A simple, novel laparoscopic feeding jejunostomy technique to prevent bowel obstruction after esophagectomy: the "curtain method".

BACKGROUND: Feeding jejunostomy (FJ) is a common treatment to support patients with esophageal cancer after esophagectomy. However, severe FJ-related complications, such as bowel obstruction, occasionally occur. We investigated the ability of our simple, novel FJ technique, the "curtain method," to prevent bowel obstruction. METHODS: In laparoscopic surgery, the main mechanism of bowel obstruction involves torsion of the mesentery accompanied by migration of the intestine across the fixed FJ through the space surrounded by a triangle comprising the ligament of Treitz, fixed FJ, and spleen rather than adhesion. Our "curtain method" involves closure of this triangle zone with omentum, and the appearance of the lifted omentum resembles a curtain. Sixty patients treated with this modified FJ were retrospectively compared with 13 patients treated with conventional FJ in terms of the incidence of bowel obstruction, peritonitis, stoma site infection, and catheter obstruction. RESULTS: From 2013 to 2017, 60 patients underwent esophagectomy and gastric conduit reconstruction accompanied by modified laparoscopic FJ. The median observation period, including the period after tube removal, was 644 days. No FJ-associated bowel obstruction, the prevention of which was the primary aim, occurred in any patient. Likewise, no peritonitis or dislodgement occurred. Eight patients (13%) developed a stoma site infection with granulation. The feeding tube became occluded in 11 patients (18%); however, a new feeding tube was reinserted under fluoroscopy for all of these patients. From 2003 to 2012, 13 patients underwent conventional FJ. The median observation period was 387 days. Three patients (23%) developed bowel obstruction by torsion 71 to 134 days after the first surgery, and all were treated by emergency operations. Other FJ-related complications were not different from those in the modified FJ group. CONCLUSION: Our simple, novel technique, the "curtain method," for prevention of laparoscopic FJ-associated bowel obstruction after esophagectomy is a safe additional surgery.

Simplified percutaneous endoscopic transgastric conduit feeding jejunostomy for dysphagia after esophagectomy.

Unexpected dysphagia is an important problem affecting life prognosis in patients who have undergone an esophagectomy for esophageal cancer. For nutritional support in patients suffering from dysphagia after a previous esophagectomy, a simplified percutaneous endoscopic transgastric conduit feeding jejunostomy approach was developed that can be performed regardless of the patient's condition. The feasibility of this procedure in 25 patients with esophageal cancer who underwent three-stage esophagectomy with retrosternal gastric conduit reconstruction from April 2009 to December 2016 was evaluated retrospectively. Under fluoroscopy, a percutaneous endoscopic transgastric conduit feeding jejunostomy catheter (9 French) was introduced into the jejunum in the epigastric region using the Seldinger's technique. The following patient data were analyzed retrospectively: operating time, complications, reasons for oral intake difficulty, and clinical data describing patients' nutritional status before and 1 month after percutaneous endoscopic transgastric conduit jejunostomy treatment, such as serum albumin and clinical course. Median patients' age was 68 years (range 50-76 years). Indications for the procedure were late swallowing dysfunction (n = 12), early swallowing dysfunction secondary to surgical complication (n = 8), anastomotic leakage (n = 3), and anorexia (n = 2). Causes of late swallowing dysfunction were radiation injury (n = 8), advanced age (n = 2), or cerebral infarction (n = 2). The median operating time was 29 minutes (range 14-82 minutes). Four patients developed mild erosions at the stoma secondary to bile reflux along the side of the catheter. No patient experienced severe complications such as ileus and peritonitis. Patients were treated for a median of 160 days (range 18-3106 days) with percutaneous endoscopic transgastric conduit jejunostomy. Patient's serum albumin significantly increased from 2.8 to 3.3 g/dl in 1 month. Of the eight patients with early swallowing dysfunction, six successfully regained sufficient oral nutrition after receiving enteral feeding nutritional management. Although all except one late swallowing dysfunction patient could not discontinue tube feeding, five patients were long-term survivors at the time this report was written. This jejunostomy procedure is simple, safe, and useful for patients with unexpected dysphagia and accompanying malnutrition after esophagectomy.

A phase II trial of perioperative chemotherapy involving a single intraperitoneal administration of paclitaxel followed by sequential S-1 plus intravenous paclitaxel for serosa-positive gastric cancer.

