細谷 好則

BACKGROUND: Intraperitoneal (IP) administration of paclitaxel (PTX) has a great pharmacokinetic advantage to control peritoneal lesions and can be combined with various systemic chemotherapies. In this study, we evaluate the efficacy and tolerability of a combination of IP-PTX and systemic S-1/oxaliplatin (SOX) for induction chemotherapy for patients with peritoneal metastases (PM) from gastric cancer (GC). PATIENTS AND METHODS: Patients with GC who were diagnosed as macroscopic PM (P1) or positive peritoneal cytology (CY1) by staging laparoscopy between 2016 and 2019 were enrolled. PTX was IP administered at 40 mg/m2 on days 1 and 8. Oxaliplatin was IV administered at 100 mg/m2 on day 1, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, repeated every 21 days. Survival time and toxicities were retrospectively explored. RESULTS: Forty-four patients received SOX + IP-PTX with a median (range) of 16 (1-48) courses, although oxaliplatin was suspended due to the hematotoxicity or intolerable peripheral neuropathy in many patients. The 1-year overall survival (OS) rate was 79.5% (95% CI 64.4-88.8%) with median survival time of 25.8 months. Gastrectomy was performed in 20 (45%) patients who showed macroscopic shrinkage of PM with a 1-year OS rate of 100% (95% CI 69.5-100%). Grade 2 and 3 histological responses was achieved in four (20%) and one (5%) patients. Grade 3/4 toxicities included neutropenia (11%), leukopenia (39%), and anemia (14%). There were no treatment-related deaths. CONCLUSIONS: Combination chemotherapy using SOX + IP-PTX regimen is highly effective and recommended as induction chemotherapy for patients with PM from GC.

BACKGROUND: Repeat intraperitoneal (IP) chemotherapy has been successfully used for treatment of peritoneal metastases (PM) from gastric cancer (GC). Exosomes play important roles not only in tumor progression but also in chemoresistance via transfer of microRNAs (miRNAs). However, there is little evidence of an effect of miRNAs in peritoneal exosomes on chemosensitivity of peritoneal lesions. METHODS: In 74 patients with advanced GC who underwent staging laparoscopy, exosomes were isolated from peritoneal fluid and expression levels of miR-21-5p, miR-223-3p, and miR-29b-3p determined using TaqMan Advanced miRNA assays. In 43 patients with PM treated with combination chemotherapy, S-1 plus Oxaliplatin together with IP Paclitaxel, the relationship between their relative expression levels and outcomes was examined. RESULTS: The ratios of miR-21-5p/miR-29b-3p and miR-223-3p/miR-29b-3p were significantly upregulated in patients with PM, especially in patients with high serum CA125 levels. They showed a mild association with Peritoneal Cancer Index (PCI) score and ascites. More impressively, the ratios were significantly higher in 16 patients with progression of PM within 1 year compared with 27 patients with an excellent tumor response (miR-21-5p/miR-29b-3p: median 17.49, range 1.83-50.90 vs. median 4.64, range 0.40-38.96, p = 0.0015, miR-223-3p/miR-29b-3p: median 1.02, range 0.23-25.85 vs. median 0.21, range 0.01-50.07, p = 0.0006). Overall survival of patients with high miR-21/miR-29b or miR-223/miR-29b ratios was significantly worse than in patients with low ratios (p = 0.0117, p = 0.0021). CONCLUSIONS: The ratios of miRNAs in peritoneal exosome correlate with survival of the patients with PM from GC and suggest the possibility that they modify the chemosensitivity against IP chemotherapy.

Traumatic injury to the main pancreatic duct requires surgical treatment, but optimal management strategies have not been established. In patients with isolated pancreatic injury, the pancreatic parenchyma must be preserved to maintain long-term quality of life. We herein report a case of traumatic pancreatic injury with main pancreatic duct injury in the head of the pancreas. Two years later, the patient underwent a side-to-side anastomosis between the distal pancreatic duct and the jejunum. Eleven years later, he presented with abdominal pain and severe gastrointestinal bleeding from the Roux limb. Emergency surgery was performed with resection of the Roux limb along with central pancreatectomy. We attempted to preserve both portions of the remaining pancreas, including the injured pancreas head. We considered the pancreatic fluid outflow tract from the distal pancreatic head and performed primary reconstruction with a double pancreaticogastrostomy to avoid recurrent gastrointestinal bleeding. The double pancreaticogastrostomy allowed preservation of the injured pancreatic head considering the distal pancreatic fluid outflow from the pancreatic head and required no anastomoses to the small intestine.

