Robotic spleen­preserving suprapancreatic and splenic hilar lymph node dissection using the preemptive retropancreatic approach in total gastrectomy for gastric cancer.

Advanced gastric cancer that has not invaded the greater curvature is a good indication for total gastrectomy (TG) with spleen-preserving suprapancreatic and splenic hilar lymph node dissection (LND). However, the suprapancreatic and splenic hilar LND increases the area of dissection of the pancreas, and prolonged pressure drainage of the pancreas is required to maintain a clear operative view. This can lead to an increased risk of postoperative pancreatic complications. To report the efficacy of our novel preemptive retropancreatic approach (PRA) for the suprapancreatic and splenic hilar LND in robotic TG (RTG). We report our experience with nine patients with gastric cancer who underwent spleen-preserving splenic hilar LND using PRA during RTG at Hokkaido University from October 2018 to November 2021. The PRA involves initial dissection of the left side of the retropancreatic space, followed by the release of the adherence between the retroperitoneum surface and the pancreas (fusion fascia), which provides a good operative field and prevents contact with the pancreas during the suprapancreatic and splenic hilar LND in RTG. The median operating time was 488 min (254-564 min). The median intraoperative bleeding was 55 mL (0-115 mL). One patient had postoperative complications (above grade II of the Clavien-Dindo classification), but there were no postoperative pancreatic complications. The spleen-preserving suprapancreatic and splenic hilar LND using PRA could help to reduce the postoperative pancreatic complications associated with RTG.Trial registration number and date of registration The Hokkaido University Hospital institutional review board approved the data collection and analysis. The trial registration number and date of registration are No. 021-0022 and July 26, retrospectively registered.

Aldehyde Dehydrogenese-1 High Cancer Stem-like Cells/Cancer-initiating Cells Escape from Cytotoxic T Lymphocytes due to Lower Expression of Human Leukocyte Antigen Class 1.

BACKGROUND/AIM: Human gastric cancer stem-like cells (CSCs)/cancer-initiating cells can be identified as aldehyde dehydrogenase-high (ALDHhigh) cells. Cancer immunotherapy employing immune checkpoint blockade has been approved for advanced gastric cancer cases. However, the effectiveness of cancer immunotherapy against gastric CSCs/CICs remains unclear. This study aimed to investigate the susceptibility of gastric CSCs/CICs to immunotherapy. MATERIALS AND METHODS: Gastric CSCs/CICs were isolated as ALDHhigh cells using the human gastric cancer cell line, MKN-45. ALDHhigh clone cells and ALDHlow clone cells were isolated using the ALDEFLUOR assay. ALDH1A1 expression was assessed via qRT-PCR. Sphere-forming ability was evaluated to confirm the presence of CSCs/CICs. A model neoantigen, AP2S1, was over-expressed in ALDHhigh clone cells and ALDHlow clone cells, and susceptibility to AP2S1-specific TCR-T cells was assessed using IFNγ ELISPOT assay. RESULTS: Three ALDHhigh clone cells were isolated from MKN-45 cells. ALDHhigh clone cells exhibited a stable phenotype in in vitro culture for more than 2 months. The High-36 clone cells demonstrated the highest sphere-forming ability, whereas the Low-8 cells showed the lowest sphere-forming ability. High-36 cells exhibited lower expression of HLA-A24 compared to Low-8 cells. TCR-T cells specific for AP2S1 showed lower reactivity to High-36 cells compared to Low-8 cells. CONCLUSION: High-36 cells and Low-8 cells represent novel gastric CSCs/CICs and non-CSCs/CICs, respectively. ALDHhigh CSCs/CICs evade T cells due to lower expression of HLA class 1.

Incidence of atrial fibrillation after esophageal cancer surgery with L-carnitine use: a preliminary single-group interventional study.

PURPOSE: We aimed to investigate the POAF rate and blood FABP4 levels after perioperative L-carnitine administration in patients with esophageal cancer. METHODS: L-carnitine (3 g in three divided doses) was administered to 15 patients 2 days before and 3 days after surgery. POAF during the study period and blood FABP4 levels (ELISA) before and after L-carnitine administration were evaluated. Accurate 95% confidence intervals (CI) for POAF incidence and changes in blood FABP4 levels were calculated. The preoperative predicted POAF rate was calculated using an application for esophageal cancer. The correlation between FABP4 levels and the predicted POAF rate was analyzed using Pearson's coefficient (r). RESULTS: Thirteen patients completed this study. The predicted POAF rate was 24% (17%, 34%) (median; interquartile range). The actual incidence of POAF was 7.7% (95% CI: 0.2-36%). Blood FABP4 levels changed from 10.3 to 7.0 ng/mL; the average change was - 3.3 (95% CI: - 6.6 to - 0.1). A positive correlation was found between preoperative FABP4 levels and the predicted POAF rates (r = 0.564). CONCLUSIONS: The POAF rate after esophageal surgery was 7.7% for L-carnitine. L-carnitine may reduce blood FABP4 levels. This preliminary study will contribute to the planning of sample sizes in future randomized trials.

