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.

Effects of a force feedback function in a surgical robot on the suturing procedure.

BACKGROUND: Currently, widely used robotic surgical systems do not provide force feedback. This study aimed to evaluate the impact and benefits of a force feedback function on the suturing procedure. METHODS: Twenty surgeons were recruited and divided into young (Y-group, n = 11) and senior (S-group, n = 9) groups, based on their years of surgical experience. The effect of the force feedback function on suturing quality was evaluated using an objective assessment system (A-LAP mini, Kyoto Kagaku Co., Ltd., Kyoto, Japan). Each participant completed the suturing task on intestinal model sheets with the robotic contact force feedback on and off. The task accomplishment time (s), maximal force (Newton, N) applied to the robotic forceps, and quality of suturing (assessed by A-LAP mini) were recorded as performance parameters. RESULTS: In total, the maximal force applied to the robotic forceps was significantly decreased with the robotic force feedback switched on (median [interquartile range]: 2.8 N (2.3-3.2)) as compared with when the feedback was switched off (3.4 N (2.7-4.0), P < 0.001). The contact force feedback function did not affect the objectively assessed suturing score (18 points (17.7-19.0) versus 18 points (17.0-19.0), P = 0.421). The contact force feedback function slightly shortened the task accomplishment time in the Y-group (552.5 s (466.5-832) versus 605.5 s (476.2-689.7), P = 0.851) but not in the S-group (566 s (440.2-703.5) versus 470.5 s (419.7-560.2), P = 0.164). CONCLUSIONS: With the contact force feedback function, the suturing task was completed with a smaller maximal force, while maintaining the quality of suturing. Because the benefits are more apparent in young surgeons, robots with the contact force feedback function will facilitate the educational process in novice surgeons.

Clinical impact of skeletal muscle mass change during the neoadjuvant chemotherapy period in patients with gastric cancer: An ancillary study of JCOG1002.

BACKGROUND: Recent studies have revealed that sarcopenia is associated with postoperative complications and poor prognosis. Although neoadjuvant chemotherapy is a promising treatment for gastric cancer, its toxicity may lead to the loss of skeletal muscle mass. This study investigates the changes in skeletal muscle mass during neoadjuvant chemotherapy and its clinical impact on patients with locally advanced gastric cancer. METHODS: Fifty patients who completed two courses of neoadjuvant chemotherapy followed by surgery were included. Skeletal muscle mass was measured using computed tomography images before and after chemotherapy. The proportion of skeletal muscle mass change (%SMC) during neoadjuvant chemotherapy and its cutoff value was explored using the receiver operating characteristic for the overall survival of patients undergoing R0 resection. Risk factors of skeletal muscle mass loss were also evaluated. RESULTS: Overall, 64% of patients had skeletal muscle mass loss during neoadjuvant chemotherapy (median %SMC -3.4%; range: -18.9% to 10.3%). Multivariable analysis identified older age (≥70 years) as an independent predictor of skeletal muscle mass loss (mean [95% confidence interval]: -4.70% [-8.83 to -0.58], p = 0.026). Among 43 patients undergoing R0 resection, %SMC <-6.9% was an independent poor prognostic factor for overall survival (hazard ratio, 11.53; 95% confidence interval, 2.78-47.80) and relapse-free survival (hazard ratio 4.54, 95% confidence interval 1.50-13.81). CONCLUSIONS: Skeletal muscle mass loss occurs frequently during neoadjuvant chemotherapy for locally advanced gastric cancer and could adversely affect survival outcomes.

Ginseng mediates its anticancer activity by inhibiting the expression of DNMTs and reactivating methylation-silenced genes in colorectal cancer.

