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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

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.

Objective This study aimed to identify factors associated with outlet obstruction and high-output stoma (HOS) after ileostomy creation. Summary of background data Ileostomy creation is effective in preventing leakage among patients undergoing low anterior resection for rectal cancer. However, major complications such as outlet obstruction and HOS can occur after surgery. Moreover, these complications cannot be prevented. Methods This retrospective study included 34 patients with rectal cancer who underwent low anterior resection and ileostomy creation at Okayama University Hospital from January 2015 to December 2018. Then, the risk factors associated with outlet obstruction and HOS were analyzed. Results Of 34 patients, 7 (21%) experienced outlet obstruction. In a multivariate logistic regression analysis, advanced T stage (P = 0.10), ileostomy with a short horizontal diameter (P = 0.01), and thick rectus abdominis (RA) muscle (P = 0.0005) were considered independent risk factors for outlet obstruction. There was a significant correlation between outlet obstruction and HOS (P = 0.03). Meanwhile, the independent risk factors of HOS were advanced T stage (P = 0.03) and thick RA muscle (P = 0.04). Conclusions Thick RA muscle and advanced T stage were the common risk factors of outlet obstruction and HOS. Therefore, in high-risk patients, these complications can be prevented by choosing an appropriate ileostomy location according to RA muscle thickness and by preventing tubing into the ileostomy.

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.

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.

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.

Background: Remnant gastric cancer (RGC) has been increasing for various reasons such as longer life span, medical progress, and others. It generally has a poor prognosis, and its mechanism of occurrence is unknown. The purpose of this study was to evaluate the clinicopathological features of and clarify the prognostic factors of RGC.Methods: Between January 2002 and January 2017, 39 patients with RGC following distal gastrectomy underwent curative surgical resection at the Okayama University Hospital; their medical records and immunohistochemically stained extracted specimens were used for retrospective analysis. Results: On univariate analysis, initial gastric disease, pathological lymph node metastasis, and pathological stage were the significant factors associated with a poor overall survival (OS) (p=0.0139, 0.0061, and 0.0158, respectively). Multivariate analysis of these 3 factors showed that only initial gastric disease caused by malignant disease was an independent factor associated with a poor prognosis (p=0.0141, odds ratio [OR]:4.151, 95% confidence interval [CI]:1.333-12.93). In addition, the presence of a left gastric artery (LGA), and tumor-infiltrating CD8+ T cell expression were higher in the benign disease group than in the malignant group (p

Purpose Although D2 lymphadenectomy is currently considered a standard procedure for advanced gastric cancer (GC) worldwide, there is room for discussion about the appropriate range of suprapancreatic D2 lymphadenectomy. Focusing on the posterior hepatic plexus (PHP), which is not well recognized, we developed a surgical technique of suprapancreatic D2 lymphadenectomy, which we have called PHP-D2, and its short-term and long-term efficacies were evaluated in comparison with non-PHP-D2. Methods GC patients who underwent distal gastrectomy with D2 lymphadenectomy between July 2006 and May 2013 were enrolled, from which patients who had peritoneal metastasis and/or were peritoneal cytology-positive during surgery were excluded. Their medical records were retrospectively reviewed. Results Ninety-two patients (non-PHP-D2: 48, PHP-D2: 44) were enrolled. Shorter operation time (330 min vs 275 min, p Conclusion PHP-D2 was a safe and feasible procedure that had the potential to reduce lymphatic recurrence, and it can be a standard procedure of D2 lymphadenectomy for advanced GC.

