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Esophageal cancer remains a highly aggressive malignancy with a poor prognosis, despite ongoing advancements in treatments such as immunotherapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAF), plays a crucial role in driving the aggressiveness of esophageal cancer. In a previous study utilizing human-derived xenograft models, we successfully developed a novel cancer treatment that targeted CAFs with near-infrared photoimmunotherapy (NIR-PIT), as an adjuvant therapy. In this study, we sought to translate our findings toward clinical practice by employing patient-derived xenograft (PDX) models and utilizing humanized mAbs, specifically sibrotuzumab, which is an antihuman fibroblast activation protein (FAP) Ab and already being investigated in clinical trials as monotherapy. PDX models derived from patients with esophageal cancer were effectively established, preserving the expression of key biomarkers such as EGFR and FAP, as observed in primary tumors. The application of FAP-targeted NIR-PIT using sibrotuzumab, conjugated with the photosensitizer IR700DX, exhibited precise binding and selective elimination of FAP-expressing fibroblasts in vitro. Notably, in our in vivo investigations using both cell line-derived xenograft and PDX models, FAP-targeted NIR-PIT led to significant inhibition of tumor progression compared with control groups, all without inducing adverse events such as weight loss. Immunohistologic assessments revealed a substantial reduction in CAFs exclusively within the tumor microenvironment of both models, further supporting the efficacy of our approach. Thus, our study demonstrates the potential of CAF-targeted NIR-PIT employing sibrotuzumab as a promising therapeutic avenue for the clinical treatment of patients with esophageal cancer., (©2024 American Association for Cancer Research.)

Progression of the physical weakness during neoadjuvant therapy (NAT) in patients with esophageal or gastroesophageal junction cancer is a serious problem; however, prehabilitation during NAT has the potential to overcome the unmet need. Nevertheless, systematic reviews on this topic have not been summarized. Therefore, this systematic review aimed to determine prehabilitation's effectiveness, acceptability, and safety during NAT for patients with esophageal or gastroesophageal junction cancer. An electronic search was performed in the MEDLINE, Web of Science, CENTRAL, CINAHL, and PEDro databases. A meta-analysis was conducted to assess the effectiveness of prehabilitation during NAT, along with a descriptive analysis of acceptance and safety. This study analyzed data from three randomized controlled trials (RCTs) and nine non-RCTs involving 664 patients. The meta-analysis of two RCTs demonstrated that prehabilitation during NAT may be more effective than usual care in enhancing tolerance to NAT and grip strength; moreover, one RCT and three non-RCTs revealed that prehabilitation may reduce the risk of postoperative complications. The adherence rates for exercise programs in two RCTs and seven non-RCTs were 55-76%. Additionally, two studies reported a 76% adherence rate for multimodal prehabilitation programs, including exercise, dietary, and psychological care. Six studies reported no serious prehabilitation-related adverse events during NAT. Prehabilitation during NAT may be a safe and beneficial intervention strategy for patients with esophageal or gastroesophageal junction cancer. However, the investigation of strategies to enhance adherence is essential. Furthermore, additional high-quality RCTs are needed to examine the effect of prehabilitation during NAT., (© 2024. The Author(s).)

Background: Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study., Methods: Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used., Results: The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA., Conclusions: Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background/aim: Diffuse-type gastric cancer (DGC) often forms peritoneal metastases, leading to poor prognosis. However, the underlying mechanism of DGC-mediated peritoneal metastasis is poorly understood. DGC is characterized by desmoplastic stroma, in which heterogeneous cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) and senescent CAFs (sCAFs), play a crucial role during tumor progression. This study investigated the CAF subtypes induced by GC cells and the role of sCAFs in peritoneal metastasis of DGC cells., Materials and Methods: Conditioned medium of human DGC cells (KATOIII, NUGC-4) and human intestinal-type GC (IGC) cells (MKN-7, N87) was used to induce CAFs. CAF subtypes were evaluated by analyzing the expression of α-smooth muscle actin (α-SMA), senescence-associated β-galactosidase (SA-β-gal), and p16 in human normal fibroblasts (GF, FEF-3). A cytokine array was used to explore the underlying mechanism of GC-induced CAF subtype development. The role of sCAFs in peritoneal metastasis of DGC cells was analyzed using a peritoneally metastatic DGC tumor model. The relationships between GC subtypes and CAF-related markers were evaluated using publicly available datasets., Results: IGC cells significantly induced α-SMA+ myCAFs by secreting transforming growth factor-β, whereas DGC cells induced SA-β-gal+/p16+ sCAFs by secreting interleukin (IL)-8. sCAFs further secreted IL-8 to promote DGC cell migration. In vivo experiments demonstrated that co-inoculation of sCAFs significantly enhanced peritoneal metastasis of NUGC-4 cells, which was attenuated by administration of the IL-8 receptor antagonist navarixin. p16 and IL-8 expression was significantly associated with poor prognosis of DGC patients., Conclusion: sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage., Methods: In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP + CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity., Results: FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8 + tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8 + TILs compared with non-treated tumors, suggesting enhanced antitumor immunity., Conclusions: Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF + tumors., (© 2024. The Author(s).)

Background: Pancreatoduodenectomy and subtotal esophagectomy are widely considered the most invasive and difficult surgical procedures in gastrointestinal surgery. Subtotal esophagectomy after pancreatoduodenectomy is expected to be extremely difficult due to complicated anatomical changes, and selecting an appropriate intestinal reconstruction method will also be a difficult task. Therefore, perhaps because the method is considered impossible, there have been few reports of subtotal esophagectomy after pancreatoduodenectomy., Case Presentation: A 73-year-old man with a history of pancreatoduodenectomy was diagnosed with superficial thoracic esophageal squamous cell carcinoma. Definitive chemoradiation therapy was recommended at another hospital; however, he visited our department to undergo surgery. We performed the robot-assisted thoracoscopic subtotal esophagectomy. There were some difficulties with the reconstruction: the gastric tube could not be used, the reconstruction was long, and the organs reconstructed in the previous surgery had to be preserved. However, the concurrent reconstruction was achieved with the help of a free jejunal flap and vascular reconstruction. All reconstructions from the previous surgery, including the remnant stomach, were preserved via regional abdominal lymph node dissection. After reconstruction, intravenous indocyanine green showed that circulation in the reconstructed intestines was preserved. On postoperative day 1, no recurrent nerve paralysis was observed during laryngoscopy. The patient could start oral intake smoothly 2 weeks after surgery and did not exhibit any postoperative complications related to the reconstruction. The patient was transferred to another hospital on postoperative day 21., Conclusions: Owing to the free jejunal flap interposition method, we safely performed one stage subtotal esophagectomy and concurrent reconstruction, preservation of the remnant stomach, and pancreaticobiliary reconstruction in patients with a history of pancreatoduodenectomy. We believe that this method is acceptable and useful for patients undergoing complicated reconstruction., (© 2024. The Author(s).)

Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC). Oncolytic viruses are known to induce the activation of host anti-tumor immunity in addition to tumor lysis. This study investigated whether a wild-type p53 -loading telomerase-specific oncolytic adenovirus (OBP-702) could elicit the remodeling of intraperitoneal macrophages and enhance the efficacy of immune therapy. Increased numbers of CD163 TAMs and few CD8 + lymphocytes were immunohistochemically observed in clinical samples with PM, which suggested that TAMs were associated with the suppression of anti-tumor immunity. OBP-702 induced immunogenic cell death and upregulated PD-L1 expression in human and murine GC cell lines. Intraperitoneal administration of OBP-702 increased recruitment of CD8 + lymphocytes into the PM via the functional remodeling of intraperitoneal macrophages from TAM toward a pro-inflammatory phenotype, resulting in significantly suppressed tumor growth for the in vivo model. Furthermore, the combination of intraperitoneal OBP-702 with anti-programmed cell death-1 antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC., Competing Interests: Y.U. is the president and CEO of Oncolys BioPharma, Inc., the manufacturer of OBP-702. H.T. and T.F. are consultants for Oncolys BioPharma, Inc., (© 2024 The Author(s).)

Background: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC)., Methods: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ., Results: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703., Conclusion: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Epidural analgesia (EDA) is a main modality for postoperative pain relief in major open abdominal surgery within the Enhanced Recovery After Surgery protocol. However, it remains unclear whether EDA is an imperative modality in laparoscopic gastrectomy (LG). This study examined non-inferiority of patient-controlled intravenous analgesia (PCIA) to EDA in terms of postoperative pain and recovery in patients who underwent LG., Methods: In this open-label, non-inferiority, parallel, individually randomized clinical trial, patients who underwent elective LG for gastric cancer were randomized 1:1 to receive either EDA or PCIA after surgery. The primary endpoint was pain score using the Numerical Rating Scale at rest 24 h after surgery, analysed both according to the intention-to-treat (ITT) principle and per protocol. The non-inferiority margin for pain score was set at 1. Secondary outcomes were postoperative parameters related to recovery and adverse events related to analgesia., Results: Between 3 July 2017 and 29 September 2020, 132 patients were randomized to receive either EDA (n = 66) or PCIA (n = 66). After exclusions, 64 patients were included in the EDA group and 65 patients in the PCIA group for the ITT analysis. Pain score at rest 24 h after surgery was 1.94 (s.d. 2.07) in the EDA group and 2.63 (s.d. 1.76) in the PCIA group (P = 0.043). PCIA was not non-inferior to EDA for the primary endpoint (difference 0.69, one side 95% c.i. 1.25, P = 0.184) in ITT analysis. Postoperative parameters related to recovery were similar between groups. More EDA patients (21 (32.8%) versus 1 (1.5%), P < 0.001) developed postoperative hypotension as an adverse event., Conclusions: PCIA was not non-inferior to EDA in terms of early-phase pain relief after LG.Registration number: UMIN000027643 (https://www.umin.ac.jp/ctr/index-j.htm)., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Post-gastrectomy syndrome (PGS) and body weight loss (BWL) decrease quality of life (QOL) and survival of the patient undergoing gastrectomy. We have introduced perioperative and post-discharge continuous nutritional counseling (CNC) to prevent BWL and improve QOL after gastrectomy. In the present study, we evaluated the effect of CNC on QOL using the Post-gastrectomy Syndrome Assessment Scale-45 (PGSAS-45). Eighty-three patients with gastric cancer (GC) who underwent curative gastrectomy between March 2018 and July 2019 were retrospectively analyzed. Patients received either pre-discharge nutritional counseling alone (control group, n  = 45) or CNC (CNC group, n  = 38) after gastrectomy. QOL at 12 months after gastrectomy was compared between the two groups. In QOL assessment, change in body weight (-7.98% vs. -12.77%, p  = 0.0057), ingested amount of food per meal (7.00 vs. 6.07, p  = 0.042) and ability for working (1.89 vs. 2.36, p  = 0.049) were significantly better in CNC group than control group. Multiple regression analysis showed that CNC was a significantly beneficial factor for abdominal pain subscale ( p  = 0.028), diarrhea subscale ( p  = 0.047), ingested amount of food per meal ( p  = 0.012), Ability for working ( p  = 0.031) and dissatisfaction at the meal ( p  = 0.047). Perioperative and postoperative CNC could improve QOL in the patient undergoing gastrectomy in addition to preventing postoperative BWL.

Near-infrared photoimmunotherapy(NIR-PIT)is a novel cancer treatment modality that employs antibody-IRDye700DX (IR700)conjugates. Recently, the clinical application of NIR-PIT has received approval in Japan for patients with inoperable head and neck cancer, specifically targeting the human epidermal growth factor receptor(hEGFR). Furthermore, NIR-PIT extends beyond the scope of tumor antigens and can be employed to eliminate specific host cells that contribute to the creation of immune-permissive environments supporting tumor growth. One of the distinguishing features of NIR-PIT is its ability to selectively eliminate various cell types within the tumor microenvironment(TME)by specifically targeting distinct antigens. By employing podoplanin(PDPN)-targeted NIR-PIT, PDPN-expressing fibroblasts were selectively eradicated, resulting in the suppression of tumor progression and a notable extension of overall survival. Additionally, we investigated the efficacy of depleting myeloid-derived suppressor cells(MDSCs)using NIR-PIT. This approach led to the selective elimination of MDSCs within tumors, and remarkable abscopal effects were observed in bilateral tumor models. Hence, NIR-PIT holds immense promise for the treatment of diverse cancer types by precisely targeting tumor cells, fibroblasts, and immune cells.

