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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.

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 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. 18F-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 18F-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. 18F-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 18F-fluorodeoxyglucose positron emission tomography/computed tomography, solitary recurrence appears to have a more favorable prognosis than multiple recurrences.

Immunohistochemistry showed the diffuse HER2 expression on the disseminated peritoneal tumor, but not normal organs, including the liver and the small intestine. Original magnification, ï‚'40

Morphological changes induced immediately after Tra-IR700-mediated PIT in HER2-ECD-transduced gastric cancer cells captured as a time-lapse movie. The cells, which were treated with the integration of Ad/HER2-ECD and Tra-IR700-mediated PIT, shrunk without proliferation. Tra-IR700-mediated PIT cells and control adenovirus (Ad/GFP)-infected cells survived without any phototoxic or virus-toxic effects.

The characteristics of SKOV-3/Luc cells. The human ovarian cancer cell line SKOV-3/Luc is known to be HER2-positive. A, Western blot analysis showed the expression of wt-HER2 protein (185 kDa) in SKOV-3/Luc cells, the same as in N87 cells. B, In flow cytometric analysis, the high HER2 expression level was confirmed in SKOV-3/Luc cells, as compared with in the parental cells. C, Immunohistochemistry showed diffuse HER2 expressions on SKOV-3/Luc cells. D, SKOV-3/ Luc cells seeded on 96-well plates at a density of 2ï‚'103 cells/ well for 24 h. Trastuzumab and Tra-IR700 were added (10 μg /mL) for 6 h, and NIR light was irradiated at 5 J/cm2. Forty-eight h after the irradiation, the cell viability was assessed. Tra-IR700-mediated PIT efficiently decreased the cell viability. *BF, bright field; ** P< 0.05 vs the other control group using a log-rank test.

A, We monitored the bioluminescence intensity of the peritoneal dissemination and compared the total fluorescence. Before treatment, mice with approximately the same luciferase intensity were selected and randomized. The time course of the bioluminescence images of tumor-bearing mice after treatment in vivo. B, The quantitative luciferase activity in mice after treatment. The total fluorescence of the integrated therapy group was remarkably suppressed as compared to that of controls. (n= 5 mice in each treatment group; *P< 0.05 vs control group using one-way repeated ANOVA).

Human gastric cancer cell lines MKN, MKN45 and N87 cells were seeded on 96-well plates at a density of 1ï‚'103 cells/well for 24 h. The anti-HER2 monoclonal antibody trastuzumab was added at the indicated concentrations of 0, 0.01, 0.1, 1.0, 10, 100, and 1000 μg/mL. The cell viability was assessed by XTT assay after 48 h. MKN1 and MKN45 cells were resistant to trastuzumab, while the growth of N87 cells was efficiently inhibited.

Focal adhesion kinase (FAK) is often up-regulated in a variety of malignancies, including gastrointestinal stromal tumor (GIST), and its overexpression seems to be associated with tumor progressiveness and poor prognosis. GIST is well known to have a mutation to c-KIT; thus, a specific c-KIT inhibitor (imatinib) is recognized as the first-line chemotherapy for GIST, although a certain type of c-KIT mutation reveals a resistance to imatinib due to as yet uncertain molecular mechanisms. To assess the c-KIT mutation-related variation of cellular responses to imatinib, murine lymphocyte-derived Ba/F3 cells, which are stably transduced with different types of c-KIT mutation, were treated with either imatinib or a FAK inhibitor (TAE226), and their antitumor effects were determined in vitro and in vivo. A mutation at exon 11 (KITdel559-560) displayed a high sensitivity to imatinib, whereas that at exon 17 (KIT820Tyr) showed a significant resistance to imatinib in vitro and in vivo. KIT820Tyr cells appeared to maintain the activities of FAK and AKT under the imatinib treatment, suggesting that FAK might play a role in cell survival in imatinib-resistant cells. When FAK activity in those cells was inhibited by TAE226, cell growth was equally suppressed and the cells underwent apoptosis regardless of the c-KIT mutation types. Oral administration of TAE226 significantly diminished tumor growth in nude mice bearing KIT820Tyr xenografts. In summary, c-KIT mutation at exon 17 displayed a resistance to imatinib with maintained activations of FAK and subsequent survival signals. Targeting FAK could be a potential therapeutic strategy for imatinib-resistant GISTs. [Mol Cancer Ther 2009;8(1):127–34]

Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate 2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens. [Mol Cancer Ther 2008;7(9):2866–75]

Supplementary Table S1 from Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor

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.

