized controlled trial: long-term outcomes of LATG/LAPG for cStage I gastric cancer: Japan Clinical Oncology Group Study JCOG1401.

BACKGROUND: A previous report confirmed the safety of laparoscopy-assisted total and proximal gastrectomies (LATG and LAPG) (JCOG1401). This report demonstrates the 5-year relapse-free survival (RFS) and overall survival (OS) after long-term follow-up to confirm the efficacy of these surgical methods as key secondary endpoints for cStage I gastric cancer. METHODS: This study enrolled patients who had histologically proven gastric adenocarcinoma and were diagnosed with clinical T1N0, T1N(+), or T2N0 tumors according to the 14th edition of the Japanese Classification of Gastric Carcinoma (3rd English edition). RESULTS: Between April 2015 and February 2017, 246 patients were enrolled, although one patient was excluded because of misregistration. Meticulous follow-up was continued for > 5 years for each patient, and the data were analyzed in March 2022. The 5-year RFS was 90.0% (95% confidence interval [CI] 85.5-93.2%), and the 5-year OS was 91.2% (95% CI 86.9-94.2%) in all enrolled patients. Grade 3 or 4 late postoperative complications were detected in 12.7% of patients. CONCLUSIONS: This single-arm study showed that the long-term outcomes of LATG/LAPG for cStage I gastric cancer were acceptable, which is considered one of the standard treatments when performed by experienced surgeons. Trail registration UMIN000017155 ( http://www.umin.ac.jp/ctr/ ).

Early endpoints of a randomized phase II trial of preoperative chemotherapy with S-1/CDDP with or without trastuzumab followed by surgery for HER2-positive resectable gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).

BACKGROUND: This randomized phase II study explored the superiority of trastuzumab plus S-1 plus cisplatin (SP) over SP alone as neoadjuvant chemotherapy (NAC) for HER2-positive resectable gastric cancer with extensive lymph node metastasis. METHODS: Eligible patients with HER2-positive gastric or esophagogastric junction cancer and extensive lymph node metastasis were randomized to receive three or four courses of preoperative chemotherapy with SP (arm A) or SP plus trastuzumab (arm B). Following gastrectomy, adjuvant chemotherapy with S-1 was administered for 1 year in both arms. The primary endpoint was overall survival, and the sample size was 130 patients in total. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180006. RESULTS: This report elucidates the early endpoints, including pathological findings and safety. The study was terminated early due to slow patient accruals. In total, 46 patients were allocated to arm A (n = 22) and arm B (n = 24). NAC was completed in 20 patients (91%) in arm A and 23 patients (96%) in arm B, with similar incidences of grade 3-4 hematological and non-hematological adverse events. Objective response rates were 50% in arm A and 84% in arm B (p = 0·065). %R0 resection rates were 91% and 92%, and pathological response rates (≥ grade 1b in Japanese classification) were 23% and 50% (p = 0·072) in resected patients, respectively. CONCLUSIONS: Trastuzumab can be safely added to platinum-containing doublet chemotherapy as NAC, and it has the potential to contribute to higher antitumor activity against locally advanced, HER2-positive gastric or esophagogastric junction cancer with extensive nodal metastasis.

Feasibility of laparoscopic/robot-assisted surgery for Borrmann type 4 gastric cancer: a comparison study with conventional open surgery.