Purpose: It remains unknown whether stroke volume variation (SVV), pulse pressure variation (PPV), and dynamic arterial elastance (Ea dyn ) are suitable for monitoring fluid management during thoracoscopic esophagectomy (TE) in the prone position with one-lung ventilation and artificial pneumothorax. Our study aimed to evaluate the accuracy of SVV, PVV, and Ea dyn in predicting the fluid responsiveness in these patients., Methods: We recruited 24 patients who had undergone TE. Patients with a mean arterial blood pressure ≤ 65 mmHg received a 200-ml bolus of 6% hydroxyethyl starch over 10 min. Fluid responders showed the stroke volume index ≥ 15% 5 min after the fluid bolus. Receiver operating characteristic (ROC) curves were generated and area under the ROC curve (AUROC) was calculated., Results: We obtained 61 fluid bolus data points, of which 20 were responders and 41 were non-responders. The median SVV before the fluid bolus in responders was significantly higher than that in non-responders (18% [interquartile range (IQR) 13-21] vs. 12% [IQR 8-15], P = 0.001). Ea dyn was significantly lower in responders than in non-responders (0.55 [IQR 0.45-0.78] vs. 0.91 [IQR 0.67-1.00], P < 0.001). There was no difference in the PPV between the groups. The AUROC was 0.76 for SVV (95% confidence interval [CI] 0.62-0.89, P = 0.001), 0.56 for PPV (95% CI 0.41-0.71, P = 0.44), and 0.82 for Ea dyn (95% CI 0.69-0.95, P < 0.001)., Conclusions: SVV and Ea dyn are reliable parameters for predicting fluid responsiveness in patients undergoing TE., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Background/aim: Diffuse-type gastric cancer (GC) frequently exhibits peritoneal metastasis, leading to poor prognosis. However, efforts to develop antitumor strategies for preventing the peritoneal metastasis of GC have been unsuccessful. As diffuse-type GC cells often carry a genetic alteration in the tumor suppressor p53 gene, p53 restoration may be a potent strategy for preventing peritoneal metastasis of GC. In this study, we investigated the therapeutic potential of p53-expressing adenoviral vectors against peritoneal metastasis of diffuse-type GC cells., Materials and Methods: Three diffuse-type human GC cell types with different p53 statuses (p53-wild type NUGC-4, p53-mutant type GCIY, and p53-null type KATOIII) were used to evaluate the therapeutic potential of p53 activation induced by the p53-expressing, replication-deficient adenovirus Ad-p53 and oncolytic adenovirus OBP-702. Viability, apoptosis, and autophagy of virus-treated GC cells were analyzed under normal and sphere-forming culture conditions using the XTT assay and western blot analysis. The in vivo antitumor effects of OBP-702 and Ad-p53 were assessed using xenograft tumor models involving peritoneal metastasis of NUGC-4 and GCIY cells., Results: Under normal and sphere-forming culture conditions, OBP-702 induced a significantly greater antitumor effect in GC cells compared with Ad-p53 by strongly inducing p53-mediated apoptosis and autophagy and receptor tyrosine kinase suppression. In vivo experiments demonstrated that intraperitoneal administration of OBP-702 significantly suppressed the peritoneal metastasis of NUGC-4 and GCIY cells compared with Ad-p53, leading to prolonged survival of mice., Conclusion: Intraperitoneal administration of OBP-702 inhibits the peritoneal metastasis of GC cells by inducing p53-mediated cytopathic activity., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1 + CAF group had worse survival than the PD-L1 - group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8 + T cells and decreased FoxP3 + regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity., (© 2023. The Author(s).)

Pancreatic ductal adenocarcinoma(PDAC)is lethal malignancy with abundant stroma. Cancer-associated fibroblasts (CAFs) exist in the PDAC stroma and contribute to progression of malignant transformation, treatment resistance, and recurrence. However, effective treatment to control PDAC stroma has not been established. We have developed tumor suppressor gene p53-armed oncolytic adenovirus(OBP-702), and have clarified therapeutic effects on PDAC cells. In this study, we investigate the therapeutic effect of OBP-702 on PDAC CAF.

The use of virtual reality for simulations plays an important role in the initial training for robotic surgery. This randomized controlled trial aimed to investigate the impact of educational video on the performance of robotic simulation. Participants were randomized into the intervention (video) group that received an educational video and robotic simulation training or the control group that received only simulation training. The da Vinci ® Skills Simulator was used for the basic course, including nine drills. The primary endpoint was the overall score of nine drills in cycles 1-10. Secondary endpoints included overall, efficiency, and penalty scores in each cycle, as well as the learning curves evaluated by the cumulative sum (CUSUM) analysis. Between September 2021 and May 2022, 20 participants were assigned to the video (n = 10) and control (n = 10) groups. The video group had significantly higher overall scores than the control group (90.8 vs. 72.4, P < 0.001). Significantly higher overall scores and lower penalty scores were confirmed, mainly in cycles 1-5. CUSUM analysis revealed a shorter learning curve in the video group. The present study demonstrated that educational video training can be effective in improving the performance of robotic simulation training and shortening the learning curve., (© 2023. The Author(s).)

The involvement of neutrophil extracellular traps (NETs) in cancer metastasis is being clarified, but the relationship between intrahepatic cholangiocarcinoma (iCCA) and NETs remains unclear. The presence of NETs was verified by multiple fluorescence staining in clinically resected specimens of iCCA. Human neutrophils were co-cultured with iCCA cells to observe NET induction and changes in cellular characteristics. Binding of platelets to iCCA cells and its mechanism were also examined, and their effects on NETs were analyzed in vitro and in in vivo mouse models. NETs were present in the tumor periphery of resected iCCAs. NETs promoted the motility and migration ability of iCCA cells in vitro. Although iCCA cells alone had a weak NET-inducing ability, the binding of platelets to iCCA cells via P-selectin promoted NET induction. Based on these results, antiplatelet drugs were applied to these cocultures in vitro and inhibited the binding of platelets to iCCA cells and the induction of NETs. Fluorescently labeled iCCA cells were injected into the spleen of mice, resulting in the formation of liver micrometastases coexisting with platelets and NETs. These mice were treated with dual antiplatelet therapy (DAPT) consisting of aspirin and ticagrelor, which dramatically reduced micrometastases. These results suggest that potent antiplatelet therapy prevents micrometastases of iCCA cells by inhibiting platelet activation and NET production, and it may contribute to a novel therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: In Japan, about 6% of esophageal cancers are adenocarcinomas, although most of them arise from Barrett's epithelium. Adenocarcinoma arising from heterotopic gastric mucosa (HGM) is very rare. Due to its rarity, there is no unified view on its treatment strategy and prognosis., Case Presentation: A 57-year-old man presented with a protruding lesion in the cervicothoracic esophagus that was detected by an upper gastrointestinal series at a medical checkup. Esophagoscopy revealed a 30 mm Type 1 tumor circumferentially surrounded by widespread HGM. Computed tomography (CT) and fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT showed no metastasis or invasion of the surrounding organs. We diagnosed the lesion as cT2N0M0 cStageIIB [Union for International Cancer Control (UICC) 8th Ed] cancer and performed subtotal esophagectomy with three-field lymph node dissection. The tumor was determined to be a well-differentiated adenocarcinoma arising from HGM, with deep invasion of the submucosa. The patient underwent no adjuvant therapy and has currently survived without any evidence of recurrence for 15 months., Conclusions: Although the treatment for adenocarcinoma arising from HGM is basically the same as that for squamous cell carcinoma (SCC) of the esophagus, it is important to determine the treatment strategy based on the characteristics of the adenocarcinoma arising from HGM., (© 2023. The Author(s).)

