Takaya Nagasaki

Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction.

Background:Interleukin-6 (IL-6) has an important role in cancer progression, and high levels of plasma IL-6 are correlated with a poor prognosis in a variety of cancers. It has also been reported that tumour stromal fibroblasts are necessary for steps in cancer progression, such as angiogenesis. There have been few reports of a correlation between fibroblast actions and IL-6 levels. In this study, we examined the correlation between cancer stromal fibroblasts and IL-6 and the utility of IL-6 as a therapeutic target in human colon cancer.Methods:The expression levels of IL-6 and VEGF of fibroblasts and cancer cell lines were evaluated using real-time PCR and ELISA. The anti-angiogenic effect of inhibiting IL-6 signalling was measured in an angiogenesis model and animal experiment.Results:We demonstrate that stromal fibroblasts isolated from colon cancer produced significant amounts of IL-6 and that colon cancer cells enhanced IL-6 production by stromal fibroblasts. Moreover, IL-6 enhanced VEGF production by fibroblasts, thereby inducing angiogenesis. In vivo, anti-IL6 receptor antibody targeting stromal tissue showed greater anti-tumour activity than did anti-IL6 receptor antibody targeting xenografted cancer cells.Conclusion:Cancer stromal fibroblasts were an important source of IL-6 in colon cancer. IL-6 produced by activated fibroblasts induced tumour angiogenesis by stimulating adjacent stromal fibroblasts. The relationship between IL-6 and stromal fibroblasts offers new approaches to cancer therapy.

Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth

Cancer tissues are composed of cancer cells and the surrounding stromal cells (e.g., fibroblasts, vascular endothelial cells, and immune cells), in addition to the extracellular matrix. Most studies investigating carcinogenesis and the progression, invasion, metastasis, and angiogenesis of cancer have focused on alterations in cancer cells, including genetic and epigenetic changes. Recently, interactions between cancer cells and the stroma have attracted considerable attention, and increasing evidence has accumulated on this. Several researchers have gradually clarified the origins, features, and roles of cancer-associated fibroblasts (CAFs), a major component of the cancer stroma. CAFs function in a similar manner to myofibroblasts during wound healing. We previously reported the relationship between CAFs and angiogenesis. Interleukin-6 (IL-6), a multifunctional cytokine, plays a central role in regulating inflammatory and immune responses, and important roles in the progression, including proliferation, migration, and angiogenesis, of several cancers. We showed that CAFs are an important IL-6 source and that anti-IL-6 receptor antibody suppressed angiogenesis and inhibited tumor-stroma interactions. Furthermore, CAFs contribute to drug-resistance acquisition in cancer cells. The interaction between cancer cells and the stroma could be a potential target for anti-cancer therapy.

Zerumbone inhibits angiogenesis by blocking NF-κB activity in pancreatic cancer.

Objectives Because angiogenesis is essential for tumor growth and metastasis, the development of antiangiogenic agents is an urgent issue in cancer treatment. Zerumbone, a component of subtropical ginger, has been shown to exhibit anticancer activities in various cancer cells; however, little is known about its biological mechanisms against angiogenesis in pancreatic cancer (PaCa). Here, we evaluated the effects of zerumbone on PaCa angiogenesis. Methods The cytotoxicity of zerumbone in PaCa was measured using premix WST-1 cell proliferation assays. The influence of zerumbone on the angiogenic factors vascular endothelial growth factor and interleukin 8 was measured using the reverse transcription–polymerase chain reaction and enzyme-linked immunosorbent assays. Changes in nuclear factor-&kgr;B (NF-&kgr;B) activities were measured using NF-&kgr;B transcription factor assays. We also examined the effects of zerumbone on PaCa-induced angiogenesis using angiogenesis assays. Results Zerumbone inhibited mRNA expression and protein secretion of angiogenic factors and NF-&kgr;B activity. Tube formation in human umbilical vein endothelial cells was enhanced by coculture with PaCa cells, and these enhancements were significantly inhibited by zerumbone treatment. Conclusions Zerumbone blocked the PaCa-associated angiogenesis through the inhibition of NF-&kgr;B and NF-&kgr;B–dependent proangiogenic gene products.