Tele-robotic distal gastrectomy with lymph node dissection on a cadaver.

The purpose of this study is to evaluate the performance of tele-robotic distal gastrectomy (tele-RDG) with lymph node dissection (LND) using a novel Japanese-made surgical robot hinotori™ (Medicaroid, Kobe, Japan) in a cadaver with a presumptive gastric cancer. The Cadaveric Anatomy and Surgical Training Laboratory (CAST-Lab.) at Hokkaido University and Kushiro City General Hospital (KCGH) are connected by a guaranteed type line (1 Gbps), and the distance between the two facilities is 250 km. A patient cart was installed at CAST-Lab, and a surgeon cockpit was installed at KCGH. Tele-RDG with D2 LND was performed on an adult human cadaver. In all surgical processes, the communication environment was stable without image degradation, and the mean round trip time was 40 milliseconds (36.5-55 milliseconds). For tele-RDG with D2 LND, the operation time was 199 minutes without any technical problems. Tele-RDG using hinotori™ was feasible and similar to local robotic RDG.

Impact of Neutrophil Extracellular Traps Identified by Citrullinated Histone H3 Immunohistochemistry for Postoperative Prognosis in Patients with Extrahepatic Cholangiocarcinomas.

BACKGROUND: Neutrophil extracellular traps (NETs) are extracellular chromatin structures composed of cytoplasmic, granular, and nuclear components of neutrophils. Recently, NETs have received much attention for their role in tumor biology; however, their impact on the postoperative prognosis of patients with extrahepatic cholangiocarcinomas (EHCCs) remains unclear. The purpose of this study was to clarify the impact of NETs identified by immunohistochemical citrullinated histone H3 (Cit-H3) staining on postoperative overall survival (OS) in patients with perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC). METHODS: This study included 318 patients with EHCC (PHCC, n = 192; DCC, n = 126) who underwent surgical resection with curative intent. Neutrophils and NETs were identified by immunohistochemistry using antibodies against CD15 and Cit-H3, respectively. Based on the distribution of CD15 and Cit-H3 expression in the tumor bed, the patients were classified into four groups: one negative group and three subgroups of the positive group (diffuse, intermediate, and focal subgroups). RESULTS: No significant difference was found in the postoperative OS rate depending on the distribution of CD15 expression in patients with PHCC or DCC. However, the three subgroups with positive Cit-H3 expression had significantly poorer OS than the negative group for both PHCC and DCC. Moreover, positive Cit-H3 was an independent OS factor in the multivariable analyses of PHCC (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.11-2.59, P = 0.0115) and DCC (HR 2.03; 95% CI 1.21-3.42, P = 0.0057). CONCLUSIONS: The presence of NETs in the tumor microenvironment may have adverse prognostic effects in patients with EHCCs.

Robot-assisted laparoscopic total gastrectomy for gastric cancer with common hepatic artery passed behind the portal vein: A case report.

INTRODUCTION: It is essential to identify variations of celiac artery (CA) and common hepatic artery (CHA), using preoperative computed tomography (CT) imaging, for safe gastrectomy and lymph node dissection in gastric cancer (GC) surgery. We report a relatively rare case with the CHA passing behind the portal vein (PV), in which we performed robot-assisted total gastrectomy (RTG) after chemotherapy as conversion surgery. CASE PRESENTATION: A 78-year-old man with GC was referred for conversion surgery. Three-dimensional CT angiography revealed an anomalous CHA passing behind the PV. The anomaly corresponded to type I according to Adachi's classification, and the patient underwent robot-assisted laparoscopic total gastrectomy D2 lymphadenectomy (RTG D2) with Roux-en-Y reconstruction. The operation time was 543 min, blood loss was 115 ml, and no intraoperative complications occurred. The postoperative course was uneventful. CLINICAL DISCUSSION: A word of caution during the surgical procedure entails the manipulation of the suprapancreatic lymph node dissection. Initially, it is crucial to identify the anterior surface of the portal vein (PV) and the nerve plexus surrounding the common hepatic artery (CHA). After completely dissecting the entire circumference, the PV is secured using vascular tape. By gently pulling the vascular tape towards the ventral aspect, a safe execution of lymph node dissection no.8 and 12 on the dorsal side of the PV can be accomplished. Meticulous handling of the anatomical abnormalities observed in the preoperative images may prevent unintended hemorrhage. CONCLUSION: We report a case with vascular anomalies in which RTG D2 was performed successfully as a conversion surgery.

