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H1299 cells stably co-transfected with KillerRed- and EGFP-expressing vectors (H1299-KillerRed-EGFP) were irradiated for 12 hours. Cells showed morphological changes following photobleaching and started to die, which could be visualized with GFP expression.

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.

Supplementary Fig. S1: Schematic diagrams of the structures of replication-deficient and conditionally; Supplementary Fig. S2: The GFP fluorescence intensity of metastatic lymph nodes in HCT116-GFP-bearing mice after treatment with TelomKiller and laser irradiation. replicating adenovirus vectors; Supplementary Fig. S2: The GFP fluorescence intensity of metastatic lymph nodes in HCT116-GFP-bearing mice after treatment with TelomKiller and laser irradiation.

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]

Purpose: Focal adhesion kinase (FAK) regulates integrin and growth factor–mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma.Experimental Design: The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro. Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo.Results: Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser136 occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226.Conclusions: These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma.

Supplementary Movie S1- MOV file 6383K, Time-lapse imaging of FUCCI-expressing CD133+ cells treated with OBP-301 or control on monolayer culture. Images were acquired every 20 min. The playback speed is 10, 800 x real time. Total imaging time = 48 hours. The cells in G0/ G1, S, or G2/M phases appear red, yellow, or green, respectively

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

Supplementary Table 1 from Dual Tyrosine Kinase Inhibitor for Focal Adhesion Kinase and Insulin-like Growth Factor-I Receptor Exhibits Anticancer Effect in Esophageal Adenocarcinoma In vitro and In vivo

PDF file 1712K, Supplementary Methods Fig. S1. OBP-301 efficiently kills CD133+ cells from MKN7 cells resistant to conventional therapies. Fig. S2. CD133+ CS-like cells can produce CD133+ CS-like cells and CD133- non-CS-like cells. Fig. S3. CD133+ MKN7 cells produce larger colonies than CD133- MKN7 cells in vitro. Fig. S4. CD133+ cells have higher tumorigenicity in nude mice than CD133− cells. Fig. S5. Flow cytometry analysis shows that OBP-301 induces a significant increase in the percentage of both CD133+ CS-like and CD133- non-CS-like cells in S phase. Fig. S6. Expression of CD133 mRNA is associated with the population of CD133+ cells. Fig. S7. OBP-301 reduces the expression of CD133 mRNA. Fig. S8. CD133+ cells show higher expressions of p53, p21 and p27 proteins compared with CD133− cells. Fig. S9. Adenoviral E1A alters cell-cycle related proteins. Fig. S10. Experimental setup in vivo. Fig. S11. Experimental setup for combination therapy of OBP-301 plus cisplatin or paclitaxel in vitro. Fig. S12. The combination therapy of OBP-301 and chemotherapy is more effective than OBP-301 monotherapy on monolayer culture. Fig. S13. OBP-301 reduces the potentiality of stemness in CD133 positive cells. Fig. S14. The combination therapy of OBP-301 and chemotherapy is more effective against larger tumors. Fig. S15. A scheme for oncolytic adenovirus killing quiescent human cancer cells

Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem–like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem–like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem–like cells.Experimental Design: We established CD133+ cancer stem–like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem–like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem–like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI).Results: CD133+ gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133+ cancer stem–like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G0–G1 to S/G2/M phases and subsequent cell death in quiescent CD133+ cancer stem–like cells by mobilizing cell-cycle–related proteins. FUCCI enabled visualization of quiescent CD133+ cancer stem–like cells and proliferating CD133− non–cancer stem–like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133+ cancer stem–like cells maintained stemness by remaining in G0–G1 phase. We showed that OBP-301 mobilized quiescent cancer stem–like cells in tumor spheres and xenografts into S/G2/M phases where they lost viability and cancer stem–like cell properties and became chemosensitive.Conclusion: Oncolytic adenoviral infection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem–like cells. Clin Cancer Res; 19(23); 6495–505. ©2013 AACR.

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

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.

Esophagogastric junction (EGJ) cancers are resected thorough esophagectomy or gastrectomy, with the incidence of postoperative complications influenced by the chosen procedure. In this prospective nationwide multicenter study, patients with cT2–T4 EGJ cancers were enrolled before surgery. Based on the protocol, surgeons performed a transthoracic esophagectomy (TTE) or a transhiatal gastrectomy (THG) and dissected all lymph nodes prespecified as the standardized procedure. Postoperative complications were correlated with the clinical factors in each procedure. A total of 345 patients were eligible for this study. TTE and THG were performed in 120 and 225 patients, respectively. Complications of Clavien-Dindo ≥ Grade II were found in 115/345 (33.3%) patients. Recurrent laryngeal nerve palsy was found only in the TTE group (p