Preoperative Serum Interleukin-6 Is a Potential Prognostic Factor for Colorectal Cancer, including Stage II Patients

Aims. To evaluate the prognostic significance of serum interleukin-6 (IL-6) in colorectal cancer (CRC). Patients and Methods. Preoperative serum IL-6 was measured in 233 CRC patients and 13 healthy controls. Relationships between IL-6 and various clinicopathological factors were evaluated, and the overall survival (OS) and disease-free survival (DFS) rates according to IL-6 status were calculated for all patients and according to disease stage. Results. The mean IL-6 level was 6.6 pg/mL in CRC patients and 2.6 pg/mL in healthy controls. Using a cutoff of 6.3 pg/mL, obtained using receiver operating characteristic curve analysis, 57 patients had a high IL-6 level. The mean value was higher for stage II disease than for stage III disease. IL-6 status correlated with C-reactive protein (CRP) and carcinoembryonic antigen levels, obstruction, and pT4 disease. The OS differed according to the IL-6 status for all patients, whereas the DFS differed for all patients and for those with stage II disease. The Cox proportional hazards model showed that pT4 disease was an independent risk factor for recurrence in all CRC patients; IL-6, CRP, and pT4 were significant risk factors in stage II patients. Conclusions. The preoperative IL-6 level influences the risk of CRC recurrence.

Evaluation of a New Stapler with Unique Surface Gripping Technology

Background: Staplers make it possible to create a gastrointestinal anastomosis quickly, easily, and securely. Staplers have undergone several improvements. We herein evaluate the effect of a new stapler with unique surface gripping technology that provides a superior tissue grip without trauma during firing. Methods: Porcine small bowel was used. The stapling devices compared were the ECHELON FLEX with White (E) and GST System White (G). The number of total malformed staples, severely malformed staples, staples malformed to the cutting side, and the absolute value of the degree of malformation were evaluated. Results: The number of malformed staples and the absolute value of the degree of malformation were significantly lower in group G. The number of occurrences of total malformations <0 was greater in group G. Comparing the inner, middle, and outer staple rows, the number of occurrences Original Research Article of malformations were lower on the outer row in group E. Comparing the front, middle, and back parts malformation was lower in the front. Conclusions: We found that a new stapler is superior to a standard stapler with regard to a reliable “B” shape formation of sta staple malformation and the strength of the suture line.

Eversion stripping of the esophagus with intraesophageal insufflation—A case report

Highlights • The indications for stripping of the esophagus have decreased due to the widespread of endoscopic mucosal resection and thoracoscopic surgery.• Even if indications for this procedure have decreased, this is an important option in the armamentarium of the esophageal surgeon.

Resection of the Gastric Tube Reconstructed through the Retrosternal Route without Sternotomy

With advances of combined modality therapy, prognoses in esophageal cancer have been improving. After resection of esophageal cancer, the development of gastric tube cancer is a risk. While such cancer in an early stage can be cured endoscopically, total gastric tube resection is indicated in advanced stages. A 68-year-old man underwent subtotal esophagectomy reconstructed with a gastric tube through the retrosternal route. Gastric cancer was found one and a half years postoperatively. The gastric tube was resected without sternotomy. This is the first report of a patient undergoing resection of the gastric tube reconstructed through the retrosternal route without sternotomy.

Port Surgery for Colorectal Cancer Patients, Involving the Use of A Single-Incision Laparoscopic Surgery Port at the Planned Stoma Site

A single-incision laparoscopic surgery (SILS) port may be used to reduce the number of surgical incisions. Here, we describe our technique, equivalent in technical difficulty to conventional laparoscopy, of using a SILS port at a planned diverting-stoma site in colorectal cancer patients. This technique is indicated for patients for whom the intent is to perform tumor resection with diverting ileostomy. Because ileostomy is usually created on the right, this technique is most useful for left-sided lesions. However, an additional port in the umbilicus enables dissection of the right colon. The SILS port is placed by the open method, with additional trocars added once pneumoperitoneum is established. One trocar port is eventually used for a drain. We use this technique not only for intersphincteric resection, wherein distal rectal stump stapling is not necessary, but also in total coloproctectomy and ultralow anterior resection, which require deep pelvis stapling or right-sided colonic dissection.