Katsushi Takebayashi

Prognostic impact of CD44-positive cancer stem-like cells at the invasive front of gastric cancer

Background:The invasive tumour front may provide prognostic information. We examined the relationship between the presence of cancer stem cells (CSCs) at the invasive tumour front and prognosis in gastric cancer (GC).Methods:CD44 is a CSC marker; accordingly, CD44 standard (CD44s), CD44 variant-6 (CD44v6), and CD44 variant-9 (CD44v9) expression were examined in 123 resected primary GCs and the clinical significance of CSCs at the invasive tumour front was analysed.Results:Thirteen (10.6%), 79 (64.2%), and 47 (38.2%) GCs were CD44s-, CD44v6-, and CD44v9-positive, respectively. Patients with CD44-positive expression at the invasive tumour front had significantly poorer disease-specific survival than those with negative expression (CD44s: P<0.00001, CD44v6: P=0.013, CD44v9: P=0.0002). CD44s expression at the invasive tumour front was an independent prognostic factor in resectable GC patients (hazard ratio=3.13; 95% confidence interval, 1.09–9.01; P=0.035) and was significantly associated with peritoneal (P<0.001), lymphatic (P<0.001), and haematogenous recurrences (P=0.008). In addition, the number of CD44 isoforms expressed in cancer cells at the invasive tumour front was associated with patient prognosis. No conventional clinicopathological factors were independently associated with CD44 expression at the invasive tumour front.Conclusions:CD44-positive cancer stem-like cells at the invasive tumour front indicate poor survival and can be a unique biological prognostic factor for GC.

Hyperthermic intraperitoneal chemotherapy using a combination of mitomycin C,5-fluorouracil, and oxaliplatin in patients at high risk of colorectal peritoneal metastasis: A Phase I clinical study

INTRODUCTION The drugs and protocols used for hyperthermic intraperitoneal chemotherapy (HIPEC) vary among institutions. Here we show the efficacy of the 3-drug combination of mitomycin C (MMC), 5-fluorouracil (5FU), and oxaliplatin (OHP) in an in vitro simulation of HIPEC and the safety of HIPEC with these drugs during a Phase I study of patients at high risk of developing colorectal peritoneal metastasis. METHODS To simulate HIPEC, we used HCT116 and WiDr cells to assess the growth inhibitory efficacy of MMC 2 μg/mL, 5FU 200 μg/mL, and OHP 40 μg/mL as single drugs or their combination after an exposure time of 30 min at 37 or 42 °C. In addition, nine patients underwent surgical resection of tumors and HIPEC with MMC, 5FU, and an escalating dose of OHP (90/110/130 mg/m²). Dose-limiting toxicity was monitored. RESULTS In the simulation, the 3-drug combination showed marked tumor-suppressive effects compared with those from ten times higher dose of OHP 400 μg/mL, with significant augmentation under hyperthermic conditions. No dose-limiting toxicity occurred in the clinical study. Dose escalation was completed at the final level of OHP. CONCLUSIONS The MMC-5FU-OHP combination showed marked growth inhibition against colorectal cancer cells under hyperthermic conditions in vitro. In the phase I study, the recommended dose of OHP was determined as 130 mg/m² when used with MMC and 5FU; HIPEC using MMC-5FU-OHP appears to be safe and feasible for patients at high risk of colorectal peritoneal metastasis.

Efficacy of transversus abdominis plane block and rectus sheath block in laparoscopic inguinal hernia surgery.

We aimed to assess the efficacy of transversus abdominis plane (TAP) block and rectus sheath (RS) block in patients undergoing laparoscopic inguinal hernia surgery. Few studies have addressed the efficacy and safety associated with TAP block and RS block for laparoscopic surgery. Thirty-two patients underwent laparoscopic inguinal hernia surgery, either with TAP and RS block (Block(+) group, n = 18) or without peripheral nerve block (Block(-) group, n = 14). Preoperatively, TAP and RS block were performed through ultrasound guidance. We evaluated postoperative pain control and patient outcomes. The mean postoperative hospital stays were 1.56 days (Block+ group) and 2.07 days (Block(-) group; range, 1-3 days in both groups; P = 0.0038). A total of 11 patients and 1 patient underwent day surgery in the Block(+) and Block(-) groups, respectively (P = 0.0012). Good postoperative pain control was more commonly observed in the Block(+) group than in the Block(-) group (P = 0.011). TAP and RS block was effective in reducing postoperative pain and was associated with a fast recovery in patients undergoing laparoscopic inguinal hernia surgery.