INTRODUCTION: We previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene Dbp and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor (Ppar)-γ and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity. RESEARCH DESIGN AND METHODS: The present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2). RESULTS: Acetylation of histone H3K9 at the promoter region of Dbp and DBP mRNA expression in omental, but not in mesenteric adipose tissue were significantly lower in DM2 than in patients without DM. PPAR-γ mRNA expression in omental adipose tissue was also lower in patients with DM2, but not in mesenteric adipose tissue. CONCLUSIONS: The changes in DBP-PPAR-γ axis observed in mice with diabetes were also detected in patients with DM2. Because adiponectin secretion is reported to be enhanced through the PPAR-γ-related mechanism, this study supports the hypothesis that omental adipose tissue is involved in the mechanism of DM2.

BACKGROUND: Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule. METHOD: We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue. RESULTS: LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. Subcutaneous (sc) transfer of LuM-1 in Balb/c mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (4Gyx3) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 μg × 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-γ production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome. CONCLUSION: These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.

The peritoneal surface is the most frequent site of metastasis disease in patients with gastric cancer. Even after curative surgery and adjuvant chemotherapy, peritoneal recurrences often develop. Exosomes play pivotal roles in tumor metastasis via the transfer of microRNAs (miRNAs). In the present study, exosomes were isolated from peritoneal lavage fluid or ascites in 85 patients with gastric cancer and the relative expression levels of miR‑29s were examined. The expression of miR‑29a‑3p, miR‑29b‑3p and miR‑29c‑3p in peritoneal exosomes were all downregulated in patients with peritoneal metastases (PM) compared to those without PM. In 30 patients who underwent curative gastrectomy with serosa‑involved (T4) gastric cancer, 6 patients exhibited recurrence in the peritoneum within 12 months. The expression levels of miR‑29s at gastrectomy tended to be lower in these 6 patients than in the other 24 patients with significant differences in miR‑29b‑3p (P=0.003). When the patients were divided into two groups based on median levels of miR‑29s, peritoneal recurrence developed more frequently in patients with low expression of miR‑29b‑3p, and lower expression of miR‑29s were related with worse overall survival. miR‑29s are thought to play a suppressive role in the growth of disseminated peritoneal tumor cells. Reduced expression of miR‑29b in peritoneal exosomes is a strong risk factor of developing postoperative peritoneal recurrence.

BACKGROUND: Despite recent progress in systemic chemotherapy, the prognosis of patients with peritoneal metastases from gastric cancer is still poor. Efficacious intraperitoneal and systemic combination chemotherapy regimens to treat patients with peritoneal metastases have recently been developed. CASE PRESENTATION: A 74-year-old man with gastric cancer T4b (transverse mesocolon) N3 M1 (peritoneum) received combination chemotherapy with intraperitoneal administration of paclitaxel, intravenous oxaliplatin, and oral S-1. Eight courses of combined chemotherapy had remarkable anti-tumor effects on the primary lesion, lymph node metastases, and peritoneal metastases. Total gastrectomy with regional lymph node dissection was performed. Pathological examination revealed no viable tumor cells in the resected specimens. After gastrectomy, the patient received 25 courses of the same chemotherapy without oxaliplatin and has no evidence of recurrence 24 months later. DISCUSSION: Therapeutic approaches including systemic chemotherapy, extended resection, and heated intraperitoneal chemotherapy have been used to treat patients with peritoneal metastases. Repeat therapy with intraperitoneal paclitaxel has been used recently. Intraperitoneal administration of paclitaxel results in prolonged retention in the peritoneal cavity with effects against peritoneal metastases. Repeated administration of paclitaxel does not cause adhesions in the peritoneal cavity. When combination chemotherapy is effective, salvage gastrectomy is a promising option with minimal morbidity and mortality. CONCLUSION: Combined chemotherapy with intraperitoneal paclitaxel and systemic chemotherapy followed by gastrectomy is a promising strategy for patients with advanced gastric cancer and peritoneal metastases.