Developing safe and effective therapeutic modalities remains a critical challenge for improving the prognosis of patients with colorectal cancer (CRC). In this regard, targeting epigenetic regulation in cancers has recently emerged as a promising therapeutic approach. Since several natural compounds have recently been shown to be important epigenetic modulators, we hypothesized that Ginseng might exert its anticancer activity by regulating DNA methylation alterations in CRC. In this study, a series of cell culture studies were conducted, followed by their interrogation in patient-derived 3D organoid models to evaluate Ginseng's anticancer activity in CRC. Genome-wide methylation alterations were interrogated by undertaking MethylationEpic BeadChip microarrays. First, 50% inhibitory concentrations (IC50) were determined by cell viability assays, and subsequent Ginseng treatment demonstrated a significant anticancer effect on clonogenicity and cellular migration in CRC cells. Treatment with Ginseng potentiated cellular apoptosis through regulation of apoptosis-related genes in CRC cells. Furthermore, Ginseng treatment downregulated the expression of DNA methyltransferases (DNMTs) and decreased the global DNA methylation levels in CRC cells. The genome-wide methylation profiling identified Ginseng-induced hypomethylation of transcriptionally silenced tumor suppressor genes. Finally, cell culture-based findings were successfully validated in patient-derived 3D organoids. In conclusion, we demonstrate that Ginseng exerts its antitumorigenic potential by regulating cellular apoptosis via the downregulation of DNMTs and reversing the methylation status of transcriptionally silenced genes in CRC.

A liquid biopsy signature for predicting early recurrence in patients with gastric cancer.

BACKGROUND: Gastric cancer (GC) patients who experience recurrence within the first year following surgery (early recurrence [ER]) exhibit worse prognosis. Herein, we established a microRNA-based liquid biopsy assay to predict ER in GC patients. METHODS: A comprehensive biomarker discovery was performed by analysing miRNA expression profiling in 271 primary GC tumours. Thereafter, the expression of these biomarkers was validated in 290 GC cases, which included 218 tissues and 72 pre-treatment sera, from two independent institutions. RESULTS: A panel of 8 miRNAs was identified during the initial biomarker discovery, and this panel could robustly predict ER in a tissue-based clinical cohort (area under the curve [AUC]: 0.81). Furthermore, a model combining the miRNA panel, microsatellite instability (MSI) status and tumour size exhibited superior predictive performance (AUC: 0.86), and was defined as a Prediction of Early Recurrence in GC (PERGC) signature, which was successfully validated in another independent cohort (AUC: 0.82). Finally, the PERGC signature was translated into a liquid biopsy assay (AUC: 0.81), and a multivariate regression analysis revealed this signature to be an independent predictor for ER (odds ratio: 11.20). CONCLUSION: We successfully established a miRNA-based liquid biopsy signature that robustly predicts the risk of ER in GC patients.

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.

Identifying Risk Factors of Complications following Total Gastrectomy for Gastric Cancer: Comparison between Splenectomy and Spleen-Preserving Surgery - A Supplementary Analysis of JCOG0110.

INTRODUCTION: Splenectomy for proximal gastric cancer was found to offer no survival benefit in a randomized trial clarifying the role of splenectomy (JCOG0110 study). Although many studies have explored risk factors for morbidities following total gastrectomy, none have assessed the risk factors for postoperative complications in spleen-preserving total gastrectomy. METHODS: Using data from 505 patients enrolled in a previous randomized trial, risk factors for postoperative complications were identified by multivariable logistic regression analysis. Then, the risk factors were assessed separately between splenectomy and spleen-preserving total gastrectomy. RESULTS: Postoperative complications were identified in 119 patients (23.6%) and were more common following splenectomy than following spleen-preserving surgery (30.7% and 16.1%, respectively, p < 0.01). Multivariable analysis revealed that age ≥65 years (p = 0.032), body mass index ≥25 (p = 0.003), and blood loss ≥350 (p = 0.019) were independent risk factors for postoperative complications in the entire cohort. Among them, only body mass index was a significant independent risk factor for complications in both spleen preservation (p = 0.047) and splenectomy groups (p = 0.017). CONCLUSION: Risk factors for postoperative complications were essentially the same between splenectomy and spleen preservation. Being overweight increased the risk of postoperative complications.

Clinical significance of Bacteroides fragilis as a potential prognostic factor in colorectal cancer.

