Search

Highlights • The authors developed a humanized anti-glypican-1 (GPC1) monoclonal antibody (clone T2) and produced an antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE). The ADC potently inhibited the growth of GPC1-positive pancreatic ductal adenocarcinoma and esophageal squamous cell carcinoma in vitro and in vivo, and exhibited bystander killing activity. Humanized GPC1-ADC(MMAE) was effective against BxPC-3-Luc#2 pancreatic cancer liver metastases in mice. Humanized GPC1-ADC(MMAE) may provide a promising therapeutic strategy for GPC1-positive tumors., An antibody-drug conjugate (ADC) is a promising therapeutic modality because selective and effective delivery of an anti-cancer drug is achieved by drug-conjugated antibody-targeting cancer antigen. Glypican 1 (GPC1) is highly expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC). Herein, we describe the usefulness of GPC1-targeting ADC. Humanized anti-GPC1 antibody (clone T2) was developed and conjugated with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC) linkers (humanized GPC1-ADC[MMAE]). Humanized GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC and ESCC cell lines via inducing cycle arrest in the G2/M phase and apoptosis in vitro. The binding activity of humanized GPC1-ADC(MMAE) with GPC1 was comparable with that of the unconjugated anti-GPC1 antibody. The humanized GPC1-ADC(MMAE) was effective in GPC1-positive BxPC-3 subcutaneously xenografted mice but not in GPC1-negative BxPC-3-GPC1-KO xenografted mice. To assess the bystander killing activity of the humanized GPC1-ADC(MMAE), a mixture of GPC1-positive BxPC-3 and GPC1-negative BxPC-3-GPC1-KO-Luc cells were subcutaneously inoculated, and a heterogenous GPC1-expressing tumor model was developed. The humanized GPC1-ADC(MMAE) inhibited the tumor growth and decreased the luciferase signal, measured with an in vivo imaging system (IVIS), which suggests that the suppression of the BxPC-3-GPC1-KO-Luc population. The humanized GPC1-ADC(MMAE) also inhibited the established liver metastases of BxPC-3 cells and significantly improved the overall survival of the mice. It exhibited a potent antitumor effect on the GPC1-positive PDAC and ESCC patient-derived xenograft (PDX) models. Our preclinical data demonstrate that GPC1 is a promising therapeutic target for ADC.

This study evaluated the prognostic value of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) together with host-related factors in patients with unresectable advanced gastric cancer. The study enrolled 262 patients who received chemotherapy for unresectable advanced gastric cancer at Kochi Medical School from 2007 to 2015. Clinicopathological information and systemic inflammatory response data were analyzed for associations between baseline cancer-related prognostic variables and survival outcomes. The median survival time was significantly lower for patients with high ALP, high LDH, high total bilirubin, high aspartate aminotransferase, high alanine transaminase, high gamma-glutamyltransferase, high creatinine, a Glasgow prognostic score (GPS) of 1 or 2 score compared to GPS 0, higher compared to lower neutrophil to lymphocyte ratio (NLR) 3.9, lower compared to higher prognostic nutrition index 36.1, T3–4 compared to T1–2 tumor and diffuse-type compared to intestinal-type histology. Multivariate survival analysis identified high ALP 322 (HR 1.808; 95% CI 1.015–3.220; P = 0.044), T2–3 (HR 2.622; 95% CI 1.224–5.618; P = 0.013), and diffuse-type gastric cancer (HR 2.325; 95% CI 1.341–4.032; P = 0.003) as significant independent predictors of worse prognosis in the studied group of cancer patients. High level of ALP is an independent, worse prognosis factor for patients receiving chemotherapy for unresectable and recurrent gastric cancer.

Background Although a recent randomized clinical trial has demonstrated that the objective response rate to nivolumab for metastatic gastric cancer was 11.2%, there was no patients confirmed complete response. Herein, we report on a case of liver metastasis arising from early gastric cancer in which a complete clinical response was achieved to nivolumab as third-line therapy. Case presentation A 77-year-old man was referred to Kochi Medical School Hospital for the treatment of liver metastases from gastric cancer. The patient had undergone laparoscopic total gastrectomy with regional lymph node dissection 30 months prior for early gastric cancer, with a final diagnosis of T1N0M0, stage IA. The patient developed solitary splenic metastasis measuring 42 mm 28 months later and underwent splenectomy because there was no evidence of further metastatic lesions in any other organ. The patient was treated with S-1 plus oxaliplatin based on negative immunohistochemical staining of the resected specimens for human epidermal growth factor receptor 2 (HER2). Four months after the splenectomy, the patient developed multiple liver metastases and was treated with ramucirumab plus paclitaxel. Because of disease progression, the patient was administered 3 mg/kg, i.v., nivolumab every 2 weeks. After 4 cycles of systemic treatment using nivolumab, abdominal computed tomography revealed marked shrinkage of the liver metastases. After 12 cycles of nivolumab, the liver metastases had disappeared completely. The patient did not develop any adverse reactions, including immune-reactive adverse events, during treatment. The patient continues to receive nivolumab, and there is no evidence of disease recurrence in the 8-month period since starting nivolumab. Conclusions To the best of our knowledge, this is the first case report in the English literature of a gastric cancer patient achieving a complete clinical response to nivolumab, and highlights the potential for successful treatment of metastatic gastric cancer using nivolumab.

The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials.