BACKGROUND: Laparoscopic surgery for early gastric cancer is regarded as a standard of care because of robust evidences obtained by several phase-III trials. Furthermore, the efficacy of laparoscopic radical surgery for advanced gastric cancer has been also reported. Meanwhile, the feasibility of laparoscopic surgery for Bormann type 4 gastric cancer, special type with unfavorable prognosis, remains unclear since excluded from eligibility of these trials. METHODS: This study included 100 patients with type 4 gastric cancer who underwent laparoscopic/robot-assisted (minimally invasive surgery (MIS) group; n = 32) or open (Open group; n = 68) curative surgery between 2008 and 2021. After propensity score matching, 30 patients in each group were extracted for analysis. Clinical data, including surgical and midterm survival outcomes, were retrospectively compared between the two groups. RESULTS: Incidences of postoperative complication (≥ Clavien-Dindo grade III) were recorded in 23.3% in the MIS group and 13.3% in the Open group, but no statistical significance was demonstrated (P = 0.50). The 3-year overall survival rate in the MIS group was better than that in the Open group (80.2% vs. 53.5%, log-rank, P = 0.03). The trend of recurrence site was similar. Multivariate analysis showed that adjuvant chemotherapy was an independent favorable prognostic factor (hazard ratio, 0.33, 95% confidence interval 0.11-0.93) for overall survival. MIS was indicated as a favorable prognostic factor (hazard ratio, 0.39, 95% confidence interval 0.39-1.07), but without statistical difference. CONCLUSION: While multidisciplinary treatment is mainstay of treatment because of the poor prognosis of this disease, minimally invasive surgery may play an important role in treatment if appropriate patient selection is done. Further analyses with larger sample size are necessary to reach a final conclusion regarding oncological efficacy.

Oncological long-term outcomes of laparoscopic versus open gastrectomy for cT3-4 gastric cancer at surgical staging: a propensity-score matched cohort study.

BACKGROUND: The oncological efficacy of laparoscopic surgery for advanced gastric cancer (AGC) has been evaluated by several randomized trials. However, the inclusion of earlier-stage disease was a limitation in previous studies. METHODS: Patients with cT3-4 gastric cancer, determined by surgical staging to minimize migration of earlier stages, treated at a tertiary cancer center from 2009 to 2018 were included. Based on the surgical approach, the patients were divided into two groups: the laparoscopic gastrectomy (LG) and the open gastrectomy (OG) and matched for age, sex, macroscopic appearance (type 4 or non-type 4), body mass index, estimated tumor size, clinical stage T3'T4, clinical N stage, pathologic T stage (T3 or T4), and type of surgery (total or distal gastrectomy). RESULTS: 588 patients (221 LG, 367 OG) were included in the analysis. After 1:1 propensity-score matching, 386 patients (193 LG, 193 OG) were assigned for analysis. In the LG group, operation time was longer with lower blood loss. The incidence of postoperative complications (≥ grade III) did not differ significantly between the groups (OG: 8.3%, vs. LG: 9.3%). Overall survival (OS) was longer in the LG group (5-year OS: 79.3 vs. 73% HR 0.66, 95% CI 0.44-0.99, P = 0.0497). Relapse-free survival (RFS) did not show a statistical difference (5-year RFS: 69.5 vs. 68.7 HR 0.88, 95% CI 0.62-1.26, P = 0.487). Subgroup analysis for OS also demonstrated equivalent outcomes. CONCLUSION: LG demonstrates comparable safety and efficacy to OG for advanced gastric cancer at surgical staging, with similar rates of severe complications and long-term oncological outcomes. Further research is needed to validate these findings, particularly for total gastrectomy and for patients from Western populations.

Surgical step recognition in laparoscopic distal gastrectomy using artificial intelligence: a proof-of-concept study.