INTRODUCTION: Bacteroides fragilis (B. fragilis) is considered to act in an anti-inflammatory manner on the intestinal tract. On the contrary, enterotoxigenic B. fragilis (ETBF), a subtype of B. fragilis, produces an enterotoxin (BFT; B. fragilis toxin), leading to asymptomatic chronic infections and colonic tumor formation. However, the impact of B. fragilis and ETBF on the clinical outcome of colorectal cancer (CRC) remains unclear. We aim to assess whether their presence affects the outcome in patients with CRC after curative resection. METHODS: We obtained 197 pairs of matched formalin-fixed paraffin-embedded samples from cancerous and adjacent non-cancerous tissues of patients with pathological stage (pstage) II and III CRC after curative resection. The presence of B. fragilis and ETBF were estimated using real-time polymerase chain reaction, and recurrence-free survival (RFS) and overall survival (OS) of the patients were analyzed. RESULTS: 16S rRNA for B. fragilis and bft DNA were detected in 120 (60.9%) and 12 (6.1%) of the 197 patients, respectively. B. fragilis-positive patients had better RFS than B. fragilis-negative patients, although that was not statistically significant. In subgroup analysis, better outcomes on RFS were observed in the presence of B. fragilis in pstage II and left-sided CRC. The association of B. fragilis positivity on OS was accentuated in the depth of T4 subgroup. No significant differences were observed in RFS and OS between ETBF and non-toxigenic B. fragilis. CONCLUSIONS: Our findings suggest that the presence of B. fragilis is associated with better outcomes in patients with pstage II and III CRC after curative resection.

A Transcriptomic Liquid Biopsy Assay for Predicting Resistance to Neoadjuvant Therapy in Esophageal Squamous Cell Carcinoma.

OBJECTIVE: The aim of this study was to establish a liquid-biopsy assay to predict response to neoadjuvant therapy (NAT) in esophageal squamous cell carcinoma (ESCC) patients. SUMMARY BACKGROUND DATA: Pretreatment prediction of resistance to NAT is of great significance for the selection of treatment options in ESCC patients. In this study, we comprehensively translated tissue-based microRNA (miRNA) and messenger RNA (mRNA) expression biomarkers into a liquid biopsy assay. METHODS: We analyzed 186 clinical ESCC samples, which included 128 formalin-fixed paraffin-embedded and a matched subset of 58 serum samples, from 2 independent institutions. We performed quantitative reverse-transcription polymerase chain reaction, and developed a resistance-prediction model using the logistic regression analyses. RESULTS: We first evaluated the potential of 4-miRNAs and 3-mRNAs panel, which robustly predicted resistance to NAT [area under the curve (AUC): 0.85]. Moreover, addition of tumor size to this panel increased predictive potential to establish a combination signature (AUC: 0.92). We successfully validated this signature performance in independent cohort, and our model was more accurate when the signature was combined with clinical predictors (AUC: 0.81) to establish a NAT resistance risk (NATRR) model. Finally, we successfully translated our NATRR model into a liquid biopsy assay (AUC: 0.78), and a multivariate regression analysis revealed this model as an independent predictor for response to NAT (odds ratio: 6.10; P < 0.01). CONCLUSIONS: We successfully developed a liquid biopsy-based assay that allows robust prediction of response to NAT in ESCC patients, and our assay provides fundamentals of developing precision-medicine.

Development of a Reliable Surgical Quality Assurance System for 2-stage Esophagectomy in Randomized Controlled Trials.

OBJECTIVE: The aim was to develop a reliable surgical quality assurance system for 2-stage esophagectomy. This development was conducted during the pilot phase of the multicenter ROMIO trial, collaborating with international experts. SUMMARY OF BACKGROUND DATA: There is evidence that the quality of surgical performance in randomized controlled trials influences clinical outcomes, quality of lymphadenectomy and loco-regional recurrence. METHODS: Standardization of 2-stage esophagectomy was based on structured observations, semi-structured interviews, hierarchical task analysis, and a Delphi consensus process. This standardization provided the structure for the operation manual and video and photographic assessment tools. Reliability was examined using generalizability theory. RESULTS: Hierarchical task analysis for 2-stage esophagectomy comprised fifty-four steps. Consensus (75%) agreement was reached on thirty-nine steps, whereas fifteen steps had a majority decision. An operation manual and record were created. A thirty five-item video assessment tool was developed that assessed the process (safety and efficiency) and quality of the end product (anatomy exposed and lymphadenectomy performed) of the operation. The quality of the end product section was used as a twenty seven-item photographic assessment tool. Thirty-one videos and fifty-three photographic series were submitted from the ROMIO pilot phase for assessment. The overall G-coefficient for the video assessment tool was 0.744, and for the photographic assessment tool was 0.700. CONCLUSIONS: A reliable surgical quality assurance system for 2-stage esophagectomy has been developed for surgical oncology randomized controlled trials. ETHICAL APPROVAL: 11/NW/0895 and confirmed locally as appropriate, 12/SW/0161, 16/SW/0098.Trial registration number: ISRCTN59036820, ISRCTN10386621.