Although some studies have reported on the relationship between appendiceal stump closure methods and postoperative complications, there is no fixed method for this procedure. This study aimed to compare treatment outcomes of the existing procedures.We retrospectively analyzed the records of 200 patients who underwent urgent laparoscopic surgeries and investigated whether the difference in the appendiceal stump closure method was a risk factor for surgical site infection. The patients were divided into the Endoloop and endostapler groups, and 45 propensity score-matched patients were included. The treatment outcomes of the two groups were compared.The patients with high body temperature showed significantly developed surgical site infection in multivariate analysis (P = .036). There was no significant difference in the appendix stump methods (Endoloop vs endostapler). Regarding postoperative complications, superficial and deep incisional surgical site infection, organ/space surgical site infection, ileus, and complications of Clavien-Dindo grade IIIa or higher; there was no significant difference between the endoloop and endostapler groups after propensity score matching (P = .725, 1.000, .645 and .557, respectively).By properly using the Endoloop and endostapler according to the severity of inflammation, the Endoloop can be safely performed in many cases. Inexpensive Endoloop as an option for stump closure methods should positively impact medical costs.

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.

The prevalence of colonic diverticular disease has been on the increase in Japan due to an increase in westernized diet and a rapidly aging population. However, solitary cecal diverticulum is rare and considered congenital in etiology. Solitary cecal diverticulitis with calcified fecaliths is even rarer. Herein, we report a case of cecal colon diverticulitis caused by a calcified fecalith in a 38-year-old woman treated with single-incision laparoscopic surgery. To the best of our knowledge, this report describes the first case of cecal colon diverticulitis caused by a calcified fecalith that was successfully treated with single-incision laparoscopic ileocolectomy.

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.

Background Programmed cell death 1 (PD-1)-based treatments are approved for several cancers. CheckMate 648, a global, phase 3 trial, showed that first-line nivolumab (anti-PD-1 antibody) plus ipilimumab (NIVO + IPI) or nivolumab plus chemotherapy (NIVO + Chemo) significantly increased survival in advanced esophageal squamous cell carcinoma (ESCC) without new safety signals versus chemotherapy alone (Chemo). Methods We evaluated the Japanese subpopulation of CheckMate 648 (n = 394/970), randomized to receive first-line NIVO + IPI, NIVO + Chemo, or Chemo. Efficacy endpoints included overall survival (OS) and progression-free survival assessed by blinded independent central review in Japanese patients with tumor-cell programmed death-ligand 1 (PD-L1) expression ≥ 1% and in all randomized Japanese patients. Results In the Japanese population, 131, 126, and 137 patients were treated with NIVO + IPI, NIVO + Chemo, and Chemo, and 66, 62, and 65 patients had tumor-cell PD-L1 ≥ 1%, respectively. In patients with tumor-cell PD-L1 ≥ 1%, median OS was numerically longer with NIVO + IPI (20.2 months; hazard ratio [95% CI], 0.46 [0.30–0.71]) and NIVO + Chemo (17.3 months; 0.53 [0.35–0.82]) versus Chemo (9.0 months). In all randomized patients, median OS was numerically longer with NIVO + IPI (17.6 months; 0.68 [0.51–0.92]) and NIVO + Chemo (15.5 months; 0.73 [0.54–0.99]) versus Chemo (11.0 months). Grade 3–4 treatment-related adverse events were reported in 37%, 49%, and 36% of all patients in the NIVO + IPI, NIVO + Chemo, and Chemo arms, respectively. Conclusion Survival benefits with acceptable tolerability observed for NIVO + IPI and NIVO + Chemo treatments strongly support their use as a new standard first-line treatment in Japanese patients with advanced ESCC. ClinicalTrials.gov ID NCT03143153.

We present a case of early gastric cancer in the pylorus with a type 3 hiatal hernia, which was treated by endoscopic submucosal dissection (ESD). A 70‐year‐old man was referred to our hospital with a hiatal hernia. Endoscopy revealed early gastric cancer, and we performed an ESD adaptation at the pylorus. The ESD was successful, but post‐ESD pyloric stenosis occurred. Symptoms of hiatal hernia worsened because of the pyloric stenosis. Laparoscopic hiatal hernia repair with Toupet fundoplication and Heineke‐Mikulicz pyloroplasty was simultaneously performed. The postoperative course was good, and follow‐up after discharge was uneventful. To our knowledge, there have been no reports in which laparoscopic hiatal hernia repair, fundoplication, and pyloroplasty were simultaneously performed for a substantial hiatal hernia with post‐ESD pyloric stenosis.

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.

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.

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