A case of early gastric cancer involving multiple submucosal gastric glands that was treated by distal gastrectomy was described in the present case report. An 85-year-old man was referred to our hospital for the treatment of gastric cancer. Esophagogastroduodenoscopy revealed an irregular, nodular, elevated lesion on the posterior wall of the middle third of the stomach, and biopsy specimens indicated well-differentiated tubular adenocarcinoma. Submucosal tumor (SMT)-like lesions were detected in the area adjacent to the nodular lesion, in the anterior wall side of the middle third of the stomach. Abdominal contrast-enhanced computed tomography showed cystic lesions in the middle part of the stomach, and no mass lesions in the liver. The patient underwent distal gastrectomy with regional lymphadenectomy. Macroscopic examination of the resected specimen showed an SMT-like lesion measuring 2.8×2.6 cm in contact with a superficial, depressed lesion measuring 1.7×0.9 mm in the middle third of the stomach, and another SMT-like lesion measuring 1.5×1.4 cm in diameter, which was also in the middle third of the stomach. The pathological diagnosis was well-differentiated tubular adenocarcinoma invading the gastric submucosal layer without lymph node metastasis, but with nearby submucosal heterotopic gastric gland (SHGG) detected. Following surgery, the patient remained symptom-free without evidence of recurrence for 3 months. The finding of SHGG remains a rare entity, and further studies are warranted to clarify the association between these submucosal lesions and the development of cancer.

A 50-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy(EGD)revealed an irregular nodular lesion with an ulcer in the esophagogastric junction, the biopsy specimens of which showed moderately differentiated adenocarcinoma. Abdominal computed tomography(CT)showed a lymph node measuring 1.2 cm in the perigastric area. A clinical diagnosis of advanced gastric cancer was made, and the patient underwent total gastrectomy with D2 lymphadenectomy followed by Roux-en-Y reconstruction. Microscopic examination confirmed that the moderately differentiated adenocarcinoma invaded the muscularis propria with 1 lymph node metastasis and lymphovascular invasion. The final diagnosis according to the Japanese classification of gastric carcinoma was UE, Less, Type 2, 3.8×1.7 cm, T2(MP), M0, H0, P0, N1(1/15), tub2, ly1, v2, StageⅡ. The postoperative course was uneventful, and he received postoperative adjuvant chemotherapy with S-1. The patient underwent periodic follow-up physical examinations, and 1 year after the surgery, CT showed a well-defined mass measuring 1.0 cm in diameter located in the middle lobe of the right lung. Because there was no evidence of further metastatic lesions in any other organs, he underwent surgical resection of the solitary pulmonary lesion by video-assisted thoracic surgery. Pathological examination confirmed the presence of moderately differentiated adenocarcinoma, and the proliferating tumor cells were positive for cytokeratin(CK)7 and CK20, and negative for thyroid transcription factor 1, which confirmed metastasis from gastric cancer. After the surgery, the patient received combination chemotherapy with S-1 plus cisplatin, followed by S-1 monotherapy. Five years after pulmonary metastasectomy, we discontinued chemotherapy because of no evidence of recurrence and the patient's wishes. The patient has remained in good health without evidence of recurrence for 7 years following the second surgery. Resection of the metastatic lesion might be a promising treatment for solitary pulmonary metastasis of gastric cancer; however, further investigations involving the accumulation of a large number of cases and prospective cohort studies are required to verify the above issue, and future development of multidisciplinary therapy is expected.

Background/Aim: One reason of poor survival rate of patients with pancreatic cancer is the development of chemoresistance. The aim of the present study was to investigate the effects of eribulin mesylate in gemcitabine-refractory advanced pancreatic cancer cell lines. Materials and Methods: Three human pancreatic cancer cell lines (AsPC-1, Panc-1, and SUIT-2) and human pancreatic endoderm (hPE) cells were used to evaluate the antitumor effects of gemcitabine and eribulin mesylate. Cell viability after treatment of cells with different concentrations of gemcitabine and eribulin mesylate was evaluated using water-soluble tetrazolium salts (WST) assays; cytotoxic effects were evaluated on the basis of morphological changes to cells. Results: Gemcitabine had no effect on cell viability of AsPC-1 nor Panc-1 cells, whereas gemcitabine reduced cell viability of SUIT-2 cells in a dose-dependent manner. Eribulin mesylate significantly reduced cell viability of both AsPC-1 and Panc-1 cells (p

The construction of a gastric substitute pouch after gastrectomy for gastric cancer has been proposed to help ameliorate postprandial symptoms and nutritional performance. Adequate reconstruction after gastrectomy is an important issue, because postoperative patient quality of life (QOL) primarily depends on the reconstruction method. To this end, jejunal pouch (JP) reconstructions were developed to improve the patient's eating capacity and QOL by creating large reservoirs with improved reflux barriers to prevent esophagitis and residual gastritis. It is important that such reconstructions also preserve blood and extrinsic neural integrity for maintaining pouch function, because JP motility is associated directly with QOL. Some problems remain to be resolved with the JP reconstructions method including gastrointestinal motility, which plays a major role in food transfer, digestion, and absorption of nutrients. Further studies including basic research and larger prospective randomized control trials are also needed to obtain definitive results. With persistent innovations in surgical techniques, JP after gastrectomy could become a safe and preferable reconstructive modality to improve patient QOL after gastrectomy.