Negative impact of intraoperative blood loss on long-term outcome after curative gastrectomy for advanced gastric cancer: exploratory analysis of the JCOG1001 phase III trial.

BACKGROUND: Recent retrospective studies have shown that increased intraoperative blood loss (IBL) during curative gastrectomy for patients with advanced gastric cancer is a negative prognostic indicator for recurrence. However, there are no reliable reports assessing this with a large-scale prospective cohort. This study aimed to evaluate the impact of IBL on long-term outcomes using data from the JCOG1001 phase III trial, which was designed to determine if bursectomy led to improved survival vs. nonbursectomy in patients with cT3/4a gastric cancer. METHODS: This study included 1203 of the 1204 patients enrolled in the JCOG1001. From the tertiles of IBL (196 ml, 400 ml), we divided the patients into three groups: IBL < 200 ml representing small blood loss (SBL, n = 404), 200 ml ≤ IBL < 400 ml representing medium blood loss (MBL, n = 393), and IBL ≥ 400 ml representing large blood loss (LBL, n = 406). The impact of IBL on relapse-free survival (RFS) was evaluated with univariable comparisons and multivariable Cox regression analyses. RESULTS: Three-year RFS after SBL, MBL, and LBL was 81.7%, 74.8%, and 70.6%, respectively. Multivariable analysis identified IBL, Eastern Cooperative Oncology Group performance status, pT, pN, and postoperative adjuvant chemotherapy as independent predictors of RFS. Compared with SBL as a reference, the hazard ratios of MBL and LBL were 1.461 (P = 0.012) and 1.520 (P = 0.009), respectively. CONCLUSIONS: Based on the analysis of data from a large-scale prospective study, an IBL of ≥ 200 ml after curative surgery for patients with cT3/4a gastric cancer was an independent predictor of reduced RFS.

Mucosal Congestion on the First Day Following Endoscopy Predicts Anastomotic Stricture After Esophagectomy.

BACKGROUND: Anastomotic stricture is a relatively common postoperative complication after esophagectomy. Previous studies have indicated that impaired perioperative blood perfusion at the anastomosis is associated with the occurrence of stricture. Therefore, we analyzed the association between endoscopically assessed blood perfusion during the early postoperative period and anastomotic stricture. METHODS: This retrospective study evaluated patients who underwent esophagectomy at Tokyo Medical and Dental University between 2010 and 2015. The patients had undergone nasal endoscopy on the 1st and 8th postoperative days. The findings were used to evaluate blood perfusion at the anastomosis and gastric tube, which was classified based on mucosal color as ischemia (white) or congestion (blue or black). Univariate and multivariable logistic regression analyses were performed to identify risk factors for anastomotic stricture. RESULTS: The study included 197 patients and anastomotic stricture was observed in 60 patients (30.4%). The multivariable analysis revealed that postoperative gastric tube congestion was a risk factor for stricture (odds ratio [OR]: 6.440, 95% confidence interval [CI]: 2.660-15.600; p < 0.001). Lower risks of anastomotic stricture were associated with pathological stage III-IV disease (OR: 0.325, 95% CI: 0.161-0.656; p = 0.002). CONCLUSION: This study revealed that endoscopically detected congestion at the anastomosis on the first postoperative day was a risk factor for anastomotic stricture.

Preliminary study for developing a navigation system for gastric cancer surgery using artificial intelligence.