PURPOSE: Laparoscopic distal gastrectomy (LDG) is a difficult procedure for early career surgeons. Artificial intelligence (AI)-based surgical step recognition is crucial for establishing context-aware computer-aided surgery systems. In this study, we aimed to develop an automatic recognition model for LDG using AI and evaluate its performance. METHODS: Patients who underwent LDG at our institution in 2019 were included in this study. Surgical video data were classified into the following nine steps: (1) Port insertion; (2) Lymphadenectomy on the left side of the greater curvature; (3) Lymphadenectomy on the right side of the greater curvature; (4) Division of the duodenum; (5) Lymphadenectomy of the suprapancreatic area; (6) Lymphadenectomy on the lesser curvature; (7) Division of the stomach; (8) Reconstruction; and (9) From reconstruction to completion of surgery. Two gastric surgeons manually assigned all annotation labels. Convolutional neural network (CNN)-based image classification was further employed to identify surgical steps. RESULTS: The dataset comprised 40 LDG videos. Over 1,000,000 frames with annotated labels of the LDG steps were used to train the deep-learning model, with 30 and 10 surgical videos for training and validation, respectively. The classification accuracies of the developed models were precision, 0.88; recall, 0.87; F1 score, 0.88; and overall accuracy, 0.89. The inference speed of the proposed model was 32 ps. CONCLUSION: The developed CNN model automatically recognized the LDG surgical process with relatively high accuracy. Adding more data to this model could provide a fundamental technology that could be used in the development of future surgical instruments.

Tumor thickness is associated with metastasis in patients with submucosal invasive adenocarcinoma of the esophagogastric junction.

In submucosal invasive adenocarcinoma of the esophagogastric junction (pT1b-SM AEG), the extent of tumor submucosal (SM) invasion is measured using the vertical depth of SM invasion with the muscularis mucosa. This study aimed to investigate whether tumor thickness and depth of invasion without accounting for muscularis mucosa were superior to the vertical depth of SM invasion as metastasis predictors. We enrolled patients with pT1b-SM AEG who underwent endoscopic resection or surgical resection (SR) at our institution between January 2011 and September 2019 and were followed up for ≥2 years. The relationship between metastasis and clinicopathological factors was examined. Metastasis was defined as pathologically confirmed lymph node metastasis in the surgical specimen or recurrence during follow-up. This study included 57 patients (44 men; median age, 72 years). Endoscopic resection and SR were performed in 16 and 41 patients, respectively. Nine patients were diagnosed with metastasis: five who underwent SR showed pathologically confirmed lymph node metastasis in the surgical specimens, and four experienced recurrences during a median follow-up of 48 months. Univariate analyses showed that tumor thickness was significantly associated with metastasis (P = 0.021), and the vertical depth of SM invasion (P = 0.48) and depth of invasion (P = 0.38) were not. Furthermore, in multivariate analysis, tumor thickness ≥2800 µm (odds ratio, 38.70; P = 0.013) was a significant predictor for metastasis. Tumor thickness may be a more convenient and useful predictor of metastasis in patients with pT1b-SM AEG than the vertical depth of SM invasion.

Surgical Techniques and Related Perioperative Outcomes After Robot-assisted Minimally Invasive Gastrectomy (RAMIG): Results From the Prospective Multicenter International Ugira Gastric Registry.

OBJECTIVE: To gain insight in global practice of RAMIG and evaluated perioperative outcomes using an international registry. BACKGROUND: The techniques and perioperative outcomes of robot-assisted minimally invasive gastrectomy (RAMIG) for gastric cancer vary substantially in literature. METHODS: Prospectively registered RAMIG-cases for gastric cancer (≥10 per center) were extracted from 25 centers in Europe, Asia and South-America. Techniques for the resection, reconstruction, anastomosis and lymphadenectomy were analyzed, and related to perioperative surgical and oncological outcomes. Complications were uniformly defined by the Gastrectomy Complications Consensus Group. RESULTS: Between 2020-2023, 759 patients underwent total (n=272), distal (n=465) or proximal (n=22) gastrectomy (RAMIG). After total gastrectomy with Roux-en-Y-reconstruction, anastomotic leakage rates were 8% with hand-sewn (n=9/111) and 6% with linear stapled anastomoses (n=6/100). After distal gastrectomy with Roux-en-Y (67%) or Billroth-II-reconstruction (31%), anastomotic leakage rates were 3% with linear stapled (n=11/433) and 0% with hand-sewn anastomoses (n=0/26). Extent of lymphadenectomy consisted of D1+ (28%), D2 (59%) or D2+ (12%). Median nodal harvest yielded 31 nodes [IQR 21-47] after total and 34 nodes [IQR 24-47] after distal gastrectomy. R0-resection rates were 93% after total and 96% distal gastrectomy. Hospital stay was 9 days after total and distal gastrectomy, and was 3 days shorter without perianastomotic drains versus routine drain placement. Postoperative 30-day mortality was 1%. CONCLUSIONS: This large multicenter study provided a worldwide overview of current RAMIG-techniques with their respective perioperative outcomes. These outcomes demonstrated high surgical quality, set a quality standard for RAMIG and can be considered an international reference for surgical standardization.