BACKGROUND AND OBJECTIVES: We carried out a phase II trial to evaluate the feasibility, efficacy, and tolerability of perioperative chemotherapy including single intraperitoneal(IP) administration of paclitaxel(PTX) followed by intravenous(IV) administrations of PTX with S-1 in a neoadjuvant setting for serosa-positive gastric cancer. METHODS: Patients with cT4a gastric cancer were enrolled. A laparoscopic survey was performed before study inclusion for the confirmation of serosal invasion, negative lavage cytology, and negative peritoneal metastasis. IP PTX (80 mg/m(2)) was administered, followed by systemic chemotherapy. Surgery was performed after the completion of chemotherapy. The primary endpoint was the treatment completion rate. RESULTS: 37 patients were recruited. The treatment completion rate was 67.6% (25/37; 90% CI, 52.8-80.1%), which was significantly higher than 50%; we set this as a threshold value (P = 2.4% [one-sided]). 14 patients had target lesions; of these, 10 showed a partial response (71.4%), three had stable disease (21.4%), and one had progressive disease(7.2%). The response rate was 71.4% (10/14). All patients underwent gastrectomy with D2 lymph node dissection. The 3- and 5-year OS rates were 78.0 and 74.9%, respectively. CONCLUSIONS: Perioperative chemotherapy including neoadjuvant IP PTX followed by sequential IV PTX with S-1 for serosa-positive gastric cancer is feasible, safe, and efficient.

Phase I clinical trial of vaccination with LY6K-derived peptide in patients with advanced gastric cancer.

BACKGROUND: Lymphocyte antigen 6 complex locus K (LY6K) has been identified as a tumor-associated antigen in lung cancers and esophageal squamous cell carcinomas. The immunogenicity of LY6K-177 peptide vaccine therapy has been demonstrated in patients with advanced esophageal cancer. This study extends this treatment to gastric cancer. METHODS: LY6K expression in clinical samples obtained from gastric cancer patients was examined by immunochemistry. As a phase I clinical trial, the safety and immunogenicity of LY6K-177 peptide vaccine emulsified with Montanide ISA 51 was evaluated in six patients with unresectable advanced gastric cancer. LY6K-177 peptide (1 mg in 1 ml sterile saline) was emulsified with incomplete Freund's adjuvant (1 ml) and intracutaneously administered to the inguinal region or axilla. One treatment course comprised four vaccinations, performed weekly for the first and second treatment courses and biweekly for the third treatment course. RESULTS: LY6K expression was confirmed in 85 % of gastric cancer tissues. Induration and redness at the vaccination site (grade I), possibly a delayed-type hypersensitivity reaction, was observed in all patients; however, no systemic toxicology was identified in any patient throughout the observation period. Three of the six patients had stable disease, and a tumor contraction effect was observed in one patient. CONCLUSIONS: LY6K was expressed in 85 % of observed gastric cancers. Vaccination with LY6K-177 peptide/Montanide ISA 51 appeared to be tolerated by advanced gastric cancer patients, and moreover anticancer efficacy was suggested. This trial was registered with ClinicalTrial.gov (no. NCT00845611).

High expression of epithelial cellular adhesion molecule in peritoneal metastasis of gastric cancer.

Intraperitoneally administrated epithelial cellular adhesion molecule (EpCAM) monoclonal antibody is a therapeutic agent in patients with malignant effusion in several types of carcinoma. However, the role of EpCAM in peritoneal metastasis (PM) lesions and primary lesions of gastric cancer (GC) is still unclear. Therefore, in this study, we investigated EpCAM expression in GC patients with PM. We investigated the expression of EpCAM in 35PM lesions and 104 biopsy samples as primary lesions. Immunohistochemical staining was performed using the Ventana Benchmark XT (Roche Diagnostics) system. EpCAM expression was evaluated by calculating the total immunostaining score, which is the product of the proportion score and the intensity score. Overexpression was defined as a total score greater than 4. All PM specimens showed overexpression of EpCAM, and GC cells in both the surface layer and the deep layer of the PM showed a high expression of EpCAM. Meanwhile, in the biopsy sample, the expression of EpCAM ranged from none to strong. The EpCAM score results for PM specimens and biopsy samples were 11.0 ± 2.0 and 6.9 ± 3.9, respectively. The difference between the scores was statistically significant (P < 0.05). The intraperitoneally administrated EpCAM antibody might have a anti-cancer effect in PM lesions of GC. Additionally, it can be assumed that only GC cells which express a high level of EpCAM might metastasize to the peritoneum.

