Yoshitomo Yanagimoto

Clinical application of ghrelin in the field of surgery.

Ghrelin was discovered as an intrinsic ligand for the growth hormone (GH)-secretagogue receptor (GHS-R) in 1999. The endogenous production of ghrelin occurs mainly in the stomach. Ghrelin has multiple functions; it has orexigenic action, stimulates GH secretion, has anti-inflammatory activities, stimulates gastrointestinal activity, stabilizes heart function and has other metabolic roles. Moreover, ghrelin is the only gastrointestinal hormone known to stimulate appetite. In the past decade, clinical applications of ghrelin have been attempted for various pathologies, based on its anabolic function, including applications for patients with anorexia nervosa and cachexia due to chronic heart, renal or pulmonary diseases. In the field of surgery, we have conducted several clinical trials using exogenous ghrelin in patients undergoing total gastrectomy, esophagectomy and neoadjuvant chemotherapy, including cisplatin treatment, and consistently obtained unique and striking benefits in these patients. Ghrelin comprehensively improves the patients’ general conditions and quality of life via its pleiotropic physiological functions. This characteristic is unique and different from the existing drugs; therefore, ghrelin may be an indispensable supplement to prevent surgical stress and postoperative sequelae. This review summarizes the recent advances toward the clinical application of ghrelin.

Prognostic Significance of Basing Treatment Strategy on the Results of Photodynamic Diagnosis in Advanced Gastric Cancer

BackgroundWe have previously reported that use of a staging laparoscopy (SL) combined with photodynamic diagnosis using 5-aminolevulinic acid (ALA-SL) improves sensitivity in detecting peritoneal dissemination in gastric cancer (GC). The purpose of this study was to examine the clinical significance of basing treatment strategies on the results of ALA-SL in patients with advanced GC.Patients and MethodsALA-SL was performed on 113 patients with advanced GC prior to determination of their first course of treatment. According to the results of ALA-SL, patients were divided into four groups, including those classified as P0 (45%), ALA-P (12%), P1 plus P2 (23%), and P3 (20%). Patients with peritoneal metastases were subjected to chemotherapy. In addition, drug responders also received a gastrectomy. Treatment outcomes and patient characteristics stratified upon the results of ALA-SL were then analyzed.ResultsThe 3-year survival rates for patients in the P0, ALA-P, P1-2, and P3 groups were 73, 72, 49, and 6%, respectively. The survival estimates of patients classified as ALA-P via ALA-SL were very similar to those of P0 patients and were significantly better than those of P1-2 and P3 patients. Moreover, the false negative rate for ALA-SL-mediated detection of peritoneal metastasis at exploration was minimal (1/40, 2.5%), possibly due to the use of ALA.ConclusionsALA-SL may enhance the accuracy of diagnosis and contribute to therapeutic advantages in advanced GC. It should be introduced for advanced GC patients, especially females, as well as for individuals with high-stage tumors and/or tumors with diffuse-type histology.

Improvement of cisplatin-related renal dysfunction by synthetic ghrelin: a prospective randomised phase II trial.

Background:Ghrelin, a 28-amino acid peptide predominantly produced by the stomach, exerts powerful renal protective effects by increasing levels of insulin-like growth factor-1 (IGF-1). The aim of this study was to evaluate the effects of ghrelin on the incidence of renal dysfunction in patients receiving cisplatin-based chemotherapy.Methods:Forty patients with oesophageal cancer receiving cisplatin-based chemotherapy were assigned to either the ghrelin group (n=20), which received ghrelin (0.5 μg kg−1 h−1) for 5 days, or a placebo group (n=20). The primary endpoint was serum creatinine. Secondary endpoints were serum cystatin C, chemotherapy-related adverse events, changes in serum ghrelin-related hormone levels, correlation between markers of renal injury and hormone concentrations, and effects on the second cycle of chemotherapy.Results:Blood acyl ghrelin, total ghrelin, and IGF-1 concentrations on day 4 were significantly higher in the ghrelin group. The renal dysfunction, serum creatinine and cystatin C levels, dose reduction, and delay in the initiation of the second cycle of chemotherapy were lower in the ghrelin group than in the control group. Serum creatinine levels were significantly correlated with serum IGF-1 levels.Conclusion:Continuous synthetic ghrelin administration during cisplatin-based chemotherapy attenuated renal dysfunction and harmful effects on subsequent chemotherapy, possibly by increasing IGF-1 levels.