Impact of Programmed Death-Ligand 1 Expression on Mismatch Repair Deficiency and Epstein-Barr Virus Status on Survival Outcomes in Patients with Stage II/III Gastric Cancer After Surgery.

BACKGROUND: The aim of this study was to investigate the prognostic impact of mismatch repair (MMR) status, programmed death-ligand 1 (PD-L1) expression, and Epstein-Barr virus (EBV) status in stage II/III gastric cancer after surgery. METHODS: This study included 679 patients diagnosed with pathological stage II/III gastric cancer who underwent curative gastrectomy followed by adjuvant chemotherapy (AC) or observation between 2007 and 2015. Clinical outcomes were retrospectively reviewed and compared with stratification by AC and other clinicopathological factors. RESULTS: Patients were divided into AC (n = 484) or surgery alone (SA; n = 195) groups and were further stratified by MMR and EBV status: MMR-deficient (DMMR) and MMR-proficient (PMMR) groups. Comparing the AC-DMMR group versus the AC-PMMR group, 5-year overall survival was 92.0% versus 74.0% (log-rank p < 0.01), and comparing the SA-DMMR group versus the SA-PMMR group, 5-year overall survival was 71.1% versus 73.7% (log-rank p = 0.89). DMMR (hazard ratio 0.25, 95% confidence interval 0.07-0.81) was identified as an independent prognostic factor in the AC group but not in the SA group. In the subgroup analysis, PD-L1-negative patients among the EBV-positive patients or in the DMMR group had a poor prognosis in both the AC and SA groups. The prognosis of the PMMR and EBV-negative patients was similar regardless of PD-L1 expression. CONCLUSIONS: DMMR was associated with a favorable prognosis in stage II/III gastric cancer after surgery and adjuvant therapy. PD-L1 expression may affect the prognosis of DMMR and EBV-positive gastric cancer.

Randomized controlled phase III trial to investigate superiority of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer patients (JCOG1907, MONA LISA study): a study protocol.

BACKGROUND: Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking. METHODS: We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer. DISCUSSION: This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer. TRIAL REGISTRATION: The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020.

A multi-institutional study to evaluate the feasibility of next-generation sequencing and genomic analysis using formalin-fixed, paraffin-embedded biopsies of gastric cancer.

BACKGROUND: Formalin-fixed, paraffin-embedded (FFPE) samples acquired and preserved adequately are expected to faithfully maintain tumor characteristics. Endoscopic biopsy tissues represent an attractive resource for identifying predictive biomarkers to evaluate pretreatment responses of patients with advanced gastric cancer (GC). However, whether genomic profiles obtained through next-generation sequencing (NGS) using biopsy samples match well with those gained from surgical FFPE samples remains a concern. METHODS: We collected 50 FFPE samples (26 biopsies and 24 surgical samples) from patients with GC who participated in phase III clinical trial JCOG1509. The quality and quantity of FFPE samples were determined for deep sequencing using NGS. We queried a 435-gene panel CANCERPLEX-JP to generate comprehensive genomic profiling data including the tumor mutation burden (TMB). RESULTS: The median DNA yields and NGS success rates of biopsy samples compared with surgical samples were 879 ng and 80.8% vs 8523 ng and 100%, respectively. Epstein-Barr virus and microsatellite instability-high were detected in 9.5% of biopsy samples. Comparing the genomic profiles of 18 paired samples for which NGS data were available, we detected identical somatic mutations in paired biopsy and surgical samples (kappa coefficient, 0.8692). TMB positively correlated between paired biopsy and surgical samples (correlation coefficient, 0.6911). CONCLUSIONS: NGS is applicable to the analysis of FFPE samples of GC acquired by the endoscopic biopsy, and the data were highly concordant with those obtained from surgical specimens of the same patients.