Surgical skills assessment of pancreaticojejunostomy using a simulator may predict patient outcomes: A multicenter prospective observational study.

BACKGROUND: Pancreatoduodenectomy, an advanced surgical procedure with a high complication rate, requires surgical skill in performing pancreaticojejunostomy, which correlates with operative outcomes. We aimed to analyze the correlation between pancreaticojejunostomy assessment conducted in a simulator environment and the operating room and patient clinical outcomes. METHODS: We recruited 30 surgeons (with different experience levels in pancreatoduodenectomy) from 11 institutes. Three trained blinded raters assessed the videos of the pancreaticojejunostomy procedure performed in the operating room using a simulator according to an objective structured assessment of technical skill and a newly developed pancreaticojejunostomy assessment scale. The correlations between the assessment score of the pancreaticojejunostomy performed in the operating room and using the simulator and between each assessment score and patient outcomes were calculated. The participants were also surveyed regarding various aspects of the simulator as a training tool. RESULTS: There was no correlation between the average score of the pancreaticojejunostomy performed in the operating room and that in the simulator environment (r = 0.047). Pancreaticojejunostomy scores using the simulator were significantly lower in patients with postoperative pancreatic fistula than in those without postoperative pancreatic fistula (P = .05). Multivariate analysis showed that pancreaticojejunostomy assessment scores were independent factors in postoperative pancreatic fistula (P = .09). The participants highly rated the simulator and considered that it had the potential to be used for training. CONCLUSION: There was no correlation between pancreaticojejunostomy surgical performance in the operating room and the simulation environment. Surgical skills evaluated in the simulation setting could predict patient surgical outcomes.

Cadaver surgical training and research using donated cadavers in the field of surgery in Japan: an overview of reports from 2012 to 2021.

PURPOSE: Subsequent to the publication of "Guidelines for cadaver dissection in education and research of clinical medicine" in 2012, cadaver surgical training (CST) was implemented in various surgical fields across Japan. This article summarizes the recent progress made in the implementation of CST using donated cadavers, and its associated research, focusing on the field of surgery, and discusses its future direction. METHODS: All reports from 2012 to 2021 registered with the CST Promotion Committee of the Japan Surgical Society were analyzed. There were 292 (24.9%) programs in the field of surgery, including acute care surgery, out of a total of 1173 programs overall. Data were classified by the purpose of implementations and fields of surgery, with subclassification by organ, costs and participation fees. RESULTS: CST and its research were introduced in 27 (33.3%) of a total 81 universities. The total number of participants was 5564 and the major (80%) purpose of the program was to advance surgical techniques. When classified by objectives, 65, 59 and 11% were for mastering operations for malignant disease, minimally invasive surgery, and transplantation surgery, respectively. CONCLUSION: CST in the field of surgery is increasing progressively in Japan, but still with disproportionate dissemination. Further efforts are needed to achieve full adoption.

Identification of antibody against wingless­type MMTV integration site family member 7B as a biliary cancer tumor marker.

Biliary cancer has a poor prognosis due to a lack of specific biomarkers and difficulty in diagnosis. The present study aimed to identify serum tumor markers for the diagnosis of biliary cancer via serological identification of antigens by recombinant cDNA expression cloning. Wingless­type MMTV integration site family, member 7 (WNT7B) was identified as a target antigen, suggesting the presence of serum antibodies against this antigen. Deletion mutants were then prepared to evaluate the response to serum antibodies. When serum antibody levels against WNT7B deletion mutants (WNT7B-92­2, -92­260, 2-260 and 184-260) were examined using amplified luminescence proximity homogeneous assay­linked immunosorbent assay, the levels of the antibody against WNT7B with amino acids 184­260 were higher in patients with biliary cancer than in healthy donors. Therefore, the region covering residues 184­260 of WNT7B was decomposed to generate seven peptides, and the levels of antibodies against these peptides were measured. Among them, the levels of antibodies against WNT7B234­253 and WNT7B244­260 were higher in patients with biliary cancers than in healthy donors (WNT7B234­253, P=0.0009; WNT7B244­260, P=0.0005). The levels of the antibody against the former were specifically high in patients with biliary cancer but not in those with esophageal, gastric, colorectal, pancreatic, or breast cancer. Furthermore, analysis by the cutoff value of WNT7B234­253 defined by ROC showed a high sensitivity of 70% in patients with biliary cancer. Therefore, the serum levels of the antibody against WNT7B234­253 may be useful as a marker for biliary cancer diagnosis.

