金丸 理人

BACKGROUND: The frequency of tumor cell dissemination in the peritoneal cavity is critically related to the progression of peritoneal metastases (PM). Recently, flow cytometry (FCM) has been successfully used to detect tumor cells in malignant effusions. METHODS: A total of 143 single cell suspensions derived from ascites or peritoneal lavages from patients with advanced gastric cancer (GC) were stained with monoclonal antibodies to CD45 and to CD326 as well as 4,6-diamidino-2-phenylindole (DAPI) and FVS780. Using FCM, tumor-leukocyte ratio (TLR) were calculated from CD45(-)CD326(+) tumor cell counts/ CD45(+)CD326(+) leukocyte counts in DAPI (+) FVS780(-) gated area. In 54 patients, the ratios of CD11b(+), CD4(+) and CD8(+) cells in CD45(+) leukocytes were evaluated in parallel. RESULTS: TLR of 69 patients with PM were significantly higher than those of 74 without PM (p < .001) and log(TLR) showed strong correlation with peritoneal cancer index scores in 51 PM (+) patients (r = 0.439). TLR in PM (+) patients also correlated with the ratio of CD11b (+) myeloid cells (r = 0.547), and correlated inversely with those of CD4(+) (r = -0.490) and CD8(+) T cells (r = -0.648). In PM (-) patients who underwent gastrectomy, TLR never exceeded 0.1% in patients with primary GC without serosal involvement (<T4). However, TLR in patients with T4 GC were significantly higher (p < .05) and peritoneal recurrence occurred in 6/8 patients whose TLR exceeded 0.1%. CONCLUSION: TLR in peritoneal fluid reflects tumor burden and the immune environment in peritoneal cavity. Multicolor FCM may provide additional information which can be used for the treatment of the patients with PM.

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: 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.

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.

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.

Many types of immune cells appear in peritoneal cavity after abdominal surgery. In patients who underwent laparotomy due to gastric cancer, peritoneal lavages were obtained before and after surgical procedure. Cells were recovered from intermediate layer after Ficoll-Hypaque centrifugation and analyzed for phenotypes and functions, especially focused on low density neutrophils (LDN). The number of CD66b (+) LDN with mature phenotype was markedly elevated in postoperative as compared with preoperative lavages. Short term culture of the purified LDN produced many threadlike structures positive for SYTOX, nucleic acid staining, as well as histone and myeloperoxidase, suggesting the NETs formation. Human gastric cancer cells, MKN45, OCUM-1 and NUGC-4, were selectively attached on the NETs, which was totally abolished by the pretreatment of DNAse I. Intraperitoneal (IP) co-transfer of the LDN with MKN45 in nude mice strongly augments the metastasis formation on peritoneum, which was strongly suppressed by the following IP administration of DNAse I. Many NETs-like structures were detected on the surface of human omental tissue resected by gastrectomy. NETs on peritoneal surface can assist the clustering and growth of free tumor cells disseminated in abdomen. Disruption of the NETs by DNAse might be useful to prevent the peritoneal recurrence after abdominal surgery.

INTRODUCTION: Spontaneous esophageal perforation, or Boerhaave's syndrome, is a life-threating condition which usually requires emergent surgery. An upside down stomach is defined as a gastric volvulus in a huge supradiaphragmatic sac. In general, this condition can result in ischemia and perforation of the stomach. This is the first report of a patient with Boerhaave's syndrome and an upside down stomach. CASE PRESENTATION: A 79-year-old woman presented with sudden epigastric pain following hematemesis. Evaluation of the patient showed both an esophageal perforation and an upside down stomach. Surgical drainage and irrigation of the mediastinum and pleural cavities were undertaken emergently. Due to the concurrent gastric volvulus, a gastrostomy was placed to fix and decompress the stomach. The patient had an uneventful hospital course and was discharged. DISCUSSION AND CONCLUSION: Boerhaave's syndrome is a rare but severe complication caused by excessive vomiting, due to a sudden elevation in intraluminal esophageal pressure resulting in esophageal perforation. Acute gastric volvulus can result in ischemia and perforation of the stomach, but has not previously been reported with esophageal perforation. The most likely mechanism associating an upside down stomach with Boerhaave's syndrome is acute gastric outlet obstruction resulting in vomiting, and subsequent esophageal perforation. Perforation of the esophagus as well as perforation of the stomach must be considered in patients with an upside down stomach although both upside down stomach and Boerhaave's syndrome are rare clinical entities.

A 72-year-old male underwent a laparoscopic low anterior resection for advanced rectal cancer. A diverting loop ileostomy was constructed due to an anastomotic leak five days postoperatively. Nine months later, colonoscopy performed through the stoma showed complete anastomotic obstruction. The mucosa of the proximal sigmoid colon was atrophic and whitish. Ten days after the colonoscopy, the patient presented in shock with abdominal pain. Abdominal computed tomography scan showed hepatic portal venous gas (HPVG) and a dilated left colon. HPVG induced by obstructive colitis was diagnosed and a transverse colostomy performed emergently. His subsequent hospital course was unremarkable. Rectal anastomosis with diverting ileostomy is often performed in patients with low rectal cancers. In patients with anastomotic obstruction or severe stenosis, colonoscopy through diverting stoma should be avoided. Emergent operation to decompress the obstructed proximal colon is necessary in patients with a blind intestinal loop accompanied by HPVG.