Patient: Female, 49-year-old Final Diagnosis: Juvenile polyposis syndrome Symptoms: Anemia Medication:— Clinical Procedure: Surgery Specialty: Gastroenterology and Hepatology • Genetics Objective: Rare disease Background: Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases. Case Report: A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing. Conclusions: JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

Endoscopic ultrasound (EUS)-guided transgastric drainage has been performed as a less invasive procedure for pancreatic fistulas and intra-abdominal abscesses occurring after surgery in recent years. However, there are no reports of EUS-guided transgastric drainage of intra-abdominal abscesses following gastrectomy. This case report describes 2 patients who developed an intra-abdominal abscess following gastrectomy and underwent EUS-guided transgastric drainage. Both patients underwent laparoscopy-assisted distal gastrectomy with Billroth-I reconstruction for gastric cancer. The intra-abdominal abscesses were caused by postoperative pancreatic fistula that developed following gastrectomy. One patient underwent naso-cystic drainage and the other underwent only a needle puncture of the abscess cavity. EUS-guided drainage was performed safely and effectively, although 1 patient developed gastroduodenal anastomotic leakage related to this procedure. In summary, EUS-guided transgastric drainage is safe and technically feasible even in post-gastrectomy patients. However, it is necessary to be careful if this procedure is performed in the early period following gastrectomy.

Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.

Laparoscopy and endoscopy cooperative surgery(LECS)is the surgical procedure used to avoid excessive resection of the gastrointestinal wall and preserve its function. We report the case of a patient who was successfully treated with inverted LECS for gastrointestinal stromal tumor(GIST)in the remnant stomach and underwent distal gastrectomy. The patient was a 75- year-old man who received distal gastrectomy for gastric ulcer 28 years before. Three years before he was diagnosed as having gastric submucosal tumor(SMT)as a gastrointestinal tumor(GIST)by using EUS. As the tumor increased, he was admitted to our hospital. Upper gastrointestinal endoscopy revealed a 30mm SMT just below the cardiac part of the remnant stomach. Biopsy by EUS-FNA revealed CD34(-), c-kit(+), S-100(-), and a-SMA(-), which indicated gastric GIST. Inverted LECS was performed. His postoperative course was good, and he was discharged from the hospital 9 days after the surgery.

The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

AIM: As a result of the difficulty in effective prevention of gastroesophageal reflux, no standard reconstruction procedure after proximal gastrectomy (PG) has yet been established. The double-flap technique (DFT), or Kamikawa procedure, is an antireflux reconstruction procedure in esophagogastrostomy. The efficacy of DFT has recently been reported in several studies. However, these were all single-center studies with a limited number of cases. METHODS: We conducted a multicenter retrospective study in which patients who underwent DFT, irrespective of disease type and reconstruction approach, at each participating institution between 1996 and 2015 were registered. Primary endpoint was incidence of reflux esophagitis at 1-year after surgery, and secondary endpoint was incidence of anastomosis-related complications. RESULTS: Of 546 patients who were eligible for this study, 464 patients who had endoscopic examination at 1-year follow up were evaluated for reflux esophagitis. Incidence of reflux esophagitis of all grades was 10.6% and that of grade B or higher was 6.0%. Male gender and anastomosis located in the mediastinum/intra-thorax were independent risk factors for grade B or higher reflux esophagitis (odds ratio [OR]: 4.21, 95% confidence interval [CI]: 1.44-10.9, P = 0.0109). Total incidence of anastomosis-related complications was 7.2%, including leakage in 1.5%, strictures in 5.5% and bleeding in 0.6% of cases. Laparoscopic reconstruction was the only independent risk factor for anastomosis-related complications (OR: 3.93, 95% CI: 1.93-7.80, P = 0.0003). CONCLUSION: Double-flap technique might be a feasible option after PG for effective prevention of reflux, although anastomotic stricture is a complication that must be well-prepared for.