Phase II study of single intraperitoneal chemotherapy followed by systemic chemotherapy for gastric cancer with peritoneal metastasis.

BACKGROUND: We conducted a phase II study involving a single administration of intraperitoneal chemotherapy with paclitaxel followed by sequential systemic chemotherapy with S-1+ paclitaxel for advanced gastric cancer patients with peritoneal metastasis. METHODS: Gastric cancer patients with peritoneal metastasis were enrolled. Paclitaxel (80 mg/m(2)) was administered intraperitoneally at staging laparoscopy. Within 7 days, patients received systemic chemotherapy with S-1 (80 mg/m(2)/day on days 1-14) plus paclitaxel (50 mg/m(2) on days 1 and 8), followed by 7-days rest. The responders to this chemotherapy underwent second-look laparoscopy, and gastrectomy with D2 lymph node dissection was performed in patients when the disappearance of peritoneal metastasis had been confirmed. The primary endpoint of the study was overall survival rate. RESULTS: Thirty-five patients were enrolled. All patients were confirmed as having localized peritoneal metastasis by staging laparoscopy. Eventually, gastrectomy was performed in 22 patients. The median survival time of the total patient population and those patients in which gastrectomy was performed was 21.3 and 29.8 months, respectively. The overall response rate was 65.7 % for all patients. The frequent grade 3/4 toxic effects included neutropenia and leukopenia. CONCLUSIONS: Sequential intraperitoneal and intravenous paclitaxel plus S-1 was well tolerated in gastric cancer patients with peritoneal metastasis.

A preliminary study of single intraperitoneal administration of paclitaxel followed by sequential systemic chemotherapy with S-1 plus paclitaxel for advanced gastric cancer with peritoneal metastasis.

AIM: A preliminary study with the aim of evaluating the safety and efficacy of a single intraperitoneal administration of paclitaxel, combined with intravenous administration of paclitaxel plus S-1, was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS: Paclitaxel was administered intraperitoneally at 80 mg/m(2). After one to two weeks, S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by seven days' rest. Paclitaxel was administered intravenously at 50 mg/m(2) on days 1 and 8. The safety, pharmacokinetic analysis and efficacy of this therapy were investigated. RESULTS: Fifteen patients were enrolled in this study. The toxic effects of the intraperitoneal chemotherapy were mild. The toxic effects with the systemic chemotherapy were acceptable. The ratio of (AUC peri)/(AUC pla) was 1065:1 in the pharmacokinetic analysis. The one-year overall survival rate was 10/15 (66.7%). CONCLUSION: A single intraperitoneal administration of paclitaxel combined with intravenous administration of paclitaxel plus S-1 is a well-tolerated and feasible treatment for patients with gastric cancer with peritoneal metastasis.

Relationship between immunological parameters and the severity of neutropenia and effect of enteral nutrition on immune status during neoadjuvant chemotherapy on patients with advanced esophageal cancer.

OBJECTIVES: Chemotherapy may cause various toxicities as well as impair immunological function. However, little is known about the relationship between toxicities and immunological parameters or the effect of enteral nutrition (EN) on immunological status during chemotherapy. METHODS: 91 patients who received neoadjuvant chemotherapy (NACT) for esophageal cancer were randomly assigned to receive either EN or parenteral nutrition (PN). Immunological parameters, including total lymphocyte count (TLC), type 1 and type 2 CD4-positive T cells (Th1/Th2) balance, human leukocyte antigen (HLA)-DR expression on monocytes, natural killer cell activity, and phytohemagglutinin-stimulated lymphocyte proliferation were measured at baseline and day 14 of the first chemotherapy cycle. RESULTS: In the PN group, patients with grade 3-4 neutropenia showed significantly lower TLC, HLA-DR expression, and Th1/Th2 balance at day 14 compared to those with grade 0-2 neutropenia. Among pretherapeutic factors, Th1/Th2 balance was the only factor significantly associated with the severity of neutropenia. Concerning the comparison of immunological parameters between the EN and PN groups, HLA-DR expression at day 14 was significantly higher in the EN group. CONCLUSIONS: Baseline Th1/Th2 balance predicted the severity of neutropenia, and EN significantly reduced the decline of monocyte HLA-DR expression in patients with esophageal cancer receiving NACT.