Differences in Chemosensitivity between Primary and Metastatic Tumors in Colorectal Cancer

Purpose We retrospectively evaluated the in vitro chemosensitivity of primary site and metastatic site tumors in colorectal cancer. Methods Various resected tumor samples (33 from lymph nodes, 42 from liver, six from lung, and 68 primary tumors) were assessed via a collagen gel droplet-embedded culture drug sensitivity test to determine chemosensitivity to a single agent or a combination of agents. Results Sensitivity to combination chemotherapy was significantly higher than that of monotherapy in the primary site group, lymph node group, and liver group. There was significant difference between chemosensitivity of primary site and that of liver metastasis in each agent (5-FU, p<0.001; SN38, p = 0.045; 5-FU/SN38, p<0.001; OHP, p = 0.037; 5-FU/OHP, p = 0.045). Conclusions Tumors showed greater in vitro chemosensitivity to combination therapy when compared with monotherapy. Further, tumors that had metastasized to the liver were more resistant to chemotherapy when compared with matched primary tumors.

Utility of a microwave surgical instrument in sealing lymphatic vessels.

BACKGROUND This study assessed the ability of a novel microwave coagulation surgical instrument (MWCX) to seal lymphatic vessels when compared with LigaSure (Valleylab, Boulder, CO), the Harmonic Scalpel (HS; Ethicon Endo-Surgery, Cincinnati, OH), and electric cautery. METHODS The burst pressure of pig inguinal lymphatic vessels was assessed after the sealing of vessels with each surgical instrument. The rate of lymphorrhea from pig mesenteric lymphatic vessels was also investigated using indocyanine green and visualized with the Photodynamic Eye system (Hamamatsu Hotoniks, Hamamatsu, Japan). RESULTS Burst pressures were higher with MWCX (average, 300 mm Hg), LigaSure (average, 290 mm Hg), and HS (average, 253 mm Hg) when compared with electric cautery (average, 152.3 mm Hg; vs MWCX: P = .002, vs LigaSure: P = .002, vs HS: P = .004). The rate of lymphorrhea was significantly lower with LigaSure (13.3%), HS (18.8%), and MWCX (13.3%) when compared with electric cautery (77.3%; vs LigaSure: P < .001, vs HS: P < .001, vs MWCX: P < .001). CONCLUSIONS MWCX was equivalent to LigaSure and HS in terms of the ability to seal lymphatic vessels.

Risk factors for complications after pharyngolaryngectomy with total esophagectomy

BackgroundPharyngolaryngectomy with total esophagectomy (PLTE) is an effective surgical treatment for synchronous or metachronous hypopharyngeal or laryngeal cancer and thoracic esophageal cancer, although it is more invasive than esophagectomy and total pharyngolaryngectomy. The aim of this study was to identify risk factors for complications after PLTE.MethodsFrom November 2002 to December 2014, a total of 8 patients underwent PLTE at the Shizuoka Cancer Center Hospital, Shizuoka, Japan. We investigated the clinicopathological characteristics, surgical procedures, and postoperative complications of these patients.ResultsOf the 8 patients, 5 underwent one-stage PLTE and 3 underwent staged PLTE. There was no mortality in this study. Two cases of tracheal necrosis, two of anastomotic leakage, and one of ileus were observed as postoperative complications. Two patients who underwent one-stage PLTE with standard mediastinal lymph node dissection developed tracheal necrosis and severe anastomotic leakage.ConclusionOne-stage PLTE and standard mediastinal lymph node dissection were identified as the risk factors for severe postoperative complications. Staged PLTE or transhiatal esophagectomy should be considered when PLTE is performed and standard mediastinal lymph node dissection should be avoided when one-stage PLTE is performed with transthoracic esophagectomy.