Background: Surgical resection of esophageal cancer is frequently performed to achieve a complete cure. However, the postoperative recurrence rate is 36.8-42.5%, leading to poor prognosis. Radiation therapy has been used to treat recurrences; solitary recurrence has been proposed as a prognostic factor for radiation therapy, though its significance is unclear. 18 F-fluorodeoxyglucose positron emission tomography is a highly accurate diagnostic modality for esophageal cancer. This retrospective study aimed to analyze the outcomes of solitary postoperative recurrences of esophageal squamous cell carcinoma diagnosed with 18 F-fluorodeoxyglucose positron emission tomography and treated with definitive radiation therapy., Methods: We examined 27 patients who underwent definitive radiation therapy for single or multiple postoperative recurrences of esophageal squamous cell carcinoma between May 2015 and April 2021. 18 F-fluorodeoxyglucose positron emission tomography/computed tomography was performed within 3 months before the commencement of radiation therapy. Kaplan-Meier, univariate, and multivariate analyses were performed to examine the overall survival and identify potential prognostic factors., Results: The 1-, 2-, and 3-year overall survival rates were 85.2%, 62.6%, and 47.3%, respectively, and solitary recurrence was the only significant factor associated with overall survival (P = 0.003). The 1-, 2-, and 3-year overall survival rates in patients with solitary recurrence were 91.7%, 80.2%, and 80.2%, respectively, and in patients with multiple recurrences they were 80.0%, 50.3%, and 25.1%, respectively. Multivariate analysis also showed solitary recurrence as a significant factor for overall survival., Conclusions: When diagnosed with 18 F-fluorodeoxyglucose positron emission tomography/computed tomography, solitary recurrence appears to have a more favorable prognosis than multiple recurrences., (© 2023. The Author(s).)

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation., (© 2023. The Author(s).)

Background: The prognosis of esophageal cancer (EC) with organ invasion is extremely poor. In these cases, definitive chemoradiotherapy (CRT) followed by salvage surgery can be planned; however, the issue of high morbidity and mortality rates persists. Herein, we report the long-term survival of a patient with EC and T4 invasion who underwent a modified two-stage operation after definitive CRT., Case Presentation: A 60-year-old male presented with type 2 upper thoracic EC with tracheal invasion. First, definitive CRT was performed, which resulted in tumor shrinkage and improvement in the tracheal invasion. However, an esophagotracheal fistula subsequently developed, and the patient was treated with fasting and antibiotics. Although the fistula recovered, severe esophageal stenoses made oral intake impossible. To improve quality of life and cure the EC, a modified two-stage operation was planned. In the first surgery, an esophageal bypass was performed using a gastric tube with cervical and abdominal lymph node dissections. After confirming improved nutritional status and absence of distant metastasis, the second surgery was performed with subtotal esophagectomy, mediastinal lymph node dissection, and tracheobronchial coverage of the fistula. The patient discharged without major complications after radical resection and has been recurrence-free for 5 years since the start of treatment., Conclusion: A standard curative strategy could be difficult for EC with T4 invasion due to differences in the invaded organs, presence of complications, and patient condition. Therefore, patient-tailored treatment plans are needed, including a modified two-stage operation., (© 2023. The Author(s).)

Background: This study aimed to determine whether nutritional education, from the preoperative to postoperative period, and nutritional management designed to improve nutritional status alone, could improve patients' health-related self-management and nutritional management skills during the postoperative period., Methods: We evaluated 101 hospitalised patients with oesophageal cancer who underwent surgery between 2015 and 2016 and received perioperative nutritional education (PERIO-N). The control group included 52 patients who underwent surgery between 2014 and 2015 and were supported only by normal interventions according to the Enhanced Recovery After Surgery protocol. The PERIO-N group paid specific attention to nutrition risk screening, nutrition assessment, nutrition monitoring, and lifestyle education., Results: The patients in the PERIO-N group were 1.8 times more likely to be able to consume food orally than the control group (p=0.010). In the PERIO-N group, 50.5% of the patients could orally consume food, 42.6% received a combination of oral and enteral nutrition, and 6.9% only underwent enteral nutrition. In comparison, in the control group, 28.8% of the patients could orally consume food, 53.8% received a combination of oral and enteral nutrition, and 17.3% were only administered enteral nutrition (p=0.004). In addition, patients in the PERIO-N group were discharged at a 1.5 times higher rate than those in the control group (p=0.027). The readmission rate for malnutrition within 3 months was 4% in the PERIO group (5.4% for home discharge only) and 5.8% in the control group (10.5% for home discharge only) (p=0.61)., Conclusion: This study found that perioperative nutrition education in patients who underwent oesophageal cancer surgery led to increase in the amount of oral intake at discharge. Moreover, the group that received nutrition education did not have an increased probability of hospitalisation due to the risk of malnutrition within 3 months after discharge.

Esophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors.