BACKGROUND: Low-density neutrophils (LDN) have been shown to be increased in peripheral blood in patients with various diseases and closely related to immune-mediated pathology. However, the frequency and function of LDN in circulating blood of the patients following abdominal surgery have not been well understood. METHODS: LDN were determined by CD66b(+) cells, which were copurified with mononuclear cells by density gradient preparations of peripheral blood of surgical patients. The effects of the purified LDN on T cell proliferation and tumor cell lysis were examined in vitro. Neutrophil extracellular traps (NETs) production was examined by extracellular nuclear staining. RESULTS: The number of LDN with an immature phenotype is markedly increased in peripheral blood samples in patients after abdominal surgery. The frequency of LDN correlated positively with operative time and intraoperative blood loss. The purified LDN significantly suppressed the proliferation of autologous T cells stimulated with anti-CD3 mAb coated on plate and partially inhibited the cytotoxicity of lymphocytes activated with recombinant interleukin-2 against a human gastric cancer cell, OCUM-1. The LDN also produced NETs after short-term culture in vitro, which efficiently trap many OCUM-1. These results suggest that surgical stress recruits immunosuppressive LDN in the circulation in the early postoperative period. CONCLUSIONS: The LDN may support the lodging of circulating tumor cells via NETs formation and inhibit T cell-mediated antitumor response in target organs, which may promote postoperative cancer metastases. Functional blockade of LDN might be an effective strategy to reduce tumor recurrence after abdominal surgery.

Aim: Peritoneal metastases (PM) frequently occur in patients with gastric cancer and result in a poor prognosis. Exosomes play pivotal roles in tumor metastasis through the transfer of microRNAs (miRNAs). We examined the exosomal miRNA profile in peritoneal fluids to identify novel biomarkers to reflect tumor burden in the peritoneum. Methods: Exosomes were isolated from peritoneal fluids of patients of gastric cancer with macroscopic (P1) or microscopic (P0CY1) peritoneal metastasis (PM) and comprehensive miRNA expression analysis was carried out. Expressions of candidate miRNAs were then validated in all 58 samples using TaqMan Advanced miRNA Assays. Results: In initial screening, we carried out comprehensive analysis of exosomal miRNA using peritoneal fluids from 11 and 14 patients with or without PM, respectively, and identified 11 dysregulated miRNAs in PM (+) samples. Validation analysis showed that four miRNAs (miR-21-5p, miR-92a-3p, miR-223-3p, and miR-342-3p) were significantly upregulated in 12 PM (+) samples, and their expression levels showed positive correlation with peritoneal cancer index. In contrast, miR-29 family were all downregulated in patients with PM (+) samples. Moreover, in 24 patients with pT4 tumor, miR-29 at gastrectomy tended to be lower in six patients with peritoneal recurrence with significant differences in miR-29b-3p (P = .012). Conclusion: Expression pattern of miRNAs in peritoneal exosomes well reflects the tumor burden in the peritoneal cavity and could be a useful biomarker in the treatment of PM.

INTRODUCTION: Gastric adenocarcinomas with low grade atypia may be difficult to diagnose as gastric cancer by preoperative biopsy. We report an extremely well-differentiated adenocarcinoma (EWDA) of the stomach which appeared like a submucosal tumor diagnosed by preoperative endoscopic submucosal dissection. PRESENTATION OF CASE: A 70-year-old male was referred with a 3-month history of a submucosal-appearing lesion in the gastric wall found on endoscopy. Biopsies of the lesion were performed and were inconclusive for neoplasia. Endoscopic ultrasonography showed a low echoic tumor growing into the fourth layer of the gastric wall. It was difficult to identify the tumor by repeat biopsy. Endoscopic submucosal dissection of the lesion was performed and revealed adenocarcinoma, and laparoscopic total gastrectomy was performed. Histopathologic evaluation showed that the tumor was stage IIA (T3N0M0). There is no recurrence 12 months after resection. DISCUSSION: Gastric EWDAs are rare lesions, accounting for 0.6% of all gastric cancers. It is difficult to diagnose gastric EWDA especially if it appears like a submucosal tumor. This lesion was finally diagnosed by endoscopic submucosal dissection. CONCLUSION: Endoscopic submucosal dissection may facilitate establishing the preoperative diagnosis of a tumor thought to be a gastric EWDA based on its endoscopic appearance and pathological findings.

A 68-year-old male was referred with dysphagia. Endoscopic findings showed circular stenosis with a protruding mass in the lower esophagus. Biopsy showed adenocarcinoma and there was no evidence of distant metastases. A subtotal esophagectomy was performed. The resected specimen revealed a mixed neuroendocrine carcinoma with adenocarcinoma. The adenocarcinoma component was on the surface of the tumor and the neuroendocrine component invaded the deeper portion. Immunohistochemically, the neuroendocrine carcinoma component stained positive for cytokeratin 7 and cytokeratin 20, suggesting that the neuroendocrine carcinoma originated from the adenocarcinoma. The adenocarcinoma component stained positive for MUC2, which suggests that the adenocarcinoma component originated from Barrett's epithelium. Taken together, the neuroendocrine carcinoma may have originated from Barrett's epithelium. A metastasis to the liver was found 2 months after the surgical resection. Chemotherapy was administered, but there was no response. Most esophageal neuroendocrine carcinomas are accompanied by adenocarcinoma or squamous cell components, suggesting that these carcinomas originate from pluripotent cells in squamous or Barrett's epithelium. Appropriate chemotherapy for these lesions should be considered based on the cell of origin.