Assessment of reports on cadaver surgical training (CST) implementation in Japan: current status and challenges.

The contents and conflicts of interest of Cadaver Surgical Training (CST) programs in Japan were reported to the Japan Surgical Society CST Promotion Committee based on professional autonomy. After receiving the reports from participating universities, the committee evaluated the validity of these reports and provided advice on the proper implementation of CST. Over the past decade, 38 universities have been using cadavers for clinical education and research, such as CST. If inappropriate entries or unclear areas were identified, the universities could be asked to resubmit their report. This review clarifies the evaluation points of the CST reporting system, shows the status and problems of its reporting, and provides suggestions for the dissemination of CST in the future.

Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer.

Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies.

Robotic real-time vessel navigation using indocyanine green fluorescence for lymph node dissection along the left gastroepiploic vessels during robotic distal gastrectomy - First experience.

Splenic infarction (SI) following gastrectomy is common; severe complications related to SI, such as splenic haemorrhage, abscess formation or rupture, can be fatal. To overcome these problems, we performed real-time vessel navigation using indocyanine green (ICG) fluorescence during robotic distal gastrectomy (RDG). The aim of study is to report the efficacy of robotic real-time vessel navigation for lymph node dissection (LND) along left gastroepiploic vessels (LGEVs). We treated seven patients with gastric cancer who underwent LND along the LGEVs using robotic real-time vessel navigation during RDG at our institution from January 2021 to July 2021. There were no complications (Clavien-Dindo classification II). There were no cases of post-operative SI or spleen-related complications. Robotic real-time vessel navigation using ICG for LND along LGEVs during RDG could help to reduce post-operative spleen-related complications associated with RDG.

Guidelines for cadaver dissection in education and research of clinical medicine (The Japan Surgical Society and The Japanese Association of Anatomists).

This article translates the guidelines for cadaver surgical training (CST) published in 2012 by Japan Surgical Society (JSS) and Japanese Association of Anatomists from Japanese to English. These guidelines are based on Japanese laws and enable the usage of donated cadavers for CST and clinical research. The following are the conditions to implement the activities outlined in the guidelines. The aim is to improve medicine and to contribute to social welfare. Activities should only be carried out at medical or dental universities under the centralized control by the department of anatomy under the regulation of Japanese law. Upon the usage of cadavers, registered donors must provide a written informed-consent for their body to be used for CST and other activities of clinical medicine. Commercial use of cadavers and profit-based CST is strongly prohibited. Moreover, all the cadaver-related activities except for the commercial-based ones require the approval of the University's Institutional Review Board (IRB) before implementation. The expert committee organized at each university for the implementation of CST should summarize the implementation of the program and report the details of the training program, operating costs, and conflicts of interest to the CST Promotion Committee of JSS.

Guidelines for cadaver dissection in education and research of clinical medicine (The Japan Surgical Society and The Japanese Association of Anatomists).

This article translates the guidelines for cadaver surgical training (CST) published in 2012 by Japan Surgical Society (JSS) and Japanese Association of Anatomists from Japanese to English. These guidelines are based on Japanese laws and enable the usage of donated cadavers for CST and clinical research. The following are the conditions to implement the activities outlined in the guidelines. The aim is to improve medicine and to contribute to social welfare. Activities should only be carried out at medical or dental universities under the centralized control by the department of anatomy under the regulation of Japanese law. Upon the usage of cadavers, registered donors must provide a written informed-consent for their body to be used for CST and other activities of clinical medicine. Commercial use of cadavers and profit-based CST is strongly prohibited. Moreover, all the cadaver-related activities except for the commercial-based ones require the approval of the University's Institutional Review Board (IRB) before implementation. The expert committee organized at each university for the implementation of CST should summarize the implementation of the program and report the details of the training program, operating costs, and conflicts of interest to the CST Promotion Committee of JSS.

Usage of cadavers in surgical training and research in Japan over the past decade.

