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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.)

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).)

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.)

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.

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.)

Background: Gastric yolk sac tumor (YST)-like carcinoma is extremely rare, and its prognosis is poor, because most patients have widespread metastases at the time of diagnosis. We report a case of gastric YST-like carcinoma with an adenocarcinoma component without metastases in which curative resection was performed., Case Presentation: A 77-year-old man complaining of melena and dizziness due to anemia was diagnosed with poorly differentiated adenocarcinoma in the gastric cardia, with a benign ulcer in the gastric body. He underwent total gastrectomy with D2 lymph node dissection for the tumor. Histological examination of the resected specimens revealed a mixture of reticular and glandular neoplastic components morphologically. In the reticular area, an endodermal sinus pattern and some Schiller-Duval bodies were confirmed. Gastric YST-like carcinoma with adenocarcinoma components, T2N0M0 Stage IB, was diagnosed. Immunohistochemical analysis showed that the YST was positive for carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP) and p53. In contrast, the adenocarcinoma was positive for p53 and negative for CEA and AFP. The patient remained healthy as of 7 years postoperatively, with no recurrence., Conclusions: Routine medical examinations or endoscopic examinations for accidental symptom may be helpful for early diagnosis and good prognosis for gastric YST-like carcinoma, although the prognosis is generally poor.

Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

Background: Although thoracoscopic esophagectomy in the prone position (TEPP) has become a standard procedure for esophageal cancer surgery, upper mediastinal lymph node dissection (UMLND) on the left side remains an issue. We have recently developed a new standardized approach to left UMLND in TEPP based on the microanatomy of the membranes and layers with the aim of achieving quick and safe surgery. The purpose of this study was to establish and evaluate our new standardized procedure in left UMLND., Patients and Methods: Patients were divided into 2 groups: a pre-standardization group (n = 100) and a post-standardization group (n = 100). Eventually, 83 paired cases were matched using propensity score matching. In our new standardized procedure, left UMLND was performed while focusing on the visceral sheath, vascular sheath, and the fusion layer between them using a magnified view., Results: The thoracoscopic operative time was significantly shorter (P < 0.001) in the post-standardization group [n = 83; 209.0 (176.0-235.0) min] than in the pre-standardization group [n = 83; 235.5 (202.8-264.5) min]. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the two groups. There was a tendency for the total postoperative morbidity to decrease in the post-standardization group. Furthermore, the left recurrent laryngeal nerve palsy rate was significantly lower in the post-standardization group (18.1% to 8.7%, P = 0.015)., Conclusion: Microanatomy-based standardization contributes to safe and efficient left UMLND.

Background: Incidence of esophagogastric junction (EGJ) carcinoma has been increasing worldwide. Several studies revealed that the distance from the EGJ to the proximal edge of the primary tumor (esophageal invasion: EI) may be a significant indicator of metastasis in the mediastinal lymph nodes in patients with Siewert type II carcinomas. However, few studies have been conducted in patients with carcinomas located at Siewert type II sequentially to upper carcinomas (Siewert type I) for mediastinal metastasis regardless of histological types., Methods: This was a single-center retrospective cohort study. EGJ carcinomas located at Siewert type I and II regions including both squamous cell carcinoma (SCC) and adenocarcinoma were analyzed in terms of lymph node metastasis patterns., Results: We included 121 patients in this study. Thirty-three (27.3%) patients had SCC. In multivariate analysis, the distance of EI (> 20 mm) was an independent risk factor (OR 11.80, p = 0.005) for lower mediastinal lymph node metastasis. In terms of above the middle mediastinal metastasis, the distance of EI (> 30 m), histological type (SCC), and tumor size (> 40 mm) were risk factors in univariate analysis. Furthermore, EI was significant (OR 13.50, p = 0.026) in multivariate analysis., Conclusions: The distance of EI was the independent risk factor for mediastinal lymph node metastasis, especially > 20 mm related with a higher risk for mediastinal lymph node metastasis. Furthermore, EGJ carcinoma patients who have EI > 30 mm, large SCC carcinoma, and multiple lymph node metastasis might be considered the middle-upper mediastinal lymph node dissection by transthoracic approach.