Background and Aims: Ulcerative colitis [UC] can lead to colitis-associated colorectal neoplasm [CAN]. Adenosine-to-inosine RNA editing, which is regulated by adenosine deaminase acting on RNA [ADAR], induces the post-transcriptional modification of critical oncogenes, including antizyme inhibitor 1 [AZIN1], leading to colorectal carcinogenesis. Therefore, we hypothesized that ADAR1 might be involved in the development of CAN in UC., Methods: We systematically analysed a cohort of 139 UC cases [40 acute phase, 73 remission phase, 26 CAN]. The degree of inflammation was evaluated using the Mayo endoscopic score [MES]., Results: The type 1 interferon [IFN]-related inflammation pathway was upregulated in the rectum of active UC, rectum of UC-CAN and tumour site of UC-CAN patients. ADAR1 expression was upregulated in the entire colon of CAN cases, while it was downregulated in non-CAN MES0 cases. ADAR1 expression in the rectum predicted the development of CAN better than p53 or β-catenin, with an area under the curve of 0.93. The high expression of ADAR1 and high AZIN1 RNA editing in UC was triggered by type 1 IFN stimulation from UC-specific microbiomes, such as seen in Fusobacterium in vitro analyses. The induction of AZIN1 RNA editing by ADAR1, whose expression is promoted by Fusobacterium, may induce carcinogenesis in UC., Conclusions: The risk of CAN can be evaluated by assessing ADAR1 expression in the rectum of MES0 UC patients, freeing UC patients from unnecessary colonoscopy and reducing their physical burden. RNA editing may be involved in UC carcinogenesis, and may be used to facilitate the prevention and treatment of CAN in UC., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This retrospective study aimed to investigate the validity of a 30-sec chair stand test (CS-30) as a simple test to assess exercise tolerance and clinical outcomes in 53 Japanese patients with esophageal cancer. There was a strong correlation between the results of CS-30 and the 6-min walk test (6MWT), the gold standard for assessing exercise tolerance (r=0.759). Furthermore, fewer patients whose CS-30 score was greater than 16 (the cutoff value defined based on 6MWT) experienced pneumonia in their postoperative course. These results suggest that exercise tolerance could be assessed using CS-30, and its cutoff value may be useful in predicting postoperative pneumonia risk., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: Cancer-associated fibroblasts (CAFs) reportedly enhance the progression of gastrointestinal surgery; however, the role of CAFs in ampullary carcinomas remains poorly examined. This study aimed to investigate the effect of CAFs on the survival of patients with ampullary carcinoma., Materials and Methods: A retrospective analysis of 67 patients who underwent pancreatoduodenectomy between January 2000 and December 2021 was performed. CAFs were defined as spindle-shaped cells that expressed α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP). The impact of CAFs on survival, including recurrence-free (RFS) and disease-specific survival (DSS), as well as prognostic factors associated with survival, was analyzed., Results: The high-α-SMA group had significantly worse 5-year RFS (47.6% vs. 82.2%, p = 0.003) and 5-year DSS (67.5% vs. 93.3%, p = 0.01) than the low-α-SMA group. RFS (p = 0.04) and DSS (p = 0.02) in the high-FAP group were significantly worse than those in the low-FAP group. Multivariable analyses found that high α-SMA expression was an independent predictor of RFS [hazard ratio (HR): 3.68; 95% confidence intervals (CI): 1.21-12.4; p = 0.02] and DSS (HR: 8.54; 95% CI: 1.21-170; p = 0.03)., Conclusions: CAFs, particularly α-SMA, can be useful predictors of survival in patients undergoing radical resection for ampullary carcinomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takagi, Noma, Nagai, Kikuchi, Umeda, Yoshida, Fuji, Yasui, Tanaka, Kashima, Yagi and Fujiwara.)

Background: Body weight loss (BWL) and skeletal muscle loss (SML) are inevitable after gastrectomy for gastric cancer (GC) and can decrease patients' quality of life (QOL) and survival., Objective: The aim of this retrospective study was to evaluate the effect of perioperative and post-discharge patient participation in continuous nutritional counseling (CNC) on post-gastrectomy BWL and SML., Methods: Ninety-three patients with GC who underwent curative gastrectomy between March 2018 and July 2019 were analyzed. Patients received either pre-discharge nutritional counseling alone (control group, n = 49) or patient-participation CNC (CNC group, n = 44) after gastrectomy. Differences between percentage BWL (%BWL), percentage SML (%SML), and nutrition-related blood parameters between the preoperative values and those at 12 months after surgery were compared between the groups., Results: Compared with the control group, %BWL was significantly lower in the CNC group at 1 month (-6.2 ± 2.5% vs. -7.9 ± 3.3%, p = 0.005), 6 months (-7.8 ± 6.6% vs. -12.3 ± 6.4%, p = 0.001) and 12 months (-7.9 ± 7.6% vs. -13.2 ± 8.2%, p = 0.002), and %SML was significantly lower in the CNC group at 12 months (-5.3 ± 10.3% vs. -12.8 ± 12%, p = 0.002). Regarding nutrition-related blood parameters, change in total cholesterol was significantly lower in the CNC group than the control group at 12 months after surgery (p = 0.02). Multivariate analysis identified no CNC as an independent risk factor for severe BWL (p = 0.001) and SML (p = 0.006) at 12 months after surgery., Conclusions: Following gastrectomy, patient-participation CNC prevented postoperative BWL and SML after surgery. These results support the induction of such a CNC program in these patients., (© 2022. Society of Surgical Oncology.)

Background/aim: It has recently been recognized that preoperative sarcopenia contributes to postoperative complications and overall survival in gastric cancer (GC). However, few studies have investigated the relationship between postoperative skeletal muscle loss (SML) and survival in GC, despite the inevitability of body weight loss after gastrectomy in most GC patients. Herein, we studied the impact of postoperative SML on GC prognosis., Patients and Methods: A total of 370 patients with GC who underwent curative gastrectomy were retrospectively evaluated in this study. Postoperative SML was assessed on computed tomography (CT) images taken before surgery and 1 year after surgery. The impact of postoperative SML on survival was evaluated., Results: Postoperative severe SML was significantly associated with presence of comorbidities, higher tumor stage, higher postoperative complication rate and longer hospital stay. Univariate and multivariate analyses of prognostic factors for overall survival revealed that SML was an independent indicator of poor prognosis, along with age, tumor stage, preoperative sarcopenia, and operation time (hazard ratio, 2.65; 95% confidence interval, 1.68-4.20, p<0.0001). There was a strong association of severe postoperative SML with decreased overall survival in patients with preoperative sarcopenia., Conclusion: To improve the prognosis of GC patients after surgery, it is important to prevent postoperative SML as well as preoperative sarcopenia. Perioperative multimodal interventions including nutritional counseling, oral nutritional supplements, and exercise are required to prevent SML after gastrectomy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment., (© 2022. The Author(s).)