// Yoshiko Mori 1, 2 , Akihiro Nyuya 3 , Kazuya Yasui 1 , Toshiaki Toshima 1 , Takashi Kawai 1 , Fumitaka Taniguchi 1 , Keisuke Kimura 1 , Ryo Inada 1 , Masahiko Nishizaki 1 , Junko Haraga 4 , Keiichiro Nakamura 4 , Yuzo Umeda 1 , Hiroyuki Kishimoto 1 , Toshiyoshi Fujiwara 1 , Yosuke Katata 3 , Yoshiyuki Yamaguchi 3 and Takeshi Nagasaka 3 1 Departments of Gastroenterological Surgery, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan 2 Clinical Genomic Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan 3 Department of Clinical Oncology, Kawasaki Medical School, Kurashiki City, Japan 4 Obstetrics and Gynecology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan Correspondence to: Takeshi Nagasaka, email: takeshin@med.kawasaki-m.ac.jp Keywords: ovarian metastases; colorectal cancer; ovarian metastatectomy; BRAF; RAS Received: August 15, 2017 Accepted: February 21, 2018 Published: March 27, 2018 ABSTRACT We clarified the clinical prevalence of ovarian metastases from colorectal cancers (CRCs) in 296 female patients with CRC and evaluated clinical outcomes with relation to their mutational profiles, such as BRAF/KRAS mutation and microsatellite instability (MSI) status. The female CRCs were categorised into three subsets: CRCs with ovarian metastases [6.4% ( n = 19), 5-year overall survival (OS) = 24.7%], CRCs with extra-ovarian metastases only [32.4% ( n = 96), 5-year OS = 34.5%] and CRCs without any recurrence or metastasis [61.2% ( n = 181), 5-year OS = 91.3%]. All patients with ovarian metastases underwent oophorectomy; of these, 9 who received preoperative chemotherapy had measurable metastases to extra-ovarian sites and the ovaries. Although 5 of 9 (56%) achieved partial response or complete response at extra-ovarian sites, no patient archived objective response at ovarian sites. Regarding the mutation profiles, in CRCs with extra-ovarian metastases only, the median survival time (MST) after initial treatments to progression to stage IV or recurrence was 13 [95% confidence interval (CI): 7–16 months] in BRAF-mutant and 34 months (95% CI: 22–58 months) in BRAF wild-type ( P = 0.0033). Although ovarian metastases demonstrated poor response to systemic chemotherapy in CRCs with ovarian metastases, the MST after initial treatments to progression to stage IV or recurrence was 22 (95% CI: 21–25 months) in BRAF-mutant and 38 months (95% CI: 24–42 months) in BRAF wild-type ( P = 0.0398). The outcomes of patients with ovarian metastases could be improved by oophorectomy regardless of their mutation profiles.

Background Sarcopenia is recognized as an important prognostic factor in various types of cancer, including gastric cancer. While long-term survival analyses typically focus on overall and disease-specific survival, death from other causes has received far less attention. Methods We reviewed medical records of 491 gastric cancer patients who underwent gastrectomy from January 2005 to March 2014 and whose preoperative computed tomography (CT) images were available for evaluation of sarcopenia. Sarcopenia was defined as the SMA/BSA index (skeletal muscle area divided by body surface area) below the sex-specific lowest quartile. Results Sarcopenia was significantly associated with age, high body mass index (BMI), presence of comorbidity, high American Society of Anesthesiologists physical status (ASA-PS), high T score, advanced stage, large blood loss, and long hospital stay, but was not significantly associated with postoperative complications. Univariate and multivariate analyses of prognostic factors for overall survival revealed that sarcopenia is an independent predictor of poor prognosis [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.01–2.09, p = 0.0454]. Our analysis of death due to other causes found that non-gastric cancer-related deaths were more frequent among sarcopenia patients with comorbidities than in the rest of our study population (p = 0.0001), while univariate and multivariate analyses revealed that sarcopenia with comorbidity was an independent risk factor for non-gastric cancer-related death (HR 1.84, 95% CI 1.31–3.61, p = 0.0308), as was age. Conclusion For gastric cancer patients, sarcopenia increases the risk of death from other causes following surgery, which reveals the importance of developing treatment strategies based not only on cancer status but also on other clinical factors, including sarcopenia and comorbidity. Electronic supplementary material The online version of this article (10.1245/s10434-018-6354-4) contains supplementary material, which is available to authorized users.