Objectives: Although tracheobronchial diverticulum (DV) rarely cause problems, attention should be paid during esophagectomy, which requires careful dissection around the trachea and bronchi. Here, we retrospectively review cases of tracheobronchial DVs among esophageal cancer patients and report two cases of bronchial DV injury during thoracoscopic esophagectomy that were successfully repaired., Methods: The thin-section CT images of esophageal cancer patients who underwent thoracoscopic esophagectomy from January 2013 to December 2015 were retrospectively reviewed. The localization, number, and size (largest axial diameter) of all detected DVs were recorded., Results: A total of 180 patients were enrolled in this study. The incidence of tracheal DV was 5.0%, and that of bronchial DV was 40.0%. The median diameter of the tracheal diverticula was 2.45 [interquartile range (IQR) 2.00-8.17] mm and that of the bronchial diverticula was 1.90 (IQR 1.51-2.46) mm. All tracheal diverticula presented at the right tracheal wall 4.5-6.0 cm below the vocal cords; bronchial diverticula presented at the subcarinal lesions. We experienced two cases with bronchial diverticulum injuries during thoracoscopic esophagectomy, which were repaired by primary closure and confirmed that there was no air leak. No postoperative complications associated with bronchial injury occurred in either patient., Conclusion: Since tracheobronchial DVs are not as rare as previously thought, careful evaluation of thin-slice CT scans is necessary before thoracoscopic esophagectomy. If a tracheobronchial DV is injured during surgery, it is important to carefully repair it and confirm that there is no air leak to avoid complications.

Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer, and the prognosis is extremely poor due to the resistance of systemic chemotherapy. Here, we demonstrate that intraperitoneal (i.p.) administration of a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency (OBP-401) synergistically suppressed the peritoneal metastasis of gastric cancer in combination with paclitaxel (PTX). OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX enhanced the antitumor effect of OBP-401 due to enhanced viral replication in cancer cells. The combination therapy increased induction of mitotic catastrophe, resulting in accelerated autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by i.p. administration of OBP-401 in an orthotopic human gastric cancer peritoneal dissemination model. PTX enhanced the deep penetration of OBP-401 into the disseminated nodules. Moreover, a non-invasive in vivo imaging system demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited growth of peritoneal metastatic tumors and the amount of malignant ascites. i.p. virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer., (© 2020 The Author(s).)

Background: Locally advanced esophageal cancer (EC) invading surrounding organs (T4b) is difficult to treat. In general, definitive chemoradiotherapy (d-CRT) has been chosen as treatment for such cases. However, the outcome has not been good. Recently, the effectiveness of d-CRT with docetaxel, cisplatin, and 5-fluorouracil (DCF-RT) has been reported. Furthermore, surgery after d-CRT has a better prognosis than d-CRT alone in some reports, although it has a high risk of surgical complications. This study investigated the effectiveness and safety of induction DCF-RT., Methods: The subjects were EC patients who underwent induction DCF-RT in Okayama University Hospital between January 2011 and December 2017. Their background characteristics, treatment details, histopathological factors, adverse events during CRT, postoperative complications, and overall survival (OS) were assessed., Results: A total of 16 cases were performed induction DCF-RT. In 10 cases, death occurred, with 9 cancer-related deaths, and 1 death due to other disease. For all cases, OS was 37.5% at 3 years. 12 cases underwent esophagectomy after DCF-RT. Their OS was 50% at 3 years. 13 patients (81.3%) had Grade 3 febrile neutropenia. In 7 cases (62.5%), fasting for the treatment of diarrhea was needed. Three patients (25%) developed anastomotic leakage. Some recurrent laryngeal nerve paralysis was observed in 6 cases (50%)., Conclusion: Although the rates of adverse events and surgical complications were slightly higher than in past reports, they were acceptable. It is useful to perform induction DCF-RT for T4b EC.