Plasma ghrelin levels as a predictor of adverse renal events due to cisplatin-based chemotherapy in patients with esophageal cancer

OBJECTIVE Although combination chemotherapy with docetaxel, cisplatin and 5-fluorouracil demonstrates high response rates in esophageal squamous cell carcinoma, patients treated with docetaxel, cisplatin and 5-fluorouracil frequently experience acute kidney injury. Ghrelin has shown renal protective effects in an experimental acute kidney injury model by reducing tubular apoptosis. In this prospective observational study, we evaluated the association between plasma ghrelin concentrations and docetaxel, cisplatin and 5-fluorouracil-related acute kidney injury. METHODS Forty consecutive patients with esophageal squamous cell carcinoma who received docetaxel, cisplatin and 5-fluorouracil from October 2013 to July 2014 were enrolled in this study. Serum creatinine and urinary α-1 microglobulin, a marker of renal tubular damage, were measured six times during chemotherapy. RESULTS The increases of creatinine level which is defined in Common Terminology Criteria for Adverse Event were observed less frequently in patients with acyl ghrelin concentrations of ≥9.6 fmol/ml (HAG group) than in those with concentrations <9.6 fmol/ml on Day 2 (LAG group) (P= 0.024). Serum creatinine was significantly lower in the HAG group than in the LAG group (Day 8: 0.79 ± 0.16 vs. 0.97 ± 0.26, P = 0.024; Day 11: 0.85 ± 0.19 vs. 1.08 ± 0.34 mg/dl, P = 0.049). Urinary α-1 microglobulin levels were significantly lower in the HAG group than in the LAG group (Day 4: 2.48 ± 1.83 vs. 3.33 ± 1.41, P = 0.011; Day 8: 4.67 ± 5.50 vs. 5.09 ± 2.54, P = 0.011; Day 11: 11.55 ± 13.78 vs. 16.43 ± 17.84 mg/l, P = 0.020). CONCLUSIONS Plasma acyl ghrelin concentrations on Day 2 of chemotherapy may be a potential predictor of docetaxel, cisplatin and 5-fluorouracil-induced acute kidney injury.

Clinical Outcomes of Gastric Cancer Patients Who Underwent Proximal or Total Gastrectomy: A Propensity Score-Matched Analysis

BackgroundTotal gastrectomy (TG) and proximal gastrectomy (PG) are used to treat upper-third early gastric cancer. To date, no consensus has been reached regarding which procedure should be selected. The aim of this study was to validate the usefulness of preserving the stomach in early upper-third gastric cancer.MethodsBetween 2004 and 2013, 201 patients underwent PG or TG at our institution for treatment of upper-third early gastric cancer. According to the defined inclusion and exclusion criteria, 192 cases were enrolled in this study. One-to-one propensity score matching was performed to compare the outcomes between the two groups.ResultsThe operation time was shorter in the PG group. Although no significant difference was observed, the PG group had less bleeding and fewer postoperative complications. R0 resection rate was 100%, and no surgery-related deaths were observed. The frequencies of reflux symptoms and anastomotic stenosis were significantly higher in the PG group, but could be controlled by balloon dilation and drug therapy. The maintenance rates of body mass index and lean body mass were significantly higher in patients who underwent PG than TG. The total protein and serum albumin values were higher in the PG group than in the TG group and remained statistically superior.ConclusionPG group exhibited better perioperative performance. Furthermore, better nutritional results were obtained in the PG group. Although the late stenosis and reflux symptoms must be addressed, the PG is a preferable surgical procedure for the treatment of early proximal gastric cancer.