Background: The standard treatment for locally advanced esophageal cancer is preoperative chemotherapy with cisplatin and 5-fluorouracil (CF), followed by surgery. Although docetaxel plus cisplatin and 5-fluorouracil (DCF) has been reported to have favorable outcomes, no study has compared its therapeutic efficacy to that of standard treatment. This study aimed to compare the therapeutic effects of CF and DCF in the real world by matching patient background factors using propensity scores., Methods: We retrospectively reviewed the data of 237 patients with esophageal squamous cell carcinoma who underwent esophagectomy between January 2008 and December 2018. Patients were divided into two groups based on the preoperative chemotherapy regimens of CF (79 patients) or DCF (158 patients), and 49 matched pairs were finally analyzed using propensity score matching. Short- and long-term outcomes were compared between groups., Results: After matching, although no significant differences in survival were observed among the groups, patients receiving DCF showed a significantly high histological response (P < 0.001). Subgroup analyses demonstrated that DCF therapy had better overall survival (P = 0.046) and relapse-free survival (P = 0.010) among pathological T3 and T4 cases. Whereas, adverse effects of chemotherapy were more frequent in the DCF group., Conclusions: Patients receiving DCF had higher pathological response and better survival than those receiving CF, especially in pathological T3 and T4 cases matched using propensity scores. Thus, the DCF regimen might be an effective treatment for locally advanced esophageal cancer. However, the adverse side effects of chemotherapy remain high and should be handled appropriately., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Purpose: To investigate if early exercise can help prevent skeletal muscle loss and improve the clinical outcomes of esophageal cancer patients receiving preoperative neoadjuvant chemotherapy (NAC)., Methods: This was a single-center, retrospective observational cohort study of 110 patients with advanced esophageal cancer. We analyzed the effect of early exercise on the risk of skeletal muscle loss (defined as > 2.98%) during NAC and the subsequent clinical outcomes. Patients in the early exercise group (n = 71) started exercise therapy 8 days earlier than those the late exercise group (n = 39)., Results: The median age of the patients was 65.4 years, the mean BMI was 21.1 kg/m 2 , and 92 (84%) of the 110 patients were men. Skeletal muscle loss occurred in 34% and 67% of the early and late exercise groups, respectively (p < 0.001). There was a lower risk of surgical site infection in the early exercise group (1% vs 16%, p = 0.021). Multivariate analysis revealed that early exercise reduced the risk of skeletal muscle loss (OR = 0.25, 95% CI 0.09-0.65, p = 0.006)., Conclusions: Our results suggest that early exercise reduces the risk of both skeletal muscle loss during NAC and subsequent surgical site infection in patients with esophageal cancer., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Verrucous carcinoma of the esophagus (VCE) is a rare tumor that is difficult to diagnose. In most cases, biopsies show nonspecific inflammatory and hyperkeratotic changes and do not show malignant findings. Most VCEs are slowly growing, locally advanced tumors with few metastases. Treatments for VCE are the same as for normal esophageal cancer, involving combined chemotherapy, surgical resection, and radiation therapy. However, it has been reported that VCE has a poor response to radiation or chemoradiotherapy (CRT). A case of VCE with complete response (CR) after CRT is presented., Case Presentation: A 70-year-old man was found to have white, irregular esophageal mucosa 4 years earlier. He had been followed up as an outpatient as having candidal esophagitis. However, his tumor grew gradually, and biopsy was performed by endoscopic mucosal resection (EMR). He was finally diagnosed with VCE. He had no metastases to distant organs, but some lymph node metastases were suspected. The tumor invaded his left bronchus. The esophagostomy and gastrostomy were constructed as emergent procedures. The patient then underwent definitive CRT. 4 weeks after the end of CRT, two-stage esophagectomy was performed. First, he underwent esophagectomy with thoracic lymph node dissection. A latissimus dorsi flap was patched to the bronchus after primary suture of the hole. 6 weeks later, reconstruction of the gastric tube was performed through the antethoracic route. The pathological findings showed CR to CRT, with no proliferative cancer cells in the specimen. The patient has had no recurrence for three and half years after the resection., Conclusions: We presented a locally advanced VCE that achieved CR to CRT. In cases that have some difficulty for local resection, CRT might be an appropriate treatment for VCE., (© 2022. The Author(s).)

Background/aim: Postoperative body weight loss (BWL) and skeletal muscle loss (SML) after gastrectomy are associated with a decline in quality of life and worse longterm prognosis in gastric cancer (GC) patients. This study aimed to evaluate the efficacy of amino acids nutrition on BWL and SML in the early period following gastrectomy., Patients and Methods: The parameters of body composition were measured by bioelectrical impedance analysis in the patients undergoing radical gastrectomy for GC and analyzed retrospectively. Patients received either peripheral parenteral nutrition (PPN) of 4.3% glucose fluid with regular diet (control group, n=43) or PPN of 7.5% glucose fluid containing amino acids plus oral nutritional supplement (ONS) rich in protein with regular diet (amino acids group, n=40) following gastrectomy. The percentages of BWL and SML from preoperative values to those at 7 days and 1 month after surgery were compared between the two groups., Results: The %BWL and %SML at 7 days after surgery were significantly lower in the amino acids group than those in the control group (%BWL, -2.4±1.7% vs. -4.2±1.8%; p<0.0001, %SML, -4.1±3.8 vs. -6.5±3.8; p=0.006). Moreover, the %BWL at 1 month after surgery was significantly lower in the amino acids group compared to that in the control group (- 4.6±2.9% vs. -6.1±2.6%; p=0.01); however, the %SML was similar between the two groups. The hematological nutritional parameters were similar between the two groups., Conclusion: Amino acids nutrition by PPN and ONS following gastrectomy prevented postoperative BWL and SML in the early period after surgery in GC patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Conventional imaging techniques are available for clinical identification of tumor sites. However, detecting metastatic tumor cells that are spreading from primary tumor sites using conventional imaging techniques remains difficult. In contrast, fluorescence-based labeling systems are useful tools for detecting tumor cells at the single-cell level in cancer research. The ability to detect fluorescent-labeled tumor cells enables investigations of the biodistribution of tumor cells for the diagnosis and treatment of cancer. For example, the presence of fluorescent tumor cells in the peripheral blood of cancer patients is a predictive biomarker for early diagnosis of distant metastasis. The elimination of fluorescent tumor cells without damaging normal tissues is ideal for minimally invasive treatment of cancer. To capture fluorescent tumor cells within normal tissues, however, tumor-specific activated target molecules are needed. This review focuses on recent advances in tumor-targeted fluorescence labeling systems, in which indirect reporter labeling using tumor-specific promoters is applied to fluorescence labeling of tumor cells for the diagnosis and treatment of cancer. Telomerase promoter-dependent fluorescence labeling using replication-competent viral vectors produces fluorescent proteins that can be used to detect and eliminate telomerase-positive tumor cells. Tissue-specific promoter-dependent fluorescence labeling enables identification of specific tumor cells. Vimentin promoter-dependent fluorescence labeling is a useful tool for identifying tumor cells that undergo epithelial-mesenchymal transition (EMT). The evaluation of tumor cells undergoing EMT is important for accurately assessing metastatic potential. Thus, tumor-targeted fluorescence labeling systems represent novel platforms that enable the capture of tumor cells for the diagnosis and treatment of cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene therapy (OBP-702) against CAFs and peritoneal metastasis of gastric cancer (GC). Higher CAF expression in the primary tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of cancer-promoting cytokines, including interleukin-6, and gained resistance to chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702 infection caused apoptosis and autophagy of CAFs and decreased the secretion of cancer-promoting cytokines by CAFs. Combination therapy using intraperitoneal administration of OBP-702 and paclitaxel synergistically inhibited the tumor growth of peritoneal metastases and decreased CAFs in peritoneal metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene therapy, offers a promising biological therapeutic strategy for peritoneal metastasis, modulating CAFs in addition to achieving tumor lysis., Competing Interests: Yasuo Urata is the president and CEO of Oncolys BioPharma, the manufacturer of OBP-702. Hiroshi Tazawa and Toshiyoshi Fujiwara are consultants for Oncolys BioPharma. The other authors have no real or potential conflicts of interest to declare., (© 2022 The Author(s).)