Supplementary Figure 1. Subgroup analysis of TILs in intra-tumoral tissues according to UICC Stage. Supplementary Figure 2. Correlation between CAFs and ratios of peri- to intra-tumoral of CD8+ or FoxP3+ TILs. Supplementary Figure 3. Quantification of cytokines secreted into cell culture supernatants. Supplementary Figure 4. Fibroblasts and cancer cells cooperate to promote the release of IL-6 in human-derived esophageal cancer cell line. Supplementary Figure 5. IL-6 suppresses tumor immunity of SCCVII subcutaneous tumors in C3H/HeJ mice. Supplementary Figure 6. Correlation between IL-6 staining and αSMA+ CAFs in human esophageal cancer specimens. Supplementary Figure 7. Correlation among αSMA+ CAFs, IL-6 and hypoxia conditions in human esophageal cancer specimens Supplementary Table 1. Correlation between CD8+ or FoxP3+ TILs and clinicopathological characteristics of esophageal cancer. Supplementary Table 2. Univariate analysis of pathologic features and tumorinfiltrating lymphocytes for OS and DFS in esophageal cancer. Supplementary Table 3. Univariate analysis of OS and DFS in the subgroups in intratumoral tissues. Supplementary Table 4. Multivariate analysis of CD8+ and FoxP3+ TILs for OS and DFS in esophageal cancer.

Supplementary Methods, Figures 1-10 from Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

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

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.

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.

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.

Cancer immune therapy is the most prominent topic in esophageal cancer. The attraction-3 trial showed that nivolumab was associated with a significant improvement in overall survival versus chemotherapy. This trial was well designed, including patients unresectable, after surgery, and after chemoradiotherapy. However, there are few reports limited to the recurrence after surgery. Here we report the outcome of Nivolumab for the recurrence after surgery with docetaxel, cisplatin, and 5-FU neoadjuvant chemotherapy (NAC-DCF). The subjects were esophageal cancer recurrent patients after NAC-DCF, except for the cases performed only best supportive care, in Okayama University Hospital between January 2014 and October 2021, excepted the cases performed only best supportive care. We assessed their background characteristics, treatment details, immune-related adverse events (irAE), and overall survival (OS). 17 patients received therapies, including Nivolumab (Nivo). 41 patients received other chemotherapies (Control). There was no significant difference in gender (Nivo: male 88%, Control male 80%), age (Nivo: 68.1±8.9, Control: 65.1±5.6), and the period from surgery to recurrence (Nivo: 5.7±3.8 months, Control: 6.1±3.7 months). The Median overall survivals were 27±7.0 months and 18±2.5 months (P=0.055, Log Rank test). The major irAEs were reported in 4 cases (ACTH deficiency: 1 event, enterocolitis: 1 event, liver dysfunction: 2 events). Nivolumab improved the outcomes of recurrent patients after NAC-DCF with a bit of tendency.

Advances in the optical instrument for endoscopic surgery have enabled the anatomical recognition of minute membranes and layers previously invisible in open surgery. Those have allowed surgeons to take the benefits of conversing with the tissue. Furthermore, the recent introduction of robot-assisted surgery has made it possible to dissect with fidelity and safety according to the layers envisaged by the surgeon. Furthermore, we are increasingly having conversations with the tissues during the surgery. Especially in the upper mediastinal lymph node dissection in esophageal cancer surgery, recognizing the delicate anatomy of the membranes and layers is an important technique. We have performed more than 600 thoracoscopic esophageal cancer surgeries in the prone position and more than 100 robot-assisted esophageal cancer surgeries. In our experience, we have tried to formulate the en bloc superior mediastinal lymph node dissection by applying the concept of microanatomy such as a visceral sheath, vascular sheath, and the meso-esophagus surrounded by a visceral sheath. We have established a technique to detach the visceral sheath from the surrounding organs, release the trachea to reveal the meso-esophagus, and dissect the lymphatic chain in en-bloc while rescuing only the recurrent nerve. The spread of the visceral sheath is not symmetrical. On the left side, it is recognized as a firm membrane up to the aortic arch, but on the right side, it seems to disappear at the cervicothoracic border. This left-right difference is understandable considering the difference in the development of the primitive aortic arch on each side during fetal heart development. In this study, we report on the technique and outcomes of upper mediastinal lymph node dissection based on the concept of the microanatomy of membranes and layers, which was developed through conversations with tissues in thoracoscopic esophageal cancer surgery, and its application to robot-assisted surgery.