Peritoneal metastatic lesions of gastric cancer exhibit low expression of human epidermal growth factor receptor 2.

The prognosis of gastric cancer patients with peritoneal metastasis is very poor. Recent findings suggest that use of trastuzumab, a monoclonal antibody-based agent that targets human epidermal growth factor receptor 2 (HER2), may improve the prognosis of gastric cancer patients with HER2 overexpression and/or gene amplification. However, whether these mechanisms of HER2 upregulation are present in gastric cancer patients with peritoneal metastasis is unclear. The status of HER2 expression in a cohort of samples obtained from 35 gastric cancer patients with peritoneal metastasis was investigated using immunohistochemistry and fluorescence in situ hybridization. In 18 cases, we also investigated the influence of induction chemotherapy on HER2 overexpression. The frequency of HER2 overexpression and gene amplification was 2.9 % (1/35) in peritoneal metastatic lesions. There was concurrence in HER2 status in the samples examined prior to and following induction of chemotherapy. Most samples from the gastric cancer patients with peritoneal metastasis did not show HER2 amplification and/or overexpression. Although our study size was small, these results suggest that trastuzumab, which is critically dependent on HER2 expression, might not be an effective agent for these patients. Consequently, other therapeutic approaches for these patients must be developed.

Phase II study of docetaxel, cisplatin and 5-fluorouracil (DCF) for metastatic esophageal cancer (OGSG 0403).

BACKGROUND: The aims of this multiple-institution phase II study were to evaluate the efficacy and tolerability of docetaxel, cisplatin and 5-fluorouracil (DCF) for the therapy of patients with metastatic squamous cell carcinoma of the esophagus (SCCE). PATIENTS AND METHODS: Eligible patients included those with previously untreated SCCE, score of ECOG 0-2 and adequate organ function. Patients received 60 mg/m(2) docetaxel and 70 mg/m(2) cisplatin on day 1, and 600 mg/m(2) 5-fluorouracil on days 1-5 every four weeks. RESULTS: Twenty-nine (22 male, 7 female) patients with metastatic SCCE (M1a: 20, M1b: 9) were enrolled. Three cases achieved complete response and seven a partial response. In addition to these patients, three patients achieved good response and underwent surgical resection, giving an overall response rate of 34.5% (95% Confidene Interval=17.9-54.3) in confirmed cases and 44.8% (95% CI=26.4-64.3) in unconfirmed cases. Grade 3 or 4 hematological toxicities were as follows: leukopenia in 15 patients (52%), neutropenia in 22 patients (76%) and febrile neutropenia in 6 patients (21%), while grade 3 or 4 non-hematological toxicities were relatively rare. CONCLUSION: This DCF regimen was well tolerated; the results of this study provide information on the potential of DCF for treatment of patients with metastatic SCCE.

Safety of intraperitoneal administration of paclitaxel after gastrectomy with en-bloc D2 lymph node dissection.

BACKGROUND: The aim of this study was to examine the safety, pharmacokinetics, and cytological efficacy against free intraperitoneal cancer cells of intraperitoneal chemotherapy (IPC) with paclitaxel after gastrectomy with en-bloc D2 lymph node dissection (GD2) in cases of gastric cancer with peritoneal carcinomatosis (PC) and/or positive cytological findings in peritoneal washings (CFPW). METHODS: Twenty-one patients with gastric cancer with PC and/or positive CFPW who underwent GD2 were treated with early, post-operative, intraperitoneal paclitaxel. Intra-chemotherapeutic toxicity and operative complication were measured using the common toxicity criteria of the National Cancer Institute, version 3.0. Intraperitoneal and plasma paclitaxel concentrations were measured using a high-performance liquid chromatography assay. RESULTS: Grade 3 anemia occurred in two patients (9.5%) and neutropenia was observed in three patients (14.3%). No grade 4 toxicity was observed. A grade 2 operative complication was a superficial surgical site infection (4.8%) that was treated with antibiotics. Cytologically, no viable cancer cells were observed in the intra-abdominal fluid 24 hr after intraperitoneal administration of paclitaxel. The intraperitoneal/plasma area under the drug concentration-time curve (AUC) ratio was 596.9:1. CONCLUSION: IPC with paclitaxel after GD2 is a safe and cytologically effective treatment modality for free intraperitoneal cancer cells. However, additional data are required to determine the effect on survival.

An immunohistochemical study of osteopontin in pigment gallstone formation.