The epithelial-mesenchymal transition (EMT), a normal biological process by which epithelial cells acquire a mesenchymal phenotype, is associated with migration, metastasis, and chemoresistance in cancer cells, and with poor prognosis in patients with esophageal cancer. However, therapeutic strategies to inhibit EMT in tumor environments remain elusive. Here, we show the therapeutic potential of telomerase-specific replication- competent oncolytic adenovirus OBP-301 in human esophageal cancer TE4 and TE6 cells with an EMT phenotype. Transforming growth factor-β (TGF-β) administration induced the EMT phenotype with spindleshaped morphology, upregulation of mesenchymal markers and EMT transcription factors, migration, and chemoresistance in TE4 and TE6 cells. OBP-301 significantly inhibited the EMT phenotype via E1 accumulation. EMT cancer cells were susceptible to OBP-301 via massive autophagy induction. OBP-301 suppressed tumor growth and lymph node metastasis of TE4 cells co-inoculated with TGF-β-secreting fibroblasts. Our results suggest that OBP-301 inhibits the TGF-β-induced EMT phenotype in human esophageal cancer cells. OBP-301-mediated E1A overexpression is a promising antitumor strategy to inhibit EMT-mediated esophageal cancer progression., Competing Interests: No potential conflict of interest relevant to this article was reported.