In the treatment of advanced cervical esophageal cancer, the availability of laryngeal preservation has a great effect on quality of life. Factors affecting laryngeal preservation include tracheal invasion of the tumor, extension to the pharyngeal side, and duplication of head and neck cancer. In our institute, we provide multimodal treatment aiming at preserving the larynx as much as possible. We report on preoperative treatment and surgical outcome for patients with advanced cervical esophageal cancer. Of the 713 cases of esophageal cancer surgery from 2014 to March 2021, 29 cases of advanced cervical esophageal cancer were examined for preoperative treatment and surgical outcome. In our institution, non-T4 cases are first introduced with Docetaxel + Cisplatin +5-FU (DCF) chemotherapy. For cT4 cases and cases who DCF therapy did not respond, we added radiation therapy to DCF for local control. For resectable cases, we performed esophagectomy actively. The primary diagnosis was StageII:III:IV = 6:19:4 (UICC 8th). Preoperative treatment was performed in 28 cases, 26 cases with neoadjuvant chemotherapy (NAC), and 2 cases with chemoradiotherapy (CRT). NAC regimen was DCF in all cases. The therapeutic effect of NAC was evaluated PR in 15 of 26 cases and SD in 11. Laryngeal preservation was possible in 11 of 15 NAC-PR cases (73.3%) and 7 of 11 NAC-SD cases (63.6%), and the laryngeal preservation rate was higher in the NAC responder group. Recurrence was observed in 15 cases. 10 cases were in the laryngeal preservation group, but only 2 cases had local recurrence. This study suggests that the response of NAC may increase the laryngeal preservation rate. Laryngectomy does not necessarily contribute to the control of local recurrence. But patients with positive margins have a poor prognosis. And it is important to make an appropriate decision as to whether radiation therapy or surgery should be performed for patients who do not respond to chemotherapy.

We introduced robot-assisted thoracoscopic surgery for esophageal cancer surgery in 2018 and have performed 143 cases so far. Compared with thoracoscopic surgery, robot-assisted surgery is overwhelmingly more stable and precise, however there are concerns about the safety because there is no sensation from the forceps. Here, we will show a video of a standardized procedure utilizing the characteristics of da Vinci and its application to advanced cancer, and discuss the safe use of da Vinci. We compared the short-term outcomes of pretreatment cStage ≤ II (n=40) and cStage ≥ III (n=53) in a total of 93 single-operator cases out of 143 da Vinci esophageal operations performed at our department since 2018. For all patients, thoracoscopic time: mean 227 minutes, blood loss: 185 ml, recurrent nerve palsy: 15 patients (16.1%), postoperative hospital stay: 29.4 days, R0 surgery achievement rate: 96.8%. By stage (cStage ≤ II vs. ≥ III), thoracoscopic time: 211 vs. 240 minutes (p We focused on the effectiveness of robot-assisted thoracoscopic esophageal surgery for advanced cancer. Although robot-assisted surgery tends to take a relatively long time, we believe that it can be performed safely and effectively even for advanced cancer by careful surgical manipulation.

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 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.

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.

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.

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. 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. 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. 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.

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. 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. Difference 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.

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.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.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%; p0.0001, %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.Amino acids nutrition by PPN and ONS following gastrectomy prevented postoperative BWL and SML in the early period after surgery in GC patients.

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.

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. 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. 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. 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.

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.

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., Graphical Abstract, Paclitaxel (PTX) enhanced the replication of telomerase-specific oncolytic adenovirus in cancer cells and the penetration of the virus into the disseminated nodules of gastric cancer (GC) in the abdominal cavity. The intraperitoneal virotherapy combined with PTX may be a novel promising therapy for peritoneal metastasis of GC.

An aberrant right subclavian artery (ARSA) is one of the famous anatomical abnormalities with a prevalence of 0.16-4.4%. In esophagectomy, anatomical abnormalities of the ARSA could cause complications with some surgical procedures. An 85-year old man was referred to our department for esophageal adenocarcinoma that was at a slightly high position for esophagectomy with the abdominal approach. However, he had a significant past medical history. This risk factor made it difficult to perform thoracoscopic esophagectomy. He underwent mediastinoscopic esophagectomy (ME) with the left cervical and laparoscopic approach. The ARSA presented no difficulties with the ME surgical technique including the dissection of the left recurrent laryngeal nerve lymph node. Although this patient had a respiratory dysfunction and some difficulties in a prone position, ME enabled a safe esophagectomy with lymph node dissection.

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 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. The thoracoscopic operative time was significantly shorter (P

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. 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. 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%). 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.