Iron is a trace but vital element in the human body and is necessary for a multitude of crucial processes in life. However, iron overload is known to induce carcinogenesis via oxidative stress. Cancer cells require large amounts of iron for their rapid division and cell growth. Iron was recently found to play a role in cancer stem cells (CSCs); it maintains stemness during development. Iron also plays an important role in stemness by moderating reactive oxygen species. Thus, iron metabolism in CSCs is a promising therapeutic target. In this review, we summarize the roles of iron in cancer cells and CSCs. We also summarize anti-cancer therapeutic studies with iron chelators and describe our expectation of a new therapeutic strategy for CSCs on the basis of our findings., Competing Interests: No potential conflict of interest relevant to this article was reported.

Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression. Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8 + or forkhead box protein 3 (FoxP3 + ) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c- nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody. Results: CD8 + TILs and CAFs were negatively correlated in intratumoral tissues ( P < 0.001), whereas FoxP3 + TILs were positively correlated ( P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8 + and increased FoxP3 + TILs, compared with cancer cells alone. In vitro , IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c ( P < 0.001) with fewer CD8 + TILs than untreated tumors ( P < 0.001), whereas no difference in BALB/c- nu/nu mice. In contrast, FoxP3 + TILs increased in IL6-treated tumors ( P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8 + TILs in intratumoral tissues. Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820-33. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Development of immunotherapy, especially checkpoint inhibitors, dramatically improved the prognosis of some malignancies. However, problems on the occurrence of severe adverse effects and limited responses to these checkpoint inhibitors remain. Recently, tumor infiltrating lymphocytes(TILs)are the predictive markers of immunotherapies based on clinical evidence. The proportion of cytotoxic T cells in the tumor has been reported to affect the antitumor effect. TILs in the tumor are thought to be controlled by the interaction between cancer and tumor microenvironment. As a cause of tumor immunosuppression, cancer-associated fibroblasts(CAFs)play the main role in the tumor microenvironment. We considered the strong involvement of tumor microenvironment, particularly the role of CAFs, and reported the interaction between CAFs and proliferation, invasion, angiogenesis, and resistance in the conventional therapy. The correlation between CAFs and tumor immunity and the immunosuppression promoted by CAFs were also evaluated. Their effects will be reported in our future studies.

Background: Gastric cancer is the second most common malignancy, overlapping with thoracic esophageal cancer (TEC). Among them, metachronous gastric tube cancers after TEC surgery have been increasing. The aims of this study were to examine the clinicopathological factors and treatment outcomes of gastric tube cancer (GTC) after TEC surgery., Methods: Thirty-three GTCs in 30 cases after TEC treated between 1997 and 2016 were investigated retrospectively., Results: Most cases were males. The median interval from TEC surgery to GTC occurrence was 57 (6.5-107.5) months. Almost 2/3 lesions occurred in the lower third of the gastric tube (21/33); 29 lesions (in 26 cases) were superficial cancers, and 4 lesions were advanced cancers. Twenty-two lesions of superficial cancer were differentiated type, and the remaining seven lesions were undifferentiated type. Treatment for superficial cancer had previously been performed with partial gastric tube resection (10 lesions), and the number of cases undergoing endoscopic submucosal dissection (ESD) had increased recently (19 lesions). Most cases with superficial cancer survived without relapse. Four lesions of advanced cancer were found after a relatively long interval following TEC surgery. Most lesions of advanced cancer were scirrhous, undifferentiated type, and they died due to GTC., Conclusion: GTCs may occur late in the postoperative course following TEC surgery. If they are discovered at an early stage, these lesions can be cured with ESD. Long-term periodic endoscopic examinations after TEC surgery are important.