The present study aimed to evaluate the efficacy and safety of trastuzumab plus chemotherapy for patients with unresectable advanced or recurrent gastric cancer. A retrospective analysis of 213 patients with unresectable advanced or recurrent gastric cancer who received systemic chemotherapy, including 15 patients who were also administered trastuzumab, at Kochi Medical School between 2007 and 2013 was performed. The overall survival was compared between patients who received trastuzumab plus chemotherapy and patients who received chemotherapy alone, and the safety and efficacy of the trastuzumab-containing regimen was evaluated. Human epidermal growth factor receptor (HER)2 status was examined in 86 patients, of whom 15 (17.4%) exhibited strong positive HER2 expression. The rate of strong positive HER2 expression was significantly higher for intestinal type tumors compared with diffuse type tumors [23.6 (13/55) vs. 6.5% (2/31); P=0.044]. The median overall survival of the patients treated with trastuzumab was significantly longer compared with that for patients who were not treated with trastuzumab (22.9 vs. 11.6 months; P=0.014). The objective response rate and disease control rate for trastuzumab plus chemotherapy were 46.7 and 86.7%, respectively. Frequently encountered grade 3-4 toxicities included neutropenia (26.7%; 4/15), anemia (13.3%; 2/15) and fatigue (13.3%; 2/15). Trastuzumab plus chemotherapy is effective for patients with HER2-positive advanced or recurrent gastric cancer, and the frequencies of hematological and non-hematological toxicities experienced by patients in the present study indicated that it can be safely administered clinically.

Herein we report on a case of two adenocarcinomas arising from an upside-down stomach in an elderly patient. An 83-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy showed two superficial depressed lesions in the stomach that were confirmed on biopsy as constituting a moderately differentiated tubular adenocarcinoma. CT and an upper gastrointestinal barium study revealed that the entire stomach and parts of the duodenum were located in the mediastinum. The patient underwent laparoscopy-assisted distal gastrectomy and regional lymph node dissection with Billroth I reconstruction, followed by reduction of the migrated stomach. The hiatal defect was closed by primary suturing of the right and left crura at the anterior space of the esophagus. The patient's postoperative course was good, and follow-up after discharge was uneventful. To the best of our knowledge, this is the first case report of multiple adenocarcinomas in an upside-down stomach treated by laparoscopy-assisted distal gastrectomy.

We report a case of intrahepatic bile duct adenoma (BDA) detected during laparoscopic distal gastrectomy for gastric cancer. A 70-year-old man was referred to our hospital for the treatment of gastric cancer. Esophagogastroduodenoscopy revealed an irregular, nodular, and elevated lesion on the greater curvature side of the middle third of the stomach. Abdominal contrast-enhanced computed tomography showed wall thickening with homogeneous enhancement in the middle part of the stomach, and no lesions in the liver. The patient underwent laparoscopic distal gastrectomy with regional lymphadenectomy, and during the operation a small whitish nodule was observed on the lateral segment of the liver surface. The lesion was excised by partial resection of the liver for the purpose of both histological diagnosis and treatment. Pathological examination of the liver lesion revealed no structural or cellular atypia, no stromal invasion, and immunohistochemical positivity for CK7 and CK19, but negativity for p53. The final diagnosis was well-differentiated adenocarcinoma invading the gastric serosal layer without lymph node metastasis, and intrahepatic BDA measuring 0.4 × 0.3 cm. Following surgery, the patient remained symptom-free without evidence of recurrence for 5 months. To the best of our knowledge, this is the first case of BDA with gastric cancer. Because it is difficult to distinguish BDA from other liver tumors including metastatic cancer due to its characteristically small size and lack of specific morphological features on standard imaging, surgical resection should be considered as the most suitable approach for both accurate diagnosis and treatment.

During the perioperative period, hyperglycemia is induced by surgical stress, which is the main risk factor for the development of postoperative infection associated with failure of neutrophil function, resulting in glucose toxicity. In elderly people with weakened immune systems, it is important to control perioperative hyperglycemia by maintaining sufficient nutrition administration. The artificial endocrine pancreas system allows strict glycemic control, which is beneficial in reducing glucose toxicity including postoperative infection not only in patients with diabetes mellitus or glucose intolerance but also in those who develop surgical diabetes during the perioperative period. Furthermore, it can contribute to the prevention of hypoglycemia and medical staff workload reduction. Therefore, the artificial pancreas is expected to come into widespread use in various fields involving glycemic control in patients.

The present case report presents a rare case of Epstein-Barr virus (EBV)-associated early gastric carcinoma with lymphoid stroma, accompanied by lymph node metastasis. A 61-year-old woman was referred to our hospital following observation of a gastric mass lesion that was initially diagnosed at a medical check-up. Esophagogastroduodenoscopy revealed a slightly elevated lesion with a central irregular depression in the middle third of the stomach. Endoscopic ultrasonography revealed a well-circumscribed hypoechoic mass located predominantly within the submucosa and the mucosa. Biopsy specimens of the lesion indicated the possibility of carcinoma with lymphoid stroma with a lymphoepithelial lesion. Abdominal contrast-enhanced computed tomography (CT) revealed a well-defined mass with homogeneous enhancement approximately 1.2 cm in diameter in the middle part of the stomach, demonstrating lymphadenopathy in the perigastric area at a maximum size of 1.4 cm in diameter. The patient underwent laparoscopic distal gastrectomy with regional lymphadenectomy due to suspicion of a gastric carcinoma with lymphoid stroma. Histopathological and immunohistochemical findings verified the diagnosis of carcinoma with lymphoid stroma, which were positive for EBV-encoded RNA (EBER-ISH) by in situ hybridization. There was one lymph node metastasis, which was in line with the CT imaging. Marked infiltration of lymphoid cells was observed in the tumor stroma, which were negative for EBER-ISH. The present case is informative of the pathological characteristics of this condition, and clinicians should recognize the features of this disease to make an accurate diagnosis and select the appropriate treatment.