Background Endoscopic resection (ER) has been widely accepted as the standard treatment for early gastric cancer (EGC). However, in patients considered to have undergone non-curative ER due to their potential risk of lymph node metastasis (LNM), additional gastrectomy is recommended. The aim of the present study was to identify EGC patients after non-curative ER at high risk of LNM. Methods A total of 150 patients who had undergone ER for EGC were diagnosed as non-curative ER due to their potential risk of LNM. Clinicopathological data and clinical outcomes were examined retrospectively. Results Additional gastrectomy with lymph node dissection was performed in 73 patients, and the remaining 77 patients were followed-up without additional gastrectomy. In patients who underwent additional gastrectomy, 8 patients had local residual tumor, and 8 patients had LNM, which were limited in the peritumoral nodes. Only lymphatic invasion (p = 0.012) was a statistically significant factor for LNM. The 5-year overall survival and recurrence-free survival were not significantly different between patients with and without additional gastrectomy. Conclusion Additional gastrectomy with lymph node dissection is recommended for patients who were diagnosed as non-curative ER with lymphatic invasion, and minimizing the extent of lymph node dissection may be allowed for these patients.

Sarcopenia is a complex syndrome defined by progressive and generalized loss of skeletal muscle mass and strength. Although sarcopenia is mainly associated with aging, cancer is also one of its causes. Sarcopenia is now drawing attention as a poor prognostic factor in cancer. In patients with gastric cancer associated with eating disorders that often leads to loss of weight and muscle, sarcopenia is particularly important. Its definition and method of assessment, however, vary between studies, thus these need to be standardized. Nevertheless, emerging evidence suggests that sarcopenia contributes independently to postoperative complications and overall survival in gastric cancer. Interventions preventing sarcopenia with targeted nutrition and exercise are currently explored. This review aims to provide an understanding of sarcopenia, emphasizing its importance in the management of gastric cancer.

Epidural analgesia (EDA) is an imperative modality for postoperative pain relief after major open abdominal surgery. However, whether EDA has benefits in laparoscopic surgery has not been clear. In this study, the effects of EDA and patient-controlled intravenous analgesia (PCIA) after laparoscopic distal gastrectomy (LDG) were compared.This was a retrospective study that included 82 patients undergoing LDG for gastric cancer. Patients received either EDA (n=67) or PCIA (n=15) for postoperative pain relief. Postoperative outcomes and analgesia-related adverse events were compared between the two modalities.EDA and PCIA patients showed no differences in the incidence of complications [9 (13%) vs. 2 (13%); P=0.99] and the length of postoperative hospital stay (9.6±4.5 d vs. 9.7±4.0 d; P=0.90), although the PCIA included poorer preoperative physical status (PS) patients. The number of additional doses of analgesics was higher in the EDA than in the PCIA (1.8±2.4 vs. 0.9±1.0; P=0.01), although postoperative pain scores were similar in the 2 groups. Though the time to first passage of flatus was shorter in the EDA (P0.05), more EDA patients developed postoperative hypotension as an adverse event (P0.01). The full mobilization day and the day of oral intake tolerance were not significantly different between the 2 groups after surgery.After LDG, EDA may not be indispensable, while PCIA may be the optimal modality for providing safe and effective postoperative analgesia and recovery.

Background: Pharmacologic prophylaxis such as enoxaparin for venous thromboembolism (VTE) is rarely used in Japan, even following abdominal cancer surgery, for which it is recommended in relevant guidelines (at least 7 days of use) along with mechanical prophylaxis with intermittent pneumatic compression. Reasons for enoxaparin’s unpopularity include concerns over postoperative bleeding and its inconvenience in clinical practice. Here, we conducted a prospective clinical study of short-term (3 days) use of enoxaparin, which is considered to minimally impact postoperative management without increasing bleeding risk. Methods: Gastric cancer patients who underwent gastrectomy received enoxaparin for 3 days from postoperative day (POD) 1 to 4. The primary endpoint was the incidence of deep vein thrombosis (DVT), which was examined primarily via Doppler ultrasonography of the lower limbs between POD 8 and 14. The planned sample size was 70, which was calculated based on an estimated incidence rate of 9% and an upper limit of incidence rate of 20%, with alpha of 0.05 and beta of 0.2. Results: A total of 70 gastric cancer patients were enrolled, and ultimately, 68 patients received the protocol intervention and DVT evaluation. Sixty-seven patients completed 6 enoxaparin injections, but 1 patient did not complete the course due to abdominal bleeding after initiation. The incidence of DVT was 4.4% (3/68), and the 95% upper confidence interval was 12.2%, lower than the 20% threshold we set as the upper limit of DVT incidence. DVT was detected only in the peripheral veins of the lower extremities in all 3 affected patients. The incidence of bleeding-related complications, which were not severe, was 1.5% (1/68). Conclusions: Short-term (3 days) use of enoxaparin was shown to be effective and safe for VTE prophylaxis, comparable to regular use (at least 7 days), in postoperative management of gastric cancer surgery.