Background: Evaluation of the blood supply to gastric conduits is critically important to avoid complications after esophagectomy. We began visual evaluation of blood flow using indocyanine green (ICG) fluorescent imaging in July 2015, to reduce reconstructive complications. In this study, we aimed to statistically verify the efficacy of blood flow evaluation using our simplified ICG method., Study Design: A total of 285 consecutive patients who underwent esophagectomy and gastric conduit reconstruction were reviewed and divided into 2 groups: before and after introduction of ICG evaluation. The entire cohort and 68 patient pairs after propensity score matching (PS-M) were evaluated for clinical outcomes and the effect of visualized evaluation on reducing the risk of complication., Results: The leakage rate in the ICG group was significantly lower than in the non-ICG group for each severity grade, both in the entire cohort (285 subjects) and after PS-M; the rates of other major complications, including recurrent laryngeal nerve palsy and pneumonia, were not different. The duration of postoperative ICU stay was approximately 1 day shorter in the ICG group than in the non-ICG group in the entire cohort, and approximately 2 days shorter after PS-M. Visualized evaluation of blood flow with ICG methods significantly reduced the rate of anastomotic complications of all Clavien-Dindo (CD) grades. Odds ratios for ICG evaluation decreased with CD grade (0.3419 for CD ≥ 1; 0.241 for CD ≥ 2; and 0.2153 for CD ≥ 3)., Conclusions: Objective evaluation of blood supply to the reconstructed conduit using ICG fluorescent imaging reduces the risk and degree of anastomotic complication., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Esophageal carcinomas are highly malignant tumors with a high frequency of lymph node and distant organ metastasis. Treatment for recurrent tumors is generally decided on an individual basis. Although multidisciplinary treatments involving chemotherapy, surgical resection, and radiation are performed, the prognosis remains poor. Here, we report a case of prolonged recurrence-free survival (38 months) after esophageal carcinoma surgery and subsequent laparoscopic adrenalectomy for right adrenal metastasis., Case Presentation: An 83-year-old man was diagnosed with type 3 esophageal squamous cell carcinoma (T3N1M0, cStage IIIA, UICC-7), spreading from the lower thoracic esophagus to the abdominal esophagus. He underwent thoracoscopic esophagectomy with a two-field lymph node dissection followed by substernal gastric tube reconstruction. The final diagnosis was moderately differentiated squamous cell carcinoma (T3N2M0, fStage IIIB). Adjuvant chemotherapy was not administered because of the advanced age and postoperative condition of the patient. Computed tomography (CT) at 14 months postoperatively showed a mass with a 2-cm diameter at the right adrenal gland. Positron emission tomography (PET)/CT revealed a high fluorodeoxyglucose (FDG) uptake in the mass. It was suspected that the mass was a metastatic lesion secondary to the primary esophageal carcinoma. No metastases to lymph nodes or other distant organs were identified. The patient underwent laparoscopic right adrenalectomy. The histopathological examination revealed moderately differentiated squamous cell carcinoma, suggesting metastasis from the primary esophageal carcinoma. He has survived without recurrence for 38 months since laparoscopic adrenalectomy to remove the right adrenal metastastic mass after the esophageal carcinoma surgery., Conclusions: We describe a very elderly male who survived laparoadrenalectomy for right adrenal metastasis following esophageal cancer surgery without recurrence for 38 months postoperatively. Therefore, surgical resection might be an option for solitary adrenal recurrence.

The esophagorespiratory fistula(ERF)is a fatal complication ofesophageal cancer, because ofadvanced oncological status and poor conditions due to pneumonia and/or malnutrition.We report here a case of patient who was successfully treated for esophageal cancer with ERF with multimodality therapy including three-stage operation. A 65-year-old woman ofesophageal cancer received preoperative chemotherapy, and developed EFR before operation. Prolonged conservative therapies for ERF let her general condition get worse. Therefore, the patient underwent esophagostomy and gastrostomy to recover her condition. She received chemo-radiotherapy followed by esophagectomy. And she was performed the reconstruction next month. She is still alive without recurrence at 20 months after resection. In previous reports, a total of 6 cases have been performed esophagectomy for esophageal cancer with ERF in Japan. Only one case was reported that had survived longer than 12 months. This multimodality therapy can be one ofthe best strategies for the patients ofesophageal cancer with ERF, even ifthey have poor condition.