A 76-year-old man was referred to our hospital with gastric cancer.Esophagogastroduodenoscopy (EGD)revealed an irregular, nodulated lesion with ulcers in the lower part of the stomach, for which biopsy specimens indicated poorly differentiated adenocarcinoma.Abdominal computed tomography(CT)showed a well-defined mass lesion measuring 5.3 cm in the posterior segment of the liver.Under the clinical diagnosis of advanced gastric cancer with liver metastasis, the patient received chemotherapy using S-1 and oxaliplatin.After 8 courses of chemotherapy, abdominal CT and EGD revealed that the size of liver metastasis was reduced to 2.3 cm. He underwent distal gastrectomy with D2 lymphadenectomy and resection of the liver metastases because there was no evidence of further metastatic lesions in any other organs after 10 courses of chemotherapy.The gross appearance of the surgically resected specimen showed a shrunk gastric tumor measuring 3.5×3.0 cm and a well-circumscribed, solid liver mass.Pathological examination confirmed the diagnosis of solid-type, poorly differentiated adenocarcinoma in the stomach that had invaded the submucosal layer with no lymph node metastasis, and necrotic change of the liver mass.The postoperative course was uneventful, and the patient has been well, receiving maintenance chemotherapy using S-1, without evidence of recurrence for 9 months following the operation.Conversion surgery following chemotherapy might be a proposed treatment for patients with advanced gastric cancer; however, further studies and assessments are needed to establish this treatment strategy.

The aim of the present study was to analyze the clinicopathologic features and treatment outcomes of gastric metastasis from other malignancies of solid organs. A review was conducted of patients with metastatic tumors in the stomach from other malignancies of solid organs detected endoscopically at the Department of Surgery, Kochi Medical School, from January 1991 to December 2015. Seven patients (four men and three women), with a median age of 64 years (range, 42-71 years), had metastatic gastric tumors. Median tumor size was 7.3 cm (range, 2.5-12.0 cm). The primary malignancy leading to metastatic tumors in the stomach was esophageal cancer in three patients, breast cancer in two patients, renal cell carcinoma in one patient, and ovarian cancer in one patient. Gastric metastasis presented as solitary lesions in six patients and as multiple lesions in one patient. Four patients had solitary gastric metastasis, whereas three had multiple metastases in other organs. The median tumor size was significantly smaller in patients with solitary rather than multiple metastases (4.6 vs. 12.0 cm, respectively; P=0.038). Three patients received systemic therapy and four underwent surgical resection of the metastatic tumor, and of these, only one was alive 58 months after surgery. Clinicians should be aware of the possible existence of metastatic gastric cancer, especially in breast carcinoma and esophageal cancer. Surgical resection may considerably improve patients' quality of life, and could be of benefit when there is a risk of bleeding and/or a solitary metastasis.

We herein report a rare case of superficially spreading early gastric cancer occurring 50 years after gastrojejunostomy. An 83-year-old woman was diagnosed with gastric cancer after complaining of epigastric discomfort. The patient had undergone gastrojejunostomy with Braun jejunojejunostomy for benign chronic peptic ulcer 50 years prior. Esophagogastroduodenoscopy revealed an irregular nodular lesion on the gastric side of the anastomosis of the gastrojejunostomy. No abnormal lesions were identified by abdominal contrast-enhanced computed tomography. The patient underwent distal gastrectomy with regional lymphadenectomy. The final diagnosis was signet ring cell carcinoma invading the gastric submucosal layer, without lymph node metastasis, located in the area surrounding the original gastrojejunostomy and measuring 9.5×4.5 cm. In addition, dilated cystic glands were found in the submucosal layer, indicating gastritis cystica profunda. Following surgery, the patient remained symptom-free without evidence of recurrence for 46 months. Although it is not clear whether the adenocarcinoma at the stomal site was associated with the superficial spreading-type tumor in the present case, the observations may provide clues as to the pathogenic process of this entity.

We evaluated the diagnostic and prognostic value of three tumor markers: carcino-embryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125), in the pretreatment serum of patients with unresectable advanced or recurrent gastric cancer. The subjects of this retrospective analysis were 245 patients with unresectable advanced or recurrent gastric cancer diagnosed at Kochi Medical School between 2007 and 2015. We ascertained the sensitivity of CEA, CA19-9, and CA125 to identify a certain survival time and then evaluated the relative prognosis of the patients. The overall positive rates for each tumor marker in the study group were as follows: 57.6% (141/245) for CEA, 38.4% (94/245) for CA19-9, and 34.3% (84/245) for CA125; the sensitivity of these three biomarkers in combination was 73.1% (179/245). The median survival time of the CA125-positive patients was 4.5 months, which was significantly shorter than that of a normal range group (18.3 months, P

A 34-year-old woman underwent total gastrectomy with D2 lymphadenectomy for gastric cancer, and the final diagnosis was T4N3M0, Stage III C, R0. Bilateral ovarian metastases were identified 51 months later, which were removed, and the patient received S-1 plus CDDP chemotherapy. Because the patient developed pubic bone metastasis 16 months after the second operation, we continued chemotherapy using paclitaxel with bisphosphonate. The patient was alive 70 months after the initial operation. The second patient was a 55-year-old woman who underwent total gastrectomy with D2 lymphadenectomy and was diagnosed with T2N2M0, Stage III A gastric cancer. Bilateral ovarian metastases were identified 72 months later, which were removed, and the patient received S-1 plus CDDP chemotherapy. The patient is alive with no signs of disease recurrence 96 months after the initial operation. For patients with ovarian metastases from gastric cancer, surgical resection in addition to chemotherapy might be an effective treatment. However, further studies and assessments of additional cases are needed to confirm the ideal treatment for this condition.