Comparison of curative surgery and definitive chemoradiotherapy as initial treatment for patients with cervical esophageal cancer

Esophagectomy and definitive chemoradiotherapy are recognized standard initial treatment modalities for cervical esophageal cancer. The goal of this study was to compare the treatment outcomes of curative surgery with those of chemoradiotherapy in patients who had potentially resectable tumor and who were candidates for surgery. We evaluated the data from 49 consecutive patients who were diagnosed with potentially resectable cervical esophageal cancer and who were deemed candidates for surgery. Thirteen patients were included in the surgery group, and 36 patients were included in chemoradiotherapy group. Baseline characteristics were balanced between the two groups. In the chemoradiotherapy group, the complete response rate was 58.3%. There was no significant difference in 5-year overall survival when comparing the surgery group and the chemoradiotherapy group (surgery, 60.6%; chemoradiotherapy, 51.4%; P = 0.89). In the chemoradiotherapy group, of the 15 patients who failed to respond to initial treatment, 11 patients subsequently underwent salvage surgery. In conclusion, curative surgery and chemoradiotherapy as initial treatment for cervical esophageal cancer have comparable survival outcomes. Chemoradiotherapy should be selected as the initial larynx-preserving treatment for patients with cervical esophageal cancer although chemoradiotherapy non-responders require additional treatment, including salvage surgery.

Fusion protein of mutant B7-DC and Fc enhances the antitumor immune effect of GM-CSF-secreting whole-cell vaccine.

B7-DC [also known as programmed death ligand 2 (PD-L2)] is a costimulatory molecule expressed predominantly on dendritic cells (DCs) and macrophages. In addition to its coinhibitory receptor, programmed death receptor 1 (PD-1), evidence suggests that B7-DC interacts with an unidentified costimulatory receptor on T cells. B7-DC mutants with selective binding capacity for the costimulatory receptor may be effective in stimulating antitumor immune responses, while avoiding the inhibitory effects of PD-1. In this study, we concomitantly administered a GM-CSF-secreting whole-cell vaccine together with a fusion protein of mutant B7-DC and Fc portion (mB7-DC-Fc), which binds selectively to the costimulatory receptor. This lead to an increased number of tumor antigen-specific cytotoxic T lymphocytes both in the spleen and at the tumor site and complete elimination of established tumors in vivo. In addition, mB7-DC-Fc increased IFN-&ggr; and IL-2 production and decreased IL-4 and IL-10 production in vitro, indicating that mB7-DC-Fc tips the Th1/Th2 balance toward Th1 dominance, which is more favorable for antitumor immunity. Furthermore, mB7-DC-Fc decreased the PD-1+ proportion of CD8+ T cells in vitro and tumor-infiltrating CD8+ T cells in vivo, suggesting that mB7-DC-Fc may maintain tumor-infiltrating CD8+ T cells in a nonexhausted state. In conclusion, mB7-DC-Fc administration during the T-cell priming phase enhances antitumor effects of vaccine by generating more tumor antigen-specific cytotoxic T lymphocytes and leading to their accumulation at the tumor site. We suggest that this combination approach may be a promising strategy for antitumor immunotherapy.

Classification of remnant stomach shape after distal gastrectomy with Billroth-I reconstruction and a comparison of the postoperative outcomes

PurposeTo classify the shape of the remnant stomach after Billroth-I (B-I) reconstruction and evaluate the relationship between the shape of the remnant stomach and the postoperative clinical outcomes.MethodsOne hundred and ninety-five consecutive patients with gastric cancer underwent distal gastrectomy with B-I reconstruction between May 2006 and October 2014. We retrospectively reviewed their medical records and radiological findings. Finally, the shapes of the remnant stomach of 150 patients were classified as either straight type (type A) or stagnant type (type B). The clinical outcomes were compared with respect to the types of remnant stomach.ResultsThe incidence of anastomotic leakage was significantly higher in the type A group than in the type B group (9.4 vs. 1.5%, p = 0.044). The body weight change ratio after surgery was significantly lower in the type B group than in the type A group [p = 0.0068, two-way repeated measures analysis of variance (ANOVA)], while the serum albumin levels showed marginally significant improvement in the type B group compared with the type A group (p = 0.0542, two-way repeated measures ANOVA).ConclusionThe shape of the remnant stomach after distal gastrectomy with B-I reconstruction might influence the degree of anastomotic leakage and long-term nutritional status.

5-fluorouracil combined with cisplatin and mitomycin C as an optimized regimen for hyperthermic intraperitoneal chemotherapy in gastric cancer

Optimized drug regimens for hyperthermic intraperitoneal chemotherapy (HIPEC) have not been standardized completely in patients with advanced gastric cancer (GC). We evaluated an optimized anti‐tumor protocol comprising 5‐fluorouracil (5‐FU) combined with cisplatin (CDDP) and mitomycin C (MMC) in vitro for clinical use of HIPEC.