Evaluating the efficacy of post-operative chemotherapy after curative resection of stage IV gastric cancer with synchronous oligo metastasis: a multicenter retrospective study.

BACKGROUND: Surgical resection of oligo-metastasis in gastric cancer (GC) is weakly recommended for patients without other incurable factors in the Japanese GC Treatment Guidelines. While post-operative chemotherapy is the standard treatment in patients with stage II or III GC, its efficacy for resected stage IV GC is unclear. This study aimed to evaluate the efficacy of post-operative chemotherapy after curative resection of GC with oligo-metastasis. METHODS: We retrospectively reviewed the medical records of patients with GC who were diagnosed with synchronous oligo-metastasis at 20 institutions in Japan between 2007 and 2012. The selection criteria were: adenocarcinoma, stage IV with oligo-metastasis at liver or lymph node without other distant metastasis, curative resection including synchronous oligo-metastasis, and no prior treatment of GC before surgery. RESULTS: A total of 110 patients were collected. Of the 94 eligible patients, 84 underwent gastrectomy with surgical resection of oligo-metastasis (39 [41%] liver metastasis and 55, [59%] distant lymph node metastasis), followed by post-operative chemotherapy with S-1 (S1: n = 55), S1 plus cisplatin (CS: n = 22), or Others (n = 7). Moreover, 10 patients did not receive post-operative chemotherapy (Non-Cx). The median overall survival (OS) was 35.2 and 11.1 months in the post-operative chemotherapy and Non-Cx groups (hazard ratio, 3.56; 95% confidence interval, 1.74-7.30; p < 0.001), respectively. In multivariable analysis, Non-Cx and age over 70 years were identified as poor prognostic factors for OS (p < 0.05). CONCLUSIONS: Curative resection followed by post-operative chemotherapy in patients with GC with synchronous oligo-metastasis showed favorable survival.

Impact of postoperative intra-abdominal infectious complications on survival outcomes in patients with gastric cancer who underwent laparoscopic surgery.

BACKGROUND: Postoperative intra-abdominal infection is known to adversely affect survival outcomes in patients with gastric cancer; however, previous reports have investigated this complication only in open surgery. This adverse effect is expected to be weakened by less invasive surgery, such as a laparoscopic approach, by way of maintaining immune function. METHODS: This study included 1223 patients with gastric cancer who underwent open (n = 439) or laparoscopic (n = 784) curative surgery between 2010 and 2015. For each approach, patients were divided into two groups based on presence or absence of postoperative intra-abdominal infection of Clavien-Dindo grade II or higher (C-group and NC-group, respectively). Survival outcomes were compared in propensity-matched cohorts to evaluate the impact of the complication. RESULTS: The incidences of Clavien-Dindo ≥ grade II postoperative intra-abdominal infectious complications were 9.7% (43/439) in open surgery and 9.8% (70/714) in laparoscopic surgery. After propensity score matching, 86 patients in open surgery and 138 in laparoscopic surgery were extracted for analysis. The 5-year overall survival rate in the open C-group (n = 43) was worse than that in the open NC-group (n = 43) but with no significant difference (70.9% vs. 82.8%, log-rank P = 0.18). The 5-year overall survival rates were equivalent between the laparoscopic C-group (n = 69) and the laparoscopic NC-group (n = 69) (90.5% vs. 90.4%, log-rank P = 0.99). CONCLUSION: In general, postoperative intra-abdominal infection adversely affects survival outcomes; however, its impact may be weakened by less invasive surgery. Further evaluation using larger datasets is necessary before reaching definitive conclusions.