An 82-year-old woman had visited her local clinic with a history of abdominal discomfort and dyspepsia related to meals over a period of several months. Esophagogastroduodenoscopy revealed a superficial spreading tumor that, on biopsy, was proven to be an adenocarcinoma, and colonoscopy revealed an ascending mass that was found to be an adenocarcinoma on biopsy, so the patient was referred to our hospital. Abdominal computed tomography revealed a mass in the ascending colon with regional lymph node swelling and a gallbladder stone measuring 1.5 cm in diameter. The patient underwent laparoscopy-assisted distal gastrectomy with cholecystectomy and right colectomy with regional lymph node dissection, resulting in a diagnosis of poorly differentiated adenocarcinoma invading the gastric submucosal layer and moderately differentiated tubular adenocarcinoma invading the colonic serosa with lymph node metastasis. Macroscopic examination of the gallbladder revealed a well-circumscribed, solid tumor measuring 0.3 x 0.3 cm with a firm consistency in the neck portion associated with lithiasis. Microscopic examination of the gallbladder tumor revealed infiltration of spindle-shaped neoplastic cells that were arranged in a fasciculated and woven pattern in abundant intersecting bundles. Immunohistochemical analyses were positive for S-100 protein and neurofilament. Although neurofibromas commonly occur in the superficial skin or subcutaneous region, isolated neurofibroma of the gallbladder is quite rare. To the best of our knowledge, this is only the 11th case of a neurofibroma of the gallbladder to be reported in English literature. In the present case, as in most previously reported cases, the tumor was found incidentally in the resected gallbladder following cholecystectomy for cholecystolithiasis.

INTRODUCTION: Cancer stem-like cells are thought to be one of the causes of cancer initiation and progression. They are associated with the resistance to radiotherapy and chemotherapy for various types of tumor including esophageal squamous cell carcinoma (ESCC). Therefore, cancer stem-like cells are promising therapeutic targets of cancer. Suppressor of cytokine signaling-1 (SOCS-1) was identified as a negative regulator of various cytokine signaling. We have previously demonstrated that overexpression of SOCS-1 showed a potent anti-tumor effect on ESCC through inhibiting of the JAK/STAT signaling pathway. This study aimed to evaluate the anti-tumor effect of SOCS-1 gene therapy using adenoviral vector (AdSOCS-1) against cancer stem-like cells in ESCC. METHODS: ESCC cell lines were separated into aldehyde dehydrogenase (ALDH) positive and ALDH negative cells by ALDEFLOUR, and then sphere formation assays were performed. The inhibitory effects of AdSOCS-1 and AdLacZ on the sphere formation were evaluated using TE8, TE14 ESCC cell lines. The inhibition of sphere formation was also evaluated using ESCC cells obtained from ESCC PDX mice (ESCC8). Next, the expression of transcription factors associated with cancer stem-like cells in ESCC was evaluated by RT-PCR. The inhibitory effects on tumor formation by AdSOCS-1 were evaluated by tumorigenicity assay using TE8 xenograft mice. RESULTS: In the sphere formation assay, ALDH positive TE8 cells and TE14 cells represented strong sphere formation capacity. Compared with AdLacZ infected ALDH positive cells, sphere formation of AdSOCS-1 infected ALDH positive cells was significantly inhibited. The inhibition of sphere formation was also confirmed in ESCC cells obtained from ESCC8 PDX mouse tumor tissue. Interestingly, the expression level of Sox2, a critical stem cell factor regulated by STAT3, was also decreased by AdSOCS-1. Furthermore, AdSOCS-1 decreased the tumorigenic activity of the ALDH positive ESCC tumor cells. CONCLUSIONS: A potent anti-tumor effect of SOCS-1 gene therapy on ESCC may be partially explained by inhibiting the expression of a STAT3 regulated transcription factor critical for cancer stem-like cells. Citation Format: Ayumi Yamamoto, Eri Munekage, Satoshi Serada, Shigehiro Tsujii, Kosuke Hiramatsu, Minoru Fujimoto, Kazuhiro Hanazaki, Tetsuji Naka. Inhibition of cancer stem-like cells in esophageal squamous cell carcinoma with SOCS-1 gene therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5309.

A closed-loop glycemic control system using an artificial pancreas has been applied with many clinical benefits in Japan since 1987. To update this system incorporating user-friendly features, we developed a novel artificial pancreas (STG-55). The purpose of this study was to evaluate STG-55 for device usability, performance of blood glucose measurement, glycemic control characteristics in vivo in animal experiments, and evaluate its clinical feasibility. There are several features for usability improvement based on the design concepts, such as compactness, display monitor, batteries, guidance function, and reduction of the preparation time. All animal study data were compared with a clinically available artificial pancreas system in Japan (control device: STG-22). We examined correlations of both blood glucose levels between two groups (STG-55 vs. control) using Clarke's error grid analysis, and also compared mean glucose infusion rate (GIR) during glucose clamp. The results showed strong correlation in blood glucose concentrations (Pearson's product-moment correlation coefficient: 0.97; n = 1636). Clarke's error grid analysis showed that 98.4% of the data fell in Zones A and B, which represent clinically accurate or benign errors, respectively. The difference in mean GIRs was less than 0.2 mg/kg/min, which was considered not significant. Clinical feasibility study demonstrated sufficient glycemic control maintaining target glucose range between 80 and 110 (mg/dL), and between 140 and 160 without any hypoglycemia. In conclusion, STG-55 was a clinically acceptable artificial pancreas with improved interface and usability. A closed-loop glycemic control system with STG-55 would be a useful tool for surgical and critical patients in intensive care units, as well as diabetic patients.