Mucin glycoproteins from the gallbladder epithelium are thought to contribute to the matrix or nucleus of gallstones and other biomineralization systems. The involved acidic glycoproteins have been reported in bile and gallstones. In addition, osteopontin (Opn) is a noncollagenous acidic bone matrix glycoprotein that possesses calcium-binding properties. To investigate the role of Opn in pigment gallstone formation, the involvement of Opn in pigment gallstone formation was studied immunohistochemically in the gallbladder wall and in the stones. Staining for Opn was strongly positive in the epithelium of stone-laden gallbladders and in their stones. The stone-laden gallbladders were infiltrated by macrophages, which intensely stained for Opn. Sections of the pigment stones, under low magnification, showed a lamellar pattern of Opn immunolabeling and showed a reticular pattern under high magnification. Our results indicate that Opn, an acidic glycoprotein from the gallbladder epithelium, seems to be involved in lithiasis. Opn from macrophages and/or the epithelium seems to help form the matrix protein.

Immunohistochemical expression of osteopontin in gastric cancer.

BACKGROUND/AIMS: Osteopontin (OPN) is significantly overexpressed in a variety of malignancies. However, little is known concerning the significance of OPN expression in human cancers. Thus, the aim of this study was to determine the relationship between the degree of OPN expression, the proliferative activity of cancer cells, and the clinicopathological findings for surgically resected gastric cancer. METHODOLOGY: We evaluated the immunohistochemical expression of OPN in 85 specimens of cancer. Additionally, we investigated a cancer cell proliferative index using an anti-MIB-1 antibody and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling staining. Levels of OPN expression in gastric cancers were classified into three groups. To compare the relationship between OPN expression and clinicopathological findings, the features of cancer lesions were classified using the TNM Classification of Malignant Tumors, 6th Edition. RESULTS: Immunohistochemical examination of OPN expression in gastric cancer revealed diffuse granular staining in the cytoplasm. High OPN expression was observed in 37 of 85 carcinomas. Strong OPN expression was significantly associated with a low apoptotic index, a high proliferative index, depth of invasion, lymphatic invasion, and venous invasion. Pathologically, intestinal type carcinoma showed strong expression of OPN. CONCLUSIONS: These data suggested that OPN may play an important role in the invasiveness and the progressive nature of gastric cancer.

Successful one-stage operation of aortoesophageal fistula from thoracic aneurysm using a rifampicin-soaked synthetic graft.

Aortoesophageal fistula secondary to thoracic aneurysm is rare, but is usually lethal, and few survivors have been reported. We report successful surgery for aortoesophageal fistula in a one-stage operation. Repair involved in situ replacement of the thoracic aneurysm using a rifampicin-soaked graft, primary repair of the esophagus, omental wrap and tube jejunostomy. This is the original report of the surgical repair of aortoesophageal fistula using a rifampicin-soaked graft.

Restoration of E-cadherin-based cell-cell adhesion by overexpression of nectin in HSC-39 cells, a human signet ring cell gastric cancer cell line.

Nectin is an immunoglobulin-like adhesion molecule that comprises a family consisting of four members, nectin-1, -2, -3, and -4. Nectin is associated with the actin cytoskeleton through afadin, a nectin- and actin filament-binding protein. The nectin-afadin and cadherin-catenin systems are associated with each other and cooperatively form cell-cell adherens junctions in intact epithelial cells. HSC-39 cells, a human signet ring cell gastric cancer cell line, express E-cadherin but do not form cell-cell adhesion. The beta-catenin gene has been shown to be truncated at the N-terminal region including the alpha-catenin-binding domain in HSC-39 cells, but overexpression of normal beta-catenin failed to form cell-cell adhesion. HSC-39 cells expressed nectin-1, -2, and afadin, but not nectin-3. Overexpression of nectin-3 or -2 formed cell-cell adhesion and accumulation of E-cadherin, but not actin filaments, at the cell-cell adhesion sites. Overexpression of a truncated form of nectin-2 incapable of interacting with afadin failed to form cell-cell adhesion. However, the nectin-formed cell-cell adhesion was not so strong as that observed in epithelial cells, such as CaCo-2 cells. Co-expression of nectin-2 and normal beta-catenin did not form strong cell-cell adhesion. These results suggest that an unidentified mechanism, by which nectin and E-cadherin form the actin cytoskeleton-associated adherens junctions to form strong cell-cell adhesion, is impaired in HSC-39 cells.