Gastrointestinal stromal tumors (GIST) in patients under 18 years of age are classified as pediatric GIST. Pediatric GIST are extremely rare, and there are no reports of laparoscopic-endoscopic cooperative surgery for these lesions. We report the use of non-exposed endoscopic wall-inversion surgery as a laparoscopic-endoscopic cooperative surgery-related procedure for the treatment of a pediatric GIST. The case involved a 17-year-old male patient who presented with anemia and was found to have a bleeding gastric tumor. The tumor was resected transorally using the non-exposed endoscopic wall-inversion surgery technique. No gene mutation of c-Kit or Platelet-Derived Growth Factor Receptor α (PDGFRα) was found, and the final pathological diagnosis was epithelial-type GIST due to a succinate dehydrogenase abnormality. Follow-up included a CT scan every 4 months. No recurrence has occurred to date.

<p>昨今の内視鏡外科手術の普及に伴い、シミュレーション教育や手術トレーニング環境の整備が進んだ。特に内視鏡外科手術では、外科医は体腔内臓器をモニタ画像情報で判断し、手術を行う。特に執刀医、助手すべてが同じ術野を共有することから、オンサイトでのトレーニングが可能である。手術映像を記録可能なことから、繰り返し再生によるオフサイトトレーニングも広く行われている。実際の手術を想定したオフサイトでのタスクトレーニングは、最善の手術を完遂する上で重要である。開腹手術に比較し多様な機材を使用する内視鏡外科手術では、高忠実度（Hi-Fi）臓器モデルによる手術トレーニングも行われている。Hi-Fiモデルでは、より実践に近い感覚でトレーニングを行うことが可能と考えられる。このような臓器モデルはシリコン樹脂やPVAなどの石油原料由来の臓器モデルが主である。ところがトレーニングモデルにおいても廃棄物の問題は重要であり、マンナンなどの植物由来原料を用いたタスクトレーニングモデルも開発されている。継続してトレーニングが必要な手術教育においては、コストを含めた持続可能なトレーニング環境の整備が必須である。</p>

INTRODUCTION: Immune thrombocytopenic purpura is an acquired thrombocytopenia. Preoperative management of thrombocytopenia is important in patients with gastric cancer. Partial splenic embolization can be effective for patients with thrombocytopenia, but could lead to ischemic necrosis of the remnant stomach when performing subtotal gastrectomy with splenectomy. PRESENTATION OF CASE: The patient is an 84-year old woman evaluated for anemia. Endoscopy revealed an advanced gastric cancer with bleeding. The patient also had immune thrombocytopenic purpura with a platelet count <50,000/μL. Administration of platelets did not increase the platelet count. Partial splenic embolization was performed followed by administration of high-dose immunoglobulin. The platelet count was over 50,000/μL preoperatively. The patient underwent combined subtotal gastrectomy and splenectomy, followed by an uneventful course. DISCUSSION: Patients with immune thrombocytopenic purpura and advanced gastric cancer can have anemia. Partial splenic embolization has been used to treat patients with refractory immune thrombocytopenic purpura as an alternative to splenectomy. Preoperative partial splenic embolization and high-dose immunoglobulin therapy resulted an increased platelet count in this patient. Elderly patients with gastric cancer have a high risk of postoperative complications. Patients with gastric cancer undergoing total gastrectomy have an impaired postoperative quality of life compared to those who undergo subtotal gastrectomy. We performed a subtotal gastrectomy and splenectomy as a function-preserving operation, completed safely by maintaining blood flow to the remnant stomach. CONCLUSION: Partial splenic embolization is effective for patients with immune thrombocytopenic purpura and gastric cancer. Combined subtotal gastrectomy and splenectomy is achieved by preserving blood flow to the remnant stomach.