A novel liver retraction method in laparoscopic gastrectomy for gastric cancer

BackgroundRetracting the lateral liver segment during laparoscopic distal gastrectomy is important for achieving an optimal surgical field. However, excessive force may injure the liver, causing temporary abnormalities of liver function tests after laparoscopic surgery. We developed a new liver retraction method and assessed its safety and utility.Patients and methodsWe retrospectively analyzed records in our surgical database of consecutive surgical patients who underwent laparoscopic distal gastrectomy for early gastric cancer. We divided the 229 patients into two groups based on the liver retraction method used, either flexible liver retraction with clipping and suturing (FLICS) or the Nathanson retractor (NR). One-to-one propensity score matching was performed to match patients, resulting in the records of 53 pairs of cases extracted from the database. Operative and postoperative outcomes were assessed, including following the values of serum liver enzymes, total bilirubin, and C-reactive protein until postoperative day 30.ResultsThere were no significant differences in patient characteristics or preoperative data in the two groups. The retraction method was not changed intraoperatively for any patients. The operative time was significantly shorter in the FLICS group, but the amount of bleeding did not differ. Liver injury was not observed as a result of liver retraction during surgery. In both groups, serum liver enzymes temporarily increased after surgery but improved rapidly thereafter. The postoperative increases in aspartate transaminase, alanine transaminase, and C-reactive protein levels were significantly lower in the FLICS than in the NR group. No serious complications associated with liver retraction were observed in either group.ConclusionsOur new liver retraction technique provided an optimal surgical field without inducing liver dysfunction. It is a simple, safe, and effective liver retraction technique.

Subclinical cancer cell dissemination in peritoneal lavage fluid detected by reverse-transcription polymerase chain reaction identifies patients at high risk for peritoneal recurrence and consequent impaired survival in the setting of preoperative chemoradiation therapy for pancreatic cancer

Background: Preoperative chemoradiation therapy is a promising strategy for pancreatic cancer. Peritoneal recurrence is a major recurrence pattern after surgery for pancreatic cancer following preoperative chemoradiation therapy, even in patients with negative peritoneal lavage fluid cytology. Previous reports have indicated that the detection of carcinoembryonic antigen mRNA by reverse transcription polymerase chain reaction is useful for evaluating subclinical tumor cell dissemination in peritoneal lavage fluid. Methods: Patients with resectable and borderline resectable pancreatic cancer treated with preoperative gemcitabine‐based chemoradiation therapy and subsequent surgery were enrolled in this study. In all patients, a conventional cytologic examination of peritoneal lavage fluid from laparotomy confirmed the negative peritoneal cytology status. Carcinoembryonic antigen mRNA was detected in the peritoneal lavage fluid at laparotomy using reverse transcription polymerase chain reaction. Recurrence patterns and survival were evaluated in association with the carcinoembryonic antigen mRNA status in the peritoneal lavage fluid. Results: The peritoneal lavage fluid from 57 of the 237 patients (24%) was carcinoembryonic antigen mRNA(+). The carcinoembryonic antigen mRNA(+) patients had a significantly higher incidence of peritoneal recurrence than the carcinoembryonic antigen mRNA(–) patients (36% vs. 15%, P < .001). The 5‐year survival rates of the carcinoembryonic antigen mRNA(+) and carcinoembryonic antigen mRNA(–) patients were 31% and 51%, respectively (P = .037). A multivariable analysis for survival revealed that borderline resectability, positive nodal status, and positive carcinoembryonic antigen mRNA status were independent variables for impaired survival. Conclusion: Carcinoembryonic antigen mRNA(+) status was associated with a significantly increased incidence of peritoneal recurrence in patients with pancreatic cancer treated with preoperative chemoradiation therapy, resulting in impaired survival.