We report a case of an elderly patient with advanced esophageal cancer who underwent multidisciplinary treatment. An 86-year-old male consulted our hospital with complaints of pharynx discomfort and difficulty in swallowing. He was preoperatively diagnosed with esophageal cancer, T3N2M0, Stage III . We performed 2 courses of cisplatin plus 5-FU therapy as neoadjuvant chemotherapy. The primary tumor and metastatic lymph nodes reduced in size, and thoracoscopic esophagectomy in the prone position was performed. Pathological findings were esophageal cancer, pT3-Ad, INF b, ly2, v1, IM0, pPM0, pDM0, pRM1, pN3, pStage III . As the radical margin was positive, chemoradiotherapy was performed. We continued postoperative chemotherapy for approximately 1 year, and the patient has survived without relapse for 4 years from esophagectomy. Even in patients over 80 years old, long-term prognosis can be expected by performing radical surgery and chemoradiotherapy.

Currently, chemoradiation is the most widely used nonsurgical treatment for esophageal cancer. However, some patients, particularly the very elderly or those with severe vital organ dysfunction, face difficulty with the chemotherapy component. We therefore examined the outcome of radiation therapy (RT) alone for patients with esophageal cancer at our facility. Between January 2005 and December 2014, 84 patients underwent RT at our hospital, and 78 of these patients received concomitant chemotherapy. The remaining 6 patients underwent RT alone; these patients were considered to be high-risk and to have no lymph node metastasis (stage I). Five of them received irradiation up to a curative dose: 4 showed a complete response (CR) and 1 showed a partial response (PR). Of the patients exhibiting CR, 3 are currently living recurrence-free, whereas 1 patient underwent endoscopic submucosal dissection (ESD) as salvage therapy for local recurrence, with no subsequent recurrence. High-risk stage I esophageal cancer patients can be treated radically with RT alone under certain conditions. In the future, to broaden the indications for RT monotherapy to include some degree of advanced cancers, a novel concurrent therapy should be identified., Competing Interests: No potential conflict of interest relevant to this article was reported.

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

A chyle leak can occur as a complication after neck or chest surgery. Such a leak prolongs the hospital stay and is sometimes life-threatening. The treatment options are conservative management, interventional radiologic embolization, and surgery. Thoracoscopic ligation of the thoracic duct has emerged as a promising and definitive treatment. The case of a 65-year-old Japanese male patient with a rare congenital right aortic arch (typeⅢB1 of Edward's classification) and a severe chyle leak that occurred after a total pharyngolaryngo-esophagectomy (TPLE) is described. The chyle leak was successfully managed by thoracoscopic ligation of the thoracic duct via a left-side approach with the patient in the prone position.

Since reported in the JCOG9907 trial, neoadjuvant chemotherapy prior to surgery has become the standard treatment for advanced (Stage II/III) esophageal cancers. However, more powerful neoadjuvant chemotherapy is required for the treatment of locally advanced cases or cases involving multiple lymph node metastases. At our institute, DCF therapy (docetaxel, cisplatin, and 5-fluorouracil) is administered selectively for the treatment of patients with far-advanced esophageal cancer. We treated 53 thoracic esophageal cancer patients who underwent surgery following neoadjuvant chemotherapy between January 2010 and December 2012. FP therapy (cisplatin and 5-fluorouracil) was administered to 43 patients, and DCF therapy to 7 patients who had far-advanced esophageal cancer. All patients treated with DCF therapy experienced grade 3 and 4 adverse events. With the exception of 1 patient, all patients who received DCF therapy could undergo curative surgery. DCF therapy could become an effective preoperative chemotherapy.