Objectives: An increasing number of patients visiting the dental office have a growing need for perioperative oral management (POM) to prevent postoperative complications. Therefore, it is necessary to determine which patients should receive preferential POM. This study investigated the dental status of patients scheduled to undergo surgery and addressed the priority for POM., Methods: This retrospective study included a total of 150 patients who were scheduled to undergo surgery at the Department of Respiratory Surgery (DRS), Department of Neurological Surgery (DNS), Department of Gynecological Surgery (DGS), Department of Breast and Endocrine Surgery (DBES), and Department of Esophageal Surgery (DES) managed by the Perioperative Management Center of Okayama University Hospital. We compared the general and dental status of patients among the five groups., Results: The DES group had significantly fewer teeth than the DBES group (p = 0.012), more severe periodontitis than both the DBES (p = 0.005) and DNS groups (p = 0.020), and poorer molar occlusal support status than both the DBES (p = 0.002) and DGS groups (p = 0.041). The DES group exhibited a significantly higher median age (p = 0.002), a higher ratio of males (p < 0.001), a higher prevalence of malignant tumors (p < 0.001), and higher proportions of smokers (p < 0.001) and drinkers (p < 0.001) than the other groups., Conclusion: Patients who underwent surgery at the DES had more dental problems than other surgery patients. Accordingly, these patients should be given the highest priority for POM triage., (© 2021. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Purpose: Although D2 lymphadenectomy is currently considered a standard procedure for advanced gastric cancer (GC) worldwide, there is room for discussion about the appropriate range of suprapancreatic D2 lymphadenectomy. Focusing on the posterior hepatic plexus (PHP), which is not well recognized, we developed a surgical technique of suprapancreatic D2 lymphadenectomy, which we have called PHP-D2, and its short-term and long-term efficacies were evaluated in comparison with non-PHP-D2., Methods: GC patients who underwent distal gastrectomy with D2 lymphadenectomy between July 2006 and May 2013 were enrolled, from which patients who had peritoneal metastasis and/or were peritoneal cytology-positive during surgery were excluded. Their medical records were retrospectively reviewed., Results: Ninety-two patients (non-PHP-D2: 48, PHP-D2: 44) were enrolled. Shorter operation time (330 min vs 275 min, p < 0.0001) and less blood loss (290 mL vs 125 mL, p < 0.0001) were observed in PHP-D2, and no pancreatic fistulas were observed in PHP-D2. More lymph nodes of #11p (1 vs 1.5, p = 0.0328) and #12a lymph nodes (0 vs 1, p = 0.0034) were retrieved in PHP-D2, with no significant differences in #8a and #9 lymph nodes. Lymphatic recurrence was significantly less in PHP-D2 (p = 0.0166), and univariate and multivariate analyses showed that non-PHP-D2 was a significant risk factor for lymphatic recurrence (p = 0.0158), although there were no significant differences between non-PHP-D2 and PHP-D2 in 5-year overall survival and 5-year relapse-free survival., Conclusion: PHP-D2 was a safe and feasible procedure that had the potential to reduce lymphatic recurrence, and it can be a standard procedure of D2 lymphadenectomy for advanced GC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The Endoscopic Surgical Skill Quantification System for qualified surgeons (QSs) was introduced in Japan to improve surgical outcomes. This study reviewed the surgical outcomes after initial experience performing laparoscopic distal gastrectomy (LDG) and evaluated the improvement in surgical outcomes following accreditation as a QS., Methods: Eighty-seven consecutive patients who underwent LDG for gastric cancer by a single surgeon were enrolled in this study. The cumulative sum method was used to analyze the learning curve for LDG. The surgical outcomes were evaluated according to the two phases of the learning curve (learning period vs. mastery period) and accreditation (non-QS period vs. QS period)., Results: The learning period for LDG was 48 cases. Accreditation was approved at the 67th case. The operation time and estimated blood loss were significantly reduced in the QS period compared to the non-QS period (230 vs. 270 min, p < 0.001; 20.5 vs. 59.8 ml, p = 0.024, respectively). Furthermore, the major complication rate was significantly lower in the QS period than in the non-QS period (0 vs. 10.6%, p = 0.044)., Conclusions: Experience performing approximately 50 cases is required to reach proficiency in LDG. After receiving accreditation as a QS, the surgical outcomes, including the complication rate, were improved., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Although the main manifestation of giant paraesophageal hernia (PEH) is disordered meal passage due to gastric torsion, the contents of the hernia sometimes squeeze the heart and lungs and induce the symptoms of respiratory or heart failure. Furthermore, the quality of life (QOL) of patients with a heavy cardiac load deteriorates. In this study, changes in a heart failure marker and symptoms of cases with a giant PEH from before to after laparoscopic surgery were examined., Methods: Levels of brain natriuretic peptide (BNP) as a heart failure marker were measured before and after radical laparoscopic surgery in cases of type III, IV type of giant PEH. Changes of the symptoms due to heart failure were also investigated., Results: A total of 75 hiatal hernia surgeries were performed in 2012-2019. Of them, 50 had a giant PEH, and 20 (40.0%) had heart failure symptoms such as fatigue and exertional dyspnea. In the giant PEH cases, BNP could be measured before and after surgery to evaluate the presence of heart failure in 23 cases; postoperative BNP levels decreased from the preoperative values in 18 of them. Furthermore, in many cases, chest symptoms also improved., Conclusions: Radical laparoscopic surgery can reduce heart failure due to giant PEH. Therefore, in addition to conventional surgical indication criteria such as vomiting and food loss, increased cardiac load may be added to the new surgical indication criteria., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We have recently standardized upper mediastinal lymph node dissection (UMLND) using a microanatomy-based concept in thoracoscopic esophagectomy in the prone position (TEPP), and introduced robot-assisted minimally invasive esophagectomy (RAMIE) using the same concept as in TEPP while aiming at solo surgery. The purpose of this study was to investigate the outcomes of RAMIE using the microanatomy-based concept in the initial introduction phase., Methods: We have performed more than 500 TEPP procedures as minimally invasive esophagectomy (MIE). After performing about 400 cases of MIE, we established a microanatomy-based standardization of UMLND. In October 2018, we introduced RAMIE, and have performed 75 procedures in 20 months. Two groups were analyzed: a group after microanatomy-based standardization in TEPP (100 cases after completing 400 cases of TEPP) and a RAMIE group (75 cases). Finally, 51 paired cases were matched using a propensity score. Furthermore, the change in postoperative short-term outcome for RAMIE in the initial introduction phase was analyzed., Results: Although there were no significant differences between the two groups in the number of upper mediastinal lymph nodes dissected, there was a significant decrease (P = 0.036) in intraoperative blood loss volume with RAMIE, representing a definite benefit for patients. The thoracoscopic operative time for RAMIE decreased by almost 100 min following less than 50 cases of experience, reaching the same level as that for recent TEPP, but with only one-tenth the operator experience. There were no significant differences in the total postoperative morbidity rate including the recurrent laryngeal nerve palsy rate., Conclusion: RAMIE has been introduced safely and smoothly using the microanatomy-based concept established in TEPP., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Multidisciplinary team (MDT) approach has become a standard for perioperative patient care, including in esophageal cancer. In our institution, the Perioperative Management Center (PERiO) has been doing an MDT approach for patients undergoing esophageal cancer surgery since 2009. On the other hand, neoadjuvant therapy has also been becoming standard for many malignancies, including esophageal cancer. In Japan, neoadjuvant chemotherapy (NAC) for esophageal cancer is standard now. However, there have been no reports about when is the best time to start the MDT approach for patients with neoadjuvant therapy. In this study, the best start time for the MDT approach for esophageal cancer patients with NAC was examined from the perspective of adverse events during chemotherapy and perioperative period., Methods: All cases underwent thoracoscopic esophagectomy in the prone position (TEPP) after NAC. The PERiO Intervention group that started before NAC (n = 100) was compared with the PERiO Intervention group that started after NAC (n = 77). Eventually, 54 paired cases were matched by propensity score matching., Results: The adverse event rate during chemotherapy, especially oral complications, was significantly decreased in the PERiO Intervention started before the NAC group (P = 0.007). Furthermore, weight loss during the period from chemotherapy to surgery was significantly reduced in the group that started before NAC (P = 0.033)., Conclusion: The MDT approach should be started before NAC in patients undergoing esophageal cancer surgery to prevent adverse events during chemotherapy and provide safe perioperative conditions., (© 2021. The Japan Esophageal Society.)

Purpose: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments., Methods: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy., Results: Of the 13 patients, 7, 3 and 3 patients were treated with 10 10 , 10 11  and 10 12 virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8 + cells and increased PD-L1 expression., Conclusion: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments., Competing Interests: Conflicts of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasuo Urata is the president and CEO of Oncolys BioPharma, Inc., the manufacturer of OBP-301 (Telomelysin). Hiroshi Tazawa and Toshiyoshi Fujiwara are consultants for Oncolys BioPharma, Inc. The other authors have no other conflicts of interest to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin (CDDP) and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. Our study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although CDDP did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Overall, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer., (© 2021 Union for International Cancer Control.)

Introduction: Intracorporeal Billroth I (B-I) reconstruction using an endoscopic linear stapler (ELS) is widely performed in total laparoscopic distal gastrectomy. However, conventional procedures require many ELSs for anastomosis. Here, we introduce the novel intracorporeal semi-hand-sewn (SHS) B-I reconstruction., Materials and Surgical Technique: After the transection of stomach and duodenum using ELS following adequate lymph node dissection, small entry holes were made on the anterior wall in the greater curvature of the stomach and the duodenal stump. The posterior walls of both the remnant stomach and the duodenum were attached with the ELS and fired to create the posterior wall of the B-I anastomosis. All the transection line of the duodenum and one-third of the transection line of the stomach were dissected; finally the anterior wall suturing at the anastomotic site was performed by the laparoscopic hand-sewn technique., Discussion: SHS procedure was performed for 17 gastric cancer patients. There were no intraoperative complications or conversions to open surgery. One intra-abdominal abscess was observed although there was no anastomotic leakage. The median reconstruction time was 48 minutes (32-63). The SHS procedure was safe, feasible, and economical, although it requires sufficient laparoscopic suturing and ligation skill., (© 2020 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)