INTRODUCTION: Gastric hyperplastic polyps are common stomach lesion and these polyps are generally benign. However, they can undergo malignant transformation. Most reported cases of malignant transformation of gastric hyperplastic polyps have been to well or moderately differentiated adenocarcinoma, and those transformed into poorly differentiated adenocarcinoma are extremely rare. No case has been reported that has changed to diffuse type adenocarcinoma with lymphatic invasion. PRESENTATION OF CASE: A 48-year-old woman presented with worsening anemia. A polyp was seen in the gastric cardia seven years prior to presentation. Helicobacter pylori infection was also found at that time. She underwent upper gastrointestinal endoscopy and biopsy of the polyp revealed signet ring cell carcinoma. Total gastrectomy was performed due to concern about possible invasion into the submucosal layer and there was no evidence of distant metastases. Histologic examination revealed both poorly differentiated adenocarcinoma and signet ring cell carcinoma surrounded by hyperplastic epithelium at the head of the polyp. Lymphatic invasion was also found, and malignant cells were limited to the mucosa. DISCUSSION: Gastric hyperplastic polyps are commonly associated with chronic gastritis which is related to Helicobacter pylori infections. Gastric hyperplastic polyps are generally benign and rarely undergo malignant transformation to adenocarcinoma with differentiated histology. The gastric hyperplastic polyp in this patient transformed to poorly differentiated adenocarcinoma with lymphatic invasion. CONCLUSION: Even small polyps may become poorly differentiated adenocarcinoma with invasion, so close follow-up or endoscopic resection are recommended as well as eradication of Helico Pylori infection when appropriate.

BACKGROUND: Thymomas are typically slow-growing tumors and AB type thymomas are considered no/low risk tumors with a better prognosis. Extra-thoracic metastases are extremely rare. To the best of our knowledge, no patient with an isolated splenic metastasis from a thymoma has been reported. We report a patient who underwent laparoscopic splenectomy for a slow-growing, isolated splenic metastasis, eight years after thymectomy. CASE PRESENTATION: The patient is a 78-year-old man. Eight years previously, the patient underwent extended thymectomy and postoperative radiation therapy for a thymoma. Five years after thymectomy, a nodule appeared in the spleen, and the lesion enlarged gradually for three years thereafter. The patient was referred for further examination and treatment. Computed tomography scan showed a sharply circumscribed 50 mm tumor slightly hypodense and heterogeneous lesion in the spleen. On T2-weighted images on Magnetic Resonance Imaging, the tumor had high intensity, equivalent to or slightly lower than that on T1-weighted images, and no decrease on diffusion-weighted images. The tumor was multinodular and showed a low-signal spoke-wheel sign in the margin, enhanced gradually in the dynamic study. Positron emission tomography-CT scan, showed relatively low accumulation. Surgical resection was undertaken, and pathological examination showed metastatic thymoma. The patient is without recurrence and has no other symptoms three years after splenectomy. CONCLUSIONS: This is the first report of an isolated splenic metastasis from a thymoma. Further cases are needed to standardize this surgery for such lesions.

Activated neutrophils release neutrophil extracellular traps (NETs), which can capture and destroy microbes. Recent studies suggest that NETs are involved in various disease processes, such as autoimmune disease, thrombosis, and tumor metastases. Here, we show a detailed in vitro technique to detect NET activity during the trapping of free tumor cells, which grow after attachment to NETs. First, we collected low density neutrophils (LDN) from postoperative peritoneal lavage fluid from patients who underwent laparotomies. Short-term culturing of LDN resulted in massive NET formation that was visualized with green fluorescent nuclear and chromosome counterstain. After co-incubation of human gastric cancer cell lines MKN45, OCUM-1, and NUGC-4 with the NETs, many tumor cells were trapped by the NETs. Subsequently, the attachment was completely abrogated by the degradation of NETs with DNase I. Time-lapse video revealed that tumor cells trapped by the NETs did not die but instead grew vigorously in a continuous culture. These methods may be applied to the detection of adhesive interactions between NETs and various types of cells and materials.

Despite recent advances in chemotherapy, outcomes of patients with peritoneal metastases (PM) from gastric cancer are still very poor and standard treatment has not been established. Although oral S-1 appears to be effective for patients with PM, the effects of systemic chemotherapy are limited. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) yield fewer benefits in patients with PM from gastric cancer than in patients with PM from other malignancies. In comparison, repeated intraperitoneal chemotherapy (RIPEC) with taxanes using an implantable peritoneal access port has a pharmacokinetic advantage for the control of peritoneal lesions and in combination with systemic chemotherapy can result in surprisingly long-term survival in patients with PM from gastric cancer. Herein, we review the results of recent clinical studies specifically targeting PM from gastric cancer and discuss future prospects for an intraperitoneal approach to the ideal treatment of patients with gastric cancer with peritoneal involvement.