An 80-year-old woman, who had been administered α-glucosidase inhibitor for diabetes, was brought to the hospital with the sensation of abdominal fullness and pain. Abdominal computed tomography indicated pneumatosis cystoides intestinalis (PCI) in the small intestinal wall, with free air within the abdomen. A blood examination showed no increases in white blood cells or C-reactive protein level. The patient's condition improved with conservative therapy. PCI with pneumoperitoneum induced by α-glucosidase inhibitor is rare, with only 27 cases (excluding the present case) reported in Japan to date. In PCI with pneumoperitoneum, differentiation from gastrointestinal perforation is important and following the clinical symptoms over time is vital.

The HSP90 molecular chaperone family is highly conserved and expressed in various organisms ranging from prokaryotes to eukaryotes. HSP90 proteins play essential housekeeping functions, such as controlling the activity, turnover and trafficking of various proteins, promoting cell survival through maintaining the structural and functional integrity of some client proteins which control cell survival, proliferation and apoptosis, and play an important role in the progression of malignant disease. HSP90 proteins are ATP-dependent chaperones and the binding and hydrolysis of ATP are coupled to conformation changes of HSP90, which facilitate client protein folding and maturation. Many natural and synthetic molecular compounds have been proposed as promising cancer therapy via disrupting the formation of complex ATP-HSP90-client proteins.

Autophagy is a cellular lysosomal degradation pathway involved in proteins and organelles recycling for promoting cell survival, development and homeostasis. It is a multistep process and genetic studies have identified many proteins that participate in autophagosome formation and fusion with lysosomes, and various signaling factors that associate with the regulation of autophagy. In general, autophagy acts as a cell protector and its dysfunction is correlated with diverse pathologies, such as neurodegeneration, liver, heart and muscle diseases, cancer, inflammation and ageing. However, its role in cell death increases the complexity of the autophagic degradation system. A broad understanding of autophagy, ranging from detailed processes, including induction, formation and degradation, to function in physiology and pathology, revealed by accumulating studies, may be helpful for formulating therapeutic strategies for autophagy-associated human diseases.

Focal adhesion kinase (FAK) is a 125-kDa non-receptor protein tyrosine. Growth factors or the clustering of integrins facilitate the rapid phosphorylation of FAK at Tyr-397 and this in turn recruits Src-family protein tyrosine kinases, resulting in the phosphorylation of Tyr-576 and Tyr-577 in the FAK activation loop and full catalytic FAK activation. FAK plays a critical role in the biological processes of normal and cancer cells including the gastrointestinal tract. FAK also plays an important role in the restitution, cell survival and apoptosis and carcinogenesis of the gastrointestinal tract. FAK is over-expressed in cancer cells and its over-expression and elevated activities are associated with motility and invasion of cancer cells. FAK has been proposed as a potential target in cancer therapy. Small molecule inhibitors effectively inhibit the kinase activity of FAK and show a potent inhibitory effect for the proliferation and migration of tumor cells, indicating a high potential for application in cancer therapy.

Focal adhesion kinase (FAK) is a 125-kDa non-receptor and non-membrane protein tyrosine. FAK can function with integrins and growth factor receptors to promote cell survival dependent kinase activity and nuclear FAK promotes cell proliferation and survival through FERM (FAK, ezrin, radixin, moesin) domain-enhanced p53 degradation independent kinase activity. Many previous studies have indicated that FAK plays a critical role in the biological processes of normal and cancer cells and FAK has been proposed as a potential target in cancer therapy. Small molecule inhibitors (PF-573,228; PF-562,271 and NVP-226) for use as potential cancer therapies have been developed. However, the detailed mechanism of the role for FAK in tumor cell generation and progression remain unclear, so future work is needed to explore these issues. New inhibitors that can be effectively inhibit the function of FAK still need to be explored due to the low specificity, and resistance.

