Masayasu Hara

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.

Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody-dependent cellular cytotoxicity

Cetuximab, a chimeric monoclonal antibody to epidermal growth factor receptor (EGFR), has been proved to have clinically significant antitumor activity against advanced colorectal cancers, but its therapeutic activity for gastric cancers remains unclear. In the present study, we investigated the antitumor effect and action mechanism of cetuximab using EGFR high‐expressing (MKN‐28) and EGFR low‐expressing (GLM‐1) gastric cancer cell lines without gene amplification. Cetuximab showed neither significant growth inhibition nor induction of apoptosis in either cell line in vitro, and only slightly inhibited ligand‐induced phosphorylation of protein kinase B and extracellular signal‐regulated kinase in MKN‐28 cells. In contrast, cetuximab significantly inhibited subcutaneous and intraperitoneal tumor growth of MKN‐28 cells, but not GLM‐1 cells, in nude mice. This antitumor activity was significantly enhanced and diminished in nude mice by treatment with interleukin‐2 (IL‐2) and antiasialo GM1 antibody, which can expand and deplete natural killer (NK) cells, respectively. Antibody‐dependent cellular cytotoxicity (ADCC) of cetuximab, as measured by 51Cr release assay, was significantly higher in MKN‐28 than in GLM‐1 cells. This ADCC activity was enhanced by IL‐2 and reduced by heat‐aggregate of human immunoglobulin G, an inhibitor for FcR‐III of NK cells. These results suggest that cetuximab in combination with IL‐2 shows significant antitumor activity against EGFR high‐expressing gastric cancer mainly through NK cell‐mediated ADCC. Combination therapy with cetuximab and IL‐2 would thus offer a new potential therapeutic approach for a subset of EGFR‐overexpressing gastric cancers. (Cancer Sci 2008; 99: 1471–1478)

Negative serum carcinoembryonic antigen has insufficient accuracy for excluding recurrence from patients with Dukes C colorectal cancer: analysis with likelihood ratio and posttest probability in a follow-up study.

PURPOSEThis study was designed to determine the efficacy of carcinoembryonic antigen (CEA) monitoring for screening patients with colorectal cancer by using posttest probability of recurrence.METHODSFor this study, 348 (preoperative serum CEA level elevated: CEA+, n = 119; or normal: CEA−, n = 229) patients who had undergone potentially curative surgery for colorectal cancer were enrolled. After five-year follow-up with measurements of serum CEA levels and imaging workup, posttest probabilities of recurrence were calculated.RESULTSRecurrence was observed in 39 percent of CEA+ patients and 30 percent in CEA− patients, and CEA levels were elevated in 33.3 percent of CEA+ patients and 17.5 percent of CEA− patients. With obtained sensitivity (68.4 percent, CEA+; 41 percent, CEA−), specificity (83 percent, CEA+; 91 percent, CEA−) and likelihood ratio (test positive: 4.0, CEA+; 4.4, CEA−; and test negative: 0.38, CEA+; 0.66, CEA−), posttest probability given the presence of CEA elevation in the CEA+ and CEA− was 72.2 and 65.5 percent, respectively, and that given the absence of CEA elevation was 20 and 22.2 percent, respectively.CONCLUSIONSWhereas postoperative CEA elevation indicates recurrence with high probability, a normal postoperative CEA is not useful for excluding the probability of recurrence.

Isolated tumor cell in lateral lymph node has no influences on the prognosis of rectal cancer patients

Background and aimsThe aim of this study was to determine the incidence of isolated tumor cells (ITC) and micrometastasis in lateral lymph nodes of patients with rectal cancer and its possible correlation with prognosis.Materials and methodsOne hundred seventy-seven rectal cancer patients who underwent curative resection with lateral lymph node dissection were enrolled. Dissected lymph nodes were examined using hematoxylin–eosin staining (HE) and immunohistochemistry (IHC) with anti-keratin antibody (AE1/AE3). States of lymph node metastasis were divisible into three groups: detectable with HE (HE+), detectable with only IHC (HE−/IHC+), and undetectable even with IHC (IHC−). Almost all the HE−/IHC+ group was classified as ITC consisting of a few tumor cells according to the UICC criteria (ITC+). Survival rates were compared among HE+, ITC+, and IHC−.ResultsITC+ were detected in 24.1% of patients with HE-negative lateral lymph nodes. No significant difference in overall 5-year survival was observed between ITC+ and IHC− patients (76.1 and 82.9%, respectively, p = 0.25). Multivariate analysis showed that perirectal HE+ lymph nodes, but not ITC+ lateral lymph nodes, was an independent prognostic factor.ConclusionsITC in lateral lymph nodes does not contribute to the prognosis of rectal cancer in patients who undergo extended lateral lymph node dissection, unlike HE+ lateral lymph node metastasis.