Background Although proximal gastrectomy (PG) is a recognized surgical procedure for early proximal gastric cancer, total gastrectomy (TG) is sometimes selected due to concern about severe gastroesophageal reflux. Esophagogastrostomy by the double-flap technique (DFT) is an anti-reflux reconstruction after PG, and its short-term effectiveness has been reported. However, little is known about the long-term effects on nutritional status and quality of life (QOL). Methods Gastric cancer patients who underwent laparoscopy-assisted PG (LAPG) with DFT or laparoscopy-assisted TG (LATG) between April 2011 and March 2014 were retrospectively analyzed. Body weight (BW), body mass index (BMI), and prognostic nutritional index (PNI) were reviewed to assess nutritional status, and the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45 was used to assess QOL. Results A total of 36 patients (LATG: 17, LAPG: 19) were enrolled. Four of 17 LATG patients (24%) were diagnosed with Stage ≥II after surgery, and half received S-1 adjuvant chemotherapy. BW and PNI were better maintained in LAPG than in LATG patients until 1-year follow-up. Seven of 16 LATG patients (44%) were categorized as “underweight (BMI2)” at 1-year follow-up, compared to three of 18 LAPG patients (17%; p = 0.0836). The PGSAS-45 showed no significant difference in all QOL categories except for decreased BW (p = 0.0132). Multivariate analysis showed that LATG was the only potential risk factor for severe BW loss (odds ratio: 3.03, p = 0.0722). Conclusions LAPG with DFT was superior to LATG in postoperative nutritional maintenance, and can be the first option for early proximal gastric cancer.

An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.

A79 -year-old woman underwent colonoscopic examination for positive occult blood. Aneoplastic lesion was seen in the orifice of the vermiform appendix. She was referred to our hospital and underwent colonoscopic examination again. The biopsy revealed poorly differentiated adenocarcinoma or mixed adenoneuroendocrine carcinoma(MANEC), and she was diagnosed with carcinoma of the appendix. She was treated by laparoscopic ileocecal resection with lymph node dissection (D3). Histopathological examination revealed goblet cell carcinoid(GCC)of the appendix with serosal invasion. No metastasis was detected in the dissected lymph nodes. This patient has been followed-up for 6 months after surgery and no recurrences have been detected.

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, early gastrointestinal cancers are treated endoscopically, as long as there are no lymph node metastases. However, once a gastrointestinal cancer invades the submucosal layer, the lymph node metastatic rate rises to higher than 10%. Therefore, surgery is still the gold standard to remove regional lymph nodes containing possible metastases. Here, to avoid prophylactic surgery, we propose a less-invasive biological ablation of lymph node metastasis in submucosally invaded gastrointestinal cancer patients. We have established an orthotopic early rectal cancer xenograft model with spontaneous lymph node metastasis by implantation of green fluorescent protein (GFP)-labeled human colon cancer cells into the submucosal layer of the murine rectum. A solution containing telomerase-specific oncolytic adenovirus was injected into the peritumoral submucosal space, followed by excision of the primary rectal tumors mimicking the endoscopic submucosal dissection (ESD) technique. Seven days after treatment, GFP signals had completely disappeared indicating that sentinel lymph node metastasis was selectively eradicated. Moreover, biologically treated mice were confirmed to be relapse-free even 4 weeks after treatment. These results indicate that virus-mediated biological ablation selectively targets lymph node metastasis and provides a potential alternative to surgery for submucosal invasive gastrointestinal cancer patients.