In our institute, we introduced PET-CT examination as the preoperative and postoperative screening for esophageal cancer patients in April 2006. During two years before the introduction of PET-CT examination, we performed an intensive local control therapy (operation, RFA, definitive chemoradiotherapy) to 13 cases with single region recurrence (including 5 cases of cervical lymph nodes recurrence, 5 of local recurrence, 3 of distant metastatic recurrence). On the other hand, we performed an intensive local control therapy to 21 cases (including 4 cases of cervical lymph nodes recurrence, 10 of local recurrence, and 7 of distant metastatic recurrence) during two years after the introduction of PET-CT examination. In any pattern, there was a tendency of improvement in the prognosis of recurrent esophageal cancer patients. These results raised the possibility that PET-CT examination was useful for an early detection of the recurrent lesions in postoperative follow-up for esophageal cancer patients. And there might be a chance of curability in patients with single region recurrence by the early detection.

We report a case of a woman in her sixties having primary duodenal carcinoma with multiple liver metastases who was treated with oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin(FOLFOX regimen). After completing 2 courses of the chemotherapy, computed tomography showed a partial response without any severe adverse events. Now at 8 months, the PR stage has been maintained. So far, no standard therapeutic strategy for metastatic duodenal carcinoma has been developed. However, we suggest a FOLFOX regimen can be highly effective as a safe approach for continuously maintaining the quality of life of patients with this rare type of cancer.

There is currently no suitable animal model of metastasis using cultured human gastrointestinal stromal tumor cells even though the molecular mechanisms of c-KIT-mediated progression and metastasis should be clarified. Ba/F3 murine lymphocyte cells transduced with mutant c-KIT have been utilized to analyze some molecular mechanisms related to a constitutively activated c-KIT signaling and to assess the efficacy of molecular-targeted inhibitors. Using this cellular system, we coincidentally discovered the development of axillary and inguinal lymph node swelling three weeks after subcutaneous injection of Ba/F3 cells with c-KIT mutation into nude mice. Mutation-specific PCR detected c-KIT mutation in the swollen lymph nodes but not in unmetastasized normal lymph nodes, indicating that the lymph nodes contain tumor cells which should come from a primary subcutaneous tumor. Microscopic observation revealed tumor cells infiltrating through lymphatic follicles with Ki-67-positive staining to distinguish them from lymphocytes. The significance of this model is helpful to understand the molecular mechanisms of c-KIT-mediated metastasis and is useful for assessments of molecular therapeutics and in vivo imaging.

Anticancer drug discovery has long been hampered by the poor predictivity of the preclinical models. There is a growing realization that the tumor microenvironment is a critical determinant of the response of cancer cells to therapeutic agents. The past 5 years have seen a great deal of progress in our understanding of how the three-dimensional microenvironment modulates the signaling behavior of tumor cells. The present review discusses how three-dimensional in vitro cell culture models can benefit cancer drug discovery through an accurate modeling of the tumor microenvironment, leading to more physiologically relevant experimental outcomes.

Amino acids, especially branched-chain amino acids such as l-leucine, have been shown to regulate activation of p70 S6 kinase and phosphorylation of 4E-BP1 through the mTOR signaling pathway. In our recent study, l-arginine was also shown to activate the mTOR signaling pathway in rat intestinal epithelial cells. l-Glutamine is an amino acid that is required for culturing of numerous cell types, including rat intestinal epithelial cells. In this study, we showed that l-glutamine inhibited the activation of p70 S6 kinase and phosphorylation of 4E-BP1 induced by arginine or leucine in rat intestinal epithelial cells. Although the molecular mechanism of l-glutamine-induced inhibition of the mTOR signaling pathway is still unknown, the presence of this novel signal pathway may indicate that individual amino acids play specific roles for cellular proliferation and growth.