Advantages of robotic gastrectomy for overweight patients with gastric cancer: a comparison study of robotic gastrectomy and conventional laparoscopic gastrectomy.

PURPOSE: A high body mass index (BMI) generally increases the risk of postoperative complications because of the intraperitoneal adipose tissue. Robotic gastrectomy (RG) decreases the surgical difficulty of conventional laparoscopic gastrectomy (LG) for these patients. We conducted the present study to identify the advantages of RG over LG for overweight patients. METHODS: We reviewed clinical data on patients who underwent either LG or RG at the National Cancer Center Hospital East between January, 2014 and May, 2022. RESULTS: The 1298 patients eligible patients were divided into a non-overweight cohort (n = 996) (LG, n = 818; RG, n = 178) and an overweight cohort (n = 302) (LG, n = 250; RG, n = 52) according to a BMI cut-off of 25 kg/m2. In the overweight cohort, the RG group had a lower incidence of grade ≥ III postoperative complications (0.0 vs. 8.8%, p = 0.01) and grade ≥ II postoperative complications (11.5 vs. 22.0%, p = 0.12) than the LG group. Multivariate analysis identified that RG was significantly associated with a lower incidence of grade ≥ II postoperative complications in the overweight cohort (odds ratio, 0.33; 95% confidence interval, 0.12-0.87; p = 0.02). CONCLUSIONS: RG may reduce the risk of postoperative complications, compared with conventional LG, in overweight patients.

[Treatment Strategy for Oligometastatic Gastric Cancer].

Oligometastases are generally defined as a small number of metastases(2-3 or less)in 1 or 2 organs. Oligometastases are rare in gastric cancer because they are often associated with peritoneal dissemination, but gastric cancer patients experience a relatively high incidence of para-aortic lymph node and liver metastases in particular. The Sixth Edition of the Japanese Gastric Cancer Treatment Guidelines weakly recommends surgical resection after medical therapy for a small number of para-aortic lymph node metastases confined to No. 16a2/b1 and a single liver metastasis in the absence of other non-curative resection factors. In Japan, the common treatment strategy is surgical resection after drug therapy, often with the addition of adjuvant chemotherapy after surgery as well. Preoperative drug therapy is generally administered for 3-4 months. Surgical resection has been shown to be relatively safe in experienced centers. Prospective clinical trials are underway in Japan and overseas to establish a higher level of evidence.

Complete response to definitive chemoradiotherapy in unresectable locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Although definitive chemoradiotherapy (CRT) is the standard therapy for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), poor survival has been reported. Although the complete response (CR) rate is strongly correlated with good prognosis, the predictive factors for CR have not been elucidated. METHODS: This registry study aimed to identify predictors of CR to definitive CRT in patients with unresectable locally advanced ESCC. "Unresectable" was defined as the primary lesion invading unresectable adjacent structures such as the aorta, vertebral body, and trachea (T4b), or the regional and/or supraclavicular lymph nodes invading unresectable adjacent structures (LNT4b). RESULTS: Overall, 175 patients who started definitive CRT between January 2013 and March 2020 were included. The confirmed CR (cCR) rate was 24% (42/175). The 2-year progression-free survival (PFS) and overall survival (OS) rates of cCR cases vs. non-cCR cases were 59% vs. 2% (log-rank p < 0.001) and 90% vs. 31% (log-rank p < 0.001), with a median follow-up period of 18.5 and 40.5 months, respectively. Multivariate analysis of clinicopathological factors revealed that tumor length ≥ 6 cm [odds ratio (OR) 0.446; 95% CI 0.220-0.905; p = 0.025] was a predictor of cCR. CONCLUSIONS: Favorable PFS and OS rates were observed in patients with cCR. Tumor length was a predictive factor for cCR.