A 64-year-old man underwent abdominal computed tomography (CT) as periodic follow-up following a distal gastrectomy with lymphadenectomy for gastric cancer and mucosal-associated lymphoid tissue (MALT) lymphoma conducted 31 months earlier. Contrast-enhanced CT demonstrated a well-circumscribed mass lesion with heterogeneous density measuring 2.2 cm in diameter located between the second segment of the duodenum and uncinate process of the pancreas. Esophagogastroduodenoscopy revealed no remarkable findings in the remnant stomach; however, the scope could not reach the duodenum due to altered anatomy by Roux-en-Y reconstruction after the distal gastrectomy. The patient underwent surgical resection of the mass lesion under the clinical diagnosis of MALT lymphoma relapse. An orange calculus was apparent in the thinly extended duodenal wall on stretching, and the hall was closed by meticulous primary suture after the duodenal resection. Macroscopically, the extracted calculus was solid and quite hard, measured 2.2 × 2.1 × 2.1 cm, and the cut surface revealed a layered structure in the outer areas with granulated contents in the center. Although duodenal diverticula are relatively common, an enterolith developing within a juxtapapillary duodenal diverticulum is rare, and to the best of our knowledge, this is the first such case due to altered anatomy after gastrectomy reported in the English literature.

AIM To investigate the factors associated with weight loss (WL) after esophagectomy for esophageal cancer. PATIENTS AND METHODS We retrospectively reviewed 136 patients who underwent esophagectomy for esophageal cancer. Preoperative characteristics, surgical methods, postoperative outcomes and weight changes at 6 months after surgery were analyzed. RESULTS Seventy-eight patients had more than 10% WL compared to their weight at surgery. On univariate analysis, higher body mass index [(BMI): ≥20.8; p=0.012] and shorter length of hospitalization [(LOH); p=0.041] demonstrated an association with more than 10% WL. On multivariate analysis, higher BMI [odds ratio (OR)=2.821; 95% confidence interval (CI)=1.238-6.426; p=0.014] and shorter LOH (OR=2.953; 95% CI=1.009-8.646; p=0.048) were independently associated with more than 10% WL. CONCLUSION Higher BMI and shorter LOH were unfavorable risk factors for WL after esophagectomy for esophageal cancer.

Herein we report on a case of synchronous large gastrointestinal stromal tumor (GIST) and adenocarcinoma of the stomach treated with radical surgery following neoadjuvant therapy with imatinib mesylate. A 58-year-old man was referred to our hospital with a large mass in the peritoneal cavity. Abdominal computed tomography showed a large mass measuring 21×20×14 cm in the left upper peritoneal cavity. Esophagogastroduodenoscopy revealed a large elevated lesion in the upper body and a depressed lesion in the lower gastric body near the lesser curvature. Biopsy specimens revealed GIST in the large elevated lesion and signet-ring cell carcinoma in the depressed lesion. Because of the large size of the GIST, the patient was treated with neoadjuvant therapy with imatinib mesylate (400 mg/day) for 5 months. After confirmation of a marked decrease in tumor size following imatinib mesylate therapy, the patient underwent total gastrectomy and regional lymph-node dissection with distal pancreatectomy and splenectomy. Pathological examination confirmed the diagnosis of high-risk GIST and signet-ring cell carcinoma invading the muscularis propria with one lymph-node metastasis. At the time of writing, the patient was receiving postoperative chemotherapy using oral fluoropyrimidine (S-1) without evidence of disease recurrence for 4 months after surgery. In addition to the present case, we provide a retrospective review of another 15 patients who were diagnosed with synchronous GIST in the stomach and primary gastric adenocarcinoma.

This study aimed to evaluate the efficacy of protein-bound polysaccharide K (PSK)-containing chemotherapy in patients with unresectable advanced or recurrent gastric cancer (AGC). We retrospectively analyzed 190 patients with AGC who received systemic chemotherapy including 69 patients who were treated with a PSK-containing regimen. Using propensity score matching, we obtained 62 matched patients in the S-1 and S-1 plus PSK groups for outcomes analysis. There was a tendency for overall survival to be higher in the S-1 plus PSK group than in the S-1 alone group. In particular, there was a tendency for overall survival in the S-1 plus PSK group to be higher in patients with a neutrophil/lymphocyte ratio (NLR)2.2 than in patients with a NLR2.2. There was a tendency for fewer changes in the NLR after the beginning of treatment in the S-1 plus PSK group than in the S-1 alone group. PSK-containing chemotherapy may contribute to improved treatment outcomes of AGC patients. In particular, it may be effective in patients with a high NLR. Further investigations, including a prospective randomized controlled trial, are expected to verify the mechanisms of interaction between cancer cells and the immunoreaction.

The incidence of diabetes is increasing at an unprecedented pace and has become a serious health concern worldwide during the last two decades. Despite this, adequate glycemic control using an artificial pancreas has not been established, although the 21st century has seen rapid developments in this area. Herein, we review current topics in glycemic control for both the wearable artificial pancreas for type 1 and type 2 diabetic patients and the bedside artificial pancreas for surgical diabetic patients. In type 1 diabetic patients, nocturnal hypoglycemia associated with insulin therapy remains a serious problem that could be addressed by the recent development of a wearable artificial pancreas. This smart phone-like device, comprising a real-time, continuous glucose monitoring system and insulin pump system, could potentially significantly reduce nocturnal hypoglycemia compared with conventional glycemic control. Of particular interest in this space are the recent inventions of a low-glucose suspend feature in the portable systems that automatically stops insulin delivery 2 h following a glucose sensor value