The "Guidelines for Cadaver Dissection in Education and Research of Clinical Medicine" drafted by the Japan Surgical Society (JSS) and the Japanese Association of Anatomists in 2012 helped dispel legal concerns over cadaver surgical training (CST) and the usage of donated human bodies for research and development (R&D) in the country. Subsequently, in the fiscal year 2018, the Ministry of Health, Labour and Welfare increased the funding for CST, prompting its wider implementation. This study analyzed data obtained in 2012-2021 through the reporting system of the JSS-CST Promotion Committee to map the usage of cadavers for clinical purposes, specifically education and R&D, in Japan. We found that the number of medical universities using cadavers for CST and R&D programs was just 5 in 2012, and it reached 38 for the decade. Thus, about half of Japan's medical universities implemented such programs over the period. Meanwhile, the total number of programs was 1,173. In the clinical field, the highest number of programs were implemented in orthopedics (27%), followed by surgery (21%), and neurosurgery (12%). Based on the purpose, the most common objective of the programs (approximately 70%) was acquiring advanced surgical techniques. Further, the highest number of programs and participants were recorded in 2019 (295 programs, 6,537 participants). Thus, the guidelines helped expand cadaver usage for clinical purposes in Japan. To further promote the clinical usage of cadavers in medical and dental universities throughout Japan, sharing know-how on operating cadaver laboratories and building understanding among the general public is recommended.

Prognostic significance of NY-ESO-1 antigen and PIGR expression in esophageal tumors of CHP-NY-ESO-1-vaccinated patients as adjuvant therapy.

The aim of this study was to determine the efficacy and the biomarkers of the CHP-NY-ESO-1 vaccine complexed with full-length NY-ESO-1 protein and a cholesteryl pullulan (CHP) in patients with esophageal squamous cell carcinoma (ESCC) after surgery. We conducted a randomized phase II trial. Fifty-four patients with NY-ESO-1-expressing ESCC who underwent radical surgery following cisplatin/5-fluorouracil-based neoadjuvant chemotherapy were assigned to receive either CHP-NY-ESO-1 vaccination or observation as control. Six doses of CHP-NY-ESO-1 were administered subcutaneously once every two weeks, followed by nine more doses once every four weeks. The endpoints were disease-free survival (DFS) and safety. Exploratory analysis of tumor tissues using gene-expression profiles was also performed to seek the biomarker. As there were no serious adverse events in 27 vaccinated patients, we verified the safety of the vaccine. DFS in 2 years were 56.0% and 58.3% in the vaccine arm and in the control, respectively. Twenty-four of 25 patients showed NY-ESO-1-specific IgG responses after vaccination. Analysis of intra-cohort correlations among vaccinated patients revealed that 5% or greater expression of NY-ESO-1 was a favorable factor. Comprehensive analysis of gene expression profiles revealed that the expression of the gene encoding polymeric immunoglobulin receptor (PIGR) in tumors had a significantly favorable impact on outcomes in the vaccinated cohort. The high PIGR-expressing tumors that had higher NY-ESO-1-specific IgA response tended to have favorable prognosis. These results suggest that PIGR would play a major role in tumor immunity in an antigen-specific manner during NY-ESO-1 vaccinations. The IgA response may be relevant.

Predictors of Long-Term Survival in Pancreatic Ductal Adenocarcinoma after Pancreatectomy: TP53 and SMAD4 Mutation Scoring in Combination with CA19-9.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a fatal cancer for which even unfavorable clinicopathological factors occasionally fail to preclude long-term survival. We sought to establish a scoring system that utilizes measurable pre-intervention factors for predicting survival following surgical resection. METHODS: We retrospectively analyzed 34 patients who died from short-term recurrences and 32 long-term survivors among 310 consecutively resected patients with PDA. A logistic regression model was used to define factors related to clinical parameters, molecular profiles of 18 pancreatic cancer-associated genes, and aberrant expression of major tumor suppressors. RESULTS: Carbohydrate antigen 19-9 (CA19-9) had the best ability to classify patients with short-term recurrence and long-term survivors [odds ratio 21.04, 95% confidence interval (CI) 4.612-96.019], followed by SMAD4 and TP53 mutation scoring (odds ratio 41.322, 95% CI 3.156-541.035). Missense TP53 mutations were strongly associated with the nuclear expression of p53, whereas truncating mutations were associated with the absence of nuclear p53. The former subset was associated with a worse prognosis. The combination of aberrant SMAD4 and mutation types of TP53 exhibited a better resolution for distinguishing patients with short-term recurrences from long-term survivors (compared with the assessment of the number of mutated KRAS, CDKN2A, TP53, and SMAD4 genes). Calibration of mutation scores combined with CA19-9 in a logistic regression model setting demonstrated a practical effect in classifying long survivors and patients with early recurrence (c-statistic = 0.876). CONCLUSIONS: Genetic information, i.e., TP53 mutation types and SMAD4 abnormalities, combined with CA19-9, will be a valuable tool for improving surgical strategies for pancreatic cancer.