PURPOSE: We are attempting to develop a navigation system for safe and effective peripancreatic lymphadenectomy in gastric cancer surgery. As a preliminary study, we examined whether or not the peripancreatic dissection line could be learned by a machine learning model (MLM). METHODS: Among the 41 patients with gastric cancer who underwent radical gastrectomy between April 2019 and January 2020, we selected 6 in whom the pancreatic contour was relatively easy to trace. The pancreatic contour was annotated by a trainer surgeon in 1242 images captured from the video recordings. The MLM was trained using the annotated images from five of the six patients. The pancreatic contour was then segmented by the trained MLM using images from the remaining patient. The same procedure was repeated for all six combinations. RESULTS: The median maximum intersection over union of each image was 0.708, which was higher than the threshold (0.5). However, the pancreatic contour was misidentified in parts where fatty tissue or thin vessels overlaid the pancreas in some cases. CONCLUSION: The contour of the pancreas could be traced relatively well using the trained MLM. Further investigations and training of the system are needed to develop a practical navigation system.

Impact of COVID-19 on gastric cancer treatment in Japanese high-volume centers: a JCOG stomach cancer study group survey.

PURPOSES: The spread of coronavirus disease 2019 (COVID-19) has affected socioeconomic and healthcare systems in many countries. Accordingly, many individuals may have canceled their annual health-check programs, including esophagogastroduodenoscopy, which would have resulted in lower numbers of newly diagnosed patients with gastric cancer in comparison to other times. METHODS: Questionnaires were distributed to 62 hospitals every week from May 2020 to August 2020 (total 744) through mailing lists of the Stomach Cancer Study Group of the Japan Clinical Oncology Group. The number of patients with gastric cancer and hospital systems during the COVID-19 pandemic were surveyed. RESULTS: In total, 74% (551 out of 744) of the questionnaires were answered and analyzed. In early May, approximately 50% of hospitals had to restrict surgical slots due to the COVID-19 pandemic. However, they gradually loosened the restrictions thereafter. The number of gastrectomies was < 80% that of the same period in the previous year, and hospitals in Tokyo were seriously affected by a 50% decrease in the number of gastrectomies. CONCLUSIONS: The number of gastrectomies was lower than that in the previous year. Further multi-center follow-up studies are required to evaluate the long-term effects of COVID-19 on the clinical outcomes of patients with gastric cancer.

The impact of lymphadenectomy on lymph node recurrence after performing various treatments for esophageal squamous cell carcinoma.

BACKGROUND: Treatment for regional lymph node recurrence after initial treatment for esophageal squamous cell carcinoma (ESCC) differs among institutions. Though some retrospective cohort studies have shown that lymphadenectomy for cervical lymph node recurrence is safe and leads to long-term survival, the efficacy remains unclear. In this study, we investigated the long-term outcomes of patients who underwent lymphadenectomy for regional recurrence after treatment for ESCC. PATIENTS AND METHODS: We retrieved 20 cases in which lymphadenectomy was performed for lymph node recurrence after initial treatment for ESCC in our hospital from January 2003 to December 2016. Initial treatments included esophagectomy, endoscopic resection (ER) and chemoradiotherapy/chemotherapy (CRT/CT). Overall survival (OS) and recurrence-free survival (RFS) after lymphadenectomy were calculated by the Kaplan-Meier method. We also used a univariate analysis with a Cox proportional hazards model to determine factors influencing the long-term outcomes. RESULTS: The five-year OS and RFS of patients who underwent secondary lymphadenectomy for recurrence after initial treatment were 50.0% and 26.7%, respectively. The five-year overall survival rates of patients who received esophagectomy, ER and CRT/CT as initial treatments, were 40.0%, 75.0% and 50.0%, respectively. The five-year OS rates of patients with Stage I and Stage II-IVB at initial treatments were 83.3% and 33.3%, respectively. CONCLUSIONS: Lymphadenectomy for regional recurrence after initial treatment for ESCC is effective to some degree. Patients with regional recurrence after initial treatment for Stage I ESCC have a good prognosis; thus, lymphadenectomy should be considered for these cases.

Spatial and Quantitative Analysis of Tumor-Associated Macrophages: Intratumoral CD163-/PD-L1+ TAMs as a Marker of Favorable Clinical Outcomes in Triple-Negative Breast Cancer.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.

Prognostic Value of Intraoperative Blood Transfusion in Patients with Adenocarcinoma of the Esophagogastric Junction.