A 59-year-old man was referred to the Kochi Medical School Hospital due to left shoulder pain. Physical examination revealed a nodular, painful mass lesion in the subcutaneous tissue of the right chest wall, with a diameter of ~2 cm. Esophagogastroduodenoscopy revealed a large ulcerated tumor in the lower gastric body near the lesser curvature, and biopsy specimens of the gastric and humeral lesions revealed poorly differentiated adenocarcinoma. Abdominal computed tomography revealed multiple low-density lesions in the liver and a well-defined, 2.2-cm mass in the subcutaneous tissue of the right chest wall. The diagnosis was advanced gastric cancer with metastases to the liver, bone and skin, and systemic chemotherapy with radiotherapy for the bone metastasis was recommended. The patient also underwent distal gastrectomy to control bleeding from the primary gastric cancer lesion due to unresolved anemia, not improving by blood transfusion, and a low hemoglobin level. The subcutaneous tumor in the right chest wall was resected at the same time, to alleviate the pain caused by the mass. Macroscopic examination of the resected specimen revealed a well-circumscribed, solid tumor, measuring 2.2×2.1 cm, with a firm consistency. Microscopic examination showed infiltration of poorly differentiated adenocarcinoma cells into the subcutaneous tissue. Subcutaneous metastasis from gastric cancer is a rare manifestation, with a reported incidence of 0.8–1.0%. Cutaneous metastasis of cancer generally appears late in the course of the disease. Surgical resection of metastatic skin tumors is occasionally undertaken as palliative treatment to improve the patient's quality of life by controlling severe symptoms, including pain and hemorrhage.

Herein we report on a case of two adenocarcinomas arising from an upside-down stomach in an elderly patient. An 83-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy showed two superficial depressed lesions in the stomach that were confirmed on biopsy as constituting a moderately differentiated tubular adenocarcinoma. CT and an upper gastrointestinal barium study revealed that the entire stomach and parts of the duodenum were located in the mediastinum. The patient underwent laparoscopy-assisted distal gastrectomy and regional lymph node dissection with Billroth I reconstruction, followed by reduction of the migrated stomach. The hiatal defect was closed by primary suturing of the right and left crura at the anterior space of the esophagus. The patient's postoperative course was good, and follow-up after discharge was uneventful. To the best of our knowledge, this is the first case report of multiple adenocarcinomas in an upside-down stomach treated by laparoscopy-assisted distal gastrectomy.

A 61 -year-old man underwent total gastrectomy with distal pancreatectomy and D2 lymphadenectomy for gastric cancer. The final diagnosis was UM, Post-Gre-Less, Type 3, 12 × 9 cm, T4b (SI), N3b (31/99), H0, P0, CY0, M0, tub2, ly3, v3, Stage IIIC, R0. Fifteen months after the operation, abdominal computed tomography showed a left adrenal tumor measuring 2.5 cm in diameter. Because it was a solitary tumor, we performed tumor resection, confirming adrenal metastasis that was negative for human epidermal growth factor receptor type 2 (HER2). Subsequently, the patient was treated with a chemotherapy regimen consisting of S-1 plus cisplatin. Because he developed left adrenal metastasis 6 months after tumor resection, we initiated chemotherapy with docetaxel plus irinotecan. Left adrenalectomy was performed owing to the tumor increasing to 3.6 cm despite chemotherapy. The patient is currently alive 50 months after the initial operation, without any signs of disease recurrence. For patients with solitary adrenal metastasis from gastric cancer, surgical resection in addition to chemotherapy might be the preferred choice of treatment.

The present study evaluated the efficacy of lafutidine, a histamine H2 receptor antagonist, for reducing gastrointestinal toxicities during adjuvant chemotherapy using oral fluorouracil anticancer drugs for gastric cancer.Patients with stage II (T1 cases excluded) or stage III gastric adenocarcinoma who underwent gastrectomy with D2 lymphadenectomy achieving R0 resection from 2011 to 2013 were prospectively enrolled in the study. Patients were randomly assigned to either S-1 treatment or S-1 plus lafutidine treatment. Quality of life and gastrointestinal toxicity were evaluated before chemotherapy and at 2, 4, and 6 weeks after the beginning of treatment.The incidence of diarrhea during chemotherapy was significantly lower in the S-1 plus lafutidine group than in the group treated with S-1 alone (10% vs. 83%, respectively; p=0.002). The grades of diarrhea and nausea during chemotherapy were also significantly lower compared to those before chemotherapy in patients receiving S-1 plus lafutidine than in those administered S-1 alone. The rate of patients requiring a dose reduction or interruption of S-1 was significantly lower in the S-1 plus lafutidine group than in the group treated with S-1 alone (30% vs. 83%, respectively; p=0.027).Lafutidine might be useful not only for preventing gastrointestinal toxicities during adjuvant chemotherapy for gastric cancer, but also for improving compliance with taking oral fluorouracil anticancer drugs. However, this indication needs to be confirmed in a larger, prospective, randomized, controlled trial.

Synchronous primary gastric adenocarcinoma and lymphoma is a rare occurrence. The aim of the present retrospective study was to analyze the clinicopathological characteristics and therapeutic outcomes of patients with this rare condition to identify post-therapeutic prognostic factors.A PubMed and MEDLINE search was performed to identify relevant articles, using the keywords 'gastric cancer' and 'gastric malignant lymphoma', while additional articles were obtained from references within these papers. A total of 57 patients who were treated for synchronous primary gastric adenocarcinoma and lymphoma were included in the study. A retrospective review was performed on the clinical characteristics of this disease.The median survival time for patients in this study was 81 months and the overall 1- and 5-year survival rates after therapy were 77.6% and 69.0%, respectively. The median survival period of patients with an advanced gastric cancer was significantly shorter than for early gastric cancer (p0.001), while the depth of gastric lymphoma invasion did not significantly affect survival time. The median survival period of patients who underwent total gastrectomy was significantly shorter than that of those who underwent distal gastrectomy (p=0.035). Gastric lymphomas were significantly larger than the gastric adenocarcinomas (6.0 vs. 2.7 cm, respectively; p=0.012).The prognosis for synchronous gastric adenocarcinoma and lymphoma might depend more on the behavior of the adenocarcinoma than on the lymphoma, in which case the treatment and therapeutic outcomes could depend on the adenocarcinoma status.