A multicenter, open-label, single-arm phase I trial of neoadjuvant nivolumab monotherapy for resectable gastric cancer.

BACKGROUND: Nivolumab monotherapy has demonstrated superior efficacy in advanced unresectable gastric cancer (GC), but its impact on resectable GC remains unknown. This phase I study aimed to evaluate safety, feasibility, and potential biomarkers of neoadjuvant nivolumab monotherapy in resectable GC. METHODS: Untreated, resectable, cT2 or more advanced gastric adenocarcinomas with clinical stage I, II, or III were treated with two doses of nivolumab before gastrectomy. Patients were excluded if their tumors may be applicable to neoadjuvant chemotherapy. The primary endpoint was the incidence of adverse event (AE) categories of special interest. RESULTS: All of the 31 enrolled patients completed 2 doses of nivolumab monotherapy. While 30 (97%) patients underwent surgery with curative intent, 1 patient discontinued before the planned surgical intervention because of a newly emerging liver metastasis. Seven patients (23%) had nivolumab treatment-related AEs, and one patient had a treatment-related AE of grade 3-4. The incidences of treatment-related AE categories of special interest ranged from 0 to 6%. Notable surgical complications included two cases of grade 3 anastomotic leakage and two cases of pancreatic fistula. The major pathologic response (MPR) assessed by the independent pathology review committee was achieved in five (16%) patients, of which one patient had a pathologic complete response. The MPR was mostly observed in patients with positive PD-L1 expression, high microsatellite instability, and/or high tumor mutation burden. CONCLUSIONS: Neoadjuvant nivolumab monotherapy is feasible with an acceptable safety profile and induces a MPR in certain patients with resectable GC. (Registration: clinicaltrials.jp, JapicCTI-183895).

Reduction in postoperative complications by robotic surgery: a case-control study of robotic versus conventional laparoscopic surgery for gastric cancer.

BACKGROUND: Robotic gastrectomy (RG) is being increasingly performed globally; it is considered an evolved type of conventional laparoscopic surgery with excellent dexterity and precision, but higher costs and longer operation time. Thus, there is a need to identify the benefits from RG and its specific candidates. METHODS: This retrospective study analyzed data from a prospectively collected clinical database at our center. Data of patients with primary gastric cancer undergoing either robotic or laparoscopic radical gastrectomy from June 2014 to June 2020 were reviewed. Surgical outcomes were compared between the two groups, and multivariable analyses were performed to elucidate the relevant factors for postoperative complications in several subgroups. RESULTS: A total of 1172 patients were divided into those who underwent RG (n = 152) and those who underwent laparoscopic gastrectomy (LG) (n = 1020). Baseline characteristics were similar in the two groups, except the RG group included more patients undergoing total/proximal gastrectomy (TG/PG) and patients at clinical stage III. Compared with the LG group, the RG group had lower incidences of postoperative complications ≥ Clavien-Dindo grade III (2/152 (1.3%) versus 72/1020 (7.1%); P = 0.004), and intraabdominal complications ≥ grade II (6/152 (3.9%) versus 119/1020 (11.7%); P = 0.004). Multivariable analysis revealed that RG was a significant relevant factor for reducing overall postoperative complications (≥ grade III) (odds ratio (OR) 0.16, P = 0.013), and intraabdominal complications (≥ grade II) (OR 0.29, P = 0.002). Subgroup analyses demonstrated that this tendency was enhanced in patients undergoing TG/PG (OR 0.29, P = 0.021) or at clinical stage II/III (OR 0.10, P = 0.027). CONCLUSIONS: RG reduces the incidence of postoperative complications compared with conventional LG and this tendency may be enhanced in technically complicated procedures with demanding anastomosis or D2 lymphadenectomy. Patients requiring such procedures would most benefit from RG.

PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer.

PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA-CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1- eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.