The Safety and Feasibility of Single-Port Laparoscopic Gastrectomy for Advanced Gastric Cancer

BackgroundSingle-port laparoscopic surgery maximizes the advantages of laparoscopic surgery by reducing damage of the abdominal wall. However, no comparative studies have addressed its application to gastrectomy for advanced gastric cancer (AGC). We therefore aimed to demonstrate the safety and feasibility of single-port laparoscopic gastrectomy (SLG) for the treatment of AGC by comparing it with conventional multi-port laparoscopic gastrectomy (MLG).MethodsWe searched the prospective gastric cancer database of our institute for patients with AGC who underwent SLG or MLG between October 2007 and December 2013. Cases of R2 resection with distant metastasis or concurrent surgery for comorbid malignant lesions were excluded. One-to-one propensity score matching was performed to reduce bias from confounding patient-related variables, and the short- and long-term outcomes were compared between the two groups.ResultsWe identified 216 patients who underwent SLG (n = 100) or MLG (n = 116). After propensity score matching, we selected 73 pairs of patients who underwent SLG (distal gastrectomy, 49; total gastrectomy, 24) or MLG (distal gastrectomy, 45; total gastrectomy, 28). While the mean operative times were comparable between the groups, the SLG group had less blood loss, a lower postoperative morbidity, and shorter postoperative hospital stays. The 5-year survival rates were 74.2% in the SLG group and 60.2% in the MLG group (P = 0.081 by log-rank test).ConclusionsSLG is shown to be safe and feasible for the treatment of AGC, with better short-term results and acceptable oncologic outcomes and may be applicable for AGC treatment.

The Feasibility and Safety of Preoperative Fluorescence Marking with Indocyanine Green (ICG) in Laparoscopic Gastrectomy for Gastric Cancer

BackgroundSecuring the surgical margin is the most essential and important task in curative surgery. However, it is difficult to accurately identify the tumor location during laparoscopic surgery for gastric cancer, and existing methods, such as preoperative endoscopic marking with tattooing and clipping, have multiple disadvantages.AimsWe investigated the feasibility and safety of indocyanine green (ICG) fluorescence marking for determining the tumor location during laparoscopic gastrectomy.MethodsWe retrospectively analyzed preoperative and perioperative data from consecutive patients with gastric cancer undergoing planned laparoscopic distal gastrectomy. Data was maintained in a prospectively compiled surgical database, and patients were categorized into ICG (n = 84) or non-ICG (n = 174) groups based on whether they underwent preoperative endoscopic mucosal ICG injection. One-to-one propensity score matching (PSM) was performed to compare outcomes between the two groups.ResultsWe included 84 patient pairs after PSM, and there were no significant differences in preoperative patient characteristics. The ICG group had shorter procedure time (p < 0.001), lower estimated blood loss (p = 0.005), and significantly shorter postoperative hospital stay (p < 0.001). Positive resection margins were confirmed in five cases (6.0%) in the non-ICG group, whereas there were none in the ICG group (p = 0.008). Real-time confirmation was possible during laparoscopy, and the injected ICG did not affect the surgical procedure or result in adverse events.ConclusionICG fluorescence imaging is feasible and safe and can potentially be used as a tumor-marking agent for determining the surgical resection line.

Successful Endoscopic Treatment of Post-esophagectomy Refractory Reflux Using OverStitch: The First Clinical Case:

Aims: The reflux of duodeno-gastric contents into the remnant esophagus (gastric tube-esophageal reflux: GTER) is a significant issues in long-term esophageal cancer survivors after radical esophagectomy. We attempted endoscopic valve (funnel) creation for prevention for GTER using OverStitch endoscopic suturing system. Methods: The OverStitch was mounted onto a standard double-channel endoscope. Under general anesthesia, the funnel creation was attempted by placing semi-full thickness sutures on the gastric wall, at 3 cm distal to the primary esophago-gastric anastomosis. The postoperative outcomes were also evaluated. Results: In total, 4 sutures were needed and the operating time was 62 minutes without complication. The endoscopic and swallowing studies, as well as pH profile, were all improved postoperatively. The patient’s quality of life was dramatically improved with complete disappearance of night-time reflux in spine position. Conclusions: Endoscopic antireflux funnel creation was feasible and safe. This procedure may become a useful treatment for patients with severe GTER after esophagectomy.