In the present study, we aimed to evaluate the efficacy and safety of trastuzumab-containing regimens in patients with unresectable advanced or recurrent gastric cancer( AGC). We retrospectively analyzed 142 patients with AGC who received systemic chemotherapy, including 10 patients treated with trastuzumab-containing regimens. Among the 72 patients, 12 (16.7)% were human epidermal growth factor receptor 2 (HER2)-positive; the HER2-positive rate was significantly greater in patients with intestinal-type than diffuse-type histology( 29.0 vs 7.3%; p=0.014). The median overall survival of patients treated with trastuzumab was significantly longer than that of patients treated without trastuzumab( 22.9 vs 11.6 months; p =0.014). Seven patients continued receiving trastuzumab therapy after disease progression, and 6 patients were treated with trastuzumab after initial chemotherapy. The objective response rate of trastuzumab-containing regimens was 40%. The frequency of hematological and non-hematological toxicities was feasible. The administration of trastuzumab therapy after disease progression may contribute to improved treatment outcomes. However, further investigations, including prospective randomized controlled trials, are needed to verify this finding.

A closed-loop glycemic control system using an artificial pancreas has been applied with many clinical benefits in Japan since 1987. To update this system incorporating user-friendly features, we developed a novel artificial pancreas (STG-55). The purpose of this study was to evaluate STG-55 for device usability, performance of blood glucose measurement, glycemic control characteristics in vivo in animal experiments, and evaluate its clinical feasibility. There are several features for usability improvement based on the design concepts, such as compactness, display monitor, batteries, guidance function, and reduction of the preparation time. All animal study data were compared with a clinically available artificial pancreas system in Japan (control device: STG-22). We examined correlations of both blood glucose levels between two groups (STG-55 vs. control) using Clarke's error grid analysis, and also compared mean glucose infusion rate (GIR) during glucose clamp. The results showed strong correlation in blood glucose concentrations (Pearson's product-moment correlation coefficient: 0.97; n = 1636). Clarke's error grid analysis showed that 98.4% of the data fell in Zones A and B, which represent clinically accurate or benign errors, respectively. The difference in mean GIRs was less than 0.2 mg/kg/min, which was considered not significant. Clinical feasibility study demonstrated sufficient glycemic control maintaining target glucose range between 80 and 110 (mg/dL), and between 140 and 160 without any hypoglycemia. In conclusion, STG-55 was a clinically acceptable artificial pancreas with improved interface and usability. A closed-loop glycemic control system with STG-55 would be a useful tool for surgical and critical patients in intensive care units, as well as diabetic patients.

It is reported that shortage of oral magnesium intake increase the incidence of diabetes. In addition, magnesium replacement therapy improves insulin resistance and glycemic control. Low levels of magnesium in the venous blood induce the disturbances of auto-phosphylation on the insulin receptor and deteriorate insulin resistance. Since magnesium is closely related to evolution and development of metabolic syndrome including diabetes mellitus and so on, magnesium is expected as potentially effective ingredient of drug therapy in the future perspectives.

An asymptomatic 72-year-old man underwent a screening esophagogastroduodenoscopy (EGD) at our hospital. The EGD showed a sessile polypoid lesion with a smooth surface in the greater curvature of the gastric antrum, which was diagnosed as a submucosal tumor (●" Fig.1a). A second slightly elevated lesion with a shallow depression was observed in the greater curvature of the lower gastric body near the polypoid lesion (●" Fig.1b). This was confirmed on biopsy to be a well-differentiated tubular adenocarcinoma. The borders of this lesion became distinct when indigo carmine dye was used in a chromoendoscopy (●" Fig.1c). Abdominal contrast-enhanced computed tomography (CT) revealed a well-circumscribed, low-density mass in the wall of the gastric antrum (●" Fig.2). The patient underwent endoscopic submucosal dissection (ESD) for the gastric cancer (●" Fig.3). Histological examination confirmed the presence of a well-differentiated tubular adenocarcinoma with dimensions of 17×15mm that was confined to the gastric mucosal layer without lymphatic and venous infiltration. Subsequently, partial resection of the stomach was carried out for the submucosal tumor. Gross and histological examination of the resected specimen revealed a well-circumscribed, encapsulated lipoma measuring 8.5×5.5cm (●" Fig.4). Follow-up after discharge was uneventful. After 8 months, there had been no evidence of metastasis. The stomach is a rare location for lipomas; only a few cases of gastric lipoma associated with early gastric cancer have been previously reported [1–3]. Interestingly, as in this case, the gastric cancer and the lipoma were also located very close to each other in the three previous cases, suggesting that these were concomitant tumors. Although lipomas are benign tumors, they can cause gastrointestinal bleeding, intussusception, and obstruction. Therefore minimally invasive therapy with ESD for early gastric cancer and partial gastric resection for large lipomas should be considered. Clinicians should examine patients with gastric tumors carefully, bearing in mind the possibility of synchronous tumors, as demonstrated by this case and the previous cases.