Trastuzumab(Tmab), a humanized monoclonal antibody that selectively targets human epidermal growth factor receptor 2(HER2), is currently used in the clinical setting for the treatment of both breast and gastric cancer. While Tmab has shown improvements in patient prognoses, acquired resistance to this agent remains an issue. While some novel HER2-targeted agents have been approved for clinical use in breast cancer, no such agent has shown treatment efficacy for gastric malignancies with Tmab-resistance. Nanotechnology, which has progressed rapidly, has been applied to medical fields in recent years. Gold nanoparticles, which are characterized by their in vivo stability and ease of surface modification, have been reported to show efficacy as the carriers of therapeutic agents, such as drugs, antibodies, peptides, and nucleic acids. In this work, we developed Tmab-conjugated gold nanoparticles and demonstrate their efficacy for the treatment of HER2-positive, Tmabresistant gastric cancer cell lines. Our findings demonstrate that Tmab-conjugated gold nanoparticles have the potential to be a novelHER2 -targeted therapeutic agent.

Trastuzumab when combined with fluoropyrimidine and cisplatin was proven to improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) in the ToGA study. The safety and efficacy of trastuzumab in combination with docetaxel and S-1 have not yet been evaluated. This study was a multicenter, phase II study. Patients with chemotherapy-naive HER2-positive advanced or metastatic GC were eligible. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 and 6 mg/kg in subsequent cycles. Docetaxel was administered intravenously at 40 mg/m2 on day 1 of each cycle. S-1 was administered at a dosage based on body surface area for 14 days in a 3-weekly cycle. The primary endpoint was progression-free survival (PFS). A total of 23 patients were enrolled. Median PFS was 6.7 months (95% CI 4.1–10.1). The response rate (RR) was 39.1%. Median overall survival (OS) and time to treatment failure (TTF) were 17.5 and 4.4 months, respectively. Major grade 3–4 adverse events were neutropenia (39.1%), leukopenia (30.4%), and febrile neutropenia (8.7%). Trastuzumab in combination with docetaxel and S-1 showed effective antitumor activity and manageable toxicities as first-line treatment for patients with HER2-positive GC.

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. Thirty-three GTCs in 30 cases after TEC treated between 1997 and 2016 were investigated retrospectively. 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. 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.

Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40–50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.

A 70-year-old man who underwent gastrectomy for Stage III C gastric cancer developed lymph node(LN)metastasis posterior to the pancreatic head 3 years after the radical surgery.He was first treated with radiotherapy(RT)followed by chemotherapy.The irradiated tumor regressed completely.However, the cancer relapsed in a single para-aortic LN and he was treated with RT to the lesion followed by chemotherapy.Although it completely regressed, later, lung metastasis was observed.The lung lesions were well suppressed by switching to docetaxel; however, the cancer relapsed again in a mediastinal LN, and it was not responsive to docetaxel.The growing mediastinal lesion was irradiated again, which resulted in stable disease.The patient has been treated for 4 years and 7 months with all lesions being well-managed, and chemotherapy is being continued.Recurrent gastric cancer after surgery tends to present as multiple lesions; therefore, the principle therapy is systemic chemotherapy and RT is unlikely to be suitable.However, especially in cases of a solitary lesion that is chemo-resistant, RT could be an optimal option and contribute to long-term survival even in patients with recurrent gastric cancer.

A 63-year-old man underwent proximal gastrectomy for early gastric cancer(pT1bN0M0, pStage I A). Twenty months after surgery, abdominal CT scans revealed multiple liver metastases. S-1 plus CDDP therapy was administered as first-line chemotherapy. After treatment, CT scans revealed tumor progression and nab-PTX was administrated. This treatment was ineffective; therefore, CPT-11 was administrated as third-line chemotherapy. Treatment with CPT-11 resulted in marked tumor reduction and improved the QOL of the patient; partial response was maintained for 8 months. After 17 courses of CPT-11 treatment, tumor regrowth was detected, and the patient was treated with S-1 plus oxaliplatin, DTX, and ramucirumab. Subsequently, the patient died of cancer 31 months after tumor recurrence. CPT-11 is potentially a key drug for the prevention of liver metastasis of gastric cancer, and using all active agents in patients with advanced gastric cancer over several lines of therapy could prolong survival.

Background Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs. Methods We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan). Results Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial–mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer. Conclusions This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.