Background and objectives: Adenocarcinoma of the esophagogastric junction (AEG) has a complicated surgical anatomy, due to which it sometimes induces excessive intraoperative blood loss that necessitates intraoperative blood transfusion (BTF). However, few reports have focused on the impact of BTF on the survival outcomes of patients with AEG. We aimed to evaluate the impact of BTF on AEG prognosis. Materials andMethods: We included 63 patients who underwent surgical resection for AEG at our hospital between January 2010 and September 2020. Clinicopathological characteristics and survival outcomes were compared between patients with (n = 12) and without (n = 51) BTF. Multivariate analysis was performed to identify the independent prognostic factors for overall survival. Results: None of the patients who underwent minimally invasive surgery received BTF. Patients who received BTF had a significantly worse 5-year survival rate than those who did not (67.8% vs. 28.3%, p = 0.001). BTF was an independent risk factor for overall survival (hazard ratio: 3.90, 95% confidence interval 1.30-11.7), even after patients who underwent minimally invasive surgery were excluded. Conclusions: BTF adversely affected the survival outcomes of patients with AEG who underwent curative surgery. To avoid BTF, surgeons should strive to minimize intraoperative bleeding.

Impact of postoperative complications on survival outcomes in patients with gastric cancer: exploratory analysis of a randomized controlled JCOG1001 trial.

BACKGROUND: Recent studies have found a negative impact of postoperative complications on long-term survival outcomes, but it has not been confirmed by data obtained from a prospective study with a large sample size. This study investigated the impact of postoperative complications on long-term survival outcomes, and considered the optimal definition of complication, using data from JCOG1001, which compared bursectomy and non-bursectomy for patients with cT3/4a locally advanced gastric cancer. METHODS: This study included 1191 of 1204 patients enrolled in the JCOG1001 trial. Complications were graded by Clavien-Dindo (C-D) classification. Impact of the grade (≥ C-D grade II or ≥ grade III) or type (any or intra-abdominal infectious) of complication on survival outcome was evaluated by univariate and multivariable analyses using the Cox proportional hazard model. RESULTS: The incidence of any ≥ C-D grade II and ≥ grade III complication was 23.0% and 9.7%, respectively, and that of ≥ grade II and ≥ grade III intra-abdominal infectious complication was 13.4% and 6.9%, respectively. Multivariable analysis showed all four definitions of complications were independent prognostic factors for overall survival. Conversely, only any ≥ C-D grade III complication was found to be an independent prognostic factor for relapse-free survival (hazard ratio, 1.445; 95% confidence interval, 1.026-2.036; P = 0.035). CONCLUSIONS: Postoperative complications adversely affect the long-term survival outcomes of patients with cT3/4a gastric cancer. Any ≥ C-D grade III complication seems to be the most suitable definition of complication for predicting negative long-term survival outcomes.

Treatment and subsequent prognosis in locally recurrent rectal cancer: a multicenter retrospective study of 498 patients.

PURPOSE: Locally recurrent rectal cancer (LRRC) has a tremendous impact on prognosis as well as the quality of life. Because of the low incidence and various recurrence patterns, the treatment outcome of LRRC is not fully elucidated. The current study aimed to evaluate the prognosis and identify the prognosticators in patients with LRRC. METHODS: We conducted a multicenter study at 24 hospitals in Japan. Patients with primary rectal cancer who underwent curative resection between 1997 and 2012 and developed local recurrence only as a first recurrent event were recruited. The primary outcome of our study was overall survival (OS) after a diagnosis of LRRC. RESULTS: Four hundred and ninety-eight patients were included in the study. Of these, 213 (42.8%) underwent surgical resection; this was associated with the best 5-year OS rate of 52%, followed by carbon ion/proton therapy (44%). Among LRRC patients, undifferentiated type, T4, high CEA level, and high CA19-9 level were independent prognosticators of OS (hazard ratio (HR) = 1.83, P = 0.008, HR = 1.54, P = 0.004, HR = 1.35, P = 0.03, and HR = 1.58, P = 0.003, respectively). CONCLUSIONS: This large-scale cohort study showed that surgical resection led to a favorable prognosis compared to other treatments for LRRC. Therefore, surgical resection should be considered whenever feasible for LRRC patients. In addition, undifferentiated type, T4, and tumor marker (CEA and CA19-9) elevation were identified as independent prognostic factors for OS among patients with LRRC.