Laparoscopic anterior resection for colorectal cancer without minilaparotomy using transanal bowel reversing retrieval.

Purpose: In laparoscopic colon resection for rectosigmoid colon cancer, minilaparotomy is usually necessary for specimen retrieval and completion of primary anastomosis. This incision may increase postoperative pain, and cause wound infection or other complications. We describe a new technique of laparoscopic anterior colon resection without requiring a minilaparotomy incision. Patients and Methods: We attempted this procedure on 9 patients with sigmoid colon or rectal cancer. We ligated the inferior mesenteric artery and divided the bowel proximally, similar to conventional laparoscopic technique. We pulled out the specimen and the rectum transanally, and performed distal colon division extracorporeally. An anvil was inserted transanally into corporeal cavity and then, inserted into the proximal stump of the colon lumen laparoscopically. We placed a purse-string suture extracorporeally around the distal colon stump, and then completed a side-to-end anastomosis intracorporeally. Results: The procedure was successfully completed in 8 of the 9 patients. Median operative time was 293 minutes and median blood loss was 47.2 mL. No major complications were observed. Conclusions: This novel technique of transanal specimen retrieval and intracorporeal anastomosis with extracorporeal purse-string placement can be performed safely and easily in patients with rectosigmoid colon cancer.Achalasia is an esophageal motility disorder for which the pathophysiology is only partially known for the idiopathic subtype. Many factors are known to be involved with the development of secondary achalasia. Neurofibromatosis is one of the most common autosomal dominant conditions affecting the nervous system, and 25% of those with the disease have been reported to have involvement of the gastrointestinal tract. Three cases of association between neurofibromatosis and achalasia have been reported in the literature so far. Laparoscopic Heller myotomy is the gold standard surgical treatment for patients with achalasia, whereas esophagectomy is reserved for the more advanced stages of disease. There have been reports of successful long-term results in patients with stage IV achalasia treated with Heller myotomy. We report the fourth case in the literature of association between achalasia and neurofibromatosis; it is the first time that such an association is successfully treated with laparoscopic Heller myotomy.

Establishment of a simple predictive scoring system for pancreatic fistula after laparoscopy-assisted gastrectomy.

The potential severity of postoperative pancreatic fistula (POPF) after laparoscopy‐assisted gastrectomy (LAG) necessitates efforts to identify predictive factors for POPF. The aim of the present study was to identify predictive factors for POPF and to establish a predictive scoring system for POPF after LAG.

Accuracy of monitoring serum carcinoembryonic antigen levels in postoperative stage III colorectal cancer patients is limited to only the first postoperative year

PurposeThe aim of the present study was to determine the accuracy of yearly postoperative monitoring of serum tumor markers to either detect or rule out recurrence in colorectal cancer patients.MethodsA total of 127 colorectal cancer patients who underwent curative surgery were enrolled. The serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were assayed, and radiological examinations were performed routinely for 5 years after surgery or until recurrence was detected. Yearly recurrence rates (number of recurrences/number of patients assessed in a given year), sensitivities, specificities, and likelihood ratios were calculated. Post-test probabilities were calculated from these values.ResultsRecurrences tended to show almost the same frequencies in the first and second year after surgery (20 of 127 patients and 18 of 107 patients, respectively). However, the post-test probability of recurrence in patients with positive and negative serum CEA levels was significantly lower in the second year than in the first year (test positive: 40.0% and 76.0%; test negative: 9.3% and 0.5%, respectively).ConclusionsMeasuring CEA can help to identify patients likely to demonstrate recurrence with high accuracy only within the first year after surgery. Another examination, such as imaging, is therefore necessary for monitoring patients at 2 or more years after surgery.

Does serum carcinoembryonic antigen elevation in patients with postoperative stage II colorectal cancer indicate recurrence? Comparison with stage III.

The aim of this study was to determine the accuracy of postoperative monitoring of serum carcinoembryonic antigen (CEA) to detect or rule out recurrence in patients with stage II colorectal cancer (CRC